Podcasts about ros1

Join us in this episode of the Oncology Brothers podcast as we dive deep into the rapidly evolving treatment landscape for metastatic non-small cell lung cancer (NSCLC) with actionable mutations in frontline therapy. Hosted by community oncologists Drs. Rahul and Rohit Gosain, we are thrilled to welcome Dr. Susan Scott, a thoracic medical oncologist from the Johns Hopkins Hospital. In this episode, we covered: •⁠  ⁠Common EGFR mutations and the latest treatment options, including osimertinib, amivantamab, and chemotherapy combinations. •⁠  ⁠The importance of comprehensive NGS testing and the need for retesting at progression. •⁠  ⁠Insights into managing side effects associated with various therapies, including the proactive management of cutaneous toxicities. •⁠  ⁠Treatment strategies for less common mutations such as ALK, ROS1, BRAF, and RET, along with their respective targeted therapies. •⁠  ⁠The role of immunotherapy in specific mutations and the importance of patient choice and preferences in treatment decisions. Whether you're a practicing oncologist or simply interested in the latest advancements in cancer treatment, this episode is packed with valuable information to help guide your practice. YouTube: https://youtu.be/LMYDAjZcn5w 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!

What if a cancer treatment worked—until it suddenly didn't? A new case report, “Acquired RUFY1-RET rearrangement as a mechanism of resistance to lorlatinib in a patient with CD74-ROS1 rearranged non-small cell lung cancer: A case report,” published in Oncotarget, reveals how a non-small cell lung cancer (NSCLC) patient developed drug resistance through a rare genetic alteration, allowing the cancer to evade therapy. This unexpected finding highlights the importance of advanced genetic testing and personalized cancer treatments. Non-Small Cell Lung Cancer, Targeted Therapy and Drug Resistance Non-Small Cell Lung Cancer is the most common type of lung cancer, accounting for nearly 85% of all cases. Some patients with NSCLC have genetic mutations, such as ROS1 gene fusions, that drive tumor growth. These patients often respond well to targeted therapies like lorlatinib, a ROS1 inhibitor that blocks cancer growth. However, cancer is constantly evolving. Over time, it can develop resistance to targeted therapies, leading to treatment failure. Understanding these resistance mechanisms is crucial for precision oncology, the approach of tailoring cancer treatment based on a patient's unique genetic profile. Full. blog - https://www.oncotarget.org/2025/03/12/a-rare-genetic-shift-that-helped-lung-cancer-evade-treatment/ DOI - https://doi.org/10.18632/oncotarget.28682 Correspondence to - Wade T. Iams - wade.t.iams@vumc.org Video short - https://www.youtube.com/watch?v=HE_qSkcRZho 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

We're only just waking up to the benefits of sunlight and red light for mitochondrial health, lowering blood glucose, and potentially treating Parkinson's disease and cancer.Dr. Glen Jeffery is at the leading edge of this research. We discuss:- Health benefits of sunlight and red light- Harmful effects of blue light & LEDs- In the 2nd half of the podcast, I ask him rapid fire practical questions that everyone wants to know about light, ranging from how much sunlight should one get to what time of day is best for infrared light exposure. Episode Show Notes: https://livelongerworld.com/p/gjefferyFind me: https://x.com/aasthajs TIMESTAMPS: 0:00 Intro0:59 Light impact on public health3:08 Light research is understudied, mitochondria is impacted by light6:05 Red and blue light impacts on mitochondria8:25 Benefits of red light - wound healing, lower glucose15:09 Are there downsides to red light?16:59 Does time of day impact red light benefits?22:05 Red light and cancer26:00 Blue light is making you pre-diabetic37:46 n=1 light experiments39:22 Mitochondria & Longevity46:21 “Sunlight offers a unique package”Rapid fire questions:53:40 Is sunlight good enough for red light?55:10 How much sunlight do we need?56:07 When should you get sunlight?56:55 Should you worry about afternoon sunlight?58:57 Can you get sunlight on cloudy days?59:38 Does sunscreen mitigate benefits of sunlight?1:00:12 Should you not wear caps and sunglasses in sunlight1:01:43 Clothing and sunlight1:05:52 Sunlight through window?1:06:16 Are blue light blocking glasses helpful? (see 1:19:31 for more context)1:08:17 Do Artificial sunlight lamps work?1:08:51 What wavelength red light is the best?1:10:56 Time in front of red light device1:12:41 Body exposure to red light1:15:37 Lighting at home at night1:19:31 Differences in blue light for mitochondria vs. circadian biology1:24:18 Stop using LEDs1:25:24 Does light impact the bioelectrics of the mitochondria?1:26:55 Mitochondria in melatonin mop up ROS1:31:29 Benefits of fire light?1:35:33 Open questions on light and health1:37:28 Support Live Longer WorldAASTHA, LIVE LONGER WORLD: X: https://x.com/aasthajs Newsletter: https://livelongerworld.com/ Instagram: https://www.instagram.com/aasthajs/ DR. GLEN JEFFERY: Bio page: https://profiles.ucl.ac.uk/7465-glen-jeffery/publicationsALSO WATCH:- Keto & Metabolic Therapy for Cancer | Dr. Thomas Seyfried: https://open.spotify.com/episode/7tYdjcJ3G4tqbAx9Z6Bix2?si=rHlCwLVqQHqiOB7yTVBtgQ

