Podcasts about pd l1

BUFFALO, NY - May 21, 2025 – A new #review was #published in Volume 16 of Oncotarget on May 19, 2025, titled “Advancements in bladder cancer treatment: The synergy of radiation and immunotherapy." Researchers from the University of California, Irvine, led by Nazmul Hasan, reviewed recent clinical and scientific advances in combining radiation therapy with immunotherapy for bladder cancer. The article summarizes growing evidence that this combined approach may strengthen the immune response and improve long-term disease control. This strategy is especially important for patients who are not candidates for surgery or who respond poorly to conventional treatments. Bladder cancer is a serious and frequent condition, particularly affecting older men. Traditional treatments—surgery, chemotherapy, and radiation—can be effective, but they often fail to prevent cancer reappearance in advanced cases. The review explores how combining radiation and immunotherapy could improve outcomes by helping the immune system detect and destroy cancer cells more effectively. Radiation therapy destroys cancer cells and triggers the release of tumor signals that attract immune cells. Immunotherapy, including drugs like pembrolizumab and nivolumab, helps the immune system work better by blocking proteins that allow cancer to evade detection. Used together, these treatments may produce a stronger, more widespread anti-tumor effect, even at distant sites not directly targeted by radiation. The review discusses several clinical trials that support this approach. One phase II study reported that combining radiation with the immunotherapy drug durvalumab led to promising survival rates and manageable side effects. Another trial in Australia tested pembrolizumab with radiation and chemotherapy, resulting in high tumor control and extended patient survival. However, the review also points out that other trials showed serious side effects when high doses or multiple immunotherapy drugs were used at once. "Joshi et al. performed a phase II study to determine the safety and efficacy of combining radiation therapy with durvalumab, a PD-L1 inhibitor, in patients who were ineligible for surgery or cisplatin-based chemotherapy." While the combination approach is promising, the authors emphasize that more research is needed to refine this treatment strategy. One major challenge is determining which patients are most likely to benefit. Future studies should focus on identifying reliable biomarkers, such as tumor mutation burden or immune activity, to guide personalized treatment plans. This review highlights the potential of combining radiation and immunotherapy to improve outcomes for bladder cancer patients. With continued research and careful treatment design, this approach could offer new treatment options for those facing aggressive or hard-to-treat forms of the disease. DOI - https://doi.org/10.18632/oncotarget.28723 Correspondence to - Nazmul Hasan - nhasan1@hs.uci.edu Video short - https://www.youtube.com/watch?v=AxrZhIUXrOQ Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28723 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - cancer, bladder cancer, immunotherapy, radiation, microenvironment, abscopal To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: Facebook - https://www.facebook.com/Oncotarget/ X - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Spotify - https://open.spotify.com/show/0gRwT6BqYWJzxzmjPJwtVh MEDIA@IMPACTJOURNALS.COM

“A lot of other disease sites, they have some targeted therapies, they have some immunotherapies [IO]. In lung cancer, we have it all. We have chemo. We have IO. We have targeted therapies. We have bispecific T-cell engagers. We have orals, IVs. I think it's just so important now that, particularly for lung cancer, you have to be well versed on all of these,” ONS member Beth Sandy, MSN, CRNP, thoracic medical oncology nurse practitioner at the Abramson Cancer Center at the University of Pennsylvania in Philadelphia, told Jaime Weimer, MSN, RN, AGCNS-BS, AOCNS®, manager of oncology nursing practice at ONS, during a conversation about lung cancer treatment. Music Credit: “Fireflies and Stardust” by Kevin MacLeod Licensed under Creative Commons by Attribution 3.0  Earn 0.5 contact hours of nursing continuing professional development (NCPD) by listening to the full recording and completing an evaluation at courses.ons.org by May 16, 2026. The planners and faculty for this episode have no relevant financial relationships with ineligible companies to disclose. ONS is accredited as a provider of nursing continuing professional development by the American Nurses Credentialing Center's Commission on Accreditation. Learning outcome: Learners will report an increase in knowledge related to lung cancer treatments. Episode Notes  Complete this evaluation for free NCPD.  ONS Podcast™ episode: Episode 359: Lung Cancer Screening, Early Detection, and Disparities ONS Voice articles: Non-Small Cell Lung Cancer Prevention, Screening, Diagnosis, Treatment, Side Effects, and Survivorship Oncology Drug Reference Sheet: Amivantamab-Vmjw Oncology Drug Reference Sheet: Cisplatin Oncology Drug Reference Sheet: Lazertinib Oncology Drug Reference Sheet: Nivolumab and Hyaluronidase-Nvhy Oncology Drug Reference Sheet: Fam-Trastuzumab Deruxtecan-Nxki Optimize Your Testing Strategy and Improve Patient Outcomes With NeoGenomics' Neo Comprehensive™–Solid Tumor Assay Clinical Journal of Oncology Nursing article: Oncogenic-Directed Therapy for Advanced Non-Small Cell Lung Cancer: Implications for the Advanced Practice Nurse ONS Biomarker Database ONS video: What is the role of the KRAS biomarker in NSCLC? Biomarker Testing in Non-Small Cell Lung Cancer Discussion Tool ONS Huddle Cards: Checkpoint inhibitors External beam radiation Monoclonal antibodies Proton therapy To discuss the information in this episode with other oncology nurses, visit the ONS Communities. To find resources for creating an ONS Podcast club in your chapter or nursing community, visit the ONS Podcast Library. To provide feedback or otherwise reach ONS about the podcast, email pubONSVoice@ons.org. Highlights From This Episode “Unfortunately, because lung cancer is pretty aggressive, we'll see lung cancer mostly in stage IV. So about 50%–55% of all cases are not caught until they are already metastatic, or stage IV. And then about another 25%–30% of cases are caught in stage III, which means they're locally advanced and often not resectable, but we do still treat that with curative intent with concurrent chemoradiation. And then 10%–20% of cases are found in the early stage, and that's stage I and II, where we can do surgical approaches.” TS 2:53 “The majority of radiation that you're going to see is for patients with stage III disease that's inoperable. At my institution, a lot of stage III is inoperable. Now, neoadjuvant immunotherapy has changed that a little bit. But if you have several big, bulky, mediastinal lymph nodes that makes you stage III, surgery is probably not going to be a great option. So we give curative-intent chemoradiation to these patients.” TS 10:51 “Oligoprogression would mean they have metastases but only to one site. And sometimes we will be aggressive with that. Particularly, there's good data, if the only site of progression is in the brain, we can do stereotactic radiation to the brain and then treat the chest with concurrent chemoradiation as a more definitive approach. But outside of that, the majority of stage IV lung cancer is going to be treated with systemic therapy.” TS 15:00 “It's important for nurses to know that there's a lot of different options now for treatment. Probably one of the most important things is making sure patients are aware of what their biomarker status is, what their PD-L1 expression level is, and make sure those tests have been done. … It's good that the patients understand that there's a myriad of options. And a lot of that depends on what we know about their cancer, and then that guides our treatment.” TS 31:05

Welcome to the Oncology Brothers podcast! In this episode, Drs. Rahul and Rohit Gosain are joined by Dr. Mark Awad, a world-renowned thoracic medical oncologist from Memorial Sloan Kettering. Together, they dived deep into the treatment landscape for metastatic non-small cell lung cancer (NSCLC) without actionable mutations in frontline settings. Episode Highlights: •⁠  ⁠The importance of next-generation sequencing (NGS) and PD-L1 levels in treatment decision-making. •⁠  ⁠Current treatment options for patients with high PD-L1 scores, including single-agent immunotherapy. •⁠  ⁠Strategies for patients with low or intermediate PD-L1 scores, including chemotherapy combined with immunotherapy. •⁠  ⁠Discussed KRAS G12C and HER2 positive disease in second-line settings, including the latest approved therapies. •⁠  ⁠Insights into the potential side effects and considerations when transitioning from immunotherapy to targeted therapies. Join us as we explored the complexities of treating metastatic NSCLC and the ongoing need for clinical trials and biomarker discovery. Don't forget to check out our other episodes for more insights on treatment algorithms and recent FDA approvals! Follow us on social media: •⁠  ⁠X/Twitter: https://twitter.com/oncbrothers •⁠  ⁠Instagram: https://www.instagram.com/oncbrothers •⁠  Website: https://oncbrothers.com/ Don't forget to like, subscribe, and hit the notification bell for more updates from the Oncology Brothers!

Discussing:Association between risk-reducing surgeries and survival in young BRCA carriers with #BreastCancer DESTINY-Breast11 Update from IndustryPALMIRA in Breast #Cancer (Palbo rechallenge)PEACE V STORM in #Prostate CancerMAGNITUDE :Niraparib and Abiraterone Acetate plus Prednisone in Met CR Prostate CancerOS EGFR-mutant AdvancedNon-Small Cell #LungCancer Treated with 1L Osimertinib Cemiplimab monotherapy as 1L treatment of patients with brain metastases from advanced #NSCLC with  PDL1 ≥50%Beyond fluorodeoxyglucose: Molecular imaging of cancer in precision medicine and more

Did you know that tumor area positivity (TAP) scoring can be completed up to 6 times faster than combined positive score (CPS)?   Credit available for this activity expires: 4/23/2026 Earn Credit / Learning Objectives & Disclosures: https://www.medscape.org/viewarticle/1002476?ecd=bdc_podcast_libsyn_mscpedu

BUFFALO, NY - April 28, 2025 – A new #research paper was #published in Oncotarget, Volume 16, on April 24, 2025, titled “PD-L1 and FOXP3 expression in high-grade squamous intraepithelial lesions of the anogenital region." Researchers Humberto Carvalho Carneiro, Rodrigo de Andrade Natal, José Vassallo and Fernando Augusto Soares from the Instituto D'Or de Pesquisa e Ensino and Rede D'Or studied early tissue changes caused by human papillomavirus (HPV) in the anal, vulvar, and penile regions. They found that high-grade pre-cancer lesions triggered stronger immune responses and showed higher levels of two immune-related markers, PD-L1 and FOXP3. These findings are important because they help explain how some HPV-related lesions progress to cancer while others heal on their own. High-risk HPV is known to cause several types of anogenital cancers. Before these cancers appear, the virus often leads to abnormal tissue changes known as high-grade squamous intraepithelial lesions. Many of these lesions disappear without treatment, but some become cancer—especially in people with weakened immune systems. This study explored how immune activity may play a role in this progression. The researchers examined tissue from 157 patients—95 males and 55 females—with either high-grade or low-grade HPV-related lesions. They found that T-regulatory cells, marked by the FOXP3 protein, were more common in high-grade lesions. These immune cells are known to suppress immune responses, which can allow infected or abnormal cells to grow. The team also found higher expression of PD-L1, a protein that helps cells evade immune detection, particularly in inflammatory immune cells. "Dense inflammatory infiltrates and high counts of FOXP3+ cells were significantly more frequent in patients with HSILs than in those with LSILsHR (p = 0.04 and 0.02, respectively). HSILs also exhibited higher PD-L1 expression (padj < 0.01 and < 0.01 for the SP142 and 22C3 clones, respectively), based on the Poisson generalized linear model.” These findings suggest that HPV may begin avoiding the immune system early in infection, even before cancer develops. The combination of high FOXP3 and PD-L1 levels may create a protective environment for infected cells, making them harder for the body to eliminate. This immune evasion may allow the lesions to remain and, over time, become cancerous. The study also compared patients with and without HIV to assess whether immune health influenced the results. While those with compromised immune systems had more extensive lesions, PD-L1 and FOXP3 expression was also found in patients with healthy immune systems. This evidence shows that immune evasion by HPV can happen regardless of a person's immune status. Understanding how PD-L1 and FOXP3 function in early HPV-related lesions may help clinicians predict which lesions are more likely to become cancer. These insights could lead to new strategies for monitoring, treating, or preventing HPV-related precancerous lesions and cancer in the anogenital region. The study highlights how early immune system changes can play a key role in the development of HPV-related cancers. DOI - https://doi.org/10.18632/oncotarget.28715 Correspondence to - Humberto Carvalho Carneiro - humberto.carneiro@rededor.com.br Video short - https://www.youtube.com/watch?v=6d8G8TUbgYc Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: Facebook - https://www.facebook.com/Oncotarget/ X - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Spotify - https://open.spotify.com/show/0gRwT6BqYWJzxzmjPJwtVh MEDIA@IMPACTJOURNALS.COM

El Dr. Ricardo Elías Brugés Maya, oncólogo médico del Instituto Nacional de Cancerología en Bogotá, Colombia, en conjunto con el Dr. Jon Zugazagoitia, oncólogo médico del Hospital Universitario 12 de Octubre en Madrid, España, presentaron recientemente en Barranquilla, Colombia, durante el congreso de CLOC, diversas opciones de tratamiento para el cáncer de pulmón de células no pequeñas (CPCNP). En su conversación, los expertos se enfocaron especialmente en el tratamiento de pacientes con PD-L1 negativo, abordando el uso de la inmunoterapia en combinación con otras terapias inmunológicas o con quimioterapia.Cobertura apoyada por el Curso Latinoamericano de Oncología Clínica (CLOC). Fecha de grabación: 07 de marzo de 2025      Todos los comentarios emitidos por los participantes son a título personal y no reflejan la opinión de ScienceLink u otros. Se deberá revisar las indicaciones aprobadas en el país para cada uno de los tratamientos y medicamentos comentados. Las opiniones vertidas en este programa son responsabilidad de los participantes o entrevistados, ScienceLink las ha incluido con fines educativos. Este material está dirigido a profesionales de la salud exclusivamente. 

Featuring a slide presentation and related discussion from Dr Adrienne G Waks, including the following topics: Updated analyses from key studies of the 21-gene Recurrence Score® for localized ER-positive breast cancer (29:30) Four-year landmark analysis of the NATALEE trial of adjuvant ribociclib with nonsteroidal aromatase inhibitor for localized breast cancer (9:49) The PADMA trial of palbociclib with endocrine therapy compared to chemotherapy induction followed by endocrine therapy maintenance for hormone receptor (HR)-positive, HER2-negative metastatic breast cancer (mBC) (11:25) Imlunestrant with or without abemaciclib for metastatic ER-positive mBC (13:18) TROP2-directed antibody-drug conjugates (ADCs) datopotamab deruxtecan and sacituzumab tirumotecan for HR-positive/HER2-negative mBC (17:50) Recent analyses from the DESTINY-Breast06 trial of trastuzumab deruxtecan (T-DXd) after endocrine therapy for HR-positive, HER2-low or HER2-ultralow mBC (21:09) The ICARUS-BREAST01 Phase II trial of the HER3-targeted ADC patritumab deruxtecan for HR-positive/HER2-negative mBC (26:02) Updates from neoadjuvant/adjuvant trials of pembrolizumab (KEYNOTE-522) and atezolizumab (NSABP B-59/GBG 96-GeparDouze) for localized triple-negative breast cancer (TNBC) (27:36) Ten-year update of the OlympiA trial of adjuvant olaparib for patients with germline BRCA1/2-mutated HER2-negative localized breast cancer (31:23) Exploratory analysis of patients who did or did not receive prior PD-1/PD-L1 inhibition in the Phase III OptiTROP-Breast01 study of sacituzumab tirumotecan versus chemotherapy for previously treated advanced TNBC (32:56) CNS efficacy of T-DXd (DESTINY-Breast12 trial) and outcomes with palbociclib combined with anti-HER2 therapy (AFT-38 PATINA trial) for HER2-positive mBC (34:04) CME information and select publications

Welcome to another episode of the Oncology Brothers! In this episode, Drs. Rahul and Rohit Gosain are joined by their brother, Dr. Timothy Brown from UT Southwestern, to discuss the latest treatment paradigms for upper gastrointestinal (GI) malignancies, specifically focusing on esophageal and gastroesophageal junction adenocarcinoma, as well as gastric cancer. Episode Highlights: •⁠  ⁠Early Disease Management: perioperative FLOT versus concurrent chemoradiation. •⁠  ⁠Adjuvant Nivolumab: Insights from the Checkmate 577 trial and its implications for patients with residual disease post-chemoradiation. •⁠  ⁠Biomarker Testing: The importance of testing for MSI, HER2, Claudin 18.2, and PD-L1 to guide treatment decisions in metastatic settings. •⁠  ⁠Patient-Centered Care: Emphasizing the significance of shared decision-making and multidisciplinary approaches in managing complex cases. Join us as we unpack the nuances of upper GI malignancies and share key takeaways from recent studies and clinical practices.  YouTube: https://youtu.be/UNyi71u2wIw Follow us on social media: •⁠  ⁠X/Twitter: https://twitter.com/oncbrothers •⁠  ⁠Instagram: https://www.instagram.com/oncbrothers •⁠  Website: https://oncbrothers.com/ Don't forget to like, subscribe, and hit the notification bell for more updates on treatment algorithms and oncology insights!  

In today's episode, supported by Summit Therapeutics, we had the pleasure of speaking with Xiuning Le, MD, PhD, about the use of ivonescimab (SMT112) in patients with PD-L1–positive non–small cell lung cancer (NSCLC). Dr Le is an associate professor in the Department of Thoracic/Head and Neck Medical Oncology in the Division of Internal Medicine at The University of Texas MD Anderson Cancer Center in Houston. The phase 3 HARMONi-2 trial (NCT05499390) investigated ivonescimab vs pembrolizumab (Keytruda) in patients with locally advanced or metastatic, PD-L1–positive NSCLC without sensitizing EGFR mutations or ALK translocations. At the preplanned interim analysis, at a median follow-up of 8.7 months (IQR, 7.1-10.3), the median progression-free survival was significantly longer in the ivonescimab arm (n = 198) vs the pembrolizumab arm (n = 200), at 11.1 months (95% CI, 7.3-not estimable) vs 5.8 months (95% CI, 5.0-8.2), respectively (stratified HR, 0.51; 95% CI, 0.38-0.69; 1-sided P < .0001). The objective response rates were 50% (95% CI, 43%-57%) and 39% (95% CI, 32%-46%) in these respective arms. In our exclusive interview, Dr Le discussed the rationale for the HARMONi-2 trial, key findings from the study, and where these findings position the potential role of ivonescimab in the PD-L1–positive NSCLC treatment paradigm.

Join us for an insightful episode of the Oncology Brothers podcast as we dive deep into the world of renal cell carcinoma (RCC) with Dr. Katy Beckermann, the Medical GU Director of Cancer Research at Tennessee Oncology. In this episode, hosts Drs. Rahul & Rohit Gosain, practicing medical oncologists, discuss the latest advancements in RCC treatment, including: •⁠  ⁠The role of Pembrolizumab in the adjuvant setting based on the Keynote 564 study and its implications for early-stage disease. •⁠  ⁠Current treatment paradigms for metastatic RCC, including dual checkpoint inhibitors, TKI with immunotherapy, and single-agent options. •⁠  ⁠The importance of patient characteristics and IMDC risk categorization in treatment decisions. •⁠  ⁠Insights into sequencing therapies, including the use of Belzutifan for refractory disease and the management of side effects. •⁠  ⁠The role of ctDNA, PD-L1 testing, and NGS in RCC. Whether you're a community oncologist or simply interested in the latest in cancer care, this episode is packed with valuable information to help you stay informed and provide the best care for your patients. YouTube: https://youtu.be/Bbv9N7-YKIM Follow us on social media: •⁠  ⁠X/Twitter: https://twitter.com/oncbrothers •⁠  ⁠Instagram: https://www.instagram.com/oncbrothers •⁠  Website: https://oncbrothers.com/ Don't forget to like, subscribe, and leave a review to let us know how we're doing and how we can continue to support you in the community!  

Dr. Shannon Westin and her guest, Dr. Breelyn Wilky, discuss the JCO article, "“Botensilimab (Fc-enhanced anti-cytotoxic lymphocyte-association protein-4 antibody) Plus Balstilimab (anti-PD-1 antibody) in Patients With Relapsed/Refractory Metastatic Sarcomas." TRANSCRIPT  Shannon Westin: Hello, everyone, and welcome to another episode of JCO After Hours, the podcast where we get in depth on research that has been published in the Journal of Clinical Oncology. I am your host, Gynecologic Oncologist and Social Media Consultant Editor of the JCO, Shannon Westin. I serve here from the University of Texas MD Anderson Cancer Center. And I am so excited to welcome Dr. Breelyn Wilky. She's an Associate Professor and the Director of Sarcoma Medical Oncology in the Department of Medicine Division of Medical Oncology, and the Cheryl Bennett & McNeilly family endowed chair in Sarcoma Research, the Deputy Associate Director of Clinical research at the University of Colorado Cancer Center. Welcome. Dr. Breelyn Wilky: Thank you so much. I'm delighted to be here. Shannon Westin: And with all those titles, I'm super impressed that she was able to complete the manuscript that we're going to discuss today, which is “Botensilimab (Fc-enhanced anti-cytotoxic lymphocyte-association protein-4 antibody) Plus Balstilimab (anti-PD-1 antibody) in Patients With Relapsed/Refractory Metastatic Sarcomas.” And this was published in the JCO on January 27, 2025. And please note, our participants do not have any conflicts of interest. So this is exciting. Let's first level set. Can you review with us just the current state of sarcoma incidents, survival outcomes, that kind of thing so we all know where we're starting? Dr. Breelyn Wilky: Yes. So, you know, sarcomas are really, I like to call them the black box cancer type. And the big thing is that there's really more than a hundred different kinds of sarcomas, which collectively altogether make up only 1% of adult cancers. And so we talk about these as being bone and soft tissue tumors, but really, the heterogeneity is just incredible. You're talking maybe 10,000 to 12,000 new cases of soft tissue sarcoma per year, which is pretty rare in the grand scheme of things. And the trouble with these is that while you can cure sarcomas if you find them early and they're localized, when they metastasize and spread and are not resectable, we're looking at median overall survivals of really only 12 to 18 months, even, you know, with our best therapies that we have. So, really there's just a dire need for new treatments for this really tough group of diseases. Shannon Westin: Yeah, I agree. I'm a gynecologic oncologist, and we have our little subset of sarcomas that I know there's a little bit out of every one. So I'm really excited to pull this manuscript as one of our podcasts offerings because I think we're all seeing these patients in the clinic and certainly our listeners that have sarcoma or have family members with sarcoma, this is so good to have a real focus on a rare group of tumors that have been a little bit lumped together. Now, with that being said, I know this is such a heterogeneous population, but can you briefly overview a little bit around the standard of care for treatment of recurrent sarcomas? Dr. Breelyn Wilky: We have actually been using the same drugs really since about the 1970s, and up until very recently, nothing had really challenged doxorubicin, the old ‘red devil', like we used to call it. And this has been the mainstay of treatment for metastatic sarcomas and really used across the board. In the GYN literature, for uterine leiomyosarcoma, we did see some promising activity with the combination of doxorubicin and trabectedin coming out of the French group. But, except for that study, no combination therapy or new drug has been proven better in terms of overall survival compared to doxorubicin monotherapy, really over 40, 50 years. So it's definitely a tough situation. Now, we do have other drugs that we use, so most patients will wind up getting doxorubicin-based therapy. There's a couple of other regimens that we'll reach to, like gemcitabine docetaxel. And once you get into the specific subtypes, we have some approvals in liposarcomas and leiomyosarcomas for some other drugs. But really the median progression for survival for most of these regimens is somewhere four to six months. And response rates typically are somewhere like 10%, 15% for most of these. So it's really just a very tough field and a tough group of patients to try to make an impact for. Shannon Westin: So let's talk a little bit more kind of getting focused on what you've studied here. What's been the role of immunotherapy thus far in the treatment of sarcomas maybe prior to this particular study? Dr. Breelyn Wilky: Clearly, we all know that immune therapy has just changed cancer care forever over the last few years for so many different types of cancers and diseases like melanoma and renal cell and lung cancer have just been transformed by checkpoint inhibitors specifically directed against PD-1 or CTLA-4 or both. And so, of course, you know, sarcoma docs we're super excited to try to see if these might potentially have activity in our tumors as well. I never had seen myself in my career getting into immunotherapy until I was able to run an investigator-initiated study during my role in Miami, where we combined pembrolizumab, so PD-1 inhibitor, with axitinib which was a pan-VEGF inhibitor. And lo and behold, like I had patients that I was seeing responses when other treatments, all those chemotherapies I was just talking about had failed. And one of my first patients I treated was about a 60-year-old lady with something called cutaneous angiosarcoma. So this is a blood vessel sarcoma all over her face. And we had treated her with 10 different therapies, all the chemotherapy regimens, targeted therapies, clinical trials, and nothing was working. But I put her on a phase 1 trial with a baby dose of CTLA-4 and this woman had a complete response. And so for me, once I saw it work in even just those couple of patients, like that was nothing that we'd ever seen with our chemotherapy regimens. And so that sort of shifted my career towards really focusing on this, and this is about the time where some of the studies started to come out for sarcomas. And the take home with sarcoma is about 20% of sarcomas have this sort of immune hot physiology. So what that basically means is if you look at gene expression of immune related gene signatures, or you look for infiltrating T-cells, sort of the SWAT team of our immune system, like you can find those in the tumors. And it's sort of evidence that the immune system had some clue for that 20% of patients that this was a foreign tumor and that it should be attacking it and maybe just needed a little help. But globally, about 80% of sarcomas are these immune cold tumors, which means the immune system has no clue that these things are even a threat. And there's almost no immune activation, very, very few antigens. In other cancer types, high neoantigens or tumor antigens help the immune system work better. And so that basically goes with what we've seen with trials of PD-1 or CTLA-4 blockade. About 20% of sarcomas, with some exceptions, can respond. But really 80% across the board, you're stuck, you just can't get them to be recognized. And so that's where I think this data is so interesting is there's some signals of activity in these immune cold tumors which, at least historically with the trials we've done so far, we really haven't seen that with sort of the traditional checkpoints. Shannon Westin: So I think now this is a great time to maybe talk about the study design in general, the eligibility and just give us kind of a run through of that. Dr. Breelyn Wilky: So this trial was a phase 1 trial of a drug called botensilimab, which is a next generation CTLA-4 directed immune modulator. So what makes botensilimab different is that the CTLA-4 end is very similar to other CTLA-4 inhibitors that are out there, but it's been engineered on the back end of the molecule that binds to Fc gamma receptors to basically bind tighter with higher affinity. And what this translates to in laboratory models and increasingly now in patients is it does a better job of priming, of educating our T cells, our, again, these highly intelligent antigen specific cells, but also natural killer cells. It does a better job of sort of educating those. It helps to activate macrophages and other supporting actors in the immune response. And so the idea here is that there's evidence that botensilimab may do a better job at creating new responses in immune cold tumors. The study combined either botensilimab as monotherapy or in combination with a PD-1 inhibitor called balstilimab. And this was all comers, really a variety of tumor types. And to date I think we're close to about 500 patients with a variety of solid tumors that have been accrued to this study, this C-800-01 phase 1 trial. This paper reports on the sarcoma patients that were enrolled as part of this study. And so, again, given what I've told you about sarcomas being really immune cold, we were just so excited to have the opportunity to enroll on a next generation immune therapy for these tumors that really we were running into roadblocks trying to use immunotherapy previously. Shannon Westin: It's a very compelling idea and I'm so excited for you to tell people what you found. I think first things first, it was an early phase trial. So why don't we talk a little bit about the safety of the regimen. Was there anything that you didn't expect? Dr. Breelyn Wilky: Right. So similar to other checkpoint inhibitors, you know, the idea is that these drugs can cause immune mediated toxicities, right? So essentially you're revving up the immune system and it can sometimes get a bit confused and start attacking our normal cells, our normal organs, leading to essentially any number of toxicities of basically head to toe, something can get inflamed and you can develop a toxicity from that. So the key take homes with this particular drug with, botensilimab with balstilimab, we saw colitis was sort of the primary immune mediated toxicity and it was about a third of patients, give or take. It happens and it can be aggressive and needs to be managed aggressively. And you know, one of the things that we learned very quickly taking part in this study is how important it is that as soon as patients start to get diarrhea, immunosuppression gets on board. So steroids, early use of TNF alpha blockade, so infliximab for example, if we jumped on it quickly and we recognized it and we got the patients treated, it would resolve fairly quickly and even some patients could remain on treatment. So I think that was sort of the first take home is “Okay if you get colitis, you treat it fast, you treat it early and you can still have patients not only recover, which essentially everybody recovered from this colitis and then being able to continue on treatment and still have their anti-tumor responses.” So that's the first point. The second thing that was really interesting is part of the engineering of botensilimab on the back end of the molecule, it's been designed to decrease complement binding and it's thought that that triggers some of these other toxicities that we've seen with prior CTLA-4 inhibitors like pneumonitis or hypophysitis. We actually don't see that with botensilimab. So there's sort of this selective toxicity that may reflect the design of the molecule. But overall the treatment was, we didn't see any new safety signals that were outside of what we would expect in class. And colitis was sort of the dominant thing that we had to be ready for and ready to manage. Shannon Westin: We've been doing it for a while now, so we kind of know what to do and we can act quickly and really try to mitigate and avoid some of the major toxicities. So that's great that that was what was reflected in what you found. And then of course I think: What about the efficacy?” Right. This is what we care about as practitioners, as patients. Does it work and are there any subtypes that seem to benefit the most from this combination? Dr. Breelyn Wilky: Right. So for the sarcoma patients, we treated 64 patients and 52 of those patients were evaluable for efficacy. So a decent size group of patients in sarcomas, where, you know, typically our trials are pretty small, they're very rare, but we had 52 evaluable with at least one post baseline scan. So that was our criteria. And basically we saw across all of the patients, and keep in mind, these are heavily pre-treated patients, as you mentioned, so a median of 3 prior lines of therapy, so most of these patients had had chemotherapies and then about 20% had also had prior immunotherapy as well. So PD-1 treatments or so on. The overall response rate by RECIST was 19.2% for all of the evaluable patients. And then with iRECIST, which is sort of that immune adapted response criteria that allows for early pseudo progression, we actually had another patient who did have that. And so that response rate was 21.2%. Overall, we were really excited to see this in a heavily pre-treated group of patients. But what was really exciting to me was when we looked at the subset of patients that had angiosarcoma, that blood vessel tumor I was talking about earlier with my other patient. So angios come in two flavors. One is this sort of cutaneous type, or meaning involving the skin that has a UV signature, a UV damage signature, very similar to melanoma. So these tumors tend to have a high mutation burden. And oftentimes there is a track record that we've seen responses with immunotherapy in cutaneous angiosarcomas. But the other group that we deal with is called visceral angiosarcomas. And so these are totally different biologically. These are often driven by mutations in MYC or KDR amplification, and they arise in organs, so primary breast angiosarcoma, not associated with radiation, or they can arise in the liver or the spleen or an extremity. So these are very, very different tumors, and the visceral ones almost never historically have responded to checkpoint inhibitors. So we had 18 patients with angio split - 9 with cutaneous, 9 with visceral. And we were just blown away because the response rate for that group was 27.8%. And if you looked at the responses between the hot ones and the cold ones, it was almost equal and a little bit better in the visceral. So we had a 33% response rate in visceral angiosarcoma, which is crazy, historically speaking, and about 20% again in the cutaneous angios. So for a disease where visceral angio gets treated with chemotherapy, might respond initially, but then rapidly progresses - like these people go through multiple lines of therapy - to have a third of patients responding, and then some of those responses were durable. Our median duration of response for the study was 21.7 months, which is just nuts for sarcomas where we just don't see those sorts of long term benefits with the drugs that we have. So I think those are kind of the two main things. There were other subtypes that had clinical benefit and responses as well in d-diff liposarcoma, soft tissue leiomyosarcoma, which are again thought to be fairly cold immune subtypes. So just really exciting to kind of see responses we hadn't expected in a very challenging group of tumors. Shannon Westin: We see all these patients and we have patients that respond so well to immunotherapy with other histotypes. And so it's so exciting to see an option for these really hard to treat tumors that our patients struggle with. So this is so, so very exciting. I wanted to make mention, you know, I was really impressed with the amount of translational work you were able to do in this early phase study. So do you want to review just maybe a few of the key findings that you guys discovered? Dr. Breelyn Wilky: It's always great. I'm a translational researcher at heart and we do a lot of immune correlative work. And I think the reason I got so excited about this field to begin with was trying to learn why it works for some patients and why it doesn't work for other patients. So I'm a huge believer in learning from every patient that we can. So it's such a testament to the company, Agenus, who sponsored this trial to invest their time and resources into correlative studies at this phase. It's huge. So we learned a couple of things. IL-6 or interleukin 6 is a cytokine that basically has, in other tumor types, been associated with worse outcomes. And what we were interested in this group is we saw the same thing. And again, sarcomas have very, very little correlative biology that's done. We're really in infancy and understanding the microenvironment and how that milieu balances out in our tumors. So we were really excited to see again that lower peripheral interleukin 6 associated with improved overall survival. So again, kind of sorting out a group of patients that might be immunologically favorable when it comes to this type of therapy. The other thing that's important to know about sarcoma is so the other tumor types are lucky and have PD-L1 expression and the tumor is a biomarker, but we never have PD-L1 expression. We can find it in sarcomas and it can be loosely correlated with a chance of benefit with immunotherapy. But I've had patients respond that were PD-L1 negative, and I've had patients that were loaded with PD-L1 that didn't seem to make a difference. And that's not just in this study. So we saw in this trial a trend towards improved overall survival with PD-L1 expression that wasn't significant, but there was like this trend. And it's really interesting because, again, this is largely a CTLA-4 directed therapy. And so what we wondered is if PD-L1 expression is an index of sort of this underlying potential immunogenicity. And actually PD-1 works very late in the whole immune process. That's really at the very end where you've got the T cell that's facing the tumor cell and it's just activating that T cell that's already grown up and already educated and ready to go. Whereas CTLA-4 is really educating in early immune responses and expanding the T cells that have potential to kill. So I'm interested to look into this in more depth in the future to see if this is actually the biomarker for CTLA-4 directed therapy that we've been looking for, because we really don't have a great sense about that. And then the last piece just to note is that in this trial, like most others, very, very few sarcomas had high mutational burden. Everybody was very low, which reflects the population. And it's just really more encouragement than an immune cold tumor with very crappy neoantigens can still respond to immunotherapy if we get them the right agents. Shannon Westin: Yeah, I mean, I'm taking notes because we have such a struggle with this across the gynecologic tumors. I'm like, “Okay, maybe this is finally it.” So hopefully your work will go on to really inspire us across a number of solid tumors that have been traditionally cold. So, so very exciting. And I would just say for my last question, obviously, congratulations on this successful study. What do you think are the next steps for this combination in sarcomas? Dr. Breelyn Wilky: So, again, just to your point, this trial enrolled a bunch of different subtypes, and sarcomas are not the only immune cold tumor that this combo has looked really promising for, microsatellite stable colorectal cancer, ovarian cancer that was platinum refractory, non-small cell lungs. So I think the future is really bright for immune cold tumors kind of across the board. So, yes, lots of hope for not just sarcomas but in terms of our patients, I just have to be so grateful to Agenus for their interest in a rare disease. Sometimes it's hard to get that interest for a very challenging group of patients that are all heterogeneous, they are not all the same and our big clinical trials are a few hundred patients. It's just a very different environment. But they have been so supportive and involved in making sure that sarcomas are represented in their priorities. So there are ongoing discussions about what the optimal way to explore this further in sarcomas is going to be and I cannot wait to have the official plans in place. But my hope is this will not be the last that we see of these drugs for our patients. Shannon Westin: Well, I support that and my vote is on your side. So, thank you so much again, Dr. Wilky. This time just flew by. This was such a great discussion and I mean, I think it's, again, a testament to your exciting data. And thank you to all of our listeners. This has been JCO After Hours' discussion of “Botensilimab (Fc-enhanced anti-cytotoxic lymphocyte-association protein-4 antibody) Plus Balstilimab (anti-PD-1 antibody) in Patients With Relapsed/Refractory Metastatic Sarcomas,” published in the JCO on January 27, 2025. So be sure to check out the full manuscript. And we hope that you enjoyed this podcast. And if you want to hear more about research published in the JCO, check this out on our ASCO JCO website or wherever you get your podcasts. Have an awesome day.   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement. Dr. Wilky Disclosures  Consulting or Advisory Role: SpringWorks Therapeutics, Deciphera, Epizyme, Adcendo, Polaris, Boehringer Ingelheim, AADi, InhibRx Research Funding: Exelixis Travel, Accommodations, Expenses: Agenus    

Welcome to the Oncology Brothers podcast! In this episode, Drs. Rahul and Rohit Gosain are joined by Dr. Anwaar Saeed, Chief of GI Medical Oncology at UPMC, to discuss the recent approval of Tislelizumab, a new checkpoint inhibitor for upper GI malignancies, including esophageal squamous cell cancer, GE junction, and gastric cancer. We dive deep into the studies that led to Tislelizumab's approval, including the Rationale 302, 305, and 306 trials. Dr. Saeed explains the unique mechanism of action of Tislelizumab, its higher binding affinity to PD-1, and how it compares to other PD-1 inhibitors like nivolumab and pembrolizumab. Key topics covered in this episode: •⁠  ⁠Overview of Tislelizumab and its mechanism of action •⁠  ⁠Insights from the Rationale 306 trial and its implications for frontline treatment •⁠  ⁠Discussion on the Rationale 305 trial focusing on adenocarcinoma •⁠  ⁠The importance of PD-L1 testing and biomarker-driven treatment decisions •⁠  ⁠Side effect profiles of Tislelizumab compared to other immunotherapies •⁠  ⁠Future directions in the use of immunotherapy for upper GI malignancies Join us for this informative discussion that highlights the evolving landscape of cancer treatment and the importance of precision oncology. If you find this episode helpful, please share it with your colleagues and leave us a review! YouTube: https://youtu.be/hQeLdpSzGCk Follow us on social media: •⁠  ⁠X/Twitter: https://twitter.com/oncbrothers •⁠  ⁠Instagram: https://www.instagram.com/oncbrothers •⁠  Website: https://oncbrothers.com/ Don't forget to subscribe for more practice-changing discussions in the world of oncology. We are the Oncology Brothers!  