BUFFALO, NY - February 6, 2025 – A new #casereport was #published in Volume 16 of Oncotarget on February 5, 2025, titled “Acquired RUFY1-RET rearrangement as a mechanism of resistance to lorlatinib in a patient with CD74-ROS1 rearranged non-small cell lung cancer: A case report." In this case report, Jenny L. Wu from Vanderbilt University School of Medicine and Wade T. Iams from Vanderbilt-Ingram Cancer Center describe a rare case of drug resistance in a patient with advanced non-small cell lung cancer (NSCLC). The patient, a 42-year-old man who had never smoked, initially responded well to lorlatinib, a targeted therapy designed to treat cancer driven by specific genetic alterations. However, after six months, his cancer began to grow again. Clinicians discovered that this was due to a new genetic change, known as the RUFY1-RET fusion. This finding highlights how cancers can adapt to treatment and the importance of ongoing genetic testing to guide therapy decisions. NSCLC is the most common type of lung cancer, and in some cases, it is driven by genetic changes that can be targeted with specific drugs. The patient's cancer originally had a ROS1 gene rearrangement, which made it responsive to lorlatinib. But as time went on, the cancer started to grow again, and tests revealed a new genetic alteration called RUFY1-RET fusion, which likely caused resistance to lorlatinib. This new genetic change was identified using RNA next-generation sequencing (RNA NGS), an advanced test that can find mutations that standard genetic tests might miss. After discovering the RUFY1-RET gene fusion, the patient was treated with a combination of lorlatinib and pralsetinib, a drug that specifically targets RET gene alterations. While this combination helped control the cancer for about four months, the patient's condition unfortunately worsened after four months. “This is the first reported case of a RET fusion as a potential mechanism of resistance to lorlatinib, it identifies a novel RET fusion partner, and it emphasizes the importance of testing for acquired resistance mutations with both DNA and RNA at the time of progression in patients with targetable oncogenic drivers.” Understanding cases like this can help clinicians and researchers develop more effective treatment strategies, including combination therapies that target multiple genetic changes to combat drug resistance. While the combined therapy in this case provided only temporary benefits, it offers important insights for future research and patient care, particularly for cancers that no longer respond to standard treatments. DOI: https://doi.org/10.18632/oncotarget.28682 Correspondence to: Wade T. Iams, wade.t.iams@vumc.org Keywords: cancer, ROS1 rearrangement, RET rearrangement, non-small cell lung cancer, targeted therapy, case report Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ 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