Dr. Neeraj Agarwal and Dr. Peter Hoskin discuss key abstracts in GU cancers from the 2025 ASCO Genitourinary Cancers Symposium, including novel therapies in prostate, bladder, and kidney cancer and the impact of combination therapies on patient outcomes. TRANSCSRIPT Dr. Neeraj Agarwal: Hello, and welcome to the ASCO Daily News Podcast. I'm Dr. Neeraj Agarwal, the director of the Genitourinary Oncology Program and professor of medicine at the Huntsman Cancer Institute at the University of Utah, and editor-in-chief of ASCO Daily News. Today, we'll be discussing practice-informing abstracts and other key advances in GU oncology featured at the 2025 ASCO Genitourinary Cancers Symposium. Joining me for this discussion is Dr. Peter Hoskin, the chair of this year's ASCO GU Symposium. Dr. Hoskin is a professor in clinical oncology in the University of Manchester and honorary consultant in clinical oncology at the Christie Hospital, Manchester, and University College Hospital London, in the United Kingdom. Our full disclosures are available in the transcript of this episode. Peter, thank you for joining us today. Dr. Peter Hoskin: Thank you so much, Neeraj. I am very pleased to be here. Dr. Neeraj Agarwal: The GU meeting highlighted remarkable advancements across the spectrum of GU malignancies. What stood out to you as the most exciting developments at the ASCO GU Symposium?  Dr. Peter Hoskin: The theme of this year's meeting was "Driving Innovation, Improving Patient Care," and this reflected ASCO GU's incredible milestone in GU cancer research over the years. We were thrilled to welcome almost 6,000 attendees on this occasion from over 70 countries, and most of them were attending in person and not online, although this was a hybrid meeting. Furthermore, we had more than 1,000 abstract submissions. You can imagine then that it fostered fantastic networking opportunities and facilitated valuable knowledge and idea exchanges among experts, trainees, and mentees. So, to start I'd like to come back to you for a second because the first day started with a focus on prostate cancer and some of the key clinical trials. And congratulations to you, Neeraj, on sharing the data from the TALAPRO-2 trial, which we were eagerly awaiting. I'd love to get your thoughts on the data that you presented. Could you tell us more about that trial, Abstract LBA18?  Dr. Neeraj Agarwal: Yes, Peter, I agree with you. It was such an exciting conference overall and thank you for your leadership of this conference. So, let's talk about the TALAPRO-2 trial. First of all, I would like to remind our audience that the combination of talazoparib plus enzalutamide was approved by the U.S. FDA in June 2023 in patients with metastatic castration-resistant prostate cancer harboring HRR gene alterations, after this combination improved the primary endpoint of radiographic progression-free survival compared to enzalutamide alone in the randomized, double-blind, placebo-controlled, multi-cohort phase 3 TALAPRO-2 trial. In the abstract I presented at ASCO GU 2025, we reported the final overall survival data, which was a key alpha-protected secondary endpoint in cohort 1, which enrolled an all-comer population of patients with mCRPC. So, at a median follow-up of around 53 months, in the intention-to-treat population, the combination of talazoparib plus enzalutamide significantly reduced the risk of death by 20% compared to enzalutamide alone, with a median OS of 45.8 months in the experimental arm versus 37 months in the control arm, which was an active control arm of enzalutamide. This improvement was consistent in patients with HRR alterations with a hazard ratio of 0.54 and in those with non-deficient or unknown HRR status, with a hazard ratio of 0.87. In a post hoc analysis, the hazard ratio for OS was 0.78 favoring the combination in those patients who did not have any HRR gene alteration in their tumors by both tissue and ctDNA testing. Consistent with the primary analysis, the updated rPFS data also favored the experimental arm with a median rPFS of 33.1 compared to 19.5 months in the control arm, and a hazard ratio of 0.667. No new safety signals were identified with extended follow-up. Thus, TALAPRO-2 is the first PARP inhibitor plus ARPI study to show a statistically significant and a clinically meaningful improvement in OS compared to standard-of-care enzalutamide as first-line treatment in patients with mCRPC unselected for HRR gene alterations. Dr. Peter Hoskin: Thank you, Neeraj. That's a great summary of the data presented and very important data indeed. There was another abstract also featured in the same session, Abstract 20, titled “Which patients with metastatic hormone-sensitive prostate cancer benefit more from androgen receptor pathway inhibitors? STOPCAP meta-analyses of individual participant data.” Neeraj, could you tell us more about this abstract? Dr. Neeraj Agarwal: Absolutely, I would be delighted to. So, in this meta-analysis, Dr. David Fischer and colleagues pooled individual participant data from different randomized phase 3 trials in the mHSPC setting to assess the potential ARPI effect modifiers and determine who benefits more from an ARPI plus ADT doublet. The primary outcome was OS for main effects and PFS for subgroup analyses. Prostate cancer specific survival was a sensitivity outcome. The investigators pooled data from 11 ARPI trials and more than 11,000 patients. Overall, there was a clear benefit of adding an ARPI on both OS and PFS, with hazard ratios of 0.66 and 0.51, respectively, representing a 13% and 21% absolute improvement at 5 years, respectively, with no clear difference by the class of agent. When stratifying the patients by age group, the effects of adding an ARPI on OS and PFS were slightly smaller in patients older than 75, than in those younger than 65, or aged between 65 and 75 years. Notably, in the trials assessing the use of abiraterone, we saw very little OS effects in the group of patients older than 75, however there was some benefit maintained in prostate-cancer specific survival, suggesting that other causes of death may be having an impact. The effects of the other ARPIs, or ‘lutamides' as I would call them, were similar across all three age subgroups on both OS and PFS. Therefore, the majority of patients with mHSPC benefit from the addition of ARPIs, and the benefits/risks of abiraterone and other ‘amides' must be considered in older patients.  Dr. Peter Hoskin: Thanks, Neeraj. Another great summary relevant to our day-to-day practice. Of course, there's ongoing collection of individual patient data from other key trials, which will allow robust comparison of ARPI doublet with triplet therapy (including docetaxel), guiding more personalized treatment.   Dr. Neeraj Agarwal: I agree with you, Peter, we need more data to help guide personalized treatment for patients with mHSPC and potentially guide de-escalation versus escalation strategies. Now, moving on to a different setting in prostate cancer, would you like to mention Abstract 17 titled, “Overall survival and quality of life with Lu-PSMA-617 plus enzalutamide versus enzalutamide alone in poor-risk, metastatic, castration-resistant prostate cancer in ENZA-p (ANZUP 1901),” presented by Dr. Louise Emmett? Dr. Peter Hoskin: Of course I will. So, ENZA-p was a multicenter, open-label, randomized, phase 2 trial conducted in Australia. It randomized 163 patients into adaptive doses (2 or 4 cycles) of Lu-PSMA-617 plus enzalutamide versus enzalutamide alone as first-line treatment in PSMA-PET-CT-positive, poor-risk, mCRPC. The interim analysis of ENZA-p with median follow-up 20 months showed improved PSA-progression-free survival with the addition of Lu-PSMA-617 to enzalutamide. Here, the investigators reported the secondary outcomes, overall survival, and health-related quality of life (HRQOL). After a median follow up of 34 months, overall survival was longer in the combination arm compared to the enzalutamide arm, with a median OS of 34 months compared to 26 months; with an HR of 0.55. Moreover, the combination improved both deterioration-free survival and health-related quality of life indicators for pain, fatigue, physical function, and overall health and quality of life compared to the control arm. Consistent with the primary analysis, the rPFS also favored the experimental arm with a median rPFS of 17 months compared to 14 months with a HR of 0.61. So, the addition of LuPSMA improved overall survival, and HRQOL in patients with high-risk mCRPC. Dr. Neeraj Agarwal: Thank you, Peter. Great summary, and promising results with Lu-177 and ARPI combination in first line treatment for mCRPC among patients who had two or more high risk features associated with early enzalutamide failure. Before we move on to bladder cancer, would you like to tell us about Abstract 15 titled, “World-wide oligometastatic prostate cancer (omPC) meta-analysis leveraging individual patient data (IPD) from randomized trials (WOLVERINE): An analysis from the X-MET collaboration,” presented by Dr. Chad Tang?  Dr. Peter Hoskin: Sure. So, with metastatic-directed therapy (MDT), we have a number of phase 2 studies making up the database, and the X-MET collaboration aimed to consolidate all randomized data on oligometastatic solid tumors. This abstract presented pooled individual patient data from all the published trials involving patients with oligometastatic prostate cancer who received MDT alongside standard of care (SOC) against SOC alone. The analysis included data from five trials, encompassing 472 patients with oligometastatic prostate cancer, and followed for a median of 41 months. Patients were randomly assigned in a 1:1 ratio to receive either MDT plus SOC or SOC alone. The addition of MDT significantly improved PFS. The median PFS was 32 months with MDT compared to 14.9 months with SOC alone, with an HR of 0.45. Subgroup analyses further confirmed the consistent benefits of MDT across different patient groups. Regardless of factors like castration status, receipt of prior primary treatment, stage, or number of metastases, MDT consistently improved PFS. In patients with mHSPC, MDT significantly delayed the time to castration resistance by nine months, extending it to a median of 72 months compared to 63 months in the SOC group with an HR of 0.58. In terms of OS, the addition of MDT improved the 48-month survival rate by 12%, with OS rates of 87% in the MDT+SOC group compared to 75% in the SOC alone group. Dr. Neeraj Agarwal: Thank you, Peter. These data demonstrate that adding MDT to systemic therapy significantly improves PFS, rPFS, and castration resistance-free survival, reinforcing its potential role in the treatment of oligometastatic prostate cancer. So, let's switch gears to bladder cancer and start with Abstract 658 reporting the OS analysis of the CheckMate-274 trial. Would you like to tell us about this abstract?  Dr. Peter Hoskin: Yes, sure, Neeraj. This was presented by Dr. Matt Milowsky, and it was additional efficacy outcomes, including overall survival, from the CheckMate-274 trial which evaluated adjuvant nivolumab versus placebo in patients with high-risk muscle-invasive bladder cancer after radical surgery. The phase 3 trial previously demonstrated a significant improvement in disease-free survival with nivolumab. With a median follow-up of 36.1 months, disease-free survival was longer with nivolumab compared to placebo across all patients with muscle-invasive bladder cancer, reducing the risk of disease recurrence or death by 37%. Among patients who had received prior neoadjuvant cisplatin-based chemotherapy, nivolumab reduced this risk by 42%, whilst in those who had not received chemotherapy, the risk was reduced by 31%. Overall survival also favored nivolumab over placebo, reducing the risk of death by 30% in all patients with muscle-invasive bladder cancer and by 52% in those with tumors expressing PD-L1 at 1% or higher. Among patients who had received prior neoadjuvant chemotherapy, nivolumab reduced the risk of death by 26%, whilst in those who had not received chemotherapy, the risk was reduced by 33%. Alongside this, the safety profile remained consistent with previous findings. Dr. Neeraj Agarwal: Thank you, Peter, for such a nice overview of this abstract. These results reinforce adjuvant nivolumab as a standard of care for high-risk muscle-invasive bladder cancer, offering the potential for a curative outcome for our patients. Dr. Peter Hoskin: I agree with you Neeraj. Perhaps you would like to mention Abstract 659 titled, “Additional efficacy and safety outcomes and an exploratory analysis of the impact of pathological complete response (pCR) on long-term outcomes from NIAGARA.” Dr. Neeraj Agarwal: Of course. Dr. Galsky presented additional outcomes from the phase 3 NIAGARA study, which evaluated perioperative durvalumab combined with neoadjuvant chemotherapy in patients with muscle-invasive bladder cancer. The study previously demonstrated a significant improvement in event-free survival and overall survival with durvalumab compared to chemotherapy alone, with a manageable safety profile and no negative impact on the ability to undergo radical cystectomy. Among the 1,063 randomized patients, those who received durvalumab had a 33% reduction in the risk of developing distant metastases or death and a 31% reduction in the risk of dying from bladder cancer compared to those who received chemotherapy alone. More patients who received durvalumab achieved a pathological complete response at the time of surgery with 37% compared to 28% in the chemotherapy-alone group. Patients who achieved a pathological complete response had better event-free survival and overall survival compared to those who did not. In both groups, durvalumab provided additional survival benefits, reducing the risk of disease progression or death by 42% and the risk of death by 28% in patients with a pathological complete response, while in those patients without a pathological complete response, the risk of disease progression or death was reduced by 23% and the risk of death by 16% when durvalumab was added to the chemotherapy. Immune-mediated adverse events occurred in 21% of patients in the durvalumab group compared to 3% in the chemotherapy-alone group, with grade 3 or higher events occurring in 3% compared to 0.2%. The most common immune-related adverse events included hypothyroidism in 10% of patients treated with durvalumab compared to 1% in the chemotherapy-alone group, and hyperthyroidism in 3% versus 0.8%. At the time of the data cutoff, these adverse events had resolved in 41% of affected patients in the durvalumab group and 44% in the chemotherapy-alone group. Dr. Peter Hoskin: Thank you, Neeraj, for the great summary. These findings further support the role of perioperative durvalumab as a potential standard of care for patients with muscle-invasive bladder cancer. Dr. Neeraj Agarwal: I concur with your thoughts, Peter. Before wrapping up the bladder cancer section, would you like to mention Abstract 664 reporting updated results from the EV-302 trial, which evaluated enfortumab vedotin in combination with pembrolizumab compared to chemotherapy as first-line treatment for patients with previously untreated locally advanced or metastatic urothelial carcinoma? Dr. Peter Hoskin: Yes, of course. Dr. Tom Powles presented updated findings from the EV-302 study, and in this abstract presented 12 months of additional follow-up for EV-302 (>2 y of median follow-up) and an exploratory analysis of patients with confirmed complete response (cCR). The study had a median follow-up of 29.1 months and previously demonstrated significant improvements in progression-free survival and overall survival with enfortumab vedotin and pembrolizumab. This is now the standard of care in global treatment guidelines. Among the 886 randomized patients, enfortumab vedotin and pembrolizumab reduced the risk of disease progression or death by 52% and the risk of death by 49% compared to chemotherapy. The survival benefit was consistent regardless of cisplatin eligibility or the presence of liver metastases. The confirmed objective response rate was higher with enfortumab vedotin and pembrolizumab at 67.5% compared to 44.2% with chemotherapy. The median duration of response was 23.3 months with enfortumab vedotin and pembrolizumab compared to 7.0 months with chemotherapy. A complete response was achieved in 30.4% of patients in the enfortumab vedotin and pembrolizumab group compared to 14.5% in the chemotherapy group, with the median duration of complete response not yet reached in the enfortumab vedotin and pembrolizumab group compared to 15.2 months in the chemotherapy group. Severe treatment-related adverse events occurred in 57.3% of patients treated with enfortumab vedotin and pembrolizumab compared to 69.5% in the chemotherapy group, while in patients who achieved a complete response, severe adverse events occurred in 61.7% of those treated with enfortumab vedotin and pembrolizumab compared to 71.9% with chemotherapy. Treatment-related deaths were reported in 1.1% of patients treated with enfortumab vedotin and pembrolizumab compared to 0.9% with chemotherapy, with no treatment-related deaths occurring in those who achieved a complete response. These findings clearly confirm the durable efficacy of enfortumab vedotin and pembrolizumab, reinforcing its role as the standard of care for the first-line treatment of patients with locally advanced or metastatic urothelial carcinoma, and no new safety concerns have been identified. Dr. Neeraj Agarwal: Thank you for this great summary. Moving on to kidney cancer, let's talk about Abstract 439 titled, “Nivolumab plus cabozantinib (N+C) vs sunitinib (S) for previously untreated advanced renal cell carcinoma (aRCC): Final follow-up results from the CheckMate-9ER trial.” Dr. Peter Hoskin: Sure. Dr. Motzer presented the final results from the phase 3 CheckMate-9ER trial, which compared the combination of cabozantinib and nivolumab against sunitinib in previously untreated advanced renal cell carcinoma. The data after more than five years follow-up show that the combination therapy provided sustained superior efficacy compared to sunitinib. In terms of overall survival, we see an 11-month improvement in median OS, 46.5 months for the cabo-nivo versus 35.5 months for sunitinib and a 42% reduction in the risk of disease progression or death, with median progression-free survival nearly doubling – that's 16.4 months in the combination group and 8.3 months with sunitinib. Importantly, the safety profile was consistent with the known safety profiles of the individual medicines, with no new safety concerns identified. Dr. Neeraj Agarwal: Great summary, Peter. These data further support the efficacy of cabo-nivo combination therapy in advanced renal cell carcinoma, which is showing a 11-month difference in overall survival. Dr. Peter Hoskin: Neeraj, before wrapping up this podcast, would you like to tell us about Abstract 618? This is titled “Prospective COTRIMS (Cologne trial of retroperitoneal lymphadenectomy in metastatic seminoma) trial: Final results.” Dr. Neeraj Agarwal: Sure, Peter. I would be delighted to. Dr Heidenrich from the University of Cologne in Germany presented the COTRIMS data evaluating retroperitoneal LN dissection in patients with clinical stage 2A/B seminomas. Seminomas are classified as 2A or B when the disease spreads to the retroperitoneal lymph nodes of up to 2 cm (CS IIA) or of more than 2 cm to up to 5 cm (CS 2B) in maximum diameter, respectively. They account for 10-15% of seminomas and they are usually treated with radiation and chemotherapy. However, radiation and chemo can be associated with long-term toxicities such as cardiovascular toxicities, diabetes, solid cancers, leukemia, particularly for younger patients. From this standpoint, Dr Heidenrich and colleagues evaluated unilateral, modified template, nerve-sparing retroperitoneal lymph node dissection as a less toxic alternative compared to chemo and radiation. They included 34 patients with negative AFP, beta-HCG, and clinical stage 2A/B seminomas. At a median follow-up of 43.2 months, the trial demonstrated great outcomes: a 99.3% treatment-free survival rate and 100% overall survival, with only four relapses. Antegrade ejaculation was preserved in 88% of patients, and severe complications such as grade 3 and 4 were observed in 12% of patients. Pathological analysis revealed metastatic seminoma in 85% of cases, with miR371 being true positive in 23 out of 24 cases and true negative in 100% of cases. It appears to be a valid biomarker for predicting the presence of lymph node metastases. These findings highlight retroperitoneal lymph node dissection is feasible; it has low morbidity, and excellent oncologic outcomes, avoiding overtreatment in 80% of patients and sparing unnecessary chemotherapy or radiotherapy in 10-15% of cases. Dr. Peter Hoskin: Great summary and important data on retroperitoneal lymphadenectomy in metastatic seminoma. These findings will help shape clinical practice. Any final remarks before we conclude today's podcast? Dr. Neeraj Agarwal: Before wrapping up this podcast, I would like to say that we have reviewed several abstracts addressing prostate, bladder, kidney cancers, and seminoma, which are impacting our medical practices now and in the near future. Peter, thank you for sharing your insights with us today. These updates are undoubtedly exciting for the entire GU oncology community, and we greatly appreciate your valuable contribution to the discussion and your leadership of the conference. Many thanks. Dr. Peter Hoskin: Thank you, Neeraj. Thank you for the opportunity to share this information more widely. I'm aware that whilst we have nearly 6,000 delegates, there are many other tens of thousands of colleagues around the world who need to have access to this information. And it was a great privilege to chair this ASCO GU25. So, thank you once again, Neeraj, for this opportunity to share more of this information that we discussed over those few days. Dr. Neeraj Agarwal: Thank you, Peter. And thank you to our listeners for joining us today. You will find links to the abstracts discussed today on the transcript of this episode. Finally, if you value the insights that you hear on the ASCO Daily News podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.  Find out more about today's speakers:   Dr. Neeraj Agarwal    @neerajaiims    Dr. Peter Hoskin Follow ASCO on social media:      @ASCO on Twitter      ASCO on Bluesky  ASCO on Facebook      ASCO on LinkedIn      Disclosures: Dr. Neeraj Agarwal: Consulting or Advisory Role: Pfizer, Bristol-Myers Squibb, AstraZeneca, Nektar, Lilly, Bayer, Pharmacyclics, Foundation Medicine, Astellas Pharma, Lilly, Exelixis, AstraZeneca, Pfizer, Merck, Novartis, Eisai, Seattle Genetics, EMD Serono, Janssen Oncology, AVEO, Calithera Biosciences, MEI Pharma, Genentech, Astellas Pharma, Foundation Medicine, and Gilead Sciences Research Funding (Institution): Bayer, Bristol-Myers Squibb, Takeda, Pfizer, Exelixis, Amgen, AstraZeneca, Calithera Biosciences, Celldex, Eisai, Genentech, Immunomedics, Janssen, Merck, Lilly, Nektar, ORIC Pharmaceuticals, Crispr Therapeutics, Arvinas Dr. Peter Hoskin: Research Funding (Institution): Varian Medical Systems, Astellas Pharma, Bayer, Roche, Pfizer, Elekta, Bristol Myers  

Dr. Jyoti Patel is back on the podcast to discuss the updates to the living guideline on therapy for stage IV NSCLC with driver alterations. She shares updated recommendations in the first- and second-line settings for patients with stage IV NSCLC and classical EGFR mutations, and the impact of these updates for clinicians and patients. We also look to the future to discuss ongoing developments in the field. Read the full living guideline update “Therapy for Stage IV Non-Small Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, Version 2024.3” at www.asco.org/living-guidelines. TRANSCRIPT This guideline, clinical tools, and resources are available at http://www.asco.org/living-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO-24-02785     Brittany Harvey: Welcome to the ASCO Guidelines Podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges and advances in oncology. You can find all the shows including this one at asco.org/podcasts.   My name is Brittany Harvey and today I'm interviewing Dr. Jyoti Patel from Northwestern University, co-chair on “Therapy for Stage IV Non-Small Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, Version 2024.3.” It's great to have you back on the show today, Dr. Patel. Dr. Jyoti Patel: Thanks so much. Happy to be here. Brittany Harvey: And then before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest Policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Patel, who has joined us here today, are available online with the publication of the guideline and in the Journal of Clinical Oncology, which is linked in the show notes. So then, to dive into the content of this update, Dr. Patel, this clinical practice guideline for systemic therapy for patients with stage IV non small cell lung cancer with driver alterations is living, meaning that it's continuously reviewed and updated. So what data prompted this latest change to the recommendations? Dr. Jyoti Patel: Thanks so much. So it's really been an exciting time in the treatment of EGFR lung cancer, particularly this past year has required us to rethink approaches to front- and second-line therapy. In this particular update, we examined what patients in the front-line setting may be offered by their clinicians. And so we're talking about the population of classical EGFR mutations, so exon 19 and exon 21 L858R substitution. And so certainly for this population, osimertinib has a high level of evidence and should be offered to all patients at the time of diagnosis when they present with advanced disease. Our last update included a recommendation that patients could also get platinum doublet chemotherapy with osimertinib or osimertinib alone. This current recommendation also introduces another alternative therapy and that's the combination of amivantamab plus lazertinib. And so now, clinicians are faced with three really good options for their patients with EGFR exon19 deletion or L858R. Brittany Harvey: It's great to hear that there's this advance in the space, particularly for patients with these classical EGFR mutations that you mentioned. So what should clinicians know as they implement these new first-line recommendations? Dr. Jyoti Patel:  I think it's become more complex than ever. Certainly, we know again that patients should get osimertinib in the frontline setting. But we've been kind of stuck at progression-free survival that's between a year and a half and two years. And so we've really been looking at opportunities to intensify therapy. So one could certainly be with chemotherapy or switching over to amivantamab, the bispecific antibody that targets EGFR and MET plus lazertinib, an oral TKI that's very similar in structure to osimertinib. And when you're talking to a patient, it's really a conversation about balancing efficacy with toxicity. Unfortunately, as we know, there aren't that many free lunches. And so if we think about what a patient is hoping for in their therapy and how we can further personalize treatment options, really is important to look at some of the analyses for this study. So in the study of amivantamab plus lazertinib, we know that there were increased toxicities with a combination of both therapies. In fact, up to 75% of patients had over grade 3 toxicities, versus about 43% of patients with osimertinib monotherapy. And we know if we look back at FLAURA2, almost two thirds of patients with osimertinib and chemotherapy had grade 3 toxicities, compared to 27% of patients with osimertinib alone. So we certainly see an increase in toxicities. Then we have to ask ourselves, are those paper toxicities or ones that really impact patients? And we know that amivantamab, for example, causes significant cutaneous toxicities. With both of these therapies, whether it's chemotherapy or adding amivantamab, there's the burden of infusional visits and increased time in the doctor's office. Certainly with chemotherapy, there can be an increased incidence of myelosuppression. And so when we're thinking about advising our patients, certainly we need to talk about the toxicities. But one thing that we've been able to do is to look at the patients that were included in this trial. And what we really find is that in higher risk cohorts, particularly those that we know historically have done less well with standard osimertinib, so patients, for example, with CNS metastasis, for those patients with co-mutations, it may be that that additive benefit is significant. And so one example I think would be from the MARIPOSA study, again, the study of amivantamab and lazertinib versus chemotherapy. What we can say is that patients who had co-mutations, so patients with EGFR mutations as well as TP53, lazertinib and amivantamab led to a hazard ratio of 0.65 compared to osimertinib alone. So that was 18.2 months versus 12.9 months. And so this may be really important to patients. And we also see conversely that patients with wild type TP53, so those patients who didn't have the mutation, probably had equivalent survival regardless of therapy. So certainly, we need to prospectively study some of these high-risk cohorts. We've only seen progression-free survival in these studies. And so at this juncture, we can advise our patients about toxicity, the improvements in certain categories of progression-free survival, but we really still don't know how this pans out in overall survival. In many of these studies, all patients do not necessarily cross over to the study arm and so they may have lost the benefit of subsequent therapy. Brittany Harvey: Absolutely. It's very important to talk about that balance of benefits and risks and particularly those toxicities that you discussed. So I appreciate reviewing that recommendation and the considerations for clinicians for first-line therapy. This update also included a second-line treatment update. What is that update for patients with EGFR alterations? Dr. Jyoti Patel: So this is where it gets super tricky because we have a frontline option with amivantamab and now we've had an update in the second line option. So what we said is that for patients who have progressed on an EGFR TKI, and in the United States, certainly that's predominantly osimertinib, or those in other parts of the world that may have gotten an earlier generation TKI, but do not have evidence of T790M or other targetable mutations, we can offer patients chemotherapy with or without amivantamab. And so certainly we have seen that this again leads to improved survival. There have also been a number of studies looking at incorporation of PD-L1 and anti-VEGF therapies. And what we can say, I think pretty clearly is that multiple phase 3 trials have really shown no benefit of the addition of PD-1 to platinum chemotherapy. But there are some emerging bispecific antibodies that may target PD-1 as well as VEGF, or combinations of antibodies that target both of those pathways that may improve outcome. At this juncture, I think we feel that the evidence surrounding chemotherapy plus amivantamab is strongest, but there is certainly work in this space that will be of interest. Now, what happens if your patient received amivantamab and lazertinib in the frontline setting and then has progression? And so we're trying to understand resistance mechanisms and opportunities for treatment. What the panel decided to recommend, based on the available evidence, was that certainly those patients should get platinum-based chemotherapy, but there may also be a role for antivascular endothelial growth factor targeting therapy such as bevacizumab in patients in whom it would be safe. Brittany Harvey: Great. I appreciate you detailing those recommendations when it gets complicated in the second-line setting. So what should clinicians know as they implement these second-line recommendations too? Dr. Jyoti Patel: So certainly the frontline setting matters significantly. So if a patient gets osimertinib in the frontline setting, we generally suggest that patients undergo repeat testing to see if they have another targetable mutation. If they don't, then I think preferred therapy would be chemotherapy with or without amivantamab. And amivantamab leads to a significant improvement in progression-free survival and response rate at the cost of increased risk of toxicity. For patients who get FLAURA2 in the frontline setting, chemotherapy plus osimertinib, it's a little bit of an unclear space. Those patients most likely would get docetaxel with or without ramucirumab. But there are other agents that we hope to have available to our patients in the near future. For patients who receive amivantamab and osimertinib, we recommend that those patients get chemotherapy probably with anti-VEGF as demonstrated by multiple trials that have shown the improved progression-free survival with introduction of an anti-VEGF agent. And we've seen evidence of amivantamab in the third line setting, so it is likely that this question about sequencing really takes center stage in our next set of trials. When you're talking to a patient, I think again, it's absolutely important to discuss: What are their goals? How symptomatic or how fast is their progression? Are there ways in which patients may benefit from spot treatment oligoprogression such as radiation? When is the right time for introduction of amivantamab and when do we think patients need chemotherapy? Is it up front or predominantly in the second-line setting? Brittany Harvey: Definitely. And then you've just touched on the goals of treatment for individual patients. So in your view, what does this update mean for patients with stage IV non-small cell lung cancer and an EGFR alteration? Dr. Jyoti Patel: For patients, this is a time in which shared decision making really needs to take center stage. So our best patients are those patients that are best informed not only about their disease but also have a good understanding about what is important to them and their families in terms of care. And so bringing that shared understanding to the table again helps us think about this particular cancer as more of a journey rather than just a one off treatment. Therapy will hopefully be prolonged, and so it's absolutely important that we address toxicities, make therapies more tolerable, again, with the shared goal of living long and living well. Brittany Harvey: Absolutely. Those are key points to making sure that patients are living both longer and have a good quality of life during that time as well. So then, before you mentioned the possibility of future sequencing trials and other ongoing developments. What additional studies or future directions is the panel examining for future updates to this living guideline? Dr. Jyoti Patel: So certainly we're thinking about trials that look at, for example, cfDNA clearance. So are there patients that do well and can we detect that early on without having to intensify therapy on day 1 so it may be that we add chemotherapy a little bit later. I think really exciting are some of the new bispecific. The HARMONi-A trial was a trial in China of a novel bispecific, ivonescimab. And this drug targets both PD-1 and VEGF and it was combined with chemotherapy. And this trial found almost a doubling of progression-free survival with this drug in combination chemotherapy in an EGFR patient population. That study is being planned and being run in the United States to see if we have similar outcomes with a more diverse population. So certainly that's exciting. There are a number of antibody drug conjugates that are being studied in the post-chemotherapy setting as well. And I think we'll likely soon see a better understanding of what co-mutations and burden of disease really mean when we're thinking about assigning treatment. So which patients, again, need intensification of therapy and which patients may do really well on just an oral agent that they're taking at home with more tolerable toxicity than dual treatment. Brittany Harvey: Yes, we'll look forward to continued developments in these fields and seeing some of those studies come to fruition. So with that, I want to thank you for your work to rapidly and continuously update this guideline, and thank you for your time today, Dr. Patel. Dr. Jyoti Patel: Thanks so much, Brittany. It's really an exciting time for lung cancer and we hope that these updates really help physicians decide the best treatments for their patients. Again, it's a rapidly evolving landscape which is fantastic, but it does become more cumbersome to stay ahead of the literature. Brittany Harvey: Definitely. And so we appreciate your time and the panel's time spent reviewing this literature and providing this much needed information to clinicians everywhere. So finally, thank you to all of our listeners for tuning into the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/living-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in the  Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  

Dr. Lyudmila Bazhenova joins us again to share the newest changes to the living guideline on therapy for stage IV NSCLC without driver alterations. She discusses new evidence reviewed by the panel and changes to second-line recommendations for patients with good performance status and HER2 overexpression, and what these updates mean in practice. We discuss ongoing evidence generation as we await further updates to these living guidelines. Read the full living guideline update “Therapy for Stage IV Non-Small Cell Lung Cancer Without Driver Alterations: ASCO Living Guideline, Version 2024.3” at www.asco.org/living-guidelines. TRANSCRIPT This guideline, clinical tools, and resources are available at http://www.asco.org/living-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO-24-02786     Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges and advances in oncology. You can find all the shows, including this one, at asco.org/podcasts. My name is Brittany Harvey and today I'm interviewing Dr. Lyudmila Bazhenova from University of California San Diego Moores Cancer Center, co-chair on “Therapy for Stage IV Non–Small Cell Lung Cancer Without Driver Alterations: ASCO Living Guideline, Version 2024.3.” It's great to have you back on the show today, Dr. Bazhenova. Dr. Lyudmila Bazhenova: It's my pleasure to be here as always. Brittany Harvey: Great. Then before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest Policy is followed for each guideline. The disclosures of potential conflicts of interest for the entire guideline panel, including Dr. Bazhenova, who has joined us here today, are available online with the publication of the guide in the Journal of Clinical Oncology, which is linked in the show notes. So then to dive into the content here, first, this living clinical practice guideline for systemic therapy for patients with stage IV non-small cell lung cancer without driver alterations has frequent updates to the recommendations. What prompted this latest update? Dr. Lyudmila Bazhenova: Living ASCO guidelines are created to keep up with rapidly changing evidence which affect treatment of our patients with lung cancer. As a committee, we review published literature on a specific topic at the regular intervals and determine if it alters any recommendations. This time, upon our literature review, we felt that there are new data that requires an update in the guidelines and therefore the guidelines were updated. Brittany Harvey: Great. Thank you for that updated information. So then it looks like the panel updated recommendations for second line and subsequent treatment options for patients with good performance status and HER2 overexpression. What is that updated recommendation from the panel? Dr. Lyudmila Bazhenova: Yes, this is correct. We now added an extra recommendation for patients with stage IV non-small cell lung cancer who have overexpression of the protein called HER2. HER2 overexpression with 2+/3+ level via immunohistochemistry is seen in approximately 8% to 20% of patients with lung cancer. And the data behind our recommendation comes from the DESTINY-Lung01 trial where patients with HER2 overexpression were treated with trastuzumab deruxtecan. And we saw that if patients with stage IV non-small cell lung cancer had a HER2 IHC score of 3+, overall response rate was seen at 53% and median duration of response was 6.9 months and, therefore, that in our opinion qualified for updated recommendation. We are still waiting for additional results that will be released later on another clinical trial where we see preliminary data presented at the World Conference of Lung Cancer in 2024. They looked at 36 patients also with HER2 overexpression and saw the overall response rate of almost 45%. It is important to highlight in this smaller study that a majority of the patients in the study were actually having EGFR mutation and the response rate in those patients who had an EGFR mutation was higher than the response rate in patients without EGFR mutations who just had a HER2 overexpression. So for now this is updated in the guidelines, but we will wait for additional data or formal publication of a World Lung Conference presentation and see if those recommendations need to be changed. Brittany Harvey: Understood, and I appreciate you providing the context of some of those ongoing developments as well. So then what should clinicians know as they implement this updated recommendation? Dr. Lyudmila Bazhenova: Number one, we should all start from remembering to test for HER2 via immunohistochemistry. There is a slight difference in what considers HER2 positive in lung versus breast. In lung, we use what's called the gastric scoring and the difference is the circumferential versus non circumferential staining of the membrane. And number two, immunohistochemistry is not always included in next generation sequencing panels. So when you order your next generation sequencing, I think it's important to know if your company that you're using is testing for HER2 via immunohistochemistry. And if it's not, make sure that you find a company that does or work with your local pathology department to make sure that this testing is offered. It is also important to know the difference between HER2 overexpression and HER2 exon 20 insertion mutation even though the treatment for those two abnormalities is the same, which is trastuzumab deruxtecan. But the benefit that you can cite your patients and the rigor of the literature supporting the usage of trastuzumab deruxtecan in mutation versus overexpression is different. Brittany Harvey: Yes. And as you mentioned, it's essential that, in the first place, patients are actually receiving the testing so that we know if they're eligible for these treatment options. So what additionally does this change mean for patients with stage IV non-small cell lung cancer and HER2 overexpression? Dr. Lyudmila Bazhenova: So for patients, it adds another treatment modality which is now FDA approved. So if there are patients listening to me, make sure that your physician has tested your tumor for HER2 overexpression. So I think proactive asking of your physician would be very appropriate in this situation. Brittany Harvey: Absolutely. And then earlier you mentioned an ongoing trial that the panel was looking to for the future. But what other additional trials did the panel review during this guideline update and what is the panel examining for future updates to this living guideline? Dr. Lyudmila Bazhenova: So at this point we reviewed three additional studies. The results of those studies did not make it into a change in guidelines. So we reviewed the HARMONi-2 trial.  HARMONi-2 trial so far does not have an official publication and, as per our strategy on how we come up with ASCO guidelines, we need to wait for an official publication. So this is one thing we're going to be expecting in the future. Once this is published, we will review it and decide if we need to make an additional change in recommendations. For those of you who are not aware, HARMONi-2 trial used bispecific monoclonal antibody against VEGF and PD-1 and was a phase III randomized trial comparing their investigational product which is called ivonescimab over pembrolizumab for patients with PD-L1 more than 50. And again, we are waiting for the final publication to make our recommendation. The second trial we reviewed was a LUNAR trial and the LUNAR trial looked at addition of tumor treating fields to chemotherapy or immunotherapy in patients whose cancer progressed with platinum doublet. The key point about this study is that immunotherapy was not required to be administered in a first line setting which is a current standard of care in the United States. And even though the study met their primary endpoint of overall survival, there were more benefits in patients who were immunotherapy naive in the second line. And we felt that given the potential lifestyle implication of wearing a device for 18 hours per day, and the lack of evidence in immunotherapy-pretreated population, and the absence of data in the first-line setting where we currently using immunotherapy in the United States, we felt that there is insufficient data to definitely recommend addition of tumor treating fields to systemic chemotherapy for most patients. And we are waiting for additional trials that are ongoing in this setting to formalize or change our recommendations. And we also reviewed- the final study that we reviewed was TROPION-Lung01. TROPION-Lung01 study was a phase III study in post platinum doublet setting which compared efficacy of Dato-DXd and docetaxel and trials showed improvement in progression free survival but not in overall survival. And progression free survival benefit was more pronounced in non-squamous carcinoma histology subgroup and we felt that the results do appear promising, but the strength of evidence which was based on unplanned subgroup analysis was not sufficient enough to make a change in treatment recommendation at this time. Brittany Harvey: I appreciate your transparency on why some of that data did not prompt a change to recommendations at this time. And additionally, we'll look forward to those future published results and potential incorporation of new data into future versions of this living guideline. So, I want to thank you so much for your work to rapidly and continuously update this guideline and for your time today, Dr. Bazhenova. Dr. Lyudmila Bazhenova: It is my pleasure. Thank you so much. Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines Podcast. To read the full guideline, go to www.asco.org/living-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in the  Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.  

In a conversation with CancerNetwork®, Marwan G. Fakih, MD, spoke about the FDA approval of sotorasib (Lumakras) plus panitumumab (Vectibix), and how it may affect the treatment paradigm for patients with KRAS G12C-mutant metastatic colorectal cancer (CRC). Fakih is a professor in the Department of Medical Oncology & Therapeutics Research, associate director for Clinical Sciences, medical director of the Briskin Center for Clinical Research, division chief of GI Medical Oncology, and co-director of the Gastrointestinal Cancer Program at City of Hope Comprehensive Cancer Center in Duarte, California. According to Fakih, the approval of this combination regimen is a “welcome step” for those with metastatic CRC harboring KRAS G12C mutations. Based on supporting data from the phase 3 CodeBreaK 300 trial (NCT05198934), sotorasib/panitumumab may prolong progression-free survival (PFS) and reduce disease burden in patients while offering improvements in other outcomes vs prior standards of care (SOC) like trifluridine/tipiracil (Lonsurf) and regorafenib (Stivarga). Topline data at the time of the approval showed a median PFS of 5.6 months (95% CI, 4.2-6.3) with sotorasib at 960 mg plus panitumumab vs 2.0 months (95% CI, 1.9-3.9) in the SOC arm, in which patients were assigned to receive trifluridine/tipiracil or regorafenib (HR, 0.48; 95% CI, 0.30-0.78; P = .005). Additionally, the overall response rate was 26% (95% CI, 15%-40%) vs 0% (95% CI, 0%-7%) in each respective arm. Looking ahead, Fakih highlighted the potential next steps for research associated with the sotorasib combination as well as other novel therapeutic strategies in the gastrointestinal cancer space. For example, he described the phase 3 CodeBreaK 301 study (NCT06252649), which will evaluate sotorasib/panitumumab as frontline therapy when administered in combination with folinic acid, fluorouracil, and irinotecan (FOLFIRI) vs FOLFIRI plus bevacizumab (Avastin) in metastatic KRAS G12C-mutant CRC. Other novel agents under development in the space include RAS inhibitors and immunotherapy regimens combining CTLA-4 inhibitors with anti–PD-L1 agents. References 1. FDA approves sotorasib with panitumumab for KRAS G12C-mutated colorectal cancer. News release. FDA. January 16, 2025. Accessed February 12, 2025. https://shorturl.at/1WviB 2. Kim TW, Price T, Grasselli J, et al. A phase 3 study of first-line sotorasib, panitumumab, and FOLFIRI versus FOLFIRI with or without bevacizumab-awwb for patients with KRAS G12C–mutated metastatic colorectal cancer (CodeBreaK 301). J Clin Oncol. 2025;43(suppl 4):TPS326. doi:10.1200/JCO.2025.43.4_suppl.TPS326

Welcome to the Oncology Brothers podcast! In this episode, hosts Drs. Rahul and Rohit Gosain are joined by Dr. Virginia Kaklamani from the UTHealth San Antonio MD Anderson Cancer Center to discuss the latest advances in the treatment of triple negative breast cancer (TNBC) as we kick off 2025. •⁠  ⁠The treatment paradigms for early-stage TNBC, including the role Sacituzumab and radiation therapy. •⁠  ⁠Insights from the SABCS 2024 conference, focusing on the keynote 522 regimen and its implications for neoadjuvant treatment. •⁠  ⁠The management of locally advanced and metastatic TNBC, including the use of immunotherapy and the importance of PD-L1 testing. •⁠  ⁠Strategies for managing toxicities associated with treatments like sacituzumab and T-DXd. Whether you're a healthcare professional or someone interested in the latest in oncology, this episode provides valuable insights into the evolving landscape of breast cancer treatment. Don't forget to like, subscribe, and hit the notification bell for more updates from the Oncology Brothers! Key Takeaways: •⁠  ⁠Current standard of care for locally advanced TNBC. •⁠  ⁠The significance of chemotherapy and immunotherapy in treatment plans. •⁠  ⁠Managing toxicities in metastatic disease. Stay tuned for more discussions on treatment algorithms, FDA approvals, and clinical pearls in oncology! YouTube: https://youtu.be/GfROoYPVb_8 Follow us on social media: •⁠  ⁠X/Twitter: https://twitter.com/oncbrothers •⁠  ⁠Instagram: https://www.instagram.com/oncbrothers

Romain Banchereau joins the show to discuss and debate this Cancer Cell paper on molecular subtypes in urothelial cancer and implications for checkpoint blockade.

In this JCO Article Insights episode, Ece Cali summarizes findings from the JCO article, "Datopotamab Deruxtecan Versus Docetaxel for Previously Treated Advanced or Metastatic Non–Small Cell Lung Cancer: The Randomized, Open-Label Phase III TROPION-Lung01 Study." TRANSCRIPT Ece Cali: Hello and welcome to the JCO Article Insights. I'm your host Ece Cali and today we will be discussing the Journal of Clinical Oncology article the “Datopotamab Deruxtecan Versus Docetaxel for Previously Treated Advanced or Metastatic Non–Small Cell Lung Cancer: The Randomized, Open-Label Phase III TROPION-Lung01 Study.”  Despite significant advances in non-small cell lung cancer treatment over the past decades, second line treatment options for non-small cell lung cancer without actionable genomic alterations have remained largely unchanged since 2000. Many clinical trials failed to demonstrate improved overall survival compared to docetaxel based regimens. TROPION-Lung01 is a global open label randomized phase 3 trial comparing the efficacy and safety of Dato-DXd to docetaxel in patients with previously treated advanced or metastatic non-small cell lung cancer. Dato-DXd is an antibody drug conjugate targeting TROP2 and delivering deruxtecan, a DNA topoisomerase 1 inhibitor, as its payload. The trial is designed with dual primary endpoints of progression free survival, as assessed by blinded independent central review, and overall survival. The initial PFS results were presented at ESMO in 2023 and this article reports more detailed data and overall survival analysis of the trial.   In the TROPION-Lung01, 299 patients were randomly assigned to receive Dato-DXd and 305 patients to receive docetaxel. Patients were stratified by the presence of actionable genomic alterations, histology, treatment with PD-1/PD-L1 immunotherapy as the last line of therapy, and geographical region. The baseline characteristics of the patient population were overall balanced between the treatment arms. I'd like to highlight a couple of key points here. The median age was 63 years in the Dato-DXd and 64 years in the docetaxel arm. Similar to the many clinical trials in the thoracic oncology field, this is younger than the median age of lung cancer diagnosis in the US, which is around 70. African American and Hispanic patients were underrepresented in this trial with 41% of patients identifying themselves as white and 39% as Asian. The Ddocetaxel arm had a slightly higher percentage of male patients, 69% versus 61%. The majority of the trial population, 73%, had adenocarcinoma. Patients with actionable genomic alterations were included in this trial if they received one or more targeted therapy and platinum based chemotherapy prior to the enrollment. 17% of the trial population had an actionable genomic alteration in this trial.  When it comes to the efficacy results in the full analysis set, the PFS improvement was statistically significant. The median PFS was reported as 4.4 months for the Dato-DXd, and 3.7 months for the docetaxel arm with the hazard ratio of 0.75 and a P value of 0.004. However, after a median follow up of 23 months, the trial did not meet its primary endpoint of overall survival. The median overall survival was 12.9 months for patients treated with Dato-DXd and 11.8 months for patients treated with docetaxel with the hazard ratio of 0.94 and a P value of 0.53. Objective response was a secondary endpoint and the confirmed objective response rate was 26% with Dato-DXd, and 13% with docetaxel.  Now let's take a closer look at some of the subgroup analyses. Exploratory analyses of key subgroups in TROPION-Lung01 demonstrated differences in efficacy based on histology. In the nonsquamous subgroup, Dato-DXd showed a longer progression free survival of 5.5 months compared to 3.6 months with docetaxel with a hazard ratio of 0.84. However, in the squamous subgroup, Dato-DXd performed worse with a progression free survival of 2.8 months compared to 3.9 months with docetaxel corresponding to a hazard ratio of 1.32. A similar trend was observed in the overall survival analyses, though confidence intervals crossed 1 in both histology subsets, in this case, the differences observed were not statistically significant. In the nonsquamous subset, the median overall survival was 14.6 months with Dato-DXd and 12.3 months with docetaxel with a hazard ratio of 0.84. In the squamous subset, both arms had shorter survival compared to the nonsquamous subset. The median overall survival with Dato-DXd was almost two months shorter, so 7.6 months, compared to 9.6 months with docetaxel corresponding to a hazard ratio of 1.32. While these analyses suggest the potential survival benefit for Dato-DXd in nonsquamous subset, this trial was not powered to test this hypothesis hence these analyses remain exploratory. Another subgroup analysis of note was the group with actionable genomic alterations. Patients with actionable genomic alterations achieved a median PFS of 5.7 months with Dato-DXD and 2.6 months with docetaxel corresponding to a hazard ratio of 0.35. Similarly, the median overall survival was longer in patients with actionable genomic alterations by almost six months, with a median overall survival of 15.6 months with Dato-DXd and 9.8 months with docetaxel corresponding to a hazard ratio of 0.65.  Now, let's talk about safety. Grade 3 or higher treatment related adverse events occurred in 26% of patients with Dato-DXd and 42% with docetaxel. The most common adverse event of any grade seen in the Dato-DXd arm were stomatitis seen in 47% of patients, nausea in 34%, and alopecia in 32%. Treatment related interstitial lung disease occurred in 8.8% of patients on Dato-DXd and 4.1% of patients on docetaxel. Of note, grade 5 drug related ILD was more frequent with Dato-DXd. Seven patients on Dato-DXd and one patient on docetaxel died secondary to drug related ILD in this trial.  In summary, TROPION-Lung01 aims to address an unmet need for patients with previously treated non-small cell lung cancer. For this population, the treatment options remain limited with poor survival outcomes. TROPION-Lung01 is a positive trial by design due to clinically modest improvement in PFS. However, the lack of overall survival improvement is disappointing. Exploratory subgroup analyses suggest Dato-DXd may offer survival advantage in specific subsets such as nonsquamous non-small cell lung cancer and patients with actionable genomic alterations. However, these findings require further validation in a prospective trial since TROPION-Lung01 was not designed to address these questions. The data from this trial alone is not sufficient to argue for a change in clinical practice. However, it informs how the future trials using this drug should be tailored. This highlights the importance of studying potential predictive biomarkers earlier in the drug development and incorporating these biomarkers prospectively into the clinical trial designs.  Due to the lack of overall survival benefit in this trial, the biologic license application for accelerated approval of Dato-DXd for patients with previously treated nonsquamous non-small cell lung cancer was voluntarily withdrawn. New BLA was submitted for Dato-DXd for patients with previously treated advanced EGFR positive non-small cell lung cancer. This BLA is based on data from TROPION-Lung05, TROPION-Lung01 and TROPION-PanTumor01. Of note, the results of TROPION-Lung05 trial have been just published in JCO.   This wraps up today's episode. Thank you for listening to JCO Article Insights. Please come back for more interviews and article summaries and be sure to leave us a rating and review so others can find our show. For more podcasts and episodes from ASCO, please visit asco.org/podcasts.   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.    

The pivotal role of programmed death-ligand 1 (PD-L1) checkpoint inhibition for treating advanced melanoma has been confirmed in findings from the KEYNOTE-006 study comparing the anti-PD-L1 antibody pembrolizumab immunotherapy with the anti-cytotoxic T-lymphocyte associated protein 4 (CTLA-4) drug ipilimumab for treating patients with unresectable advanced or metastatic melanoma. Results from the study were reported at the European Society for Medical Oncology (ESMO) 2024 Annual Congress, held in Barcelona, Spain.

JCO PO author Dr. David R. Gandara at UC Davis Comprehensive Cancer Center, shares insights into his JCO PO article, “Plasma Proteome–Based Test for First-Line Treatment Selection in Metastatic Non–Small Cell Lung Cancer,” one of the Top Articles of 2024. Host Dr. Rafeh Naqash and Dr. Gandara discuss how the PROphet® blood test supports first-line immunotherapy treatment decisions for metastatic NSCLC patients. TRANSCRIPT  Dr. Rafeh Naqash: Hello and welcome to JCO Precision Oncology Conversations where we bring you engaging conversations with authors of clinically relevant and highly significant JCOPO articles. I'm your host, Dr. Rafeh Naqash, Podcast Editor for JCO Precision Oncology and Assistant Professor at the OU Health Stephenson Cancer Center at the University of Oklahoma.  Today, we are absolutely thrilled to be joined by Dr. David R. Gandara, Professor of Medicine Emeritus, Co-Director of the Center for Experimental Therapeutics and Cancer and Senior Advisor to the Director at UC Davis Comprehensive Cancer Center and also the senior author of the JCO Precision Oncology article entitled “Plasma Proteome–Based Test for First-Line Treatment Selection in Metastatic Non–Small Cell Lung Cancer.” This was one of the top performing articles of 2024, which is one of the reasons why we wanted to bring it in for a podcast discussion. At the time of this recording, our guest's disclosures will be linked in the transcript.  David, it is an absolute pleasure to have you today. For somebody like you who's led the field of lung cancer over the years, I'm really excited that you are going to be talking to us about this very interesting article, especially given that I think you're one of the big proponents of liquid biopsies and plasma-based testing. So, for the sake of our listeners - which comprises of academic oncologists, community oncologists, trainees - could you tell us where the biomarker landscape for non-small cell lung cancer is currently, and then we can try to take a deeper dive into this article. Dr. David Gandar: Okay. Well, thank you, Rafeh. It's a pleasure to be with you here today. And I think the current landscape for biomarkers for immunotherapy in non-small cell lung cancer is a mess. There's no better way to describe it. That makes this paper describing a new plasma proteomic assay even more important. So I'll just give you a perspective. There are 14 trials, phase three trials, that were done in first line non-small cell lung cancer advanced stage of immunotherapy versus chemotherapy and some other aspects, although they vary tremendously. Some of them were checkpoint monotherapy, some combined with chemotherapy, some combined with CTLA-4 inhibitors and so forth. 12 out of the 14 were positive, 12 got FDA approval. So there are 12 different options that an oncologist could use. Some of them were squamous cell only, some non-squamous, some used PD-L1 as a biomarker driven part of the study. Some used TMB, tumor mutational burden, some were agnostic. So when you put all of this together, an oncologist can pick and choose among all these various regimens. And by and large, it's PD-L1 that is the therapeutic decision maker.  ASCO actually, I think, has done the very best job of making a guideline, and it's, as you well know, called a living guideline, it's dynamic. And it is much easier to interpret, for me and I think for oncologists, than some of the other guidelines. It's got a green light and a red light, it may be kind of orange. And so the green light means this is a strong recommendation by the guideline committee. The orange means it's weak. For this purpose, non-small cell lung cancer, advanced stage, only a very few of the recommendations were green. It's mainly monotherapy and patients with cancers with a PD-L1 over 50%. In our surveys, at our meetings, less than 50% of oncologists in the United States are following these guidelines. Why? Because they don't trust the biomarker. And TMB has the same sort of limitations. They're not bad biomarkers, they're incomplete. They're only looking at a part of the story. So that means we need a new biomarker. And this is one that, I think, the data are quite impressive and we'll discuss it more. Dr. Rafeh Naqash: Absolutely. Like you said, abundance of many therapy options, but not necessarily everything works the same in different subsets of PD-L1 positivity or different subsets of patients with different levels of tumor burden. And like you said, again, difficulty in trying to identify the right biomarker. And that's a nice segue to this PROphet test that you guys ran. So can you tell us a little bit about the plasma proteomic assay? Because to the best of my knowledge, there's not a lot of validated plasma proteomic assays. A lot has been done on the tumor tissue side as far as biomarkers are concerned, but not much on the blood side, except for maybe ctDNA MRD testing. So what was the background for trying to develop a plasma-based proteomic test? And then how did this idea of testing it in the lung cancer setting come into play? And then we can go into the patient population specifics, the cohort that you guys have. Dr. David Gandara: Okay. Well, of course there's a company behind this assay, it's called OncoHost, and I'm a consultant for them. And they came to me two years ago and they said, “We have something different from anyone else.” And they explained the science to me, as well as some other lung cancer experts here in the United States. I'm not a proteomic expert, of course, but they developed an AI machine learning platform to assess plasma proteins in normal people and in people with cancer, and specifically then in people with non-small cell lung cancer. They identified over 7,000 proteins that had cancer implications for therapy, for resistance, for prognosis, etc., and they categorized them based on the literature, TCGA data, etc., and used this machine learning process to figure out which proteins might be most specific for non-small cell lung cancer. And that's where they started. And so out of that 7,000 proteins, where they've identified which ones are angiogenic, which ones are involved with EMT or cell cycle or whatever it might be, they distilled it down to 388 proteins which they thought were worth testing in non-small cell lung cancer. And that's when I became involved.  They had a retrospective cohort of patients that had been treated with various immunotherapies. They looked at the analytic validation first, then applied it to this cohort. It looked good. Then they had a very large cohort, which they split, as you usually do with an assay, into a test set and then a validation set. For the test set, they wanted something more than a response. They wanted some indicator of long term benefit because that's where immunotherapy differentiates itself from chemotherapy and even targeted therapy. And so they picked PFS at 12 months. And I became involved at that point and it looked really good. I mean, if you look at the figures in the manuscript, the AUC is superb about their prediction and then what actually happened in the patient. And then in this paper, we applied it to a validation set of over 500 patients in a prospective trial, not randomized, it's called an observational trial. The investigator got to pick what they thought was the best therapy for that patient. And then in a blinded fashion, the proteomic assay experts did the analysis and applied it to the group.  And so what that means is some of the patients got chemotherapy alone, some got checkpoint immunotherapy monotherapy, some got in combination with chemotherapy. None of the patients in this study got a CTLA-4 inhibitor. That work is ongoing now. But what the study showed was that this assay can be used together with PD-L1 as what I would call a composite biomarker. You take the two together and it informs the oncologist about the meaning of that PD-L1. I'll give you an example. If that patient has a PD-L1 over 50% in their cancer and yet the PROphet test is negative, meaning less than 5 - it's a 0 to 10 scale - that patient for survival is better served by getting chemotherapy and immunotherapy. However, if the PROphet test is positive and the PD-L1 is over 50%, then the survival curves really look equivalent. As I said earlier, even in that group of patients, a lot of oncologists are reluctant to give them monotherapy. So if you have a test and the same sort of example is true for PD-L1 0, that you can differentiate. So this can really help inform the oncologist about what direction to go. And of course then you use your clinical judgment, you look at what you think of as the aggressiveness of the tumor or their liver metastases, etc. So again, that's how this test is being used for non-small cell lung cancer. And maybe I'll stop there and then I'll come back and add some other points. Dr. Rafeh Naqash: I definitely like your analogy of this therapy de-escalation strategy. Like you mentioned for PD-L1 high where the PROphet test is negative, then perhaps you could just go with immunotherapy alone. In fact, interestingly enough, I was invited to a talk at SITC a couple of weeks back and this exact figure that you're referring to was one of the figures in my slide deck. And it happened by chance that I realized that we were doing a podcast on the same paper today.  So I guess from a provocative question standpoint, when you look at the PD-L1 high cohort in the subset where you didn't see a survival difference for chemo plus immunotherapy versus immunotherapy alone, do you think any element of that could have been influenced by the degree of PD-L1 positivity above 50%? Meaning could there have been a cohort that is, let's say PD-L1 75 and above, and that kind of skews the data because I know you've published on this yourself also where the higher the PD-L1 above 50%, like 90% PD-L1 positivity survival curves are much better than 50% to 89%. So could that have somehow played a role? Dr. David Gandara: The first thing to say is that PD-L1 and the PROphet score, there's very little overlap. I know that sounds surprising, but it's also true for tumor mutational burden. There's very little overlap. They're measuring different things. The PD-L1 is measuring a specific regulatory protein that is applicable to some patients, but not all. That's why even in almost all of the studies, people with PD-L1 0 could still have some survival benefit. But in this case they're independent. And not in this paper, but in other work done by this group, the PROphet group, they've shown that the PROphet score does not seem to correlate with super high PD-L1. So it's not like the cemiplimab data where if you have a PD-L1 of greater than 90%, then of course the patient does spectacularly with monotherapy. The other thing that's important here is they had a group of around a little less than 100 patients that got chemotherapy alone. The PROphet score is agnostic to chemotherapy. And so that means that you're not just looking at some prognostic factor. It's actually clinical utility on a predictive basis. Dr. Rafeh Naqash: I think those are very important points. I was on a podcast a couple of days back. I think there's a theme these days we're trying to do for JCO Precision Oncology, we're trying to do a few biomarker based podcasts, and the most recent one that we did was using a tissue transcriptome with ctDNA MRD and you mentioned the composite of the PD-L1 and the PROphet test and they use a composite of the tissue transcriptome. I believe they called it the VIGex test as well as MRD ctDNA. And when your ctDNA was negative at, I believe, the three month mark, those individuals had the highest inflamed VIGex test or highest infiltration of T cells, STING pathway, etc. So are there any thoughts of trying to add or correlate tissue based biomarkers or ctDNA based correlations as a further validation in this research with the company? Dr. David Gandara: Right. So there are many things that are being looked at, various composites looking at the commutations that might affect the efficacy of immunotherapy and how they correlate with profit positivity or negativity. And I'll just give the examples of STK11 and KEAP1. As you know, there's some controversy about whether these are for immunotherapy, whether they're more prognostic or predictive. I'm one of the co-authors among many in the recently published Nature paper by Dr. Skoulidis and the group at MD Anderson which report that for KEAP1 positive especially, but also SDK11 mutated getting immunotherapy, that that's where the CTLA-4 inhibitors actually play the greatest role. So realizing that this is still controversial, there are preliminary data, not published yet, that'll be presented at an upcoming meeting, looking at many of these other aspects, P53, SCK11, KEAP1, other aspects, TMB, that's actually already published, I think in one of their papers. So yes, there's lots of opportunities.  The other cool thing is that this isn't a test, it's a platform. And so that means that the OncoHost scientists have already said, “What if we look at this test, the assay in a group of patients with small cell lung cancer?” And so I just presented this as a poster at the world conference in San Diego. And it turns out if you look at the biology of small cell, where neither PD-L1 nor TMB seem to be very important, if you look at the biology of small cell and you form an assay, it only shares 44 proteins out of the 388 with non-small cell. It's a different biology. And when we applied that to a group of patients with small cell lung cancer, again it had really pretty impressive results, although still a fairly small number of patients. So we have a big phase three study that we're doing with a pharmaceutical company developing immunotherapy where we are prospectively placing the PROphet test in a small cell trial.  The platform can also be altered for other cancer types. And at AACR, Dr. Jarushka Naidoo presented really impressive data that you can modify the proteins and you can predict immunotherapy side effects. So this is not like a company that says, “We have one test that's great for everything.” You know how some companies say, “Our test, you can use it for everything.” This company is saying we can alter the protein structures using AI machine learning assisted process to do it and we can have a very informed assay in different tumor types and different situations. So to me, it's really exciting. Dr. Rafeh Naqash: Definitely to me, I think, combining the AI machine learning aspect with the possibility of finding or trying to find a composite biomarker using less invasive approaches such as plasma or blood, definitely checks a lot of boxes. And as you mentioned, trying to get it to prospective trials as an integral biomarker perhaps would be likely the next step. And hopefully we see some interesting, exciting results where we can try to match or stratify patients into optimal combination therapies based on this test.  So now to the next aspect of this discussion, David, which I'm really excited about. You've been a leader and a mentor to many. You've led ISLC and several other corporate group organizations, et cetera. Can you tell us, for the sake of all the listeners, junior investigators, trainees, what being a mentor has meant for you? How your career has started many years back and how it's evolved? And what are some of the things that you want to tell people for a successful and a more exciting career as you've led over the years? Dr. David Gandara: Well, thank you for the question. Mentoring is a very important part of my own career. I didn't have an institutional mentor when I was a junior investigator, but I had a lot of senior collaborators, very famous people that kind of took me under their wing and guided me. And I thought when I basically establish myself, I want to give back by being a mentor to other people. And you wouldn't believe the number of people that I'm even mentoring today. And some of them are not medical oncologists, they're surgeons, they're radiation oncologists, they're basic scientists. Because you don't have to be an expert in that person's field to be a mentor. It helps, but in other words, you can guide somebody in what are the decision making processes in your career. When is it time to move from this institution onward because you can't grow in the institution you're in, either because it's too big or it's too small? So I established a leadership academy in the Southwest Oncology Group, SWOG. I've led many mentoring courses, for instance, for ISLC, now for International Society Liquid Biopsy, where I'm the executive committee liaison for what's called The Young Committee. So ISLB Society, totally devoted to liquid biopsy, six years old now, we have a Young Committee that has a budget. They develop projects, they publish articles on their own, they do podcasts. So what I'm saying is those are all things that I think opens up opportunities. They're not waiting behind senior people, they are leading themselves.  We just, at our International Lung Cancer Congress, reestablished a fellows program where a group of fellows are invited to that Huntington beach meeting. It's now in its 25th year and we spend a day and a half with them, mentoring them on career building. I'll just give you my first, I have the “Letterman Top 10”. So my first recommendation is if all you have is lemons, make lemonade. And what I'm meaning is find what you can do at your institution if you're a junior person, what you can claim to be your own and make the very best of it. But then as you get further along in my recommendations, one of them is learn when to say ‘no'. Because as a junior investigator the biggest threat to your career is saying ‘yes' to everybody and then you become overwhelmed and you can't concentrate. So I'll stop there. But anyway, yes, mentoring is a big part of my life. Dr. Rafeh Naqash: Well, thank you, David. This is definitely something that I'm going to try to apply to my career as well. And this has been an absolute pleasure, especially with all the insights that you provided, not just on the scientific side but also on the personal career side and the mentorship side. And hopefully we'll see more of this work that you and other investigators have led and collaborated on. perhaps more interesting plasma based biomarkers. And hopefully some of that work will find its home in JCO Precision Oncology. Thank you again for joining us today. Dr. David Gandara: My pleasure. Dr. Rafeh Naqash: And thank you for listening to JCO Precision Oncology Conversations. Don't forget to give us a rating or review and be sure to subscribe so you never miss an episode. You can find all ASCO shows at asco.org/podcasts.   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service organization, activity or therapy should not be construed as an ASCO endorsement.   Dr. David Gandara Disclosures: Consulting or Advisory Role Company: Henlius USA, Foundation Medicine, Janssen Pharma, Merck & Co, Mirati Therapeutics, Regeneron, AstraZeneca, Guardant Health, Genentech, Exact Sciences  Research Funding Company: Amgen, Genentech, Astex Pharma  

Good morning from Pharma and Biotech daily: the podcast that gives you only what's important to hear in Pharma e Biotech world. Johnson & Johnson has made a significant move in the neurology field by acquiring Intra-Cellular for $14.6 billion, gaining access to assets such as Caplyta for schizophrenia and bipolar depression. Biogen has submitted an offer to acquire Sage Therapeutics after facing regulatory and clinical challenges. Gilead is diversifying with a potential $1.7 billion inflammation pact with Leo, focusing on targeting stat6. The FDA's evolving biomarker focus was highlighted by a committee's decision to limit the use of Keytruda and Opdivo in certain cancers based on PD-L1 expression levels. AGC Biologics is offering representative scale-down data for gene of interest candidates before committing to a GMP contract, potentially accelerating timelines by up to 6 months. Other news includes GSK's acquisition of Idorsia targeting rare cancer, AbbVie absorbing the cost of a schizophrenia failure, and collaborations between Merus and Biohaven. Additionally, five novel FDA approvals have been achieved in 2024, while Passage Bio is cutting staff to extend cash runway.The FDA's evolving focus on biomarkers is reflected in the scrutiny of Keytruda and Opdivo for stomach and esophageal cancers based on PD-L1 expression levels. This trend leverages ever-maturing datasets to make more informed decisions about drug approvals. In addition, five novel FDA approvals in 2024 included new mechanisms of action in oncology and neurosciences. Gene therapies for cardiovascular diseases like congestive heart failure and cardiomyopathy are advancing in the clinic, benefiting from technological advancements and positive early data. The NextGen Class of 2025 startups are focusing on ADCs, radiopharmaceuticals, and cell and gene therapies. Pfizer's subcutaneous PD-1 blocker showed positive results in bladder cancer trials, while Denali and AbbVie/Calico faced setbacks in ALS trials. The FDA is proposing setting a bar for weight-loss therapies as the obesity space heats up, with Metsera touting powerful weight loss results.

The pivotal role of programmed death-ligand 1 (PD-L1) checkpoint inhibition for treating advanced melanoma has been confirmed in findings from the KEYNOTE-006 study comparing the anti-PD-L1 antibody pembrolizumab immunotherapy with the anti-cytotoxic T-lymphocyte associated protein 4 (CTLA-4) drug ipilimumab for treating patients with unresectable advanced or metastatic melanoma. Results from the study were reported at the European Society for Medical Oncology (ESMO) 2024 Annual Congress, held in Barcelona, Spain.

CME credits: 0.75 Valid until: 20-12-2025 Claim your CME credit at https://reachmd.com/programs/cme/the-importance-of-pd-l1-testing-shaping-the-future-of-treatment-in-escc/29791/ This online CME activity focuses on the first-line treatment of advanced or metastatic esophageal squamous cell carcinoma (ESCC) with the addition of an immune checkpoint inhibitor (ICI) to chemotherapy. Participants will learn about anti-PD-1 agents for ESCC that are either approved or are actively being investigated, along with their differentiating features; practice-changing data; and current guideline recommendations to inform first-line treatment selection decisions for patients with metastatic ESCC. Strategies to monitor and mitigate adverse effects associated with the use of combination ICI and chemotherapy regimens to optimize treatment adherence and patient outcomes will also be explored. Please stay tuned for additional content to this program available for credit. The maximum amount of credit available for the entire activity 0.75.

Featuring perspectives from Dr Heather Wakelee, including the following topics: Introduction (0:00) Cases: A man in his late 50s with metastatic carcinoma of the lung, no actionable genomic alteration (AGA), PD-L1-negative, and a man in his early 60s with metastatic squamous cell carcinoma of the lung, PD-L1-negative — Brian P Mulherin, MD and Taral Patel, MD (8:08) Case: A man in his late 60s presenting with metastatic adenocarcinoma of the lung, multiple bone metastases, no AGA; PD-L1 20%; enrolled on ECOG-EA5163 — Priya Rudolph, MD, PhD (21:45) Current and Emerging Immunotherapeutic Strategies for Metastatic Non-Small Cell Lung Cancer (mNSCLC) (30:55) Case: An African American man in his early 60s with 6.2-cm squamous cell carcinoma of right upper lung receives neoadjuvant treatment as per CheckMate 816 — Dr Rudolph (39:16) Case: A man in his late 60s with pT2aN0 invasive adenocarcinoma of the right lower lung, no AGA; PD-L1 5% — Zanetta S Lamar, MD (44:57) Antibody-Drug Conjugates and Other Management Approaches for mNSCLC without AGAs (48:51) Case: A woman in her early 60s diagnosed in 2014 with metastatic adenocarcinoma of the lung treated on ECOG 5508 (carboplatin/paclitaxel/bevacizumab) receives nivolumab on disease progression — Dr Rudolph (56:35) CME information and select publications

CME credits: 1.00 Valid until: 27-11-2025 Claim your CME credit at https://reachmd.com/programs/cme/innovations-in-oncology-learning-center-from-guidelines-to-practice-lung-cancer/29133/ This online CME activity, presented in collaboration with the National Comprehensive Cancer Network (NCCN), focuses on translating oncology guidelines into practical strategies for treating non-small cell lung cancer (NSCLC). Participants will learn how to integrate clinical trial data into guideline-concordant testing and treatment plans for patients with resectable and metastatic NSCLC. The program highlights the importance of evidence-based approaches in the perioperative setting and the use of immunotherapy and targeted therapies for advanced disease. Attendees will also explore emerging data that could influence future treatment guidelines and develop region-specific therapeutic strategies aligned with NCCN recommendations. As of November 12, 2024, a new Biologics License Application (BLA) for datopotamab deruxtecan (Dato-DXd) has been submitted to the FDA for accelerated approval in the US for patients with previously treated advanced EGFR-mutated NSCLC. The previously submitted BLA for patients with advanced nonsquamous NSCLC has been voluntarily withdrawn.

Host Dr. Davide Soldato and Dr. Aaron Mitchell discuss the JCO article "Quality of Treatment Selection for Medicare Beneficiaries With Cancer" TRANSCRIPT Dr. Davide Soldato: Hello and welcome to JCO After Hours, the podcast where we sit down with authors from some of the latest articles published in the Journal of Clinical Oncology. I am your host, Dr. Davide Soldato, medical oncologist at Hospital San Martino in Genoa, Italy. Today, we are joined by JCO author Dr. Aaron Mitchell. Dr. Mitchell is a medical oncologist working at Memorial Sloan Kettering Cancer Center where he is also part of the Department of Epidemiology and Biostatistics. Dr. Mitchell specializes in treating genitourinary malignancy and has a research focus on improving how the healthcare system helps people with these and other cancers. So today, Dr. Mitchell will be discussing the article titled, “Quality of Treatment Selection for Medicare Beneficiaries with Cancer.” Thank you for speaking with us, Dr. Mitchell. Dr. Aaron Mitchell: Well, thank you for inviting me. I'm very glad to be here. Dr. Davide Soldato: So I just wanted to introduce the topic by asking a couple of questions, very general, about the background of the article. So basically you reported the data using the SEER-Medicare to assist to assess the determinants of optimal systemic therapies delivery and selection. So, in particular, you focused on individuals that were diagnosed with cancer who were Medicare beneficiaries and in particular were part of the low income subsidy, which is also known as LIS. So I just wanted to ask you if you could briefly explain to our listeners how this program works, and what was the rationale of the study, and if there is any element of novelty in your study compared to what was done before the study was published. Dr. Aaron Mitchell: Yeah. So that's a lot to cover, but yeah, a lot of opportunity to introduce the low income subsidy program which is a very important part of the Medicare program for prescription drugs, but often one that flies under the radar a little bit in the policy discussion. So this subsidy was created synchronously back with the Medicare Part D Program, which was created in 2006. There was some anticipation that for some high cost drugs, not all patients would be able to afford them even with the Part D program insurance as it was being created. And so they created a pathway to give an additional subsidy to some patients who had low income, who were anticipated to being at need and needing that assistance to afford high cost drugs. As the number of high cost drugs has really risen since 2006, this program has played an important role in helping patients afford drugs, especially those who need very expensive cancer drugs.  And what this program does is, once you meet the eligibility requirements, which require patients to have both quite a low income. So if you're single, that is at 135% of the federal poverty limit or below, and it also places some restrictions on assets. You also have to have low assets, so low income and low assets in order to qualify for the subsidy. But then once you do, the subsidy is really quite large. Patients who qualify for the LIS at the full subsidy level will pay about $10 per month per drug, even for specialty cancer drugs. So if you think about drugs such as those that we use to treat prostate cancer, my specialty, drugs like enzalutamide or XTANDI that run $15,000 to $20,000 per month, the out of pocket cost for a low income subsidy beneficiary is $10. So that is a huge discount. $10 isn't nothing, but even for someone with a low income, if they've got one or two cancer drugs that are at this rate, it's something that they can often afford.  This program applies to Part D cancer drugs that are prescription drugs basically. By and large, these are oral pills that patients are taking on a daily basis at home. These are the drugs that the low income subsidy program applies to. So if a patient needs a drug like that to treat their cancer, then they are able to receive it at very low cost. And what you'll see is a patient- in the studies that have been done, when a patient has low income, low enough for them to be able to qualify for this program, they then have better access to these drugs. You see increased adherence rates, you see increased prescription fill rates. And then when someone, when their income is just high enough to no longer qualify for this program, and they go back to regular Medicare Part D coverage, that's when the problems arise. So it's like as your income moves up the scale, you actually get more problems affording your cancer drugs. So that's the state of the literature so far.  And what we realize though, is that all these studies that have looked at the low income subsidy have really focused on just the Part D drugs themselves, the oral drugs. And that's certainly not all of cancer care. There is a growing number of oral drugs, but for many cancers, especially when you're talking about immunotherapy drugs or new systemic radioligand therapies, these are not Part D drugs, these are Part B drugs. And so even if you are low income and you're qualifying for this subsidy, it's not going to help you if you need a Part B drug. Yes, there are certainly a whole host of other programs and different avenues that we can get patients assistance, but some percentage of them, even though they're low income and high need, would not have assistance with a Part B drug.  So now, in coming back, the long answer to your question, our rationale was, let's look at these Part D low income subsidy patients and let's see what their access looks like, not just to the oral drugs, but to cancer care writ large. And can we study where they're fitting into the system, not only when they need oral drugs, but when they need any kind of cancer care across the board? Dr. Davide Soldato: So basically, just to summarize, it was an extension of previous literature, but specifically evaluating whether novel regimens that use, for example intravenous drugs, they were covered at the same level and whether there were any inequities in access to cancer treatment under this specific program, which is the LIS. Dr. Aaron Mitchell: Yes, I'd say that's a fair summary. Dr. Davide Soldato: Okay. So more or less, you included 9,000 patients inside of the study and 25% of them were beneficiaries of the LIS program. And you specifically looked at factors that could be associated with not receiving therapies at all, and also whether the quality of care that these patients were receiving were any different compared to those who were not part of the LIS program. So I just wanted to see if you could guide us a little bit in the results, whether you see any kind of differences when we look at access to any type of systemic therapies and whether being a part of the LIS program modified access to the drugs. Dr. Aaron Mitchell: Let me take this opportunity also to highlight a feature of our study that differentiates us a little bit from previous work that's been done. And this is around the specific definition of quality that we use. I know quality is in the title of the manuscript, but I think it's important to emphasize exactly what we mean in this study when we say quality, and it's something very specific. So our measure of quality references back to the NCCN guidelines, which I don't think our audience needs much of an introduction to that. It's the most worldwide recognized standard of care guidelines for oncology practice. And we specifically looked not only at the NCCN guidelines, but at their evidence block scoring system. So what we did was we looked not only at one set of guidelines, but we looked at guidelines across time. We looked at guidelines across our full study period, which was, give or take, 2015-2018, depending on the cancer. And we looked at each point in time to see what was the treatment regimen that was recommended by the NCCN guidelines as being preferred. Some of them make that designation, some of them don't. If there was not a designation of preferred, then we turned to the evidence blocks. And the evidence blocks, we then apply several different measures to kind of rank treatments from those that get high scores for efficacy and safety to those that get low scores for efficacy, safety and the quality of evidence. So we basically come up with a kind of a rank list of the recommended treatments at each point in time. And then we look at the ones that are the highest, we say which are the most highly recommended treatments at any given point in time. That then becomes our definition of quality treatment. And I'm saying this with air quotes, we use the term “optimal treatment” in the study. Did they get that treatment? If there were ties, you could have gotten either of the two treatments that got the equally good score, did you get that treatment versus did you get anything else?  So then getting back to our analysis, what we really did was kind of a two-stage study. First, we put all of our patients into our pool, into one big analytic model. And we looked to see what are the factors that predict or are associated with a patient either getting no systemic therapy or any systemic therapy. And then as a second question, we look at the patients who got some form of systemic therapy, and then we ask, again, what percentage of those got the optimal treatment or high quality treatment as opposed to one of the more lowly recommended treatment regimens? So that's how we asked it. We found that patients who were low income subsidy recipients, the low income ones, they were both less likely to receive any systemic therapy. And then even the ones that receive systemic therapy, the ones who made it in the door to see their doctor or their part of the system, they still were less likely to get the optimal treatment that was recommended for their cancer type at the time that they were diagnosed. Dr. Davide Soldato: So basically, even when you are a part of this subsidiary program, you still have a lower access to any type of treatment. And even if you get treatment, you kind of get the ones that were not the preferred according to the NCCN guidelines, or at least they were not scoring as well as those specific regimens. But I think that what our audience might be wondering about is that frequently there are also some other types of characteristics, for example, age or number of comorbidities, which can be associated with having a low socioeconomic status. So I was wondering whether in the analysis you kind of looked specifically also at patient factors, for example, income rather than age or comorbidities, and whether you found any significant association with those and whether it was something that you planned to do in your study. Dr. Aaron Mitchell: Yes. So we looked at many patient factors and those included age and they included the degree of comorbidity. And what we saw with respect to those characteristics was not too surprising. We saw that patients who were older were less likely to receive systemic therapy. We saw that patients who had more comorbidities were also less likely to get systemic therapy. And then across our different designations of treatments, we saw that those patients were also less likely to get the optimal treatment for their cancer. This result though, we would say it certainly needs more study in the future, but it's not immediately concerning. And that is because for patients who have more age, more comorbidity, those often correlate with frailty. And so it could be that these patients aren't getting optimally treated or it could be that their oncologists are just making clinically appropriate decisions about patient selection.  We saw as we were doing this work that the treatment regimens that are often getting the highest recommendations from the NCCN, hence, it would become our definition of high quality optimal treatment, are often ones that are aggressive. They're often ones that are multi-drug combinations. They're often ones that it's not just your old antineoplastics, it's the antineoplastics plus an additional immunotherapy or plus a targeted drug. So it's the ones that are more aggressive by and large, and that might be in some cases more than a patient who is older, more frail, could be able to tolerate. And so the oncologist might be making inappropriate judgment to say I'm going to do something a little bit less aggressive here and make an appropriate trade off between anti cancer efficacy and safety.  I think we've got kind of a bookmark there and we can look at those trends in the future. So we saw that kind of as expected, and then we turned and looked towards the low income subsidy. And our premise there is, well, your income shouldn't predict what you're getting clinically. In an ideal world, you'd be able to get the appropriate treatment for a patient, and not depend on whether their income is above or below 135% of the poverty limit. So that one seems more like on its face an immediate concern. Dr. Davide Soldato: Thank you very much for the explanation. I was just wondering, did you make some kind of selection when you were analyzing specific diseases or settings where you included just metastatic patients or you also included patients with early stage neoadjuvant treatments? Because I think that it is also very interesting from the perspective of the objectives that we have as oncologists when we are administering systemic treatments. Dr. Aaron Mitchell: Yeah, thank you for bringing that up. That was also one of the goals of our study was to be broad. And we wanted to look for factors, whether it be low income subsidy, whether it be age, socioeconomic background, etc., things that would be broad predictors of outcomes, and by which I mean care delivery outcomes across the board. So not just for, let's say, metastatic breast cancer, but also across any cancer that a patient might walk in the door with, what are the systemic predictors. And so when you mentioned before that our overall cohort is approximately 9,000 patients, that's 9,000 patients split over a variety of what we call clinical scenarios or clinical indications. And that includes multiple solid tumor as well as liquid tumor malignancies. It includes both patients who are initiating systemic therapy with palliative intent for metastatic disease. It also includes several groups of patients who are getting adjuvant therapy. So we want it to be as broad as possible. Our selection of those scenarios was really done with the goal of being as broad as possible and really bringing in everything that we could within the constraints of our data source. And that was really the only limitation that we applied in concept was tumor types that are common enough to have a meaningful sample of patients to analyze. So, one, are there enough patients? And then two, are you able to identify this specific group of patients within SEER-Medicare data? Because when the NCCN divides groups of patients by biomarkers that are not available in SEER-Medicare, we can't really say, “Oh, we're going to study this group of patients.” That would then be one that we have to leave on the side and not include. But everything else where one of those things didn't apply, we tried to include it as best we could. Dr. Davide Soldato: Thank you very much for the explanation. And among the scenarios that you included in the study, were there any striking differences in terms of access to treatment and access to quality treatment the way you define the study? Dr. Aaron Mitchell: Yes, there were differences between these different cancer types, these different cancer indications, but they're not differences that I want to over interpret or read too much into. Certainly, every cancer indication is going to be different, but when we start getting into the individual cancer types, the sample size does get smaller. And we've not done formal tests of comparison or heterogeneity among cancer types. So I don't want to say that the differences which we certainly do see, like numerically, there are differences in the proportion of patients who are getting optimal treatment versus no treatment. I don't want to say that it's because the low income subsidy status or patient age has a bigger impact, let's say for lung cancer than breast cancer. I want to say that is heterogeneity for potential future study when we are able to do a similar follow up analysis with say a larger sample size. I don't want to over interpret those differences at the moment. Dr. Davide Soldato: I was just wondering in case there was anything in particular that you wanted to highlight. But in the end, I think that we also have to acknowledge that the data are based on claims data, observational data. So maybe you're right when you say we should not over interpret this type of difference.  And this is just to speculate a little bit, do you think that if you would look at this same specific question in a more contemporary diagnosis frame, like for example, you refer to the fact that most of the diagnoses were between 2016 and 2018. Now that we have more and more of these drugs that would qualify as Part B in the adjuvant or new adjuvant setting, do you think that you would see more differences compared to what you observed in the current study or do you think that it would be more or less the same? Of course this was not part of the analysis that you did, but it's just to have your opinion on the topic in general. Dr. Aaron Mitchell: My expectation would be that since not much has changed with respect to the low income subsidy program from the time period of our study until now, my baseline expectation would be that those results would hold. On the other hand, it is the case that there have been improvements to the standard Medicare Part D benefit since the time of our study. So the low income subsidy patients would be paying the same low out of pocket costs that I mentioned before, about $10 a month give or take, for a specialty cancer drug. But what has started to happen is that for everyone else, their coverage has improved. Because in the US we're in the process of closing, or I think now we finally finished, but you know, a few years lag in claims data, we've closed what used to be called the donut hole, where there was this big coverage gap where patients had to pay a large amount out of pocket for drugs. So there might therefore be a narrowing of the difference, let's say between our low income subsidy participants, the lowest income patients, and then everyone else. But not so much because the low income subsidy status improved or changed, but just because the baseline level of coverage for everyone else may have improved, narrowing that gap. So I'd say that would be very possible.  And if your question is more geared towards not so much policy changes, but treatment landscape changes, I would say the big thing that I would maybe guess, and again, this is very much speculation, but you introduce the speculation in TBD on follow up. I think the big change in the landscape has been the broadening indication and uptake of immunotherapy drugs, our PD-1, PD-L1 inhibitors, for a variety of cancer types. And I think the way that that would manifest in our data, were we to repeat it in a more contemporary data set, would be, I think that the access for, let's say, that any systemic therapy among older patients might change. And that is because rather than just having your cytotoxics in hand, the clinical oncologists now know that for many cases there's if not first line therapy, then second line therapy for patients who don't qualify, you can go straight to it, to someone who's not a chemo candidate, you've got a much more tolerable treatment in your back pocket. And so I think that for patients who are more old or more comorbid, we might start to see that a greater proportion of them receive some systemic therapy, it just might not be the cytotoxic agent that is still most highly recommended. It might be, say a single agent, PD-L1 inhibitor, because their oncologist wants to be able to give them something. So I wouldn't be surprised if that gap starts to narrow as well if you're measuring no systemic therapy versus any systemic therapy. Dr. Davide Soldato: And going back to the policy part of the study that you did, do you think that the results of the study that you published in the JCO can better inform policy makers on how to make these treatments more available and be sure that the largest possible proportion of patients gets a systemic treatment and gets the optimal systemic treatment? Dr. Aaron Mitchell: Yes, I do think that this study has some direct and indirect policy implications. I think that our finding is one to highlight the low income subsidy program and maybe help it not to fly under the radar so much anymore. I think all the work that has been done on how much it has helped patients who need oral cancer medications is great, and it shows how beneficial this program can be. We're now shining the light kind of everywhere else and saying, “Okay. That's great. Here's how well it can work when it covers an oral drug, but we've got this group of low income patients who are still at need and they're still very clearly not able to access everything else. When it's not axitinib that they need, it's a pembrolizumab, they're still very much behind the curve and they need some help.” So I think that's one thing just to call attention to this as an ongoing problem. Low income patients, it's not a solved problem yet. It's something that needs further attention.  And then for direct policy implications that are on the table, I think we're about to see the Medicare program be able to start negotiating not just Part D drugs, but also in future years, Part B covered drugs and try to lower the price for everyone, both for insurance, both for Medicare itself. And then to the extent that that boils over to the patient's out of pocket responsibility, it'll start to reduce the patient out of pocket costs as well. So I think we can look forward to hopefully an aggressive negotiation program by Medicare to start to directly lower the prices of Part B cancer drugs that these patients are unable to afford. Dr. Davide Soldato: Thank you very much. You did the research you published in the JCO, but you really seem very passionate about the topic of care delivery and quality of care and policy. So I just wanted to ask on a personal note, how did you come to this area of research which is frequently not one that is very cared for by oncologists? It's more frequently something that biostatisticians or public health scientists put their attention to. I just had this curiosity and I wanted to ask you if you could explain a little bit how you came to this area of research. Dr. Aaron Mitchell: Thank you for asking. That's a great question. I'll tell my favorite story about my journey there. I entered medical school planning to be a clinical investigator or maybe even a basic science researcher, and I had some background in that. I went to medical school at NYU where the teaching hospital is Bellevue, which is a large, well known public hospital within New York City. And my eyes started to open regarding the inequities in the system. You always hear about it, you read about the problems in the US healthcare system, but then when you see it on a day to day basis and you can walk four blocks from a private, very well resourced hospital to see a patient with a similar condition four blocks down the road at a under resourced public hospital getting very different treatments and receiving very different outcomes, the injustice in the system really hits you on a visceral level. And it was really, I would say, as soon as I started my clinical rotations in medical school that I realized maybe that's where I can make the most impact with my career and just really fell into it. By the time I was done with medical school, I then knew that I wanted to do something that was in the health policy space. And then by the time I was done with residency, I was like, “Oh, someone had mentioned the words health services research” and the light went on. It's like, “Oh, that's me. That's what I want to do.” Dr. Davide Soldato: Thank you very much. That was a nice story. And I really think that we should all work towards trying to make sure that the inequities inside of the system are eliminated as much as possible.  So I think that this concludes our interview for today. So thank you again, Dr. Mitchell, for joining us. Dr. Aaron Mitchell: You're very welcome and thank you so much for your interest. Dr. Davide Soldato: We appreciate you sharing more on your JCO article titled, “Quality of Treatment Selection for Medicare Beneficiaries with Cancer.”  If you enjoy our show, please leave us a rating and review and be sure to come back for another episode. You can find all ASCO shows at asco.org/podcasts.   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  Guests on this podcast express their own opinion, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.

Host: Charles Turck, PharmD, BCPS, BCCCP Guest: Steven Maron, MD, MSc Given the recent identification of actionable biomarkers like PD-L1 and MSI-H,1-3 it's important to test patients with gastroesophageal cancer for these biomarkers as they may provide insights into options for a patient's treatment plan.4,5 To learn more about how we can detect biomarkers and other key considerations for biomarker screening in gastroesophageal cancer, Dr. Charles Turck speaks with Dr. Steven Maron, a gastrointestinal oncologist at Memorial Sloan Kettering Cancer Center in New York. References: The Cancer Genome Atlas Network. Nature. 2014;513:202-209. Fontana E, et al. Ther Adv Med Oncol. 2016;8:113-125. Yang B, et al. J Exp Clin Cancer Res. 2019;38:283. American Cancer Society. https://www.fightcancer.org/sites/default/files/Improving%20Access%20to%20Biomarker%20Testing_FINAL.pdf. Accessed July 20, 2024. Catenacci DVT, et al. Future Oncol. 2019;15:2073-2082. ©2024 Amgen Inc. All rights reserved. USA-OCF-82400 9/24

Interview with Maria E. Cabanillas, MD, author of Anti–Programmed Death Ligand 1 Plus Targeted Therapy in Anaplastic Thyroid Carcinoma: A Nonrandomized Clinical Trial. Hosted by Vivek Subbiah, MD. Related Content: Anti–Programmed Death Ligand 1 Plus Targeted Therapy in Anaplastic Thyroid Carcinoma

Interview with Maria E. Cabanillas, MD, author of Anti–Programmed Death Ligand 1 Plus Targeted Therapy in Anaplastic Thyroid Carcinoma: A Nonrandomized Clinical Trial. Hosted by Vivek Subbiah, MD. Related Content: Anti–Programmed Death Ligand 1 Plus Targeted Therapy in Anaplastic Thyroid Carcinoma

Send us a textGood morning, digital pathology trailblazers! Welcome to another exciting exploration of digital pathology and AI. I'm thrilled to have our global community here with us today from so many different time zones. Before we dive into today's content, a quick note: my equipment is being a bit finicky, but that's life in the digital world!Integrating Image Analysis with AILet's kick off with a recap of some recent updates. Yesterday, I had the privilege of presenting to a mixed group at Cincinnati Children's Hospital. We discussed AI in image analysis, an essential tool bridging radiology and pathology as these fields rapidly evolve with new technologies like foundation models and large language models. A diverse audience—ranging from radiologists to pathologists—prompted me to adapt my presentation style on the spot. It was a dynamic discussion about the advancements in healthcare that shared perspectives from both sides.Lymphovascular Invasion: A Case StudyOur first paper today focuses on a deep learning model for identifying lymphovascular invasion (LVI) in lung adenocarcinoma. This significant prognostic factor is crucial for advancing diagnostic consistency and reliability. Unlike broad foundation models, this work engages with dedicated image analysis applications targeting specific diagnostic challenges. The study demonstrated reduced pathologist evaluation time by nearly 17% and even more in complex cases, aligning with previous findings that AI enhances efficiency by around 21%.AI Collaborations: Human and Veterinary PathologyNext, we delve into a collaborative effort between human and veterinary pathologists, emphasizing the promise of AI integration in telepathology and digital pathology. These fields are converging to enhance information exchange, teaching, and research. I'm particularly excited about this paper due to my own veterinary pathology background and the potential it offers for both educational and clinical practices.Spatial Profiling and Immuno-OncologyWe then journey into the intricate landscape of immuno-oncology with a study on PD-1 and PD-L1 in osteosarcoma microenvironments. Utilizing deep learning and multiplex fluorescence immunohistochemistry, researchers highlighted the spatial orchestration of these markers, providing insights into potential immunotherapeutic strategies. This work is an exemplar of how AI can illuminate complex biological landscapes, offering a path for future therapies.ConclusionThank you all for joining this vibrant discussion. Whether you're tuning in from early morning in Atlanta or late at night in Algeria, your engagement enriches our learning experience. Keep an eye out for more content and upcoming courses designed to unpack these groundbreaking developments in AI and digital pathology.Until next time, keep blazing trails in digital pathology!Support the showBecome a Digital Pathology Trailblazer get the "Digital Pathology 101" FREE E-book and join us!

Dr. Wright discusses key studies regarding medical outcomes in cardiac arrest, surgical patient care, and advanced lung cancer treatment. A GEMMA Network Open study highlights that anterior-posterior defibrillator pad placement improves return to spontaneous circulation in out-of-hospital cardiac arrests compared to anterior-lateral placement, although it did not affect survival rates to hospital discharge. A British Journal of Surgery analysis shows that RN understaffing in England's surgical wards correlates with longer hospital stays and increased risks of conditions like DVT and pneumonia. Lastly, the HARMONY-2 trial, presented at the 2024 World Conference on Lung Cancer, reveals ivanesimab as a promising first-line treatment for PD-L1 positive advanced non-small cell lung cancer, extending progression-free survival significantly more than pembrolizumab.

Approval of BMS's first-in-class schizophrenia drug is good news for patients and the company's thinning pipeline alike, but maximizing Cobenfy's commercial potential depends on readouts in additional indications. On the latest BioCentury This Week podcast, BioCentury's editors assess the significance of the new therapy and what the pharma needs to do to make its launch a success.They also discuss the impact of the withdrawal of Pfizer's sickle cell therapy; the work left unfinished on biotech-related legislation in Congress; BioAge's NASDAQ IPO; and the importance of FDA's Oncologic Drugs Advisory Committee meeting on the use of PD-1 inhibitors in patients with certain tumors expressing low levels of PD-L1. This episode of BioCentury This Week was sponsored by Parexel Biotech.View full story: https://www.biocentury.com/article/65373200:01 - Sponsor Message: Parexel BioTech01:41 - BMS Schizophrenia Drug12:28 - Pfizer Withdrawal's Oxbryta18:26 - ODAC and PDL123:56 - D.C. Update26:51 - BioAge IPOTo submit a question to BioCentury's editors, email the BioCentury This Week team at podcasts@biocentury.com.Reach us by sending a text

Good morning from Pharma and Biotech daily: the podcast that gives you only what's important to hear in Pharma e Biotech world.Bristol Myers has received approval for a first-of-its-kind schizophrenia drug, Cobenfy, and plans to sell it despite potential insurance barriers for patients. Biogen and UCB are planning a large study for their lupus medicine, Biohaven is seeking approval for a neurological disorder drug, and Amgen claims success for immune drugs. Scientist.com discusses streamlining IND applications for cell and gene therapy innovations, while Arch raises $3 billion for a biotech fund. The article also covers strategies to keep clinical trials on schedule and provides insights into the market strategies of drugmakers. Additionally, upcoming events and trending news in the biopharma industry are highlighted. Biopharma Dive offers in-depth journalism and insights into the biotech and pharma industries, covering topics such as clinical readouts, FDA approvals, gene therapy, drug pricing, and research partnerships.Bristol Myers Squibb (BMS) has received FDA approval for KarXT, the first new schizophrenia therapy in 35 years. The drug targets muscarinic receptors and is considered ahead of competition from AbbVie and Neurocrine Biosciences. Pfizer's withdrawal of Oxbryta has left the sickle cell community scrambling, as the therapy was predicted to reach $750 million in sales. Sanofi and Regeneron's Dupixent has received approval for use in chronic obstructive pulmonary disease. The FDA's oncology drugs advisory committee has recommended limiting the use of Keytruda and Opdivo in stomach and esophageal cancer patients with low PD-L1 expression. Additionally, AbbVie's acquisition of Cerevel is showing promise with a phase III win in Parkinson's disease. Cassava has agreed to pay a $40 million fine to resolve an SEC probe, while Roche is looking to push Gazyva into lupus nephritis with positive late-stage data. Lilly is facing scrutiny over drug pricing compared to Novo Nordisk. The BACE credential is highlighted as a way to advance a career in the biotech industry.Senators have introduced a bill to establish cybersecurity standards for healthcare providers, health plans, and business associates. A study found that hospital acquisitions provide a one-time efficiency boost to margins but do not continue to improve operating metrics in the long term. Canopy CEO Shan Sinha discusses healthcare workplace violence and technology's role in protecting workers. The unexpected consequences of hospital quality scores are explored, suggesting a reexamination of the federal hospital-acquired condition reduction program. AI is being integrated into healthcare to give back time and prioritize people in day-to-day tasks. In other news, hospitals in Florida are preparing for Hurricane Helene, a major U.S. prison is criticized for substandard healthcare, and families in states banning health care for transgender teens may have to travel for care. Healthcare Dive provides in-depth journalism on topics such as health IT, policy, insurance, and more for decision-makers in the industry.The FDA recently approved Bristol Myers Squibb and Karuna Therapeutics' new drug, KarXT, now known as Cobenfy, for schizophrenia. This marks the first new mode of action approved for the condition in decades. The drug showed promising results in clinical trials, with patients on Cobenfy actually losing weight compared to gaining weight on other medications. However, there is still room for improvement as over 50% of patients discontinued treatment. The approval of Cobenfy highlights Bristol Myers Squibb's deal-making skills and sets the stage for a new generation of treatments for schizophrenia. Other upcoming drugs in the field may further shake up the market. Pharmaceutical companies are continuously working on market strategies to successfully launch new drugs post-FDA approval, as turning a new drug into a successful asset remains a challenge in the

Featuring a slide presentation and related discussion from Dr Tiffany A Traina, including the following topics: Extended follow-up with pembrolizumab/chemotherapy for patients with previously untreated PD-L1-positive metastatic triple-negative breast cancer (mTNBC) (0:00) ASCENT trial: Survival advantage with sacituzumab govitecan versus physician's choice of chemotherapy for patients with relapsed/refractory TNBC (2:49) Treatment-associated side effects with sacituzumab govitecan (5:32) Activity of sacituzumab govitecan irrespective of TROP2 expression level and in patients with brain metastases (6:48) Ongoing Phase III studies evaluating sacituzumab govitecan in earlier lines of treatment (eg, ASCENT-03, ASCENT-04) (8:51) Efficacy and tolerability of trastuzumab deruxtecan in patients with HER2-low and HER2-ultralow metastatic breast cancer (10:26) Activity and ongoing investigations of other novel agents and strategies for mTNBC (20:05) CME information and select publications

Paraneoplastic neurologic syndromes can present with manifestations at any level of the neuraxis. In patients with high clinical suspicion of a paraneoplastic neurologic syndrome, cancer screening and treatment should be undertaken, regardless of the presence of a neural antibody. In this episode, Katie Grouse, MD, FAAN, speaks with Anastasia Zekeridou, MD, PhD, author of the article “Paraneoplastic Neurologic Disorders,” in the Continuum August 2024 Autoimmune Neurology issue. Dr. Grouse is a Continuum® Audio interviewer and a clinical assistant professor at the University of California San Francisco in San Francisco, California. Dr. Zekeridou a senior associate consultant in the departments of neurology, laboratory medicine, and pathology, and for the Center for Multiple Sclerosis and Autoimmune Neurology at Mayo Clinic in Rochester, Minnesota. Additional Resources Read the article: Paraneoplastic Neurologic Disorders Subscribe to Continuum: shop.lww.com/Continuum Earn CME (available only to AAN members): continpub.com/AudioCME Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): continpub.com/Aloud More about the American Academy of Neurology: aan.com Social Media facebook.com/continuumcme @ContinuumAAN Guest: @ANASTASIA_ZEK Transcript Full transcript available here   Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum, the premier topic-based neurology clinical review and CME journal from the American Academy of Neurology. Thank you for joining us on Continuum Audio, which features conversations with Continuum's guest editors and authors who are the leading experts in their fields. Subscribers to the Continuum journal can read the full article or listen to verbatim recordings of the article and have access to exclusive interviews not featured on the podcast. Please visit the link in the episode notes for more information on the article, subscribing to the journal, and how to get CME.   Dr Grouse: This is Dr Katie Grouse. Today, I'm interviewing Dr Anastasia Zekeridou about her article on classical paraneoplastic neurologic disorders, which is part of the August 2024 Continuum issue on autoimmune neurology. Welcome to the podcast, and please introduce yourself to our audience.   Dr Zekeridou: Hi. Thank you, Dr Grouse. I'm always excited to talk about paraneoplastic neurological diseases. So, I'm an autoimmune neurologist at Mayo Clinic in Rochester, and I spend my time between the lab and seeing patients in the autoimmune neurology clinic.   Dr Grouse: Thank you so much for joining us, and we're really excited to talk about this really important topic. So, to start, I'd like to ask what, in your opinion, is the key message from this article.   Dr Zekeridou: That's a good question - there are a lot of messages, but maybe if I can distill it down. For me, one of the first things is that paraneoplastic neurological diseases can actually affect any level of the neuraxis. It can manifest with different types of presentations. If we do suspect a paraneoplastic neurological syndrome, then we need to look for the cancer, and then if we're not certain, even do an immunotherapy trial. A negative antibody does not make for an absence of a paraneoplastic neurological disease (because, often, we depend a lot on them), but you can see patients with paraneoplastic disease that do not have neural antibodies. And then, we always need to be thinking that if we have a paraneoplastic neurological disease, we actually need to be thinking of both the cancer and the immune response together - so, we need to be treating the cancer, we need to be treating the immune response – because, essentially, paraneoplastic neurological syndrome is evidence of this antitumor immune response. So, the main (if I can distill this down in one) is probably that we need to be discussing all of these patients with the treating oncologist, because they have complicated care.   Dr Grouse: Great. Thank you so much for that summary. It's very helpful. While many of our listeners are likely familiar with paraneoplastic disorders in their workup (which you've mentioned just now), the concept of neurologic autoimmunity in the context of immune checkpoint inhibitor therapy has more recently become widely recognized. Can you summarize this briefly for our listeners who may be less familiar with this?   Dr Zekeridou: I think that we learn more and more about this and we see more and more patients with immune checkpoint inhibitor-related neurological immunity, so, I always think about it in a very straightforward way. So, I think the way we think about immune responses is a balance between tolerance and regulation and immune activations. And then, immune checkpoints are the molecules that help us maintain self-tolerance. So, our immune system - it's probably the best tool that we have to fight against cancer. So, essentially, when we inhibit the immune checkpoints, we actually use our own immune system to fight cancer, but taking the breaks of the immune system essentially can lead to a lot of complications that are immune-mediated. Some of them are neurological - the neurological complications are rare, especially the ones that we need to do something about (so, it's 1% to 4%, in some cases up to 14%), and they do increase when you use multiple immune checkpoint inhibitors together. The main thing for me with the neurological complications is that, sometimes, they are difficult to recognize, they can (again) affect every level of the neuraxis - like, it can be the neuromuscular or the central nervous system (even though neuromuscular complications are much more common than central nervous system complications) - and then a lot of them (the vast majority) will happen within the first three months, but they can also happen even after you stop the immune checkpoint inhibitor. But this three-month interval, it's sometimes useful when you're in a diagnostic silence - it kind of helps you make the decision more towards an immune-related adverse event affecting the nervous system. And then, I think that, practically, once we have diagnosed this patients, we still are not very certain how to treat. All of them will get steroids upfront, but some of them will be difficult to treat, so then, we have to decide on the next treatment depending on evolution. And then, I will just say that (I mentioned it previously, but) these are the patients that the coordination with other subspecialties is one of the main things that we need to do (eg, oncologists) - they often have immune-related adverse events from other systems, so, there is a lot of coordination of care. And, always, the question at the end comes up, Should we be putting these patients back to their immune checkpoint inhibitor cancer immunotherapy that might help them with the cancer? And I think that this is difficult sometimes, and it needs to be decided - most cases - in a case-by-case basis, even though there are some recommendations that I've been discussing in the Continuum article.   Dr Grose: That's great, and I encourage everyone to read more about this, because it is a very complex and fascinating topic. On the note of the immune checkpoint inhibitor neurologic dysfunction - I would imagine these are pretty rare - how common are these? And I would suspect they're getting missed a lot - is that correct?   Dr Zekeridou: I think it's a very good question. Essentially, what we say for the neurological immune-related adverse events (the ones that we need intervention) - so, they are at least of grade two. (I think that there are less than 4%, mostly, probably close to 1.5%.) There was a study where they used double immune checkpoint inhibitors (so CTLA-4 and PD-1, PD-L1) - they were up to 14%, but this was any grade (so, a little bit of tingling, a little bit of headache), while the ones that we actually need to act upon and we need to actually do something about, they are probably closer to 1.5%. So, are they being missed? I am certain that some of them never make it to the neurologist. So, the ones that we know that we are underestimating is definitely the meningitis - because I think it's more common – but, often, when the patients present, they have something else as well. So, the oncologists will put them on steroids and then they will get better - so, we don't really see them in the neurology clinic (the ones with the very mild side effects). And then, also, these patients are often very sick, and they have a lot of things going for them, so they sometimes do not make it to the diagnosis.   Dr Grouse: So then, I want to just take a step back and ask you, what's the most challenging aspect of paraneoplastic neurologic disorders in your opinion?   Dr Zekeridou: I think, for me, one of the main things, the classic paraneoplastic disorders - and when I say “classic paraneoplastic disorders”, they are the ones that we think more of with antibodies that are mostly biomarkers of the immune response, and they suggest a cytotoxic T-cell mediated disorder (so, like PCA1 [or anti-Yo] or ANNA-1 [or anti-Hu]) - these patients are very sick often, and we don't have a lot of good treatments for them. And then, even if we treat them, we actually sometimes do not manage to reverse their course - the best that we can do is stabilize. So, I think that this is part of the discussion that we have upfront with these patients - but it is quite challenging, because most of them, we will be giving them a cancer diagnosis ourselves, because we recognize the paraneoplastic neurological syndrome, and we look for the cancer, and then we'll be giving them a cancer diagnosis. And even if we treat their cancer and we treat the immune system, sometimes, then, we don't make a real improvement – like, we stabilize their disease and we sometimes get improvement, but there are cases that we do not and they continue to progress – so, that has been the most challenging aspect of this, and I think that's kind of where we really need more things coming – like, we need more treatments, we need to better understand these diseases and get more straightforward.   Dr Grouse: I agree. I think that's absolutely, uh, what we all hope for these types of disorders, and I can imagine we all can remember at least one case just like this where someone had this type of problem and just didn't respond to treatment. So, strong hopes that there will be improvement with this in the years coming. Another question I have for you is, what in your article do you think would come as the biggest surprise to our listeners?   Dr Zekeridou: I think that, because we discussed that immune checkpoint inhibitors (maybe we don't know as well), so one of the main things for me is when we first started thinking of neurological complications of immune checkpoint inhibitors, there was a lot of myasthenia gravis mentioned (patients presenting with myasthenia gravis), and then some of them antibody-positive, some of them antibody-negative. Now, with the time that has passed by, we recognize that myasthenia gravis is very rare. Like, I've seen tons of patients (probably more than that, actually) – and then, maybe I've seen one patient with de novo myasthenia gravis. We realize that the immune checkpoint inhibitor myasthenia gravis that we were thinking of are – they're mostly the immune checkpoint inhibitor myocytes cases - so, then, this is one of these myopathies that looks like no other. So, it really has a very predominant oculobulbar involvement (that's why everybody was thinking that this is myasthenia gravis), but, practically, the EMGs are negative, the patients do not respond to pyridostigmine - so, practically, these are really myopathy cases. And why is that important? Because 30% to 40% of these cases might also have a cardiomyopathy, for example, and then we're putting all these patients on pyridostigmine and medications that they do not necessarily need. So, I think one of the chains in concepts that we have in the later years is that, really (and this is one of the most common immune-related adverse events that we see in our clinic), that these patients with ICI myositis really present with the oculobulbar involvement and proximal involvement that we can see in myasthenia, but they do not have a neuromuscular junction problem.   Dr Grouse: Now, we've all struggled with identifying a primary malignancy in patients where a paraneoplastic syndrome was strongly suspected. Do you have any tips on how to make this workup as high yield as possible?   Dr Zekeridou: Yeah, I think that's a difficult question. I think it depends a little bit on your patient as well. So, if you have an antibody that makes things easier (and we can discuss about that, but), practically, for me, a patient that I have a high suspicion, that we get a CT chest, abdomen, and pelvis upfront - and often, we don't get PET scans, right, directly, because we have insurance companies maybe playing a role in what we would do. So, I would get this for a woman - she has to have a mammogram. For a man, they have to have a testicular ultrasound. That's the basics for me. And then, when we see more younger women or when we suspect an MDA, then they will need to have the ultrasound to look for the ovarian teratomas or an MRI of the abdomen - so, the PET scan for me, if I have a high suspicion, it will always be the next step. Like, we have increased diagnostic yield with PET scans, but we also need to remember, what are the tumors that you will not find on a PET scan? Teratomas are not PET-avid, and, often we say, “Oh, we found the lesion in the ovary and the PET scan was negative.” That doesn't matter. In an NMDA-receptor antibody patient, if you find the lesion in the ovary, you need to make certain it's not a teratoma, because PET scans will not necessarily pick up a teratoma - it's not an avid malignancy. So, if the patient is a smoker and I suspect small-cell lung cancer, so I would always get the PET scan. If I have a patient with a high-risk antibody like PCA1 (or anti-Yo) and I didn't really find the tumor with the CT chest, abdomen, and pelvis and the mammogram, I will always get the PET scan. Same for the patients with the smoking history. I will also say that, sometimes, we forget other malignancies. So, for example, we have neuronal intermediate filament antibodies (so, ANNA-3 antibodies), and some of them will have Merkel cell. So, depending on the patient, on the antibody, and if we didn't find anything else, I would do a skin check. If they have GI symptoms, I would look for the GI tumor as well. So, even though the basics are what I mentioned, I will adapt depending on the patient symptoms. And all of these patients should have age-appropriate cancer screening, so if they didn't have a colonoscopy, they will have to have a colonoscopy. So, this is part of the main things. And then, the question for me that always comes up is, “Who is the person that you're going to keep on repeating the screen?” And then, practically, if you have a low-risk paraneoplastic antibody that comes (let's say LGI1), we know it's a low risk, so I would actually do the cancer screening - I will look for the thymoma once, and then that would be it. But if you have a patient with a high-risk paraneoplastic antibody (let's say ANNA-1 [or anti-Hu] or anti-Yo [anti-PCA1]), these are the patients that I will keep on screening - and then I will do every four to six months for two years (that's the current recommendation), but I will probably continue yearly after. And then, we need to also remember that whenever you have a neurological relapse, that's exactly when you need to be looking for the cancer as well - so, you must be thinking that the idea is that maybe you have the immunological relapse because there is cancer somewhere. So, these are the types of things that I kind of adapt to specific patients. But I think when we're not certain, broad screening is what we need. And then, again, the PET scan - for me, it's a great test, but we need to know its limitations. So, that's the other thing that comes up a lot in the phone calls or in the patients that I see that we do a PET scan - but practically, it's not good for some of the malignancies that we're looking for.   Dr Grouse: That's really great to point out, and I'm glad you brought up the risk level of the particular syndrome. You have a great table in your article that summarizes the risk level of some of the various syndromes - so, you know, just a reminder for everyone to check that out if you want to have more information about this and how this applies to the screening - so very helpful. What is the easiest mistake to make, and also maybe to avoid, when treating patients with paraneoplastic neurologic disorders?   Dr Zekeridou: That's a great question, actually. So, there are two things here. One is that we need to be thinking about paraneoplastic neurological syndromes, because if you don't think about them, then you don't look for them. So that's the one thing. So, patients that come with a subacute onset of neurological dysfunction - they have systemic features, or they are smokers, they have autoimmunity in the family (all those things) – like, we need to be thinking about paraneoplastic neurological syndromes. On the other side, we also see a little bit more of overdiagnosis that's coming in the later years. So, one of the things that we see a lot is that we kind of have difficulties with the interpretation of the neural antibodies - so, sometimes, we will get a neural antibody, and then it will not fit, but we will base our diagnosis on the neural antibody presence. And then, some neural antibodies are great - we don't really see false-positives - but some of them are not great and we do see false-positives. So, for me, the main thing that I would say is that we need to have a clinical suspicion - we're treating the patient and the clinical syndrome if it is compatible with a paraneoplastic neurological disorder, and then the neural antibodies are the ones that are going to help us, like, diagnose or point to a cancer - but we are really treating the patient. And then, if we give a treatment and it doesn't make sense how the patient evolves, we actually need to reassess the diagnosis, because we do have both overdiagnosis, but also we have underdiagnosed in patients that it's not suspected - so I think it's kind of the increased awareness that helps, but we also need to be going back always to the clinical manifestations of the patient.   Dr Grouse: Really great points to make, and thank you so much for that. What is the most common misconception you've encountered in treating patients with paraneoplastic disorders?   Dr Zekeridou: So, one of the things that we see a lot is that patients wait to be treated - even with high suspicion of paraneoplastic neurological syndromes - until we have the neural antibodies, and sometimes, if the neural antibodies are negative, we have patients that are not given a paraneoplastic neurological syndrome or autoimmune neurological syndrome diagnosis because of the negativity of the antibodies. So, for me, one of the main things is that the patients actually fit clinically with a paraneoplastic neurological syndrome - and there are scores that can help us, clinical manifestations that can actually help us make this diagnosis. We need to be looking for the cancer and treating them, regardless of the presence of the antibody. Some patients will not have the antibodies for weeks. The second aspect to this is that, often, we want to say, “Oh, it's a paraneoplastic neurological syndrome. They will treat the cancer and, like, that's the oncologist's job.” But, practically, I think that the neurologist will really need to be involved with this. I think the patients need treatment of the immune response and treatment of the tumor. So, I think we are part of the treatment team for these patients and it's not only the oncologists that are treating the tumor.   Dr Grouse: Where do you think the next big breakthrough in this area will be?   Dr Zekeridou: Where I hope it would be - and I'm hoping that it's actually what it is going to be – is, really, better understanding and treating the classic paraneoplastic neurological diseases, that they are T-cell mediated disorders that lead to neural cell distraction, and we don't have good treatments for these patients and we cannot get any improvement. So, there is a lot of research going on there. How can we prevent? How can we treat? But, I think that would be the next big milestone for us, because the antibody-mediated diseases - so we now have a lot of good treatments. Like NMDA-receptor encephalitis, AMPAR encephalitides - these antibody-mediated disorders, we have good treatments. The disorders that the antibodies are biomarkers  - and they are the cytotoxic diseases, the effectors of the autoimmunity - we don't. So, that's where I hope and think our breakthrough will be.   Dr Grouse: Definitely hoping to see more advancements in this area and already, I think, very quickly developing field. So, I wanted to talk a little bit more about you and what brought you to this area of neurology I think which most of us find to be a very fascinating field  that would love to hear more about what brought you to it. How did you become interested in this area of neurology?   Dr Zekeridou: I did my medical school in Greece. So, in Greece, towards the end of the sixth year, you need to decide what your specialty would be, and for the life of me, I could not decide between oncology and neurology - I was changing my mind all the time. And then, I decided that the diagnosis is more important to me in terms of a physician - that's why I went more with neurology and I was clear on my choice. So, practically, then, I went and did my residence in Switzerland, and something happened and I found myself in the outpatient autoimmune neurology multiple sclerosis clinic for a year, and it was evident to me that this is my passion. Like, the multiple sclerosis, I thought was a great disease, but it was the cases that they were not multiple sclerosis, that they were the ones that they were the most fascinating for me. So, then, I did my peripheral nerve year - so even more, it was clear for me that this is the immune system interactions, the cancer, and the neurological symptoms - that's what I wanted to do. And practically, I pursued a fellowship in Lyon in the French Reference Center for Paraneoplastic Diseases, and I was sold. There was nothing else for me. So, eventually I came here at Mayo (and then I stayed) - but it was very clear, even since the beginning - and I really found something that combined both of my passions even from medical school.   Dr Grouse: What are you most excited about in this field? And, specifically, you know, what might you impart to other trainees who are thinking about choosing this field for themselves?   Dr Zekeridou: So, I think that there are many things. So, autoimmune neurology or paraneoplastic neurological syndromes, they can affect every level of the neuraxis, so, practically, your clinician, that we see everything - we'll see central nervous system, peripheral nervous system, neuromuscular junction – so, that's actually very fascinating for me. The second part of it is that we have diseases that we can actually treat. We see differences in patients that we will intervene and we will really change their disease course. And the other thing for me is all the research that is ongoing. So, practically, the research in paraneoplastic syndromes or neurological immunity is directly translational to the patient - like, we have kind of a bed-to-bedside type of research that is going on. And basic research is important and there is a lot of advances, but you can see them directly, like, being translated in patients - so, essentially, the research is directly translational to clinic, and that makes it very exciting.   Dr Grouse: I think that your excitement about this field is very inspirational and will hopefully inspire many future trainees who are interested in this field. So, when you're not learning more about paraneoplastic syndromes and their treatment and diagnosis, what else do you like to do? Tell us something about your outside interests.   Dr Zekeridou: So, again, I come from a very diverse background and the way that I arrived in the states, but, I really like traveling. So, we would travel a lot lately. We travel more in Greece, because when you're coming from Greece and you're not living there, your summers are always there - but we try to explore different places there. And one of my main things and passions that I like is, essentially, cooking. So that relaxes me, that helps me - cooking and having friends over – so, that's my favorite thing of doing outside of work.   Dr Grouse: Well, I have to say it's hard right now to imagine anything more fun than traveling and enjoying good food and Greece. So, I think your hobby seems like one we can all get behind.   Dr Zekeridou: It's relaxing the mind.   Dr Grouse: Yes, yes. This has been a really great discussion on what I think is a very interesting area of neurology, and we really appreciate you taking the time to talk with us today.   Dr Zekeridou: Thank you so much for having me. It was great talking to you.   Dr Grouse: Again, today, I've been interviewing Dr Anastasia Zekeridou, whose article on classical paraneoplastic neurologic disorders appears in our most recent issue of Continuum on autoimmune neurology. Be sure to check out Continuum Audio episodes from this and other issues. And thank you to our listeners so much for joining us today.   Dr Monteith: This is Dr Teshamae Monteith, Associate Editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information important for neurology practitioners. Use this link in the episode notes to learn more and subscribe. AAN members, you can get CME for listening to this interview by completing the evaluation at Continpub.com/audioCME. Thank you for listening to Continuum Audio. Full transcript available at URL to come

Dr. Allison Zibelli and Dr. Erika Hamilton discuss the results of the DESTINY-Breast06 trial in HR+, HER2-low and HER2-ultralow metastatic breast cancer and the A-BRAVE trial in early triple-negative breast cancer, the results of which were both presented at the 2024 ASCO Annual Meeting. TRANSCRIPT Dr. Allison Zibelli: Hello, I'm Dr. Allison Zibelli, your guest host of the ASCO Daily News Podcast. I'm an associate professor of medicine and breast medical oncologist at the Sidney Kimmel Cancer Center of Jefferson Health in Philadelphia. My guest today is Dr. Erika Hamilton, a medical oncologist and director of breast cancer research at the Sarah Cannon Research Institute. We'll be discussing the DESTINY-Breast06 trial, which showed a progression-free advantage with the antibody-drug conjugate trastuzumab deruxtecan (T-DXd) compared to chemotherapy in hormone receptor-positive HER2-low or HER2-ultralow metastatic breast cancer. We'll address the implications of this study for the community, including the importance of expanding pathology assessments to include all established subgroups with HER2 expression, and the promise of expanding eligibility for antibody-drug conjugates. We'll also highlight advances in triple-negative breast cancer, focusing on the A-BRAVE trial, the first study reporting data on an immune checkpoint inhibitor avelumab in patients with triple-negative breast cancer with invasive residual disease after neoadjuvant chemotherapy.  Our full disclosures are available in the transcript of this episode.  Erika, it's great to have you on the podcast today. Dr. Erika Hamilton: Thanks so much, Allison. Happy to join. Dr. Allison Zibelli: Antibody-drug conjugates are rapidly changing the treatment landscape in breast cancer. The data from the DESTINY-Breast06 trial suggests that trastuzumab deruxtecan may become a preferred first-line treatment option for most patients with HER2-low or HER2-ultralow metastatic breast cancer after progression on endocrine therapy. First, could you remind our listeners, what's the definition of HER2-ultralow and what were the findings of this trial? Dr. Erika Hamilton: Yeah, those are fantastic questions. Ultralow really has never been talked about before. Ultralow is part of a subset of the IHC zeros. So it's those patients that have HER2-tumor staining that's less than 10% and incomplete but isn't absolutely zero. It's even below that +1 or +2 IHC that we have classified as HER2-low. Now, I think what's important to remember about D-B06, if you recall, D-B04 (DESTINY-Breast04) was our trial looking at HER2-low, is that D-B06 now included HER2-low as well as this HER2-ultralow category that you asked about. And it also moved trastuzumab deruxtecan up into the frontline. If you recall, D-B04 was after 1 line of cytotoxic therapy. So now this is really after exhausting endocrine therapy before patients have received other chemotherapy. And what we saw was an improvement in progression-free survival that was pretty significant: 13.2 months versus 8.1 months, it was a hazard ratio of 0.62. And you can ask yourself, “well, was it mainly those HER2-low patients that kind of drove that benefit? What about the ultralow category?” And when we look at ultralow, it was no different: 13.2 months versus 8.3 months, hazard ratio, again, highly significant. So I think it's really encouraging data and gives us some information about using this drug earlier for our patients with hormone receptor-positive but HER2-negative disease.  Dr. Allison Zibelli: I thought this study was really interesting because it's a patient population that I find very difficult to treat, the hormone receptor-positive metastatic patient that's not responding to endocrine therapy anymore. But it's important to mention that T-DXd resulted in more serious toxicities compared to traditional chemotherapy in this study. So how do you choose which patients to offer this to? Dr. Erika Hamilton: Yeah, those are both great points. So you're right, this is after endocrine therapy. And in fact, about 85% of these patients had received at least 2 prior lines of endocrine therapy. So I have some people kind of asking, “Well, if endocrine therapy really isn't benefiting everyone in the second-line setting post-CDK, should we just move to the ADCs?” And, no, probably we should really make sure that we're exhausting endocrine therapies for those patients that are going to benefit. And once we determine somebody has endocrine-resistant disease, that's when we would think about switching. In terms of the side effects, I think you're right. It's mainly ILD that's probably the more serious side effect that we worry about a little bit with trastuzumab deruxtecan. The good news is, through multiple trials, we've gotten a little bit better at managing this. We've pretty much all but eliminated any fatal cases of ILD, definitely less than 1% now. ILD rates, depending on what study you look for, kind of ranges in that 10% to 15% range. Any grade ILD on D-B06 was 11.3%. So really kind of making sure that we look for ILD at scans, making sure that patients are educated to tell us about any new pulmonary symptoms: cough, exertional dyspnea, shortness of breath at rest, etc. But I think the most common side effects that we really deal with on a daily basis with trastuzumab deruxtecan, luckily, is nausea, which we've gotten better at managing with the 2- or 3-drug antiemetic regimen, and probably a little bit of fatigue as well. Dr. Allison Zibelli: Thank you. So, I think for most people in the community, the sticking point here will be expanding pathology assessments to include all of the subgroups, including the ultralow. Most patients in the community are not testing for HER2-low and HER2-ultralow now. Dr. Erika Hamilton: Historically, we kind of all did HER2 IHC, right? And then as FISH became available, there were a lot of institutions that moved to FISH and maybe didn't have IHC anymore. And now, at least in my institution, we do both. But I think it's a very important point that you made that IHC was really designed to pick out those patients that have HER2-high, the 3 pluses or the FISH amplified cases. It was not to tell the difference between a 1+ or a 2+ or a 0 that's not quite a 0 and a 1+. So I think you're right. I think this is tough. I probably have a little bit more of an interesting take on this than some people will. But data from ASCO, not this year but in 2023, there was actually a pretty eloquent study presented where they looked at serial biopsies in patients, and essentially, if you got up to 4 or 5 biopsies, you were guaranteed to have a HER2-low result. Now, this didn't even include ultralow, which is even easier. If we know we include ultralow, we're really talking about probably 85% to 90% of our patients now that have some HER2 expression. But if we biopsy enough, we're guaranteed to get a HER2 low.  And so I think the question really is, if we know IHC wasn't really designed to pick out these ultralows, and we know kind of greater than 90% of patients are going to have some expression, did we kind of develop this drug a little bit backwards? Because we thought we understood HER2, and the reality is this drug is a little bit more like a sacituzumab govitecan, where we don't test for the TROP2. Should we really be kind of serial biopsying these patients or should maybe most patients have access to at least trying this drug?  Dr. Allison Zibelli: So I don't think that most of my patients will really be happy to sign up for serial biopsies. Dr. Erika Hamilton: Agreed. Dr. Allison Zibelli: Do we have any emerging technologies for detecting low levels of HER2? You talked about how the IHC test isn't really designed to detect low levels of HER2. Do you think newer detection techniques such as immunofluorescence will make a difference, or will we have liquid biopsy testing for this? Dr. Erika Hamilton: Yeah, I think liquid biopsy may be a little bit hard, just because some of those circulating tumor cells are more of a mesenchymal-type phenotype and don't necessarily express all of the same receptors. Normally, if they're cytokeratin-positive, they do, but certainly there is a lot out there looking at more sensitive measures. You mentioned immunofluorescence, there are some even more quantitative measures looking at lower levels of HER2. I definitely think there will be. I guess, ultimately, with even the IHC zeros that are the less than 10% incomplete staining, having a PFS that was absolutely no different than the HER2 low, I guess the question is, how low can we really go? We know that even the IHC zeros doesn't mean that there's no HER2 expression on the cell surface. It just means that maybe there's a couple of thousand as opposed to 10,000 or 100,000 copies of HER2. And so it really appears that perhaps this drug really is wedded to having a lot of HER2 expression. So ultimately, I wonder how much we're going to have to use those tests, especially with what we know about tumor heterogeneity. We know that if we biopsy 1 lesion in the liver, biopsy a lymph node, or even another lesion in the liver, that the HER2 results can have some heterogeneity. And so ultimately, my guess is that most people have some HER2 expression on their breast cancer cells. Dr. Allison Zibelli: So maybe we're going to be using this for everybody in the future. Dr. Erika Hamilton: It certainly seems like we keep peeling back the onion and including more and more patients into the category that are eligible to receive this. I agree. Dr. Allison Zibelli: Let's move on to triple-negative breast cancer, namely the A-BRAVE trial. This was an interesting trial for patients that did not get neoadjuvant immunotherapy and testing 2 groups. The first group was those with residual disease after neoadjuvant conventional chemotherapy. The second group was people with high-risk disease identified upfront that had upfront surgery. The study found that adjuvant avelumab did not improve disease-free survival versus observation, which was the study's primary endpoint. But interestingly, there was a significant improvement in 3-year overall survival and distant disease-free survival. Can you give us your thoughts on that? Dr. Erika Hamilton: Yeah, I think this study was really interesting. Right now, the standard for our patients with larger or node-positive triple-negative cancers is KEYNOTE-522. It's a pretty tough regimen. It's kind of 2 sequential uses of 2 chemotherapies, so 4 chemotherapy agents total with pembrolizumab. But you're right, this study looked at those that had residual disease after neoadjuvant that didn't include immunotherapy, or those patients that didn't get neoadjuvant therapy, went to surgery, and then were receiving chemotherapy on the back end. I'm going to give you the numbers, because you're right. The 3-year disease-free survival rates were not statistically significant. It was 68.3% among those that had avelumab, 63.2% with those that had observation only. So the difference was 5.1% in favor of avelumab, but it wasn't statistically significant. A p value of 0.1, essentially. But when we looked at the 3-year overall survival rates, we saw the same pattern, those patients with the avelumab doing better, but it was 84.8% overall survival and not, unfortunately, dying, versus 76.3%. So the magnitude of benefit there was 8.5%, so about 3% higher than we saw for disease-free survival, and this was statistically significant.  So is this going to change practice for most patients? I probably don't think so. I think for our patients that have larger tumors that's recognized upfront or have node positivity, we're probably going to want to use neoadjuvant chemo. Being able to get a PCR is very prognostic for our patients and enables us to offer things on the back end, such as PARP inhibitors or further chemotherapy of a different type of chemotherapy. But for our patients that go to surgery and maybe the extent of their disease just isn't recognized initially, this could be an option. Dr. Allison Zibelli: I agree. I think this will be a really useful regimen for patients where we get the surprise lymph node that we weren't expecting, or somebody who comes to us, maybe without seeing the medical oncologist, who got upfront surgery. So I thought this was really interesting. What kind of translational studies do you think we're going to do to try and understand which patients would benefit from avelumab? Dr. Erika Hamilton: Yeah, I think that's a great question, and honestly, it's a question that we haven't really answered in the neoadjuvant setting either. Immunotherapy in breast cancer is just a little bit different than it is in some other diseases. We have a benefit for those patients that are PD-L1 positive in the first line. We really haven't seen benefit for metastatic outside of first line. And then in neoadjuvant, it was among all comers. We don't have to test for PD-L1. And now we have this avelumab data from A-BRAVE. I think the question is, is there's probably a subset of patients that are really getting benefit and a subset that aren't. And I don't know that PD-L1 testing is the right test. We know a lot of people are looking at TILs, so kind of lymphocytes that are infiltrating the tumor, a variety of other kind of immunologic markers. But my guess is that eventually we're going to get smart enough to tease out who actually needs the immunotherapy versus who isn't going to benefit. But we're not quite there yet. Dr. Allison Zibelli: Thank you, Erika, for sharing your valuable insights with us on the ASCO Daily News Podcast today. Dr. Erika Hamilton: Thanks so much for having me.  Dr. Allison Zibelli: And thank you to our listeners for joining us. You'll find the links to all the abstracts discussed today in the transcript of this episode. Finally, if you like this podcast and you value our insights, please take a moment to rate, review, and subscribe wherever you get your podcasts. It really helps other people to find us. So thank you very much for listening today.   Disclaimer:   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.   Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.    Find out more about today's speakers:  Dr. Allison Zibelli Dr. Erika Hamilton @ErikaHamilton9   Follow ASCO on social media:  @ASCO on Twitter    ASCO on Facebook    ASCO on LinkedIn      Disclosures: Dr. Allison Zibelli:  None Disclosed   Dr. Erika Hamilton: Consulting or Advisory Role (Inst): Pfizer, Genentech/Roche, Lilly, Daiichi Sankyo, Mersana, AstraZeneca, Novartis, Ellipses Pharma, Olema Pharmaceuticals, Stemline Therapeutics, Tubulis, Verascity Science, Theratechnologies, Accutar Biotechnology, Entos, Fosun Pharma, Gilead Sciences, Jazz Pharmaceuticals, Medical Pharma Services, Hosun Pharma, Zentalis Pharmaceuticals, Jefferies, Tempus Labs, Arvinas, Circle Pharma, Janssen, Johnson and Johnson   Research Funding (Inst): AstraZeneca, Hutchison MediPharma, OncoMed, MedImmune, Stem CentRx, Genentech/Roche, Curis, Verastem, Zymeworks, Syndax, Lycera, Rgenix, Novartis, Millenium, TapImmune, Inc., Lilly, Pfizer, Lilly, Pfizer, Tesaro, Boehringer Ingelheim, H3 Biomedicine, Radius Health, Acerta Pharma, Macrogenics, Abbvie, Immunomedics, Fujifilm, eFFECTOR Therapeutics, Merus, Nucana, Regeneron, Leap Therapeutics, Taiho Pharmaceuticals, EMD Serono, Daiichi Sankyo, ArQule, Syros Pharmaceuticals, Clovis Oncology, CytomX Therapeutics, InventisBio, Deciphera, Sermonix Pharmaceuticals, Zenith Epigentics, Arvinas, Harpoon, Black Diamond, Orinove, Molecular Templates, Seattle Genetics, Compugen, GI Therapeutics, Karyopharm Therapeutics, Dana-Farber Cancer Hospital, Shattuck Labs, PharmaMar, Olema Pharmaceuticals, Immunogen, Plexxikon, Amgen, Akesobio Australia, ADC Therapeutics, AtlasMedx, Aravive, Ellipses Pharma, Incyte, MabSpace Biosciences, ORIC Pharmaceuticals, Pieris Pharmaceuticals, Pieris Pharmaceuticals, Pionyr, Repetoire Immune Medicines, Treadwell Therapeutics, Accutar Biotech, Artios, Bliss Biopharmaceutical, Cascadian Therapeutics, Dantari, Duality Biologics, Elucida Oncology, Infinity Pharmaceuticals, Relay Therapeutics, Tolmar, Torque, BeiGene, Context Therapeutics, K-Group Beta, Kind Pharmaceuticals, Loxo Oncology, Oncothyreon, Orum Therapeutics, Prelude Therapeutics, Profound Bio, Cullinan Oncology, Bristol-Myers Squib, Eisai, Fochon Pharmaceuticals, Gilead Sciences, Inspirna, Myriad Genetics, Silverback Therapeutics, Stemline Therapeutics

Featuring an interview with Dr Kimberly H Allison, including the following topics: Contemporary practices in pathology and reporting biomarkers of interest (0:00) HER2 testing across numerous solid tumor types (2:47) ER-low reporting category and pathologic interpretation (6:28) PD-1/PD-L1 testing methodology and challenges with bone biopsies (10:53) CME information and select publications

In this episode of JCO Article Insights, Rohit Singh interviews Dr. Ticiana Leal on the editorial, "Back to the Drawing Board: Overcoming Resistance to PD-1 Blockade." TRANSCRIPT The guests' disclosures can be found in the transcript. Dr. Rohit Singh: Hello and welcome to JCO's Article Insights. I am your host Rohit Singh and today we will be discussing the JCO article, “Back to the Drawing Board: Overcoming Resistance to PD-1 Blockade.” And we are joined by the senior author of the article, Dr. Ticiana Leal. Dr. Leal is an Associate Professor in the Department of Hematology and Medical Oncology at Emory University School of Medicine, and she serves as director of Thoracic Medical Thoracic Oncology Medical Program and Multidisciplinary Thoracic Oncology Leader at the Winship Cancer Institute. She also served as a member of the Board of Directors at the Georgia Society of Clinical Oncology.  Dr. Leal, welcome to our podcast and thank you for joining us. Dr. Ticiana Leal: Thank you, Rohit. Thank you for this interesting opportunity to discuss our editorial. My co-authors and I are very glad to be here today. So, Dr. Jennifer Carlisle and Dr. Liu were co-authors with me on this editorial. Dr. Rohit Singh: It's a really good article. And just for our audiences, the article again, titled “Back to the Drawing Board: Overcoming Resistance to PD-1 Blockade,” it discusses the challenges and the potential strategies for overcoming resistance to immune checkbox inhibitors in patients with non-small cell lung cancer. In this article, Dr. Leal and colleagues talk about the second line of drug when the patient developed disease progression while immunotherapy and they develop resistance and their definitions and what to do.  So, to Dr. Leal, can you please explain the mechanisms of primary and acquired resistance to immune check prohibitors in non-small cell lung cancer? I also saw in your article you proposed the definition of immunotherapy resistance in solid tumors, distinguishing between primary resistance and acquired resistance. So, if you can please share your thoughts and explain their mechanism. Dr. Ticiana Leal: So primary resistance and acquired resistance are related to tumor intrinsic and tumor extrinsic factors. And this is mainly clinically defined as of now according to previous response patterns and timing of occurrence, and these definitions can be heterogeneous, and we certainly think that biologically they can be very different. And it can be different according to prior therapy, whether patients got immunotherapy as PD-1, PD-L1 inhibitor alone or combination strategy with CTLA-4, or the combination with chemotherapy. But the patterns of resistance can be very different and can be based on defects and antigen presentation. It can also be due to tumor microenvironment immunosuppressive effects, and there are also additional inhibitory checkpoints that can be involved.  The definition in terms of when to call it primary or acquired resistance at this point has really been based on consensus guidelines by SITC, by Esmo, as well as our group Lung-MAP has developed clinical trials in this space. Specifically, through Lung-MAP, we've defined and incorporated the definition of acquired resistance as patients who have had prior exposure of 84 days or greater and then have had progression of their disease.  Dr. Rohit Singh: I can see why it is so challenging to come up with a standard definition for immune checkpoint resistance and I think incorporating these definitions and predictive biomarkers for clinical trial design is going to be more important going forward. Your article talks about CONTACT-01 study, so can you please discuss the CONTACT-01 study and how the shifting treatment paradigm in the first-time study impacted it and at the same time also discuss the potential implication of the differential outcome observed between the men and women in the CONTACT-01 study. Dr. Ticiana Leal: CONTACT-01 was a much-awaited study. The authors, Dr. Neal et al, looked at a very important question in the area of immunotherapy resistance. So, CONTACT-01 was a randomized phase three global study that investigated the combination of cabozantinib plus atezolizumab versus docetaxel in patients previously treated with chemotherapy and immunotherapy. And as background, cabozantinib is an inhibitor of multiple receptor tyrosine kinases including VEGFR-2, MET, RET and TAM family kinases. Preclinically, cabozantinib could lead to immuno permissive tumor microenvironment and so it was rational to combine it with a PD-1 inhibitor. In early results of a phase 1B expanded cohort of COSMIC-021 showed really promising results of this combination which led to the rationale of CONTACT-01. In this study, however, patients that were included had different prior treatment sequences. They could have had prior immunotherapy alone followed by chemo or the opposite, or they could have had prior immunotherapy and then upon progression gotten a combination of immunotherapy plus chemotherapy. That to say that immunotherapy rechallenge is something that people are doing in clinical practice given the unmet need and the desire to overcome immunotherapy resistance. But perhaps that also includes a more resistant population of patients, and these patients certainly could have had heterogeneous mechanisms of resistance which could have impacted these results.   The study did not meet the primary endpoint of overall survival. We saw a median overall survival of 10.7 months with the combination of atezo plus cabo and 10.5 months with docetaxel alone. In terms of the differences between sex that we saw in the CONTACT-01 study, just to go back in terms of the preclinical studies that have been done, there have been some preclinical studies that demonstrated that perhaps there may be some biological differences in models of different genders in mice. However, in the clinical setting, there have been, I think, contradicting results. A meta-analysis showed that perhaps women derive less benefit than men. Other studies have shown that perhaps women have more adverse events to immunotherapy. In this study specifically, only about 20% of the patients enrolled were women and the majority actually had non squamous histology. And we saw here less benefit for immunotherapy in women. But again, I think the numbers here are quite small. This is an exploratory analysis and I do think it highlights though the importance of making sure that we include populations and have higher rates of accrual, not only in women, but in other representative populations. In this study, only about 1% of the patients were black. Dr. Rohit Singh: Yeah. Thank you so much for highlighting those disparities. I think it's very important to make sure that we have proper representation of all the groups in our trials. I think based on just coming off the VEGF inhibitors, I think the Lung-MAP trial S1800A, showed a significant improvement in median OS with the combination of pembrolizumab and ramucirumab compared to standard of care. Do you envision any future commission therapies targeting the VEGF pathway with immune prohibitors in non-small cell lung cancer?  Dr. Ticiana Leal: I definitely think that targeting VEGF with multikinase TKIs based on the studies that we have seen, several now randomized phase 3 studies showing that this strategy is ineffective. So, this has been quite disappointing. But we've now seen the results of CONTACT-01, that we're just discussing here, but also other studies, including SAPPHIRE, which was also a randomized phase 3 that investigated nivolumab plus another VEGF multikinase TKI, sitravatinib. And then we also saw LEAP-008, which was a negative study investigating lenvatinib plus pembrolizumab. There still is a question though, whether you can target the VEGF pathway inhibition with a monoclonal antibody, so that's ramucirumab targeting VEGFR-2 plus ICI, and whether that can actually be an effective strategy. In our Lung-MAP trial, the S1800A, this study was a randomized phase 2. Here we used the definition of acquired resistance of patients receiving prior immune checkpoint inhibitor for a minimum of 84 days, and they were randomized to the combination of pembrolizumab plus ramucirumab versus investigator's choice of standard of care, which did include docetaxel, ramucirumab, docetaxel gemcitabine and methotrexate. This was a positive study. It led to significant improvement in median overall survival and there weren't any significant safety signals here. And we're waiting for another confirmatory study called the Pragmatica-Lung study.  Dr. Rohit Singh: Yeah, I did have one patient who raced through pembro, and I utilized this combination and was able to get some responses.  You mentioned Pragmatica-Lung trial. Can you provide more information about the ongoing Pragmatica-Lung trial and its potential impact on the treatment paradigm? Dr. Ticiana Leal: Yeah, the Pragmatica-Lung trial is an ongoing study, S2302. This is an effort that is ongoing. Dr. Karen Reckamp is the chair of this study. And this is a study that actually has a very, I think, modern study design. The term Pragmatica, this is an effort that is supported by the NCI to really propose a clinical trial design that is pragmatic to promote diversity and inclusion in clinical trials. The aim of this trial specifically is to validate what we saw in terms of overall survival in S1800A. So, in this study, patients with previously treated advanced non-small cell lung cancer are randomized 1:1 to the combination of pembrolizumab plus ramucirumab versus standard of care for patients previously treated with immunotherapy and chemotherapy for stage 4 recurrent non-small cell lung cancer. Primary endpoint here is overall survival. And I think this kind of highlights what we were talking about in terms of empowering investigators to treat patients in a clinical trial more so like a real-world setting. And I think this can be paradigm changing and decrease barriers to enrollment and also include now the real-world population that we see in clinical practice. Dr. Rohit Singh: Yeah, changing gears a little bit. I think your article also mentioned other agents that have been tested in ICI resistance settings, like lenvatinib-sitra. However, those trials results have been disappointing. What are the possible reasons behind those dose point results with multikinase inhibitors?  Dr. Ticiana Leal: We saw some really interesting, promising overall survival results with these combinations in phase two setting. In the phase 1B expansion with CONTACT-01, we saw prolonged overall survival that we thought would be promising enough to investigate in a phase 3. Ultimately, I don't know because there weren't any biomarkers that we could really tease out what was going on. Again, to highlight that both in LEAP-008 as well as CONTACT-01, there was no definition of immunotherapy resistance, which could have impacted, and we did choose the definition for SAPPHIRE, that patients had to have acquired resistance and immunotherapy had to be the most recent prior therapy. Ultimately, one potential reason for why these are not effective could be that this targeting with a multikinase TKI with multiple targets is ineffective, and you really have to target VEGF more precisely, which is the case here of ramucirumab, which targets VEGFR-2, and whether there are differences between a TKI and a monoclonal antibody may also impact the outcomes here.  Dr. Rohit Singh: You mentioned biomarkers. Do you think, are there any other potential biomarkers beyond PDL-1 or human mutation burden expression that can help us predict the response image checkpoint, especially in non-small cell lung cancer? Dr. Ticiana Leal: I think that's a great question. I definitely think that more effort needs to be dedicated, and of course, there are multiple efforts in this direction. One of the challenges, obviously, has been to obtain tissue to do this biomarker testing in clinical trials. When you look at CONTACT-01, they did PDL-1 expression, but this was all based on archival tissue and it was all based on standard of care, local testing. So, a lot of heterogeneity there, and certainly using PDL-1 at baseline from initial diagnosis for a second line trial may have significant flaws there. Ultimately, right now, for clinical practice, there isn't anything that's ready for prime time. But certainly, it sounds like, based on what we're seeing, that combining biomarkers is more likely to improve the accuracy. And I think a single biomarker alone is probably going to have insufficient predictive capacity. It'd be great to be able to better comprehensively characterize an individual's tumor, to individualize immunotherapy strategies in this relapse setting.  Dr. Rohit Singh: Yeah, definitely. We need more, better biomarkers. Coming to your point of heterogeneity, PD-L1. I myself had a patient, when we got PDL expressions from one site, they gave us one to 49%. However, for the testing, I sent the patient to a further lab at outset and PDL turned out to be 80%. But that was from a different site because of the bio sets only. Yeah, to your point, it's very heterogeneous and definitely we need to be more cautious interpreting those.  In that trial, in CONTACT-01, we have, through the patient who have oncogenetic lung cancer. Are there any plans to explore the role of immune checkpoint in oncogenetic lung cancer, especially like non-EGFR, non ALK? I know those are the ones that we have seen in multiple studies that don't respond but are other oncogenetic lung cancer is getting more and more target treatments coming out for non-small lung cancer? Dr. Ticiana Leal: Yeah. So, for patients with driver mutations, the paradigm has been well established that if there is a driver mutation, the patient should receive the appropriate targeted therapy. Immunotherapy as monotherapy has been ineffective in a lot of the patients with driver mutations beyond EGFR and ALK, certainly RET and HER2, ROS1, or other driver mutations that we believe that immunotherapy alone is ineffective. However, we are seeing some interesting ongoing clinical trials, or completed clinical trials investigating immunotherapy in patients with driver mutations. Going back to the EGFR population, we recently saw the results of HARMONi-A, which investigated ivonescimab, which is a bispecific antibody hitting PD-1, and VEGF, that in combination with chemotherapy, improved progression free survival in patients with EGFR mutated, non-squamous, non-small cell lung cancer with progression on prior TKI treatment. So, I think it is still an area of active investigation, and I do think that ongoing trials, perhaps with different PD-1, PD-L1 combination strategies such as bispecifics may be interesting but does require investigation. Dr. Rohit Singh: Yeah, definitely. It looks like combination therapy is going to be the most likely answer coming forward with more research, we're able to figure out the best possible treatment in this subgroup of patients. Considering the current challenges and ongoing research efforts, how do you see the field of non-small cell treatment evolving in coming years? Dr. Ticiana Leal: This is an interesting and important question. I think it's been really exciting to be working in thoracic oncology research. We have seen that these research efforts have led to advancement in the field. I think we need to continue to partner and collaborate with institutions, partner with industry, and also with patients and patient advocates to design clinical trials that are really going to focus on the needs of our patients in clinical trials. The gap in the second line and beyond after immunotherapy failure is a significant one. So, I do think that the challenges are to continue to develop biomarkers, to really understand who will benefit from immunotherapy strategies, who benefits from combinations, and most importantly, who does nothing. I think biomarkers are going to be something that we need to continue to incorporate in clinical trials, and I do think that there's a lot of room for hope and promise in the field. We've seen some interesting results with antibody drug conjugates and the combinations there may also be of interest. And then other important strategies, we're looking at T Cell engagers and different drugs with different mechanism of actions, including CAR T and vaccines. So beyond immune checkpoint inhibitors, I think we have different classes of drugs that may lead to different treatment strategies for patients in second line and beyond.  Dr. Rohit Singh: Yeah, certainly we have seen such extensive development in lung cancer. However, there's still a lot to be done as you just mentioned.  Thank you so much Dr. Leal for your time and great insights discussing your article with us. Dr. Ticiana Leal: Thank you. Dr. Rohit Singh: Thank you for listening to JCO Article Insights. Don't forget to give us a rating or review and be sure to subscribe so you never miss an episode. You'll find all ASCO shows at asco.org/podcast.    The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.   Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.     Dr. Leal Disclosures Consulting or Advisory Role Company name: Novocure Company name: Amgen Company name: Roche Company name: AstraZeneca Company name: Regeneron Company name: Novocure Company name: Takeda Company name: Jazz Pharmaceuticals Company name: Catalyst Pharmaceuticals Company name: Pfizer Company name: Janssen Company name: Genentech Company name: Novartis Company name: Sanofi Company name: BMS GmbH & Co. KG Company name: Abbvie Company name: OncoC4 Research Funding Company name: Pfizer Company name: Daiichi Sankyo/Astra Zeneca Travel, Accommodations, Expenses Company name: Regeneron Company name: Sanofi  

Featuring perspectives from Dr Kevin Kalinsky and Dr Heather McArthur, including the following topics: Introduction (0:00) Case: A woman in her mid 80s with a 2.7-cm residual tumor after neoadjuvant pembrolizumab/chemotherapy for localized triple-negative breast cancer (TNBC) — Ranju Gupta, MD (3:31) Question and Comments: Approach to neoadjuvant therapy and defining residual disease; PD-L1 status and efficacy of pembrolizumab in the localized and metastatic settings — Kapisthalam (KS) Kumar, MD (8:04) Case: A woman in her mid 60s with node-positive TNBC and a single lung metastasis who receives neoadjuvant therapy based on the KEYNOTE-522 trial — Dr Kumar (17:18) Case: A woman in her early 70s with localized TNBC and residual disease after poorly tolerated neoadjuvant pembrolizumab/chemotherapy and lumpectomy — Dr Kumar (23:29) Case: A woman in her late 60s with widely metastatic ER-negative, HER2-low disease after multiple lines of treatment — CDH1 and ERBB2-V697L mutations, microsatellite stable, tumor mutational burden 3 mut/Mb — Dr Gupta (29:13) Question and Comments: Adjuvant therapy selection for patients with localized TNBC with a BRCA mutation and residual disease; risk of acute myeloid leukemia/myelodysplastic syndromes associated with PARP inhibitor therapy — Dr Kumar (40:52) Case: A woman in her early 70s who develops recurrent metastatic ER-negative, HER2-low breast cancer after nab paclitaxel/atezolizumab and receives sacituzumab govitecan — Dr Gupta (46:49) CME information and select publications

Dr. Neeraj Agarwal and Dr. Rana McKay discuss promising studies in GU cancers featured at the 2024 ASCO Annual Meeting that highlighted improved outcomes in urothelial carcinoma, improved survival in renal cell carcinoma, and the role of ctDNA as a potential biomarker for predicting outcomes.   TRANSCRIPT Dr. Neeraj Agarwal: Hello and welcome to the ASCO Daily News Podcast. I'm Dr. Neeraj Agarwal, your guest host of the ASCO Daily News Podcast today. I am the director of the Genitourinary Oncology Program, a professor of medicine at the University of Utah's Huntsman Cancer Institute, and editor-in-chief of the ASCO Daily News.  I am delighted to welcome Dr. Rana McKay, a GU medical oncologist and associate professor at the University of California San Diego. Today, we'll be discussing some key GU abstracts featured at the 2024 ASCO Annual Meeting. Our full disclosures are available in the transcript of this episode. Rana, we're thrilled to have you on the podcast today to share your insights on key advances in GU oncology from ASCO24. Dr. Rana McKay: Thank you so much, Neeraj; it's a pleasure to be here. Dr. Neeraj Agarwal: So, Rana, let's start with some bladder cancer abstracts. Could you tell us about Abstract 4503, titled “Impact of exposure on outcomes with enfortumab vedotin in patients with locally advanced or metastatic urothelial cancer”? Dr. Rana McKay: Of course, I would be delighted to. First, I would like to remind our listeners that enfortumab vedotin (EV) was approved as a monotherapy for the treatment of locally advanced or metastatic urothelial cancer based on the results of EV-201 and EV-301 trials. In these pivotal studies, EV was initiated at a dose of 1.25 mg/kg, and dose modifications, such as reductions and interruptions, were used to manage adverse events. In the abstract presented at ASCO 2024, Dr. Daniel Petrylak and colleagues conducted a post-hoc exploratory analysis to evaluate the association between EV plasma exposure and outcomes. They used multiple pharmacokinetic samples collected during the first two cycles and pre-dose samples from 3 EV monotherapy studies, namely EV-101, EV-201, and EV-301, that were conducted in patients with previously treated locally advanced or metastatic urothelial carcinoma. Dose reductions to 1 mg/kg were required in 42.1% and 35.1% of patients in the EV-201 and EV-301 trials, respectively, and reductions to 0.75 mg/kg were required in 13.6% and 11.1% in the EV-201 and EV-301 trials, respectively. Higher EV exposure during the first two cycles was associated with a higher objective response rate. The ORR was 21.4% for the dose of 0.75 mg/kg, while it was 18.5% for the dose of 1.0 mg/kg. Interestingly, increasing the dosage to 1.25 mg/kg improved the ORR, which ranged from 40 to 51.1% across various studies. In the EV-301 trial, when comparing the efficacy of EV to chemotherapy, EV improved PFS and OS across all dose quartiles, and there was no evidence that recommended dose modifications impacted long-term efficacy outcomes. Dr. Neeraj Agarwal: Thank you, Rana, for this great summary. I would like to add that the meticulously conducted pharmacokinetic studies demonstrated that serum levels of EV correlated with responses. Importantly, patients who had to decrease the dose did not experience compromised outcomes as EV improved PFS and OS outcomes vs chemotherapy in across all exposure quartiles in the EV-301 trial where EV was compared with chemotherapy. These findings highlight the need to start at the recommended dose of 1.25 mg/kg and reduce it, if necessary, however, clinicians should not start at a lower dose.  Dr. Rana McKay: I totally agree with you, Neeraj. Now, moving on to a different setting in bladder cancer, what can you tell us about LBA4517, titled “Perioperative sacituzumab govitecan alone or in combination with pembrolizumab for patients with muscle-invasive urothelial bladder cancer: SURE-01/02 interim results”? Dr. Neeraj Agarwal: Of course! So, SURE was a multicohort, open-label, phase 2 study in patients with muscle-invasive bladder cancer assessing sacituzumab govitecan as a neoadjuvant therapy either alone in SURE-01 or as a combination with pembrolizumab followed by adjuvant pembro in SURE-02 in a flexible design allowing a bladder-sparing approach. In the abstract presented at ASCO 2024, Dr. Antonio Cigliola and colleagues report interim results of the SURE-01 study. Patients with cT2-4N0M0 urothelial carcinoma who were ineligible for or refused cisplatin-based neoadjuvant chemotherapy were planned to receive 4 cycles of neoadjuvant sacituzumab govitecan at a dose of 10 mg/kg followed by radical cystectomy.  An extensive assessment was performed at baseline and after the 4 cycles for response assessment. Patients with clinical complete response defined with negative MRI, cystoscopy and ctDNA assays refusing radical cystectomy were offered redo transurethral resection of the bladder tumor or repeat TURBT followed by observation in the absence of viable high-grade tumor in the bladder. The primary endpoint was pathological complete response rate, while secondary endpoints included pathological downstaging rate and safety. After the first 8 patients were enrolled, the protocol was amended due to the occurrence of grade 3 and 4 neutropenia and diarrhea in 75% and 50% of patients, respectively, and 2 deaths – one of which was deemed to be treatment-related due to sepsis. Key protocol changes included the reduction of the dose of sacituzumab govitecan to 7.5 mg/kg, the introduction of G-CSF as primary prophylaxis, and the exclusion of patients at high risk of febrile neutropenia per ASCO guidelines.  Among 21 patients who received at least one cycle of sacituzumab govitecan and included in the intention-to-treat population, 47.6% had a complete pathological response, and 52.4% had pathological downstaging. 11 patients underwent radical cystectomy, while 7 received repeat-TURBT due to complete clinical response or patient preference. Regarding the safety profile, grade 3 or more adverse events occurred in 42.5% of patients. Treatment-related adverse events leading to dose interruptions or discontinuations were more common before the protocol amendment. It is noteworthy that 3 patients died after treatment discontinuation, with one deemed treatment-related, as previously mentioned. Dr. Rana McKay: Thank you, Neeraj, for a great summary. The pathological complete responses observed show promising activity for sacituzumab govitecan as a neo-adjuvant therapy and a window for bladder-sparing approaches, which is definitely exciting news for our patients! However, although the 3 deaths encountered in a neo-adjuvant setting could be concerning, the improvement of the safety profile after protocol amendments is reassuring and supports the continuation of the study. Dr. Neeraj Agarwal: Before wrapping up the bladder cancer section, would you like to share your insights with our listeners on Abstract 4518, titled “Quantitative circulating tumor DNA (ctDNA) assessment in patients with advanced urothelial carcinoma treated with pembrolizumab or platinum-based chemotherapy from the phase 3 KEYNOTE-361 trial”?  Dr. Rana McKay: Sure. So, the KEYNOTE-361 trial was a randomized phase 3 study with 3 arms that included pembrolizumab plus chemotherapy, pembrolizumab monotherapy, or chemotherapy alone in patients with previously untreated advanced urothelial carcinoma. The results showed that neither the combination of pembrolizumab plus chemotherapy nor pembrolizumab monotherapy improved survival outcomes compared to the chemotherapy arm. So, in this exploratory analysis presented at ASCO24, Dr. Tom Powles and colleagues sought to assess the role of ctDNA as a potential biomarker between the pembrolizumab monotherapy arm and the chemotherapy arm. Tumor tissue mutations were evaluated using whole exome sequencing, and plasma ctDNA was assessed with the Guardant 360 assay. Changes in ctDNA from pre-treatment cycle 1 to on-treatment cycle 2, so 3 weeks post-baseline assessment, were quantified by the maximum variant allele frequency of tumor tissue-specific mutations.  Results showed that lower baseline ctDNA levels were associated with improved clinical outcomes of response in the pembrolizumab arm but not in the chemotherapy arm. This improvement in the pembrolizumab arm was also robust to adjustment for tumor mutational burden and PD-L1. Additionally, chemotherapy led to a ctDNA clearance rate of 41% compared to 11% in the pembrolizumab arm. Patients who had a large ctDNA reduction with pembrolizumab had significantly improved outcomes compared to those achieving a large reduction with chemotherapy with a hazard ratio of 0.25. However, this did not replicate in patients who did not achieve a large reduction, as these patients had similar outcomes across both arms. Let's switch gears to kidney cancer and start with Abstract 4508, reporting the final OS analysis from the JAVELIN Renal-101 trial. Neeraj, what would you like to tell us about this abstract? Dr. Neeraj Agarwal:  Well, as a quick reminder, the JAVELIN Renal-101 was a randomized phase 3 trial where patients with previously untreated advanced or metastatic clear cell renal cell carcinoma were randomized to receive either the combination of avelumab plus axitinib or sunitinib. In previous analyses, the combination of avelumab and axitinib significantly improved PFS compared to sunitinib and was subsequently approved by the FDA for the first-line treatment of patients with advanced RCC in 2019. This superiority in PFS was maintained across the different analyses; however, OS data remained immature. In the abstract presented at ASCO24 by Dr. Robert Motzer from Memorial Sloan Kettering Cancer Center and colleagues, the authors reported OS results at a median follow-up of around 73 months and a minimum of 68 months for all patients, which is the longest follow-up for any ICI-TKI combination in RCC. The final analysis in the overall population favored the combination of avelumab plus axitinib with a median OS of 44.8 months compared to 38.9 months with sunitinib, however, this did not reach statistical significance with a hazard ratio of 0.88. The PFS results and safety profile were consistent with previous analyses.  Dr. Rana McKay: Thank you, Neeraj, for such a nice overview of this abstract. These new data could make this regimen less optimal than other ICI-TKI combinations in the first-line mRCC setting.   Dr. Neeraj Agarwal: I concur, Rana. Moving on to perhaps one of the most exciting GU abstracts featured, Abstract 4506, titled “Circulating kidney injury molecule-1 biomarker analysis in IMmotion010: A randomized phase 3 study of adjuvant atezolizumab vs placebo in patients with renal cell carcinoma at increased risk of recurrence after resection.” Rana, what are your thoughts on this abstract? Dr. Rana McKay: Well, first, I would like to take a step back and remind our audience that in the IMmotion010 trial, patients with resected intermediate to high-risk RCC with clear cell and/or sarcomatoid component were randomized in a 1:1 ratio to receive either atezolizumab or placebo. Investigator-assessed disease-free survival, which was the primary endpoint, favored the atezolizumab arm but did not reach statistical significance. In the abstract featured at ASCO24, Dr. Laurence Albiges and colleagues build on data previously reported in the ASSURE and CheckMate 914 trials and report provocative findings regarding a molecule known as kidney injury molecule 1 or KIM-1, which is a type 1 membrane glycoprotein that has been identified as a minimally invasive potential peripheral blood circulating biomarker. The KIM-1 level of 86 pg/ml was identified as the optimized threshold for defining post-nephrectomy KIM-1 high vs KIM-1 low subgroups in the IMmotion010 trial. KIM-1 levels were measured at baseline or pre-treatment, at cycle 4 day 1, and at disease recurrence or discontinuation without disease recurrence. Baseline characteristics were balanced between the KIM-1 high and KIM-1 low groups, except perhaps for a slightly higher pathological stage in the KIM-1 high subgroup.  I would like to highlight 3 key takeaways from this abstract. First, KIM-1 high level was associated with significantly worse DFS with a hazard ratio of 1.75. Second, patients in the KIM-1 high subgroup receiving atezolizumab had a 28% reduction in the risk of recurrence or death compared to those receiving placebo, while those in the KIM-1 low subgroup had comparable outcomes across both treatment arms. Third, patients in the KIM-1 high subgroup receiving atezolizumab were significantly less likely to experience an on-treatment increase in KIM-1 levels, which was associated with worse DFS in both high and low KIM-1 subgroups, regardless of treatment arm. Thus, these findings support the use of KIM-1 as both a predictive and prognostic biomarker in patients with RCC. Dr. Neeraj Agarwal: Yes, Rana, this is amazing data! I would like to add that these results warrant larger and, ideally, prospective studies to validate the utility of KIM-1 as a noninvasive biomarker for identifying minimal residual disease after nephrectomy and for predicting outcomes to immune checkpoint inhibitors. Dr. Rana McKay: Also, in the field of biomarkers, 2 abstracts interrogating different biomarkers in a different setting, so in patients with advanced or metastatic RCC were presented. Neeraj, could you tell us more about these abstracts? Dr. Neeraj Agarwal: Of course! I think you are referring to Abstracts 4504 and 4505. In abstract 4504, Dr. Toni Choueiri and colleagues sought to assess the clinical implications of different biomarkers in the CLEAR trial, which was a randomized phase 3 trial that led to the approval of the combination of pembrolizumab plus lenvatinib in the first-line mRCC setting. On the other hand, in abstract 4505, Dr. Brian Rini presented biomarker results in KEYNOTE-426, which was also a randomized phase 3 trial based on which the combination of pembrolizumab plus axitinib was approved in patients with mRCC. The authors in both trials sought to investigate the role of biomarkers in predicting treatment outcomes from 3 different angles. Starting with PD-L1 expression, the superiority of the combination arms over sunitinib was not impacted by PD-L1 status in both trials. Moving on to RCC driver gene mutations on whole exome sequencing, such as VHL, SETD2, PBRM1, and BAP1, ICI combination therapies improved outcomes regardless of mutation gene status, and this improvement was statistically significant with PBRM1 mutations in KEYNOTE-426 compared to wild-type PBRM1, but this did not replicate in the CLEAR trial. Finally, using transcriptomic signatures derived from RCC trials, especially the IMmotion 151 and JAVELIN Renal 101 trials, where 7 clusters or molecular subtypes were identified, the combination arms outperformed sunitinib in all clusters in both trials and the magnitude of this benefit differed across clusters.  Dr. Rana McKay: Thank you for this very interesting summary and comparison of the results of these 2 abstracts. These findings support the use of ICI-based combinations in all patients with mRCC as a first-line option. Although these abstracts could not identify specific biomarkers that could guide us clinicians in treatment selection, they provide very interesting biological insights on these molecular biomarkers that are, however, not yet clinically actionable. Dr. Neeraj Agarwal: Very interesting point, Rana. Moving on to prostate cancer, let's start with abstract LBA5000 titled, “Cabazitaxel with abiraterone versus abiraterone alone randomized trial for extensive disease following docetaxel: The CHAARTED2 trial of the ECOG-ACRIN Cancer Research Group (EA8153).” Rana, what is your takeaway on this abstract? Dr. Rana McKay: As a reminder to our audience, the CHAARTED2 trial was a randomized open-label phase 2 study that compared the combination of cabazitaxel and abiraterone to abiraterone alone in patients with mCRPC previously treated with ADT plus docetaxel in the hormone-sensitive setting. The primary endpoint was progression-free survival. After a median follow-up of 47.3 months, Dr. Christos Kyriakopoulos and colleagues reported in LBA5000 that patients receiving the combination of cabazitaxel plus abiraterone had a 27% reduction in the risk of progression or death. However, there was no significant difference in overall survival between the two arms, with a median OS of 25 months in the cabazitaxel+abiraterone arm and 26.9 months in the abiraterone arm, although the study was underpowered for this endpoint. Regarding the toxicity profile, the combination of cabazitaxel and abiraterone was overall well tolerated with more cytopenias, as expected.  Dr. Neeraj Agarwal: Very nice summary of this abstract, Rana. I would like to add that the treatment landscape of patients with mHSPC has evolved since the design of the study and now includes combination therapies of ADT + ARPI with or without docetaxel, and ADT + docetaxel is no longer a standard of care, which limits the applicability of these results in clinical practice today.  Dr. Rana McKay: Excellent point, Neeraj. Let's discuss Abstract 5001, titled “CYCLONE 2: A phase 3 study of abemaciclib with abiraterone in patients with metastatic castration-resistant prostate cancer”. Dr. Neeraj Agarwal: Sure! In the abstract featured at ASCO24, Dr. Matthew Smith and colleagues report the primary results of the CYCLONE 2 trial, which was a randomized phase 2/3 study that investigated the combination of abemaciclib plus abiraterone versus abiraterone monotherapy in patients with mCRPC. Stratification factors included radiographic progression at study entry, presence of measurable disease, and prior docetaxel for mHSPC. Part 1 of the study established the recommended phase 2 dose of abemaciclib at 200 mg twice daily. In part 2, patients were randomized to placebo or abemaciclib, and an adaptive interim analysis using prespecified criteria was performed and recommended the expansion of the study to part 3. The primary endpoint was investigator-assessed radiographic progression-free survival by RECIST 1.1 and PCWG3 criteria in the intention-to-treat population. At the time of the primary analysis, adding abemaciclib to abiraterone did not improve rPFS, with a hazard ratio of 0.83. The median rPFS was 22 months for the combination arm and 20.3 months for the abiraterone arm. The combination was well tolerated, and the safety profile was consistent with the known adverse events. Dr. Rana McKay: So, the addition of abemaciclib to abiraterone did not improve outcomes in patients with mCRPC. These findings suggest that no further investigation is warranted for abemaciclib or CDK4/6 inhibitors in biomarker-unselected patients with prostate cancer.  Dr. Neeraj Agarwal: Rana, what's your take-home message on Abstract 5006, titled “Health-related quality of life results from PRESTO (AFT-19), a phase 3 randomized trial of intensification of androgen blockade in patients with high-risk biochemically relapsed castration sensitive prostate cancer”? Dr. Rana McKay: So, as a reminder to our audience, the PRESTO trial was a randomized phase 3 study that assessed the effects of intensified androgen receptor blockade in patients with biochemically recurrent prostate cancer following local therapies. Patients with a PSA doubling time of less than 9 months and no evidence of metastatic disease were randomized to receive either 52 weeks of ADT alone, ADT plus apalutamide, or ADT plus apalutamide plus abiraterone. In their paper published earlier this year in the Journal of Clinical Oncology, the authors showed that patients receiving ADT plus apalutamide with or without abiraterone had significantly longer PSA-progression-free survival than those receiving ADT alone. In the oral presentation featured at ASCO24, Dr. Ronald Chen and colleagues report health-related quality of life outcomes that were assessed using various questionnaires or scales at baseline, at cycle 7, which is around 6 months on treatment, and at the end of treatment. Results showed that this intensified approach with apalutamide did not significantly increase severe adverse events, did not lengthen the time to testosterone recovery, and did not meaningfully increase common treatment-related symptoms such as hormonal symptoms, sexual dysfunction, hot flash interference, and fatigue. Importantly, additional intensification with abiraterone did not further improve PSA-PFS but did increase the rate of serious adverse events, lengthened the time to testosterone recovery, and increased hot flash interference.  Dr. Neeraj Agarwal: So, in conclusion, the PRESTO trial supports using intensified androgen blockade with apalutamide to improve PSA-PFS in patients with high-risk biochemically recurrent prostate cancer without compromising health-related quality of life. However, adding abiraterone did not offer additional benefits and increased side effects.  Dr. Rana McKay: Let's move on to LBA5002 titled, “A randomized, double-blind, placebo-controlled trial of metformin in reducing progression among men on expectant management for low-risk prostate cancer: The MAST (Metformin Active Surveillance Trial) study.” Would you like to share your insights on this abstract with our listeners? Dr. Neeraj Agarwal: Absolutely. MAST was a randomized, double-blinded, placebo-controlled trial that investigated the impact of metformin on the progression of low-risk localized prostate cancer in patients choosing to undergo active surveillance. Eligible patients had biopsy-proven, low-risk, localized prostate cancer diagnosed within the past 6 months, characterized by a Gleason score of less than 6 observed in less than one-third of the total cores, less than 50% positivity in any one core, a PSA level of less than 10 ng/ml, and a clinical-stage between T1c and T2a. Patients were randomized in a 1:1 ratio to receive either metformin 850 mg twice daily or placebo for three years. All patients underwent repeat prostate biopsy at 18 and 36 months. The primary endpoint was time to progression, defined as the earliest occurrence of primary prostate cancer therapy, such as prostatectomy, radiation, hormonal therapy, or pathological progression on subsequent biopsies, which was defined as more than 1/3 of total cores involved, at least 50% of any one core involved, or Gleason pattern 4 or higher. The study included 407 patients, with 204 receiving metformin and 203 receiving a placebo. Results presented by Dr. Anthony Joshua showed no statistically significant difference in progression-free survival, including therapeutic and pathologic progression, with an unadjusted hazard ratio of 1.08.  Interestingly, there was a signal that patients with a BMI more than 30 had a detriment to taking metformin with a higher risk of progression compared to those receiving placebo with an unadjusted HR of 2.39 and a p-value of 0.01. Dr. Rana McKay: I would like to add that this study showed that metformin use does not prevent the progression of low-risk localized prostate cancer on active surveillance and could represent a potential detriment for patients with high BMI at study entry. Dr. Neeraj Agarwal: Yes, Rana, I concur. Any final remarks before we conclude today's podcast? Dr. Rana McKay:  Thank you, Neeraj; it's been wonderful being here with you today and you having me on the podcast to highlight these important advances and the amazing work that many investigators are conducting and the patients who were involved in the context of these trials. It's really excellent to see these updated results.   Dr. Neeraj Agarwal: Before we wrap up this podcast, I would like to say that we have reviewed a selection of abstracts addressing prostate, bladder, and kidney cancer, which are significantly impacting our medical practices now and in the near future. Rana, thank you for sharing your insights today. These updates are undoubtedly exciting for the entire GU oncology community, and we greatly appreciate your valuable contribution to the discussion. Many thanks. And thank you to our listeners for joining us today. You will find links to the abstracts discussed today on the transcript of this episode. Finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts.   Find out more about today's speakers:    Dr. Neeraj Agarwal   @neerajaiims   Dr. Rana McKay  @DrRanaMcKay     Follow ASCO on social media:      @ASCO on Twitter      ASCO on Facebook      ASCO on LinkedIn         Disclosures:        Dr. Neeraj Agarwal:         Consulting or Advisory Role: Pfizer, Bristol-Myers Squibb, AstraZeneca, Nektar, Lilly, Bayer, Pharmacyclics, Foundation Medicine, Astellas Pharma, Lilly, Exelixis, AstraZeneca, Pfizer, Merck, Novartis, Eisai, Seattle Genetics, EMD Serono, Janssen Oncology, AVEO, Calithera Biosciences, MEI Pharma, Genentech, Astellas Pharma, Foundation Medicine, and Gilead Sciences     Research Funding (Institution): Bayer, Bristol-Myers Squibb, Takeda, Pfizer, Exelixis, Amgen, AstraZeneca, Calithera Biosciences, Celldex, Eisai, Genentech, Immunomedics, Janssen, Merck, Lilly, Nektar, ORIC Pharmaceuticals, Crispr Therapeutics, Arvinas      Dr. Rana McKay:   Consulting or Advisory Role: Janssen, Novartis, Tempus, Exelxis, Pfizer, Bristol-Myers Squibb, Astellas Medivation, Dendreon, Bayer, Sanofi, Merck, Vividion, Calithera, AstraZeneca, Myovant, Caris Life Sciences, Sorrento Therapeutics, AVEO, Seattle Genetics, Telix, Eli Lilly, Pfizer, Bayer, Tempus

Visit nascentmc.com for the full writup of this episode and medical writing assistance.  Visit learnamastyle.com for free downloads directed towards medical writing and editing. • The FDA has approved the 21-valent pneumococcal conjugate vaccine, CAPVAXIVE™ (Merck), for the prevention of invasive disease and pneumonia in adults aged 18 years and older caused by 21 Streptococcus pneumoniae serotypes. Capvaxive includes eight serotypes not covered by other pneumococcal vaccines, addressing approximately 27% of IPD cases in adults aged 50 and older, and 30% in adults aged 65 and older, based on CDC data from 2018-2021. The approval follows an FDA Priority Review and is based on immune responses measured in the Phase 3 STRIDE-3 trial, with continued approval contingent upon verification of clinical benefit in a confirmatory trial.  • The FDA has approved delandistrogene moxeparvovec-rokl (Elevidys) for Duchenne muscular dystrophy (DMD) in ambulatory individuals aged 4 and older with a confirmed mutation in the DMD gene, as well as granting accelerated approval for non-ambulatory individuals. Elevidys, a one-time intravenous gene therapy, delivers a working copy of the DMD gene to address the muscle degeneration caused by mutations in this gene. The approvals are based on findings from a confirmatory trial that, while not meeting its primary endpoint, showed success in several secondary measures, with the Phase 3 ENVISION study underway to serve as a postmarketing requirement. • The FDA has approved adagrasib (Krazati) plus cetuximab for adults with KRAS G12C-mutated locally advanced or metastatic colorectal cancer (CRC) who have received prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy. Adagrasib targets the KRAS G12C mutation, a common driver mutation in several cancers including colorectal cancer, while cetuximab enhances its antitumor activity. The approval was based on findings from the KRYSTAL-1 trial, which demonstrated a confirmed overall response rate (ORR) of 34% and a median duration of response (DOR) of 5.8 months. • The FDA has approved pembrolizumab (Keytruda) in combination with carboplatin and paclitaxel, followed by pembrolizumab monotherapy, to treat primary advanced or recurrent endometrial carcinoma in adults, marking the third endometrial carcinoma indication for Keytruda in the US. Keytruda enhances the body's immune response against tumor cells by blocking the interaction between PD-1 and its ligands, PD-L1 and PD-L2. The approval is based on results from the phase 3 KEYNOTE-868 clinical trial, which demonstrated significant improvements in progression-free survival for patients treated with Keytruda plus chemotherapy compared to those receiving a placebo with chemotherapy.  • The FDA has approved risankizumab-rzaa (Skyrizi) for the treatment of moderately to severely active ulcerative colitis in adults, making it the first specific anti–interleukin 23 monoclonal antibody indicated for both ulcerative colitis and moderate to severe Crohn's disease. Risankizumab-rzaa inhibits interleukin-23 (IL-23), a cytokine involved in inflammatory and immune responses, thereby reducing inflammation. The approval is based on data from two phase 3 clinical trials, INSPIRE and COMMAND, which demonstrated the achievement of clinical remission and endoscopic improvement. • A supplemental Biologics License Application (sBLA) has been submitted for guselkumab (Tremfya) for the treatment of adults with moderately to severely active Crohn's disease. Guselkumab, a fully-human, dual-acting monoclonal antibody that blocks IL-23 and binds to CD64, was previously approved for moderate-to-severe plaque psoriasis and active psoriatic arthritis. Support for the BLA is based on findings from the Phase 3 GALAXI and GRAVITI clinical trials.

Drs. Vamsi Velcheti and Nathan Pennell discuss key lung cancer abstracts from the 2024 ASCO Annual Meeting, including data from LUMINOSITY and ADAURA, novel therapies in KRASG12C-mutant advanced NSCLC, and the need for effective adjuvant therapies for patients with rare mutations. TRANSCRIPT Dr. Vamsi Velcheti: Hello, I am Dr. Vamsi Velcheti, your guest host for the ASCO Daily News Podcast today. I'm a professor of medicine and director of thoracic medical oncology at Perlmutter Cancer Center at NYU Langone Health. Today, I'm delighted to welcome Dr. Nathan Pennell, the co-director of the Cleveland Clinic Lung Cancer Program and vice chair of clinical research at the Taussig Cancer Center. Dr. Pennell is also the editor-in-chief of the ASCO Educational Book. Dr. Pennell is sharing his valuable insights today on key abstracts in lung cancer that will be presented at the 2024 ASCO Annual Meeting. You'll find our full disclosures in the transcript of the episode.  Nate, it's great to have you here on the podcast. Thank you for being here. Dr. Nathan Pennell: Thanks, Vamsi, for inviting me. I'm always excited for the ASCO Annual Meeting, and we have a tremendous amount of exciting lung cancer abstracts. I know we're not going to discuss all of them on this podcast, but even exciting Plenary presentations coming up.  Dr. Vamsi Velcheti: So, one of the abstracts that caught my attention was Abstract 103, the LUMINOSITY trial, which will be presenting the primary analysis at the meeting. So, there's a lot of buzz and excitement around ADCs. Can you comment on this abstract, Nate, and what are your thoughts on key takeaways from this abstract?  Dr. Nathan Pennell: Absolutely, I agree. This is really an exciting new potential target for lung cancer. So historically, when we think about MET and lung cancer, we think about the MET exon 14 skipping mutations which are present in 3% or 4% of adenocarcinoma patients. And we have approved tyrosine kinase inhibitors, small molecule inhibitors that can be very effective for those. What we're talking about here is actually an antibody drug conjugate or ADC telisotuzumab vedotin, which is targeting the MET protein over expression in non-squamous EGFR wild type advanced non-small cell lung cancer. The LUMINOSITY was a single arm, phase 2 study of teliso, and first of all, I think we have to define the patient population. So, these were MET over expressing non-small cell lung cancer by immunohistochemical staining. So, it included both what they considered MET high expression and MET intermediate expression, both of which had to be 3+ IHC positive on 25% to 50% of cells in the intermediate and 50% or higher in the high expressing group. They were treated with the ADC and had pretty promising results, a response rate of 35% in the MET high group and 23% in the intermediate group. Duration of response at nine months and 7.2 months in those two groups, and the PFS was five and a half and six months. So I would say in a previously treated population, this was relatively promising and potentially defines a completely new and unique subgroup of biomarker defined patients. So, Vamsi, I'm curious, though, if this ends up moving forward to further development, what your thoughts are on adding yet another biomarker in non-small cell lung cancer? Dr. Vamsi Velcheti: Yeah, I think it's certainly exciting. I think for this population, we really don't have a lot of options beyond the second line, and even in the second line, docetaxels are low bar. So,I think having more options for our patients is certainly outcome development. And I think MET IHC is relatively easy to deploy in a clinical setting. I think we already test for MET PD-L1 IHC routinely, and now recently, as you know, HER2 IHC given approval for ADCs, HER2 ADCs there in that space. So, I think from a technical standpoint, I don't see a big barrier in terms of adding an additional IHC marker. And usually, the IHC testing is pretty quick. And I think if you have a therapeutic approval based on IHC positivity, I think certainly from an operational standpoint, it shouldn't be a very complicated issue. Dr. Nathan Pennell: Yeah, I agree. This is cheap. It's something that can be done everywhere in the world. And as you said, in addition to diagnostic IHC, we're already looking at PD-L1, and probably moving towards doing that for HER2. This is really wonderful that we're moving into kind of the era of the ADCs, which is opening up a whole new therapeutic group of options for patients. Dr. Vamsi Velcheti: So, the other abstract that caught my attention was like, the Abstract 8005. This is the molecular residual disease MRD analysis from the ADAURA trial. The ADAURA trial, as you all know, is the trial that led to the FDA approval of adjuvant use of osimertinib in patients with EGFR mutant stage 1B through 3A non-small cell lung cancer. And in this trial, osimertinib demonstrated significant improvements in DFS and OS. And in this particular study, Abstract 8005, the authors looked at the role of MRD in predicting DFS in the study. And after 682 patients who were randomized, 36% of the patients had samples to look at MRD post- surgery. And in the trial the MRD status predicted DFS or event free survival at 36 months with a hazard ratio of 0.23. And the MRD status had a median lead time of 4.7 months across both the arms, both osimertinib and the placebo arm. So, suggesting that MRD could potentially identify high risk subgroups of patients post-surgery to tailor personalized approaches potentially in this population. So, Nate, in your practice, of course, we don't have a clinically validated approach yet to kind of use MRD in this setting, but if we have an option to use an MRD based assay, do you think that would potentially be an opportunity to perhaps escalate or de-escalate adjuvant strategies with TKIs in the adjuvant setting? Do you see value in using MRI assays post- surgery? Dr. Nathan Pennell: Yeah, I think this is a really important study because this is such an important topic around adjuvant targeted treatment. So, of course, ADAURA really changed how we treated people with EGFR mutant lung cancer who underwent surgical resection, because we know that the three years of osimertinib significantly improved disease-free survival and overall survival. But there's still a lot of questions being asked about, is that affordable? Obviously, we're putting a lot of resources into three years of treatment, and not everyone necessarily needs it. There may well be people who are cured with surgery alone and adjuvant chemotherapy. And then what about duration? Is three years enough? Do we need even longer treatment, or do we need shorter treatment? And up to date, we haven't really been able to tell people at risk of recurrence other than the pure odds-based risk based on their stage.   And the assay that was used in the ADAURA study was a personalized tumor informed assay based on the resected tumor. It's unclear to me whether this was just a subgroup of people that had this done or whether they tried to do it in all 600 patients and only, it looks like they were successful in about 32% of people. Maybe about a third were able to successfully have a tumor informed assay. So, the first question is, “Can you use this to help guide who needs treatment or not?” And I think what they showed was only about 4% of people in osimertinib arm in 12% had MRD positive at baseline after surgery. So probably, upfront testing is not really going to be all that helpful at determining who's at high risk and needs to be treated.   Interestingly, of those who were positive, though, most of them, or 80% of them, did go MRD negative on osimertinib. And what I found really interesting is that of those who did have a recurrence, 65% of them did have the MRD test turn positive. And as you mentioned, that was about five months prior to being picked up radiographically, and so you can pick them up sooner. And it also looks like about two thirds of recurrences can be identified with the blood test. So that potentially could identify people who are recurring earlier that might be eligible for a more intensive treatment. The other thing that was really interesting is of those who recurred in the osimertinib arm, 68% of them happened after stopping the osimertinib, suggesting that for the majority of patients, even those not necessarily cured, they seem to have disease control while on the osimertinib, suggesting that maybe a longer duration of treatment for those patients could be helpful. The problem is it still isn't necessarily helpful at identifying who those people are who need the longer duration of treatment. So, definitely an important study. I think it could be useful in practice if this was available clinically, especially at monitoring those after completion of treatment. I think as the sensitivity of these MRD assays gets better, these will become more and more important. Dr. Vamsi Velcheti: I think it's a little bit of a challenge in terms of standardizing these assays, and they're like multiple assays, which are currently commercially available. And I think the field is getting really complicated in terms of how you incorporate different assays and different therapeutics in the adjuvant space, especially if you're kind of looking at de-escalating immunotherapeutic strategies at the adjuvant setting, I think, makes it even more challenging. I think exciting times. We definitely need more thoughtful and better studies to really define the role of MRD in the adjuvant space. So, I guess more to come in this space. Dr. Nathan Pennell: Vamsi, I wanted to ask you about another really interesting Abstract 8011. This is a subgroup of the AEGEAN perioperative study for early-stage resected non-small cell lung cancer. This abstract is specifically looking at baseline N2 lymph node involvement in stage 2A-3B with N2 positive patients in an exploratory subgroup analysis. What are your key takeaways from the study?   Dr. Vamsi Velcheti: I felt this was a very interesting abstract for a couple of reasons. As you know, this is the AEGEAN trial, the phase 3 trial that was reported earlier last year. This is a perioperative study of durvalumab plus new adjuvant chemotherapy versus new adjuvant chemotherapy alone and adjuvant durvalumab plus placebo. The study obviously met its primary endpoint, as we all saw, like the event-free survival. And here in this abstract, the authors present an exploratory subgroup analysis of patients who had N2 lymph node involvement prior to study enrollment. So, in this study, they were focusing on perioperative outcomes. And one of the issues that has come up multiple times, as you know, in a lot of these preoperative studies, is the impact of neoadjuvant chemo immunotherapy on surgery or surgical outcomes. And consistently, across a lot of these trials, including the CheckMate 816, about 20% of patients don't end up making it to surgery. So in that light, I think this study and the findings are very interesting. In this study, they looked at patients who had N2 nodal involvement and of the patients with N2 nodal involvement, the surgical operability or the number of patients who completed surgery was similar in both the groups. So, there was no significant difference between patients who received durva versus chemotherapy and also among patients who had N2 subgroup who had surgery, similar proportions of durvalumab and placebo arms had open versus minimally invasive versus pneumonectomy. So durvalumab didn't have a negative impact on the type of surgery that the patients had at the time of surgery. So overall, the findings were consistent with other trials, perioperative trials that we have seen. So, the surgical outcomes were not negatively impacted by adding immunotherapy in the neoadjuvant perioperative space. So, this is consistent with other trials that we have seen. And also, the other issue, Nate, I'd like to get your opinion on is, across the board, in all the perioperative trials we have seen that about 20% of the patients actually don't end up making it a surgery. And of course, most of these perioperative trials, a lot of these patients are stage 3 patients. And my take on this was that there's probably a little bit of a patient selection issue. We generally tend to err on the side of operability when we have a stage 3 patient discussed in the tumor board, sometimes feel like the patient may downstage and could potentially go to surgery. But even in the real world, in stage 3 operable patients, what proportion of patients do you think don't end up going to surgery? Dr. Nathan Pennell: That is such an important question that I don't think we have the best answer to. You're right. All of these perioperative studies have a relatively high- sort of 20% to 30% of people who enroll on the studies don't necessarily go to surgery. And I don't think that they've done as great a job as they could in all of these trials describing exactly what happens to these patients. So in the real world, obviously not everyone would be fit enough to go to surgery or might progress in the time between when they were diagnosed and the time as planned for surgery. But probably more of them would go to surgery if they weren't getting neoadjuvant treatment, because that would be their initial treatment. The question is, of course, is that the right choice? If someone gets 12 weeks or nine weeks of neoadjuvant treatment and then a restaging scan shows that they've had progression with metastatic disease, are those really the people that would have been optimally treated with surgery upfront, or would they just have had recurrence on their first postoperative scan? So, it's really an important question to answer. I think the bigger one is, is the treatment preventing them through toxicity from going to treatment? And I think the studies have generally felt that few patients are missing out on the option of surgery because of toxicity being caused by the IO. And in the AEGEAN study, for example, in this subgroup, a slightly numerically higher percentage of patients in the durvalumab arm actually underwent surgery compared to those who got neoadjuvant chemo. So, it doesn't seem like we're necessarily harming people with the neoadjuvant treatment. But I know that this is a concern for patients and doctors who are undergoing this approach. Dr. Vamsi Velcheti: Definitely, I think having multiple data sets from perioperative trials, looking at the relative impact of IO on the safety and the nature of the surgery is going to be important, and this is a very important study for that reason. Dr. Nathan Pennell: Can I ask you another thing that I thought really interesting about this particular one is they looked at the difference between those with single station N2 and multi station N2. And I know this is one of those, should we be operating on people who have multi station N2 disease? And the AEGEAN study did include people who had multiple N2 stations where perhaps in the pre-IO era, these would have been treated with definitive chemoradiation and not surgery at all. But the disease-free survival hazard ratio was essentially the same for multi station N2 as it was in the overall population. So, has that changed the way we're approaching these patients in these multidisciplinary discussions? Dr. Vamsi Velcheti: Absolutely, Nate. I think surgical operability is in the eye of the beholder. I think it depends on which surgeon sees the patient or how the discussion goes in the tumor boards, as you know. Certainly, I think with this optionality of having a chemo IO option and potential for downstaging, kind of pushes, at least in our practice, more of these patients who are multistation, who would have otherwise gone down the chemoradiation route are now actually going through neo adjuvant chemo IO and with the hope that they would make it to surgery. So, I think it's an interesting change in paradigm in managing our locally advanced patients. So, I think it's certainly interesting, but I guess to your point, there clearly are some patients who probably should just have chemoradiation upfront, and we may be kind of like delaying that definitive chemoradiation approach for at least a subset of patients. So, at the end of the day, I think it's a lot of clinical decision-making and I think there's going to be a little bit of art to managing these patients and it's going to be really hard to define that population for a clinical trial.  Dr. Nathan Pennell: Yeah, clearly, multidisciplinary discussion, still very important for earliest age non-small cell lung cancer patients. If we move back to metastatic lung cancer, let's talk about Abstract 8510 looking at one of our newer, exciting biomarkers, which are the KRASG12Cmutant non-small cell lung cancer. So this is a study of a second generation KRASG12Cinhibitor, olomorasib, which was combined with pembrolizumab, the anti PD-1 antibody, in patients with advanced KRASG12C mutant non-small cell lung cancer. This is something that has been tried before with first generation G12C inhibitors, with some concerns about how safe it was to do that. So, Vamsi, what did you learn from this abstract? Dr. Vamsi Velcheti: Definitely, I think one of the concerns that we've had in other trials is like the cumulative toxicity of adding checkpoint inhibition to G12C inhibitors, especially the sotorasib CodeBreaK trial, where we see increased rates of grade 3, 4 transaminitis. So, it is encouraging to see that some of the newer agents have less of those issues when it comes to combining the checkpoint inhibition. So especially with KRASG12C, as you know, these are patients who are smokers, and often these are patients who have high PDL-1 could potentially also benefit from immunotherapy. In order for these KRASG12C inhibitors, in order to move these targeted therapy options for these patients to the front line, I do think we need to have substantial comfort in combining the checkpoint inhibitors, which is a standard treatment approach for patients in the frontline setting. I think this is exciting, and I think they're also like, as you know, there are other KRASG12C inhibitors also looking to combine with checkpoint inhibition in the frontline settings. So, we'll have to kind of wait and see how the other agents will perform in the setting. Dr. Nathan Pennell: Yeah, I completely agree. I think this is such an important area to explore specifically because unlike our other targeted oncogenes like EGFR and ALK, we have multiple options for these patients, both immunotherapy and targeted treatments. And if we could think about sequencing them or even combining them and if it could be done safely, I think that would be well worth investigating. There still was significant toxicity in this trial; 30% of people had diarrhea, even at the reduced dose, and there was transaminitis at sort of about 20% or so, although probably at a manageable level. But the response rate was really quite promising. And these are all previously IO and mostly G12C TKI pre-treated patients still had a response rate of 63%. And in those who were naive to IO and TKIs, it was 78% response rate. So, if it could be done safely, I think it's definitely worth pursuing this in further trials. Dr. Vamsi Velcheti: And also, there's some data, preclinical data, like looking at G12C inhibition. And also we have known with MET inhibition for a long time that it could potentially augment immune responses and could be having some synergistic effect with IO. So, we'll have to wait and see, I think. But safety is really the top in mind when it comes to combining these agents with checkpoint inhibitors. So, it's really encouraging to see that some of the newer agents may be more combinable IO. Now moving on to the next abstract, and moving on to, again, the early-stage setting. So, Abstract 8052 from our colleagues in Princess Margaret reported outcomes in early-stage non- small cell lung cancer in patients with rare targetable mutation. This is actually becoming increasingly more relevant because we are seeing at least, like with the ALINA data, with the ALK and EGFR, now with ADAURA, we know that these patients don't benefit with adjuvant immunotherapy, especially some of these rare oncogene living mutations, other than like G12C. So I always struggle with this. When you have early-stage patients, with, let's say, a ROS or a RET, where we just don't have data, and we know that those are poor actors because biologically these are aggressive tumors. So, there's a really odd clinical question to ask in terms of, what is the role of adjuvant immunotherapy? Of course, this trial and this abstract are not really addressing that. But what is your take on this abstract? If you could just summarize the abstract for us. Dr. Nathan Pennell: Sure. Well, I think this is incredibly important, and this is an area near and dear to my own heart. And that is, of course, the whole landscape of how we manage early-stage patients has changed with both ADAURA, because we now have effective treatment in the adjuvant setting for EGFR mutant patients, and now more recently with the ALINA trial for adjuvant alectinib for ALK positive patients now being FDA-approved. So, what that means is we actually have to be testing people at diagnosis even before they would be getting adjuvant treatment, and potentially before even surgery to look for these targets. We need the PD-L1 status, we need EGFR and ALK. And if you're going to be looking at these biomarkers, I think there is a reasonable argument to be made that you should be doing broad testing for all of the targetable oncogenes in these patients. There are some studies suggesting that there's value to this and identifying them for treatment at the time of recurrence. But we also know that these patients are at high risk of recurrence and probably need to be investigated, at least in trials for the adjuvant setting. So, this particular study looked at 201 resected, mostly adenocarcinoma patients, and then they basically sequenced them for all of the targeted oncogenes. And they were quite common, perhaps even more common than you might expect in an advanced population. So, 43% of them had KRASG12C mutations, 13% had EGFR Exon 20 mutation, ERBB2 or HER2 mutations found in 11%, MET mutations in 10%, ALK in 7%, ROS1 in 6%, BRAF in 5%, and RET in 2%. So quite common to find these targetable oncogenes in this particular population, perhaps a somewhat biased population at Princess Margaret Hospital, but very common. And then they looked at the outcomes of these patients without targeted adjuvant treatment. And what they found was there was a very high rate of recurrence. So, relapse-free survival was pretty high in these patients across different stages, and generally their prognosis was worse than the more common KRASG12C patients. Most of these, in particular the HER2 mutant patients, seem to have a significantly worse relapse free survival. Interestingly enough, though, that did not carry over to overall survival. Overall survival was better in those who had targetable oncogenes. And my guess is that that probably had to do with the availability of targeted treatments at the time of recurrence that may have impacted overall survival. But I do think that this particularly highlights the need, the unmet need for effective adjuvant treatment in these patients. And most of them, with the exception of KRAS and perhaps BRAF, perhaps MET unlikely to benefit from adjuvant immunotherapy, as you mentioned. And so, I think we really need to be investing in trials of adjuvant targeted treatments in these populations.  Dr. Vamsi Velcheti: Yeah, this is an area that we really don't have a lot of data. But Nate, a question for you. So tomorrow you have a patient with RET fusion, stage 2, N1 disease. What would you do? Would you offer them an adjuvant RET inhibitor? Dr. Nathan Pennell: I think I would search really hard for a trial to give them access. But if you really want to know what I think, and I'm usually willing to tell people what I think, I think the proof of concept is there. I think we know that in the setting of highly effective and very tolerable adjuvant targeted treatment in the EGFR space with osimertinib, in the ALK space with alectinib, if anything, drugs like selpercatinib and pralsetinib in RET fusion positive lung cancer in the advanced setting are just as well tolerated and easily as effective and long lasting. And so, I think if you did a trial and they are doing trials looking at these drugs in the adjuvant space, almost certainly you're going to see the same really dramatic disease-free survival benefit from these treatments, which, at least in the EGFR space, seems to have translated into an improvement in overall survival. And so if I had a stage II or a resected stage 3, especially a RET fusion positive patient today, I would definitely talk to them about off-label use of a RET inhibitor if I could not find a trial. Now, I understand that there are going to be reimbursement issues and whatnot associated with that, but I think the extrapolation is worth discussing. Dr. Vamsi Velcheti: Yeah, I think it's really challenging because some of these fusions are so rare and it's hard to really do large adjuvant trials for some of these rarer subgroups. Nate, fascinating insights. Our listeners will find links to the abstracts we discussed today in the transcript of the episode. And Nate, I look forward to catching up with you at the Annual Meeting, and again after the meeting for our wrap up podcast to discuss the practice-changing lung cancer abstracts and highlights from the Plenary Session. Thank you so much for joining us and sharing your insights today. Dr. Nathan Pennell: Thanks for inviting me. Vamsi. I look forward to touching base after we get to see all the late-breaking abstracts. Like I said, this is, I think, a year for lung cancer with a lot of exciting data, and I know we'll have a lot to talk about. Dr. Vamsi Velcheti And thank you so much to all our listeners for your time. If you value the insights that you hear from the ASCO Daily News Podcast, please take a moment to rate and review and subscribe wherever you get your podcast.   Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.   Find out more about today's speakers: Dr. Vamsi Velcheti @VamsiVelcheti   Dr. Nathan Pennell @n8pennell   Follow ASCO on social media:   @ASCO on Twitter   ASCO on Facebook   ASCO on LinkedIn     Disclosures: Dr. Vamsi Velcheti: Honoraria: ITeos Therapeutics Consulting or Advisory Role: Bristol-Myers Squibb, Merck, Foundation Medicine, AstraZeneca/MedImmune, Novartis, Lilly, EMD Serono, GSK, Amgen, Elevation Oncology, Taiho Oncology, Merus Research Funding (Inst.): Genentech, Trovagene, Eisai, OncoPlex Diagnostics, Alkermes, NantOmics, Genoptix, Altor BioScience, Merck, Bristol-Myers Squibb, Atreca, Heat Biologics, Leap Therapeutics, RSIP Vision, GlaxoSmithKline   Dr. Nathan Pennell:   Consulting or Advisory Role: AstraZeneca, Lilly, Cota Healthcare, Merck, Bristol-Myers Squibb, Genentech, Amgen, G1 Therapeutics, Pfizer, Boehringer Ingelheim, Viosera, Xencor, Mirati Therapeutics, Janssen Oncology, Sanofi/Regeneron  Research Funding (Inst): Genentech, AstraZeneca, Merck, Loxo, Altor BioScience, Spectrum Pharmaceuticals, Bristol-Myers Squibb, Jounce Therapeutics, Mirati Therapeutics, Heat Biologics, WindMIL, Sanofi 

BUFFALO, NY- May 22, 2024 – A new research paper was published in Oncotarget's Volume 15 on May 17, 2024, entitled, “GZ17-6.02 kills PDX isolates of uveal melanoma.” In this new study, researchers Laurence Booth, Jane L. Roberts, Ivan Spasojevic, Kaitlyn C. Baker, Andrew Poklepovic, Cameron West, John M. Kirkwood, and Paul Dent from Virginia Commonwealth University, Duke University School of Medicine, Genzada Pharmaceuticals, Texas Tech University Health Sciences Center, and University of Pittsburgh Cancer Institute defined the biology of GZ17-6.02 in UM cells and in parallel determined its interaction with irreversible ERBB inhibitors (afatinib, neratinib) and with the cytotoxic agent doxorubicin. “GZ17-6.02 is a novel compound, containing the synthetically manufactured components: curcumin, harmine and isovanillin and has undergone phase I safety evaluation in cancer patients (NCT03775525).” GZ17-6.02 has undergone phase I evaluation in patients with solid tumors (NCT03775525). The RP2D is 375 mg PO BID, with an uveal melanoma patient exhibiting a 15% reduction in tumor mass for 5 months at this dose. Studies in this manuscript have defined the biology of GZ17-6.02 in PDX isolates of uveal melanoma cells. GZ17-6.02 killed uveal melanoma cells through multiple convergent signals including enhanced ATM-AMPK-mTORC1 activity, inactivation of YAP/TAZ and inactivation of eIF2α. GZ17-6.02 significantly enhanced the expression of BAP1, predictive to reduce metastasis, and reduced the levels of ERBB family RTKs, predicted to reduce growth. GZ17-6.02 interacted with doxorubicin or ERBB family inhibitors to significantly enhance tumor cell killing which was associated with greater levels of autophagosome formation and autophagic flux. Knock down of Beclin1, ATG5 or eIF2α were more protective than knock down of ATM, AMPKα, CD95 or FADD, however, over-expression of FLIP-s provided greater protection compared to knock down of CD95 or FADD. Expression of activated forms of mTOR and STAT3 significantly reduced tumor cell killing. GZ17-6.02 reduced the expression of PD-L1 in uveal melanoma cells to a similar extent as observed in cutaneous melanoma cells whereas it was less effective at enhancing the levels of MHCA. The components of GZ17-6.02 were detected in tumors using a syngeneic tumor model. “Our data support future testing GZ17-6.02 in uveal melanoma as a single agent, in combination with ERBB family inhibitors, in combination with cytotoxic drugs, or with an anti-PD1 immunotherapy.” DOI - https://doi.org/10.18632/oncotarget.28586 Correspondence to - Paul Dent - paul.dent@vcuhealth.org Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28586 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - cancer, autophagy, ER stress, GZ17-6.02, doxorubicin, afatinib, neratinib About Oncotarget Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science. Oncotarget is indexed and archived by PubMed/Medline, PubMed Central, Scopus, EMBASE, META (Chan Zuckerberg Initiative) (2018-2022), and Dimensions (Digital Science). To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: Facebook - https://www.facebook.com/Oncotarget/ X - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Spotify - https://open.spotify.com/show/0gRwT6BqYWJzxzmjPJwtVh MEDIA@IMPACTJOURNALS.COM

Featuring a slide presentation and related discussion from Dr Sunnie Kim, including the following topics: Year in Review: Novel Treatments and Strategies in Gastroesophageal Cancer — Dr Kim (0:00) Case: A man in his mid 50s with poorly differentiated mismatch repair-deficient advanced gastric cancer receives first-line nivolumab/ipilimumab (49:22) Case: A man in his early 70s with HER2-positive gastroesophageal junction (GEJ) adenocarcinoma who experienced disease progression on FOLFOX/trastuzumab receives trastuzumab deruxtecan (54:48) Case: A man in his mid 60s with Stage IV, PD-L1-positive GEJ adenocarcinoma (58:11) Case: A man in his early 40s with metastatic CLDN18.2-positive gastric/GEJ adenocarcinoma receives zolbetuximab (1:01:10) CME information and select publications

Doctors Vamsi Velcheti, Sandip Patel, and Michael Zervos discuss recent updates on the management of early-stage non-small cell lung cancer (NSCLC), including the optimization of neoadjuvant and adjuvant treatment options for patients and the role of surgery in the era of targeted therapy and immuno-oncology in lung cancer. TRANSCRIPT Dr. Vamsi Velcheti: Hello, I'm Dr. Vamsi Velcheti, your guest host for the ASCO Daily News Podcast today. I am a professor of medicine and director of thoracic medical oncology at the Perlmutter Cancer Center at NYU Langone Health. On today's episode, we'll be discussing recent updates on the management of early-stage non-small cell lung cancer (NSCLC), including the optimization of neoadjuvant and adjuvant treatment options for our patients, and the evolving role of surgery in the era of targeted therapy and immuno-oncology in lung cancer.  Today, I am delighted to be joined by two renowned experts in this space, Dr. Sandip Patel and Dr. Michael Zervos. Dr. Patel is a professor of medicine and a medical oncologist specializing in lung cancer at UCSD. Dr. Mike Zervos is the clinical chief of the Division of Robotic Thoracic Surgery and Director of General Thoracic Surgery at NYU Langone. Our full disclosures are available in the transcript of this episode, and disclosures relating to all episodes of the podcast are available at asco.org/DNpod. Dr. Patel and Dr. Zervos, it's a great honor to have you on the podcast today. Welcome aboard. Dr. Sandip Patel: Great to be joining you.  Dr. Vamsi Velcheti:  Let's get started with Dr. Patel. As you know, over the last decade we've had dramatic advances in systemic therapy options for patients with metastatic non-small cell lung cancer, in both the realms of targeted therapy and immunotherapy. These have significantly improved outcomes for our patients with metastatic lung cancer. What's exciting is that more recently, we've seen the incorporation of these agents, both targeted therapies and immunotherapies, in early-stage non-small cell lung cancer. Dr. Patel, can you tell our listeners about these exciting recent advances and why do you think it's so important to incorporate these personalized systemic therapy options for our early-stage patients? Dr. Sandip Patel: I think it's a great point and a great question. And so, I think one thing to understand is that non-small cell lung cancer is actually multiple diseases. We give it one name based on how it looks under the microscope, but the vast majority of our advances to improve outcomes for patients have come from our ability to understand specific subgroups.  Many of our therapies have had activity in the advanced setting. We have our patients with metastatic or more widespread disease, which naturally led to the thought that could we utilize these therapies in earlier stage disease and potentially increase the rate of cure for many of our patients, lung cancer being the most common cancer killer worldwide. And so to your point, trying to understand how to best treat a patient really involves personalized medicine, typically driven by understanding the genomic profile of their tumor and two of the genes that have graduated from being tested for in the metastatic setting and now in the localized setting are EGFR and ALK. And these in particular are mutations that confer sensitivity to small molecule inhibitors, EGFR with osimertinib, ALK in the localized setting with alectinib based on the data that we've seen.  And so, one of the areas that's been particularly exciting is our ability to maximize a patient's chance for durable remissions by integrating these therapies after surgery, after chemotherapy when appropriate, and continuing generally for a finite amount of time, two to three years depending on the agent in the study we're discussing for these patients. Additionally, immunotherapy, which has revolutionized our treatment of patients with metastatic disease, may be particularly well-suited for the localized setting of non-small cell lung cancer as well. Dr. Vamsi Velcheti: Excellent points, Sandip. You're absolutely right, in the metastatic setting, we've all come to accept molecular testing, sequencing, and biomarker profiling as a standard, but unfortunately, that hasn't quite yet percolated into the early-stage setting. Can you talk about some of the challenges that we face as we have these therapeutic options available now for more early-stage patients? Dr. Sandip Patel: So, I think there are 3 flavors of localized therapy in non-small cell lung cancer. One is the advanced, unresectable stage 3, for which the approach is often concurrent chemo-radiation followed by some form of consolidated therapy. We're about to hear the results of LAURA, which is the study looking at EGFR-mutated non-small cell lung cancer.  For other patients, historically, the treatment has been durvalumab, an anti-PD-L1 directed immunotherapy. The other two are operative treatment of localized cancer: adjuvant treatment after surgery, or neoadjuvant or perioperative, in which chemoimmunotherapy begins before surgery. And testing depends on the settings. For the stage 3 patient who's likely getting concurrent chemo-radiation, they may have a very small amount of tissue, and so often these are done by pulmonary EBUS biopsies and that's how we pathologically confirm that advanced stage 3B. There may not be a lot of tissue available for molecular testing. In fact, if you look at the PACIFIC analysis, just looking at PD-L1, which is just an IHC off a single slide, a third of patients weren't able to even get a PD-L1, let alone a genomic result. And so, I think that's one of the areas of LAURA that's going to be particularly interesting to see as we try to implement it into our practice after seeing the full data.  I think in the adjuvant setting, we're lucky because our surgeons, Dr. Mike Zervos here, will get us a large amount of tissue in the surgical resection specimen, so we tend to get enough tissue to do genomics while they're under chemotherapy, there tends to be time to wait for their genomic result. Where this really gets complicated is in the neoadjuvant or perioperative setting, where time is everything.  The most important thing we can do for a patient in the localized space is get them to the operating room, get them started on radiation, their curative local modality, and that's where we have a time pressure but also a sample pressure because that is a diagnostic biopsy. It's a very small piece of tissue. Initially, there are multiple stains that have to be done to identify this lung cancer as opposed to another tumor. And so that's an area that I think we're going to need additional approaches given that cell-free DNA tends to have lower yield in lower stage disease in giving us a result. Dr. Vamsi Velcheti: Great points, Sandip. How do you deal with this issue in San Diego? The challenge is now we have a lot of trials, we'll talk about those neoadjuvant immunotherapy trials, but we know that immunotherapy may not be as effective in all patients, especially those with EGFR or ALK or some of these non-smoker, oncogene-driven tumors. So, we don't want to be giving patients treatments that may not necessarily be effective in the neoadjuvant space, especially when there is a time crunch, and we want to get them to surgery and all the complications that come with giving them targeted therapy post-IO with potential risk for adverse events. Dr. Sandip Patel: Absolutely. It is a great point. And so, the multidisciplinary team approach is key, and having a close relationship with the interventional pulmonary oncs, interventional radiology surgery, and radiation oncology to ensure that we get the best treatment for our patients. With the molecularly guided therapies, they are currently more on the adjuvant setting in terms of actually treating. But as you mentioned, when we're making a decision around neoadjuvant or perioperative chemo IO, it's actually the absence of EGFR now that we're looking for because our intervention at the current time is to give chemoimmunotherapy. Going back to the future, we used to use single gene EGFR within 24 hours, which was insufficient for a metastatic panel, but it often required five slides of tissue input. ALK can be done by IHC, and so some of these ‘oldie but goodie' pathologic techniques, and that pathologists, if I haven't emphasized, understanding what we're trying to do at a different context is so key because they are the ones who really hold the result. In the neoadjuvant and perioperative setting, which many of us favor, especially for stage 3A and stage 2B disease, understanding how we can get that result so that we can get the patient to the operating room in an expeditious way is so important. There is a time pressure that we always had in the metastatic setting, but I think we feel much more acutely in the neoadjuvant and perioperative setting in my opinion. Dr. Vamsi Velcheti: Fascinating insights, Dr. Patel.  Turning to Dr. Zervos, from a surgical perspective, there has been an evolution in terms of minimally invasive techniques, robotic approaches, and enhanced recovery protocols, significantly improving outcomes in our patients post-surgery. How do you see the role of surgery evolving, especially with the increasing complexity and efficacy of these systemic therapies? How do you envision the role of surgery in managing these early-stage patients, and what are the key considerations for surgeons in this new era? Dr. Michael Zervos: Thanks, Vamsi. Thanks, Sandip. Thank you for having me on the podcast. Obviously, it's an honor to be a part of such a high-level discussion. I have to say, from a surgeon's perspective, we often listen to you guys talk and realize that there's been a lot of change in this landscape. And I think the thing that I've seen is that the paradigm here has also changed. If we were having this discussion 10 years ago, a lot of the patients that I am operating on now, I would not be operating on. It really has been amazing. And I think the thing that stands out to me the most is how all of this has changed with neoadjuvant chemotherapy checkpoint inhibition. I think, for us as surgeons, that's really been the key. Whether it's CheckMate 816 or whatever you're following, like PACIFIC, the data supports this. And I think what we're seeing is that we're able to do the surgery, we're able to do it safely, and I think that the resectability rates are definitely high up there in the 90% range. And what we're seeing is pretty significant pathologic responses, which I think is really amazing to me.  We're also seeing that this has now shifted over to the oligometastatic realm, and a lot of those patients are also being treated similarly and then getting surgery, which is something that we would not have even thought of ever. When you look at the trials, I think a lot of the surgery, up to this point, has been done more traditionally. There's a specific reason why that happens, specifically, more through thoracotomy, less with VATS, and less with robotic. Sandip, I think you guys have a pretty robust robotic program at UCSD, so I'm sure you're pretty used to seeing that.   As you guys have become so much more sophisticated with the treatments, we have also had to modify what we do operatively to be able to step up to the plate and accept that challenge. But what we are seeing is yes, these treatments work, but the surgeries are slightly more complicated. And when I say slightly, I'm minimizing that a little bit.  And what's complicated about it is that the treatment effect is that the chemo-immune check inhibition actually has a significant response to the tumor antigen, which is the tumor. So it's going to necrose it, it's going to fibrose it, and wherever there is a tumor, that response on the surgical baseline level is going to be significant. In other words, there are going to be lymph nodes that are stuck to the pulmonary artery, lymph nodes that are stuck to the airway, and we've had to modify our approaches to be able to address that.   Now, fortunately, we've been able to innovate and use the existing technology to our advantage. Personally, I think robotics is the way we have progressed with all this, and we are doing these surgeries robotically, mainly because I think it is allowing us, not only to visualize things better, but to have sort of a better understanding of what we're looking at. And for that matter, we are able to do a better lymph node dissection, which is usually the key with a lot of these more complicated surgeries, and then really venturing out into more complicated things, like controlling the pulmonary artery. How do we address all this without having significant complications or injuries during the surgery? Getting these patients through after they've successfully completed their neoadjuvant treatment, getting them to surgery, doing the surgery successfully, and hopefully, with minimal to no morbidity, because at the end, they may be going on to further adjuvant treatment. All of these things I think are super important. I think although it has changed the landscape of how we think of things, it has made it slightly more complicated, but we are up for the challenge. I am definitely excited about all of this. Dr. Vamsi Velcheti: For some reason, like medical oncologists, we only get fixated on the drugs and how much better we're doing, but we don't really talk much about the advances in surgery and the advances in terms of outcomes, like post-op mortality has gone down significantly, especially in larger tertiary care centers. So, our way of thinking, traditionally, the whole intergroup trials, the whole paradigm of pneumonectomies being bad and bad outcomes overall, I think we can't judge and decide on current treatment standards based on surgical standards from decades ago. And I think that's really important to recognize.  Dr. Michael Zervos: All of this stuff has really changed over the past 10 years, and I think technology has helped us evolve over time. And as the science has evolved for you with the clinical trials, the technology has evolved for us to be able to compensate for that and to be able to deal with that. The data is real for this. Personally, what I'm seeing is that the data is better for this than it was for the old intergroup trials. We're able to do the surgery in a better, more efficient, and safer way. The majority of these surgeries for this are not going to be pneumonectomies, they are going to be mostly lobectomies. I think that makes sense. I think for the surgeons who might be listening, it doesn't really matter how you're actually doing these operations. I think if you don't have a very extensive minimally invasive or robotic experience, doing the surgery as open is fine, as long as you're doing the surgery safely and doing it to the standard that you might expect with complete lymph node clearance, mediastinal lymph node clearance, and intrapulmonary lymph node clearance. Really, I think that's where we have to sort of drive home the point, really less about the actual approach, even though our bias is to do it robotically because we feel it's less morbidity for the patient. The patients will recover faster from the treatment and then be able to go on to the next phase treatments. Dr. Vamsi Velcheti: In some of the pre-operative trials, the neoadjuvant trials, there have been some concerns raised about 20% of patients not being able to make it to surgery after induction chemo immunotherapy. Can you comment on that, and why do you think that is the case, Sandip?  Dr. Sandip Patel: Well, I think there are multiple reasons. If you look, about half due to progression of disease, which they might not have been great operative candidates to begin with, because they would have early progression afterwards. And some small minority in a given study, maybe 1% to 2%, it's an immune-related adverse event that's severe. So, it's something that we definitely need to think about. The flip side of that coin, only about 2 in 3 patients get adjuvant therapy, whether it be chemotherapy, immunotherapy, or targeted therapy. And so, our goal is to deliver a full multimodal package, where, of course, the local therapy is hugely important, but also many of these other molecular or immunologically guided agents have a substantial impact.  And I do think the point around neoadjuvant and perioperative is well taken. I think this is a discussion we have to have with our patients. I think, in particular, when you look at higher stage disease, like stage 3A, for example, the risk-benefit calculus of giving therapy upfront given the really phenomenal outcomes we have seen, really frankly starting with the NADIM study, CheckMate816, now moving on into studies like KEYNOTE-671, AEGEAN, it really opens your eyes in stage 3. Now, for someone who's stage 1/1b, is this a patient who's eager to get a tumor out? Is there as much of an impact when we give neoadjuvant therapy, especially if they're not going to respond and may progress from stage 1 and beyond? I think that's a reasonable concern. How to handle stage II is very heterogeneous. I think two points that kind of happen as you give neoadjuvant therapy, especially chemo-IO that I think is worth for folks to understand and this goes to Mike's earlier point, that is this concept if they do get a scan during your neoadjuvant chemo immunotherapy, there is a chance of that nodal flare, where the lymph nodes actually look worse and look like their disease is progressing. Their primary tumor may be smaller or maybe the same. But when we actually go to the OR, those lymph nodes are chock-full of immune cells. There's actually no cancer in those lymph nodes. And so that's a bit of a red herring to watch out for.   And so, I think as we're learning together how to deliver these therapies, because the curative-intent modality is, in my opinion, a local modality. It's what Mike does in the OR, my colleagues here do in the OR. My goal is to maximize the chance of that or really maximize the long-term cure rates. And we know, even as long as the surgery can go, if only 2 or 3 patients are going to get adjuvant therapy then 1 in 10, of which half of those or 1 in 20, are not getting the surgery and that's, of course, a big problem. It's a concern. I think better selecting towards those patients and thinking about how to make these choices is going to be hugely important as we go over. Because in a clinical trial, it's a very selective population. A real-world use of these treatments is different. I think one cautionary tale is that we don't have an approval for the use of neoadjuvant or perioperative therapy for conversion therapy, meaning, someone who's “borderline resectable.” At the time at which you meet the patient, they will be resectable at that moment. That's where our best evidence is, at the current time, for neoadjuvant or perioperative approaches.  Dr. Vamsi Velcheti:   I think the other major issue is like the optimal sequencing of immune checkpoint here. Obviously, at this point, we have multiple different trial readouts, and there are some options that patients can have just neoadjuvant without any adjuvant. Still, we have to figure out how to de-escalate post-surgery immunotherapy interventions. And I think there's a lot of work that needs to be done, and you're certainly involved in some of those exciting clinical trials. What do you do right now in your current clinical practice when you have patients who have a complete pathologic response to neoadjuvant immunotherapy? What is the discussion you have with your patients at that point? Do they need more immunotherapy, or are you ready to de-escalate?  Dr. Sandip Patel: I think MRD-based technologies, cell-free DNA technologies will hopefully help us guide this. Right now, we are flying blind along two axes. One is we don't actually know the contribution of the post-operative component for patients who get preoperative chemo-IO. And so this is actually going to be an ongoing discussion. And for a patient with a pCR, we know the outcomes are really quite good based on CheckMate816, which is a pure neoadjuvant or front-end only approach. Where I actually struggle is where patients who maybe have 50% tumor killing. If a patient has only 10% tumor killing ... the analogy I think in clinic is a traffic light, so the green light if you got a pCR, a yellow light if you have that anywhere from 20%-70% residual viable tumor, and then anything greater than that, you didn't get that much with chemo-IO and you're wondering if getting more chemo-IO, what would that actually do? It's a bit of a red light. And I'm curious, we don't have any data, but my guess would be the benefit of the post-op IO is because patients are in that kind of yellow light zone. So maybe a couple more cycles, we'll get them an even more durable response. But I am curious if we're going to start relying more on MRD-based technologies to define treatment duration. But I think it's a very complicated problem. I think folks want to balance toxicity, both medical and financial, with delivering a curative-intent therapy. And I am curious if this maybe, as we're looking at some of the data, some of the reasons around preferring a perioperative approach where you scale it back, as opposed to a neoadjuvant-only approach where there's not a clean way to add on therapy, if you think that makes sense. But it's probably the most complicated discussions we have in clinic and the discussion around a non-pCR. And frankly, even the tumor board discussions around localized non-small cell lung cancer have gone very complex, for the benefit of our patients, though we just don't have clean data to say this is the right path.   Dr. Vamsi Velcheti: I think that the need for a really true multidisciplinary approach and discussing these patients in the tumor board has never been more significant. Large academic centers, we have the luxury of having all the expertise on hand. How do we scale this approach to the broader community is a big challenge, I think, especially in early-stage patients. Of course, not everyone can travel to Dr. Zervos or you for care at a large tertiary cancer centers. So, I think there needs to be a lot of effort in terms of trying to educate community surgeons, community oncologists on managing these patients. I think it's going to be a challenge. Dr. Michael Zervos: If I could just add one thing here, and I completely agree with everything that has been said. I think the challenge is knowing beforehand. Could you predict which patients are going to have a complete response? And for that matter, say, “Okay. Well, this one has a complete response. Do we necessarily need to operate on this patient?” And that's really the big question that I add. I personally have seen some complete response, but what I'm mostly seeing is major pathologic response, not necessarily CR, but we are seeing more and more CR, I do have to say. The question is how are you going to predict that? Is looking for minimal residual disease after treatment going to be the way to do that? If you guys could speak to that, I think that is just tremendously interesting.  Dr. Vamsi Velcheti: I think as Sandip said, MRD is looking very promising, but I just want to caution that it's not ready for primetime clinical decision making yet. I am really excited about the MRD approach of selecting patients for de-escalation or escalation and surgery or no surgery. I think this is probably not quite there yet in terms of surgery or no surgery decision. Especially for patients who have early-stage cancer, we talk about curative-intent treatment here and surgery is a curative treatment, and not going to surgery is going to be a heavy lift. And I don't think we're anywhere close to that. Yet, I'm glad that we are having those discussions, but I think it may be too hard at this point based on the available technologies to kind of predict CR. We're not there.  Dr. Michael Zervos: Can I ask you guys what your thought process is for evaluating the patient? So, when you're actually thinking about, “Hey, this patient actually had a good response. I'm going to ask the surgeons to come and take a look at this.” What imaging studies are you actually using? Are you just using strictly CT or are you looking for the PET? Should we also be thinking about restaging a lot of these patients? Because obviously, one of the things that I hate as a surgeon is getting into the operating room only to find out that I have multiple nodal stations that are positive. Which really, in my opinion, that's sort of a red flag. And for me, if I have that, I'm thinking more along the lines of not completing that surgery because I'm concerned about not being able to provide an R0 resection or even having surgical staple lines within proximity of cancer, which is not going to be good. It's going to be fraught with complications.  So, a lot of the things that we as surgeons struggle with have to do with this. Personally, I like to evaluate the patients with an IV intravenous CT scan to get a better idea of the nodal involvement, proximity to major blood vessels, and potentially even a PET scan. And though I think in this day and age, a lot of the patients will get the PET beforehand, not necessarily get it approved afterwards. So that's a challenge. And then the one thing I do have to say that I definitely have found helpful is, if there's any question, doing the restaging or the re-EBUS at that point to be particularly helpful.  Dr. Sandip Patel: Yeah, I would concur that having that pathologic nodal assessment is probably one of the most important things we can do for our patients. For a patient with multinodal positive disease, the honest truth is that at our tumor board, that patient is probably going to get definitive chemoradiation followed by their immunotherapy, or potentially soon, if they have an EGFR mutation, osimertinib. For those patients who are clean in the mediastinum and then potentially have nodal flare, oftentimes what our surgeons will do as the first stage of the operation, they'll actually have the EBUS repeated during that same anesthesia session and then go straight into surgery. And so far the vast majority of those patients have proceeded to go to surgery because all we found are immune cells in those lymph nodes.  So, I think it's a great point that it's really the pathologic staging that's driving this and having a close relationship with our pathologists is key. But I think one point that I think we all could agree on is the way that we're going to find more of these patients to help and cure with these therapies is through improved utilization of low-dose CT screening in the appropriate population in primary care. And so, getting buy-in from our primary care doctors so that they can do the appropriate low-dose CT screening along with smoking cessation, and find these patients so that we can offer them these therapies, I think is something that we really, as a community, need to advocate on. Because a lot of what we do with next-generation therapies, at least on the medical oncology side, is kind of preaching to the choir. But getting the buy-in so we can find more of these cases at stage 1, 2 or 3, as opposed to stage 4, I think, is one of the ways we can really make a positive impact for patients. Dr. Vamsi Velcheti: I just want to go back to Mike's point about the nodal, especially for those with nodal multistation disease. In my opinion, those anatomic unresectability is a moving target, especially with evolving, improving systemic therapy options. The utilization for chemo radiation has actually gone down. I think that's a different clinical subgroup that we need to kind of think differently in terms of how we do the next iteration or generation of clinical trials, are they really benefiting from chemo-IO induction? And maybe we can get a subset of those patients in surgery. I personally think surgery is probably a more optimal, higher yield to potentially cure these patients versus chemo radiation. But I think how we identify those patients is a big challenge. And maybe we should do a sequential approach induction chemo-IO with the intent to kind of restage them for surgery. And if they don't, they go to chemo consolidation radiation, I guess. So, I think we need to rethink our approach to those anatomically unresectable stage 3s. But I think it's fascinating that we're having these discussions. You know, we've come to accept chemo radiation as a gold standard, but now we're kind of challenging those assumptions, and I think that means we're really doing well in terms of systemic therapy options for our patients to drive increased cures for these patients. Dr. Michael Zervos: I think from my perspective as a surgeon, if I'm looking at a CT scan and trying to evaluate whether a patient is resectable or not, one of the things that I'm looking for is the extent of the tumor, proximity to mediastinal invasion, lymph nodes size. But if that particular patient is resectable upfront, then usually, that patient that receives induction chemo checkpoint inhibition is going to be resectable afterwards. The ones that are harder are the ones that are borderline resectable upfront or not resectable. And then you're trying to figure out on the back end whether you can actually do the surgery.  Fortunately, we're not really taking many patients to the operating room under those circumstances to find that they're not resectable. Having said that, I did have one of those cases recently where I got in there and there were multiple lymph node stations that were positive. And I have to say that the CT really underestimated the extent of disease that I saw in the operating room. So, there are some challenges surrounding all of these things. Dr. Sandip Patel: Absolutely. And I think for those patients, if upfront identification by EBUS showed multi nodal involvement, we've had excellent outcomes by working with radiation oncologists using modern radiotherapy techniques, with concurrent chemo radiation, followed by their immunotherapy, more targeted therapy, at least it looks like soon. I think finding the right path for the patient is so key, and I think getting that mediastinal pathologic assessment, as opposed to just guessing based on what the PET CT looks like, is so important. If you look at some of the series, 8% to 10% of patients will get a false-positive PET on their mediastinal lymph nodes due to coccidioidomycosis or sarcoidosis or various other things. And the flip side is there's a false-negative rate as well. I think Mike summarized that as well, so I think imaging is helpful, but for me, imaging is really just pointing the target at where we need to get pathologic sampling, most commonly by EBUS. And getting our interventional pulmonary colleagues to help us do that, I think is so important because we have really nice therapeutic options, whether it's curative-intent surgery, curative-intent chemo radiation, where we as medical oncologists can really contribute to that curative-intent local therapy, in my opinion.  Dr. Vamsi Velcheti: Thank you so much Sandip and Mike, it's been an amazing and insightful discussion, with a really dynamic interplay between systemic therapy and surgical innovations. These are really exciting times for our patients and for us. Thank you so much for sharing your expertise and insights with us today on the ASCO Daily News Podcast.   I want to also thank our listeners today for your time. If you value the insights that you hear today, please take a moment to rate, review, and subscribe to the podcast wherever you get your podcasts. Thank you so much. [FH1]   Dr. Sandip Patel: Thank you. Dr. Michael Zervos: Thank you.   Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.   Follow today's speakers: Dr. Vamsidhar Velcheti @VamsiVelcheti Dr. Sandip Patel @PatelOncology Dr. Michael Zervos   Follow ASCO on social media: @ASCO on X (formerly Twitter) ASCO on Facebook ASCO on LinkedIn   Disclosures:  Dr. Vamsidhar Velcheti: Honoraria: ITeos Therapeutics Consulting or Advisory Role: Bristol-Myers Squibb, Merck, Foundation Medicine, AstraZeneca/MedImmune, Novartis, Lilly, EMD Serono, GSK, Amgen, Elevation Oncology, Taiho Oncology, Merus Research Funding (Inst.): Genentech, Trovagene, Eisai, OncoPlex Diagnostics, Alkermes, NantOmics, Genoptix, Altor BioScience, Merck, Bristol-Myers Squibb, Atreca, Heat Biologics, Leap Therapeutics, RSIP Vision, GlaxoSmithKline   Dr. Sandip Patel: Consulting or Advisory Role: Lilly, Novartis, Bristol-Myers Squibb, AstraZeneca/MedImmune, Nektar, Compugen, Illumina, Amgen, Certis, Eli Lilly, Roche/Genentech, Merck, Pfizer, Tempus, Iovance Biotherapeutics. Speakers' Bureau: Merck, Boehringer Ingelheim Research Funding (Inst.):Rubius, Bristol-Myers Squibb, Pfizer, Roche/Genentech, Amgen AstraZenece/MedImmune, Fate, Merck, Iovance, Takeda   Dr. Michael Zervos: No relationships to disclose

Immunotherapy is a type of novel cancer therapy that leverages the body's own immune system to target cancer cells. In this episode, we focused on the most common type of immunotherapy: immune checkpoint inhibitors or ICIs. ICIs are monoclonal antibodies targeting immune “checkpoints” or brakes to enhance T-cell recognition against tumors. ICI has become a pillar in cancer care, with over 100 approvals and 5,000 ongoing trials. ICIs can lead to non-specific activation of the immune system, causing off-target adverse events such as cardiotoxicities. ICI-related myocarditis, though less common, can be fatal in 30% of cases. Clinical manifestations vary but can include chest pain, dyspnea, palpitations, heart failure symptoms, and arrhythmias. Diagnosis involves echocardiography, cardiac MRI, and endomyocardial biopsy. Treatment includes high-dose corticosteroids with potential additional immunosuppressants. Baseline EKG and troponin are recommended before ICI initiation, but routine surveillance is not advised. Subclinical myocarditis is a challenge, with unclear management implications. So let's dive in and learn about cardiotoxicity of novel immunotherapies with Drs. Giselle Suero (series co-chair), Evelyn Song (episode FIT lead), Daniel Ambinder (CardioNerds co-founder), and Tomas Neilan (faculty expert). Audio editing by CardioNerds Academy Intern, Dr. Maryam Barkhordarian. This episode is supported by a grant from Pfizer Inc. This CardioNerds Cardio-Oncology series is a multi-institutional collaboration made possible by contributions of stellar fellow leads and expert faculty from several programs, led by series co-chairs, Dr. Giselle Suero Abreu, Dr. Dinu Balanescu, and Dr. Teodora Donisan.  CardioNerds Cardio-Oncology PageCardioNerds Episode PageCardioNerds AcademyCardionerds Healy Honor Roll CardioNerds Journal ClubSubscribe to The Heartbeat Newsletter!Check out CardioNerds SWAG!Become a CardioNerds Patron! Pearls and Quotes - Cardiotoxicity of Novel Immunotherapies Immune checkpoint inhibitors (ICI) play a crucial role in current oncology treatment by enhancing T-cell recognition against tumors. ICI-related cardiac immune-related adverse events (iRAEs) include myocarditis, heart failure, stress-cardiomyopathy, conduction abnormalities, venous thrombosis, pericardial disease, vasculitis, and atherosclerotic-related events. ICI myocarditis can be fatal; thus, prompt recognition and treatment is crucial. Management includes cessation of the ICI and treatment with corticosteroids and potentially other immunosuppressants. Close monitoring and collaboration with cardiology and oncology are crucial. Rechallenging patients with immunotherapies after developing an iRAE is controversial and requires careful consideration of risks and benefits, typically with the involvement of a multidisciplinary team. Show notes - Cardiotoxicity of Novel Immunotherapies What are immune checkpoint inhibitors (ICIs)? ICIs are monoclonal antibodies used to enhance the body's immune response against cancer cells. Currently, there are four main classes of FDA-approved ICIs: monoclonal antibodies blocking cytotoxic T lymphocyte antigen-4 (CTLA-4), programed cell death protein-1 (PD-1), lymphocyte-activation gene 3 (LAG3), and programmed cell death ligand-1 (PD-L1). ICIs can lead to non-specific activation of the immune system, potentially causing off-target adverse events in various organs, including the heart, leading to myocarditis.    The mechanisms of cardiac iRAEs are not fully understood, but they are believed to involve T-cell activation against cardiac antigens, which leads to inflammation and tissue damage.  What are the cardiotoxicities related to ICI therapies? ICI-related cardiac immune-related adverse events (iRAEs) include myocarditis, heart failure, stress-cardiomyopathy, conduction abnormalities, venous thrombosis, pericardial disease, vasculitis,

Welcome to another insightful episode of the Oncology Brothers podcast! In this episode, hosts Rahul and Rohit Gosain are joined by Dr. Sam Klempner, a medical oncologist specializing in upper GI malignancies. Together, they delve into the current treatment strategies for esophageal, GE junction, and gastric adenocarcinoma. The discussion covers a range of topics, including the evolving paradigms in neoadjuvant and adjuvant therapies, the importance of biomarker testing such as MSI and PD-L1, and the potential impact of new targets like Claudin 18.2 in upper GI cancers. Dr. Klempner also shares insights on the management of metastatic disease, including the role of targeted therapies like TDXD and Zolbetuximab. Whether you're a healthcare professional or simply interested in the latest advancements in oncology, this episode provides valuable information on the current landscape of upper GI malignancies. Stay informed and join the Oncology Brothers as they navigate the complexities of treating these challenging cancers. Don't miss out on this informative discussion! Tune in to the Oncology Brothers podcast for more expert insights and discussions on oncology topics. Remember to like, share, and subscribe for more content on the latest developments in cancer care. Thank you for listening!

Doctors James Ferriss, Linda Duska, and Jayanthi Lea discuss the promise and the challenges of targeting the immune system with immune checkpoint inhibitors, or ICIs, in cervical and endometrial cancers. They also examine emerging data that support the use of ICIs in recurrent cervical cancer, the potential for curing some patients with advanced endometrial cancer, and molecular factors that make cervical cancer a good target for immunotherapy. TRANSCRIPT Dr. James Stuart Ferriss: Hello, and welcome to the ASCO Daily News Podcast. I'm Dr. James Stuart Ferriss, your guest host of the ASCO Daily News Podcast today. I'm an associate professor of gynecology and obstetrics and the Gynecologic Oncology Fellowship Program Director at Johns Hopkins Medicine. In today's episode, we'll be discussing the use of immunotherapy in cervical and endometrial cancers to advance the treatment of these malignancies. I'm delighted to be joined by two acclaimed experts in this space, Dr. Linda Duska and Dr. Jaya Lea.   Dr. Duska is a professor of obstetrics and gynecology and serves as the associate dean for clinical research at the University of Virginia School of Medicine. Dr. Lea is a professor of obstetrics and gynecology and chief of gynecologic oncology at the University of Texas Southwestern Medical Center.  Our full disclosures are available in the transcript of this episode, and disclosures related to all episodes of the podcast are available at asco.org/DNpod. Drs. Duska and Dr. Lea, it's great to have you on the podcast today.  Dr. Linda Duska: Thanks, Dr. Ferriss.  Dr. Jayanthi Lea: Thanks, Dr. Ferriss.  Dr. James Stuart Ferriss: So, let's get started. In recent years, we've had a revolution in the treatment of advanced endometrial and cervical cancers with improved outcomes for patients treated with immunotherapy. And when we say immunotherapy, we're specifically talking about immune checkpoint inhibitors today. A few of these agents have actually been approved in the United States for the management of these diseases. In our discussion, I'd like to review the promise and challenges of targeting the immune system in patients with advanced endometrial and cervical cancers, as well as review the most recent evidence we have in these spaces.  Let's start with cervix. We've had a lot of improvements in outcomes here, Dr. Lea, and with cervical cancer, we've seen improved overall survival with the incorporation of immunotherapy along with chemotherapy and anti-angiogenic therapy for advanced and recurrent disease. Can you remind us why cervical cancer is a good target for immunotherapy?  Dr. Jayanthi Lea: Yes, Dr. Ferriss. Immunotherapy for cervical cancer is supported by several molecular factors. And I think first and foremost, it's so important to remember that the majority of cervical cancers are HPV-positive. And HPV-positive cancers can induce a high level of inflammation, but this high level of inflammation actually contributes to evasion of immune surveillance. What it also does is that it's responsible for the induction of PD-L1. And we've seen several studies that have shown that cervical cancers express PD-L1 anywhere from 50 to 90 percent of cases. Other pertinent factors to consider are that cervical cancer can be considered a tumor with a high tumor mutational burden. So, the number of somatic mutations that we see in the DNA can be considered as a proxy for neoantigens. And so the higher the level of neoantigens, the more immunogenic the tumor. And then lastly, about 1 in 10 cervical cancers present with microsatellite instability, which is an already established key biomarker for the response team in care.  Dr. James Stuart Ferriss: So, thinking about targeting PD-L1, what clinical evidence do we have that supports the use of immune checkpoint inhibitors in recurrent cervical cancer?  Dr. Jayanthi Lea: We now have several studies that have shown a benefit for immune checkpoint inhibitors. For example, KEYNOTE-158 was a phase 2 basket [trial] that investigated the antitumor activity of pembrolizumab, which is a PD-1 inhibitor, in multiple cancer types. And specifically for patients with previously treated advanced cervical cancer, we were able to see an overall response rate of about 15% in those patients who had PD-L1 positive. And similarly, the EMPOWER CERVICAL-1 study, which was a phase 3 randomized trial that investigated the efficacy of cemiplimab, which is another PD-1 inhibitor, versus investigator's choice of single agent chemotherapy, showed a significant difference in median overall survival and progression-free survival in the cemiplimab group. There are several other studies that have investigated the efficacy of PD-1 or PD-L1 inhibitors in cervical cancer. One specific PD-1 inhibitor is nivolumab. In CHECKMATE-358, nivolumab was associated with an overall response rate of 26% in women who had recurrent/metastatic cervical cancer.  Dr. James Stuart Ferriss: Dr. Duska, do you have any thoughts?  Dr. Linda Duska: I'm really interested in PD-L1 as a biomarker because in the KEYNOTE-A18 study, which we're going to get to, 95% of patients were PD-L1 positive by CPS, which is the scoring system that we use in cervix cancer. And some of the studies that you already mentioned, including BEATcc, which we're also going to talk about, reported results where PD-L1 wasn't even considered. And so it begs the question, since PD-L1 is actually – again, depending on when in the course of disease you look at it, but more recent studies suggest 95% of cervical cancers express PD-L1, and – agnostic is the word I was looking for – it seems at least in BEATcc and similar trials that PD-L1 is agnostic, but I wonder if PD-L1 is really a good biomarker for response to checkpoint inhibitor therapy and I wonder what your thoughts are.  Dr. Jayanthi Lea: I think that's an excellent question. To your point, that's correct that we saw in KETYNOTE-A18 that more than 90% of the patients had PD-L1 positivity and the result is sort of generalizable to all comers. That's still a matter of debate as to how we see PD-L1 as a biomarker to incorporate checkpoint inhibitors in the treatment of patients.  Dr. James Stuart Ferriss: So, let's talk about the use of immune checkpoint inhibitors in the frontline setting. Until recently, we haven't seen much improvement in overall survival since the introduction of anti-angiogenic therapy to the chemotherapy backbone, and that was in GOG 240. Let's talk about the changes that have recently occurred in this space.  Dr. Jayanthi Lea: So, we've had some very exciting data specifically from initially KEYNOTE-826 and its primary metastatic or first line salvage settings. So, KEYNOTE-826, which was a phase 3 randomized, controlled trial was very practice-changing for us because it showed that incorporation of pembrolizumab to the first-line treatment of patients with metastatic or recurrent cervical cancer, really changed the landscape for treatment in this group of patients. So, keep in mind that prior to the study, the standard of care was carboplatin, or cisplatin with paclitaxel plus or minus bevacizumab, which yielded a median overall survival range in anywhere from 13 to 17 months depending on whether you use bevacizumab or not. And then adding pembrolizumab to that regimen, increase the median overall survival to 24 months, which is very promising.  Dr. James Stuart Ferriss: If I remember correctly, KEYNOTE-826 allowed investigators choice, use of bevacizumab, and initially we were unsure about which regimen was best. Has there been additional data since?  Dr. Jayanthi Lea: There has been additional data since. And another study that was done in the same vein was the BEATcc trial, which also looked at the different checkpoint inhibitors, atezolizumab in combination now with bevacizumab and platinum-based chemotherapy. And the control arm for this study was the GOG 240 regimen, which included bevacizumab. And this study showed both a progression-free and overall survival difference. The median overall survival in this study was 32 months with the incorporation of the checkpoint inhibitor to the bevacizumab and platinum-based chemotherapy. So, the way that I look at it is that the BEATcc trial basically confirmed the findings of KEYNOTE-826 and highlights that it is important for us to incorporate checkpoint inhibition with immunotherapy along with bevacizumab when we're treating patients with a recurrence.  Dr. James Stuart Ferriss: Also, folks with primary advanced treatment for cervical cancer, this would be a great regimen, is that right?  Dr. Jayanthi Lea: Absolutely. Primary advance, we would want to use the same regimen for that.  Dr. James Stuart Ferriss: Okay. What about locally advanced in primary treatment? What advances have we seen?  Dr. Jayanthi Lea: So we've had some major changes in that field as well, especially with the recent KEYNOTE-A18 data where pembrolizumab was administered in combination with external beam radiation and concurrent chemotherapy. And this study showed that there was significant and clinically meaningful improvement in progression-free survival compared to chemoradiation alone. Specifically, the progression-free survival at 24 months using pembrolizumab with chemoradiation was 68%, and 57% when in the placebo group. The hazard ratio for disease progression was 0.7 and no new safety signals were observed, which is fantastic, especially given the 0.7 hazard ratio that received PFS.  Dr. James Stuart Ferriss: Yeah, absolutely. These patients with locally advanced cervical cancer often are quite symptomatic, and the prospect of adding chemo, radiation, and now immunotherapy on top of that is really encouraging to see that it was such a well-tolerated regimen. I believe that there were patient-reported outcomes recently reported at SGO.  Dr. Jayanthi Lea: Absolutely. So, the safety profile of pembrolizumab and chemoradiation was consistent with the known profile of the individual treatment components. And no new safety signals emerged in the pembrolizumab chemoradiation arm. So, you're right. It was very well tolerated.  Dr. James Stuart Ferriss: What would you say are the takeaways for folks who are seeing these patients in the community? These locally advanced cervical cancer patients that are now adding immunotherapy in a space that we have not used routinely in the past in terms of combining it with chemo radiation in gynecologic cancer. What are some things they should be looking out for?  Dr. Jayanthi Lea: Well, I think that with the hazard ratio of 0.7 and the patient-reported outcomes showing no new signal, I think we can say that there is a positive benefit-to-risk profile of adding pembrolizumab in combination with chemoradiation, and that we should feel comfortable using this regimen. Now, of course, we have individualized patient care, and be able to know when to use bevacizumab, when to use immunotherapy. So, taking the whole patient into consideration becomes important. But for those individuals who are able to receive these drugs who don't have concrete issues to not receive these drugs [then I'd say we could] incorporate them since the safety profile is set.  Dr. Linda Duska: I would add to that, Dr. Ferriss, that right now we only have FDA approval in the U.S. for stage 3-4A disease, and that's 2014 staging. Mind you, we are now in 2018, so we should be very careful in and follow the correct FIGO staging. But the FDA only gave approval for stage 3-4A disease, even though the study included patients with earlier stage disease and positive nodes.  Dr. James Stuart Ferriss: That's a great point, thank you.  So, Dr. Duska, thinking about endometrial cancer and advanced endometrial cancer, we have seen a similar revolution in the care of patients over the past few years, with major shifts in our approach. Can you remind us how we got here?  Dr. Linda Duska: Yes, I would say in the ‘90s and before, and maybe even in the early 2000s, we used a lot of radiation for endometrial cancer as adjuvant therapy following surgery. The general consensus and what we were all taught was that this was a chemotherapy-resistant disease. And then we learned from a variety of GOG at the time, Gynecologic Oncology Group trials, that this disease is actually chemosensitive. And we went through a series of chemotherapy drugs, ranging from adriamycin cisplatin to taxel adriamycin cisplatin, and finally to taxel and carboplatin, demonstrating that this disease is actually quite chemosensitive.  With this realization came the idea that maybe it would be important to combine chemotherapy and radiation particularly in high-risk endometrial cancer cases, so those with positive nodes or patients with high-risk histology such as clear cell or serous cancers. So two very important trials were done, one of them was PORTEC-3 and the other was GOG-258, which looked at combining chemo and radiation together to see if we could do better than one or the other alone. And they were very different trials, and they looked at different populations of patients and they looked at different things. For example, PORTEC-3 randomized patients to receive chemotherapy and radiation versus radiation alone, while 258 looked at chemotherapy and radiation versus chemotherapy alone. Without going into a great amount of detail, I think what we learned from both of those studies, and I think surprised many of us, that the arms that included chemotherapy, those patients did better.  In fact, the results of GOG-258 can be interpreted – and this is somewhat controversial – but can be interpreted that many of these high-risk patients don't need radiation at all, or perhaps need tumor-directed radiation. For example, chemotherapy followed by tumor-directed radiation either to the vaginal cuff, because the vaginal cuff is at risk for recurrence, or perhaps to an area of concern, maybe the cervix if there were cervical involvement or if there is a particular concern for local recurrence in a particular patient. So, I think the pendulum has swung from almost always using radiation alone to, in more modern day, using chemotherapy and using radiation much more sparingly, and then comes immunotherapy.  Dr. James Stuart Ferriss: So, update us on the results of NRG-GY018 and RUBY?  Dr. Linda Duska: So, we've already talked about the KEYNOTE basket trials, which really contributed a lot to our understanding of the importance of MMR deficiency and microsatellite unstable disease. The KEYNOTE-158 study and the GARNET study showed us how important it was for women with MMRd and MSI endometrial cancer to receive checkpoint inhibition, and actually with remarkable response rates to women who had already been pretreated. But we also learned from the GARNET trial, which included MMRp patients, that the response rates in MMRp were not that great. And that led to KEYNOTE-775, which looked to combine pembrolizumab with a VEGF inhibitor, lenvantinib, to see if we could make the cold tumor hot. And indeed, we could. And not only could we improve the response rate in patients with MMRp tumors, but we could also improve the response rate in patients with MMRd tumors. They did better with the combination than they did with pembro alone.  That led to the idea of combining checkpoint inhibitors with chemo upfront. The idea there was we were going to take paclitaxel and carboplatin, which were our backbone for advanced or recurrent endometrial cancer, and add immunotherapy to that. And to your point, GY018 and RUBY trials did just that. And they allowed MMRd and MMRp patients and combined paclitaxel and carboplatin, either with dostarlimab in the case of RUBY, or pembrolizumab in the case of GY018. These studies, both of which were reported and published in the New England Journal of Medicine last year, showed remarkable findings in the upfront setting and potentially in the curable setting. And the OS data for RUBY were presented at SGO this year and were remarkable for MMRd patients. In the whole population, in the whole group in RUBY, there was a 16.4-month improvement in overall survival with the addition of dostarlimab which is just huge.  When you look at the MMRd group, I think Dr. Powell described the overall survival improvement as unprecedented. I believe that was the word that he used. Also, he called it very robust, with a hazard ratio of 0.32 for the group that got dostarlimab, and a median OS that was not reached. So really remarkable. In addition, in the MMRp group, there was a seven-month improvement in OS that was significant. So that's really amazing in the RUBY trial. It's also of note that the RUBY trial allowed carcinosarcomas, whereas the GY018 study did not. So, I think it's fair to say that these results apply to carcinosarcomas.  It's also really important to note that many of the patients in the immunotherapy group who received placebo, 41% of them got IO in a later treatment line, and these OS data still stand. So that's really interesting and hypothesis-generating. For GY018, we don't have mature OS data yet, so we can't talk about OS. But we saw a similar improvement in PFS in both arms, in the d and the pMMR, with an OS trend in both arms that was also reported at SGO. GY018 was a little bit different though, because they unblinded at the time of the PFS reporting last year, and so those patients were unblinded a lot earlier than the RUBY patients were. So, to interpret the data in that vein, the OS data is not mature, but we anticipate looking at the PFS curves and the preliminary OS curves, that the OS data will also be statistically significantly improved in core pembrolizumab in GY018.  What's also really interesting, and we haven't talked about molecular subtypes, is that when we look at the molecular subtypes in RUBY, and I'm sure we're going to see data on the molecular subtypes in GY018 coming up, different molecular subtypes of endometrial cancer respond differently to IO. And so, there's going to be lots of really interesting data coming our way soon that we're really excited to see, and that will help us triage patients appropriately into treatment regimens.  Dr. James Stuart Ferriss: Dr. Lea, did you have a thought?  Dr. Jayanthi Lea: Yeah, I just wanted to comment that looking at the dMMR survival curve in the file that was presented recently, one thing that really strikes me is the importance of adding the IO at the time of initial treatment. The separation of the curves persists. And, like you just mentioned, Dr. Duska, I mean, some of those patients who received placebo then later on went to get an IO treatment, but at the same time, we still see a vast separation of those curves. So, I think it's really important to note that immunotherapy should be used upfront, especially in dMMR.  Dr. Linda Duska: Yeah, I completely agree with that. And I think that might be– I mean, this is just a hypothesis, but I think that that might be why we saw a difference with the addition of immunotherapy in the MMRp group, because it's possible that the chemotherapy created an immune environment that made the checkpoint inhibitor work more successfully than it would have otherwise. So, a really good point. You definitely need to include dostarlimab or pembrolizumab with the chemotherapy and then as maintenance therapy after.  Dr. James Stuart Ferriss: So, you mentioned, we're increasingly thinking about endometrial cancer in smaller and smaller buckets of patients with very prescribed molecular profiles. We don't yet have enough information to specifically tailor treatment. How are you approaching that today in patients that you see in clinic?  Dr. Linda Duska: Well, the MMR, and I'm interested in what you both are doing also, it's easy with the MMRd and MSI high patients. Those patients all should receive a checkpoint inhibitor, no question. The patients that are p53 mut, I test them for HER2, because we do have data to suggest that atezolizumab or TDX-d might be useful in those individuals, HER2 positive. And then the remaining patients, also called the NSMPs. That's a difficult group. I'm interested to know how you all manage them. I think that's the group where more clinical research is really needed to determine what the best treatment regimen for them is. But I'm interested in both of your thoughts on that.  Dr. James Stuart Ferriss: Dr. Lea?  Dr. Jayanthi Lea: I would have to say that I do exactly like you do, Dr. Duska.  Dr. James Stuart Ferriss: And I would say our approach is very similar. And we have a robust discussion always about the use of immunotherapy with chemotherapy and in patients who are proficient MMR. But I think that most of us believe that the PFS data is certainly compelling. And now the OS data from RUBY, very compelling in both groups. And so, we are routinely recommending the use of immunotherapy along with chemotherapy in these advanced patients.  Dr. Linda Duska: I've heard the argument made that GY018 required measurable disease, and so does not necessarily apply to patients without measurable disease. I'm not sure that I agree with that. I think there were clinical trial reasons why that was a requirement rather than biologic reasons. In addition, as we already discussed, RUBY included carcinosarcomas and GY018 did not. I don't think there's a reason to only use dostarlimab for carcinosarcomas, but that said, I don't know that pembrolizumab has an indication for carcinosarcomas. The devil's in the details, don't get too lost in the weeds. I think the take-home message here is that it's really important to use IO, particularly for the MMRd patients with endometrial cancer, upfront. And based on the OS that we saw in both RUBY and preliminarily in GY018, we may be curing some people with this regimen, and I think we should focus on that. The overall survival for advanced endometrial cancer is not great, and if we can improve that and potentially cure some people, that's a huge advance for our patients.  Dr. James Stuart Ferriss: Do you envision a day that we might even ask the question, “Do we need to do surgery?”  Dr. Linda Duska: So, the rectal data would support that assertion. I'm not sure that endometrial cancer and rectal cancer are the same thing. And I think that taking out a postmenopausal woman's uterus is a lot less morbid than potentially radiating or taking out somebody's rectum. I think a different question would be, is there a day when we would stop doing no dissection? We could definitely debate that, but I don't see that happening. Do you see that happening anytime soon? A stopping of hysterectomy for endometrial cancer? Dr. Jayanthi Lea: I don't see that happening anytime soon. And I think, as you said, taking out the uterus, tubes, and ovaries, it does provide us with some information about whether you're even dealing with a secondary primary. But also, it's from a quality-of-life standpoint. If a woman has a large uterus, that's uncomfortable. Postmenopausal bleeding, avoiding bleeding during the course of treatment, so many reasons why I wouldn't be in too much of a hurry to want to not do surgery for these patients. Dr. James Stuart Ferriss: So, we'll put a plug in for our fellow gynecologic oncologists that we still have a role to play in the incorporation of treatment regimens for patients with advanced uterine cancer. So it's not just medicine, there's still a role for surgery.  Dr. Linda Duska: I think that's very fair, yeah. Dr. James Stuart Ferriss: Okay. I think that's all the time we have for today.  I want to thank our listeners for their time, and you'll find the links to all the studies we've discussed today in the transcript of this episode. And finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts. Thank you.  Dr. Linda Duska: Thank you. Dr. Jayanthi Lea: Thank you. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care, and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.    Find out more about today's speakers: Dr. James Stuart Ferriss Dr. Linda Duska @LDuska Dr. Jayanthi Lea   Follow ASCO on social media:  @ASCO on Twitter  ASCO on Facebook  ASCO on LinkedIn    Disclosures: Dr. James Stuart Ferriss: Honoraria: National Board of Medical Examiners Dr. Linda Duska: Consulting or Advisory Role: Regeneron, Inovio Pharmaceuticals, Merck, Ellipses Pharma Researching Funding (Inst): GlaxoSmithKline, Millenium, Bristol-Myers Squibb, Aeterna Zentaris, Novartis, Abbvie, Tesaro, Cerulean Pharma, Aduro Biotech, Advaxis, Syndax, Pfizer, Merck, Genentech/Roche, Cerulean Pharma, Ludwig Institute for Cancer Research, Leap Therapeutics Patents, Royalties, Other Intellectual Property: UpToDate, Editor, British Journal of Ob/Gyn Dr. Jayanthi Lea: Consulting or Advisory Role: Roche