Dr. Evan Yu presents the new evidence-based guideline on genetic testing for metastatic prostate cancer. He discusses who should receive germline and somatic testing with next-generation sequencing technologies, what samples are preferred for testing, and the therapeutic & prognosistc impacts of genetic testing. Dr. Yu emphasizes the need for awareness and refers to areas of active investigation and future research to improve personalized therapies for patients with metastatic prostate cancer.  Read the full guideline, “Germline and Somatic Genomic Testing for Metastatic Prostate Cancer: ASCO Guideline” at www.asco.org/genitourinary-cancer-guidelines. TRANSCRIPT This guideline, clinical tools, and resources are available at http://www.asco.org/genitourinary-cancer-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-24-02608 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. Evan Yu from the University of Washington and Fred Hutchinson Cancer Center, lead author on “Germline and Somatic Genomic Testing for Metastatic Prostate Cancer: ASCO Guideline”. Thank you for being here today, Dr. Yu. Dr. Evan Yu: Thanks for having me on. 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, including Dr. Yu, who has joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes. So then, Dr. Yu, to start us off on the content of this guideline, could you first provide an overview of both the purpose and scope of this guideline? Dr. Evan Yu: Yeah, absolutely. So I think the one key thing to recognize is that prostate cancer is the highest incidence of all cancers in males. Additionally, it's the second highest cause of mortality in males, and that's about 35,000 deaths in 2024. So with that being said and done, it's a disease where we need to do better. And part of that is recognizing that we now have many targeted therapies, precision medicine type of therapies, but unlike a lot of other cancers out there, prostate cancer patients are not always getting sequencing, next generation DNA sequencing, let's say, to identify both inherited and also spontaneously develop what we call somatic mutations in their tumor. And I suspect that's partially because other cancers like breast cancer, we're so used to- in the first line, you present the patient, you throw out their estrogen receptor status, progesterone receptor status, HER2, ER/PR HER2; in lung cancer it's EGFR, ALK, ROS1, etc. In things like prostate cancer, things like BRCA2 have major important patient treatment implications and potentially family counseling and downstream cascade testing implications. But it hasn't made their way into that first-line presentation yet. And for that reason, there are some studies out there that show that testing in the community may be as low as 15% of patients with metastatic prostate cancer. We want to bring awareness to that and hopefully increase testing down the road so that we can better help our patients with metastatic prostate cancer. Brittany Harvey: Absolutely. It's important to get these targeted therapies to the patients who can benefit most. Using that context, I'd like to next review the key recommendations of this guideline across the six clinical questions that the panel addressed. So, starting with: Who should receive germline testing with next generation sequencing technologies? Dr. Evan Yu: Yeah. We think that it's common enough that everyone with metastatic prostate cancer should receive germline genetic testing. And the reason for that is there have been studies that have looked at this and have shown that 12% of men with metastatic prostate cancer have some sort of inherited germline mutation in a gene, mostly DNA repair genes. But 12% have something that is inherited and that loved ones, first degree relatives, siblings, offspring might have also inherited. Now, most of these are in the DNA repair genes, but that being said and done, there's not only treatment implications for the patient, where there are newer drugs that that patient could get treated with, but other loved ones that might have inherited these gene mutations, that these things can cause other cancers as well - not just prostate cancer, but breast cancer, endometrial cancer, ovarian cancer, pancreatic cancer. So, it's very important to test, with as high of an incidence as 12%, to test, and if you identify it in a patient, it's our job to talk to the patient about it and talk to them about the pros and cons of family counseling and talking to their loved ones and potentially having their loved ones get tested. Because if they test positive, then their doctors may want to know and may screen them very, very aggressively and differently for a whole host of other cancers. And the whole idea is you find the cancer very early and cure the patients before the cancer really takes hold and has the ability to spread so we can save a lot of lives down the road. Brittany Harvey: Absolutely. This germline testing is important not just for the patient, but has wider implications for their families as well, as you mentioned. So then, beyond those recommendations for germline testing, which patients should receive somatic testing with next-generation sequencing technologies? Dr. Evan Yu: So let's talk a little bit about somatic testing. So germline again, as we know, is inherited. The patient inherited it in every single cell in their body, then it becomes very easy, many of these are cancer predispositions for them to lose the other allele and then to have biallelic loss and then develop the cancer. Now, somatic just means it spontaneously occurred. Certainly, it's not going to occur in every cell in the body, but you can get one hit, lose one allele and then lose the other allele. And if that gene is truly carcinogenic and leading to that cancer, then that can have implications potentially for treatment as well. So we recommend that all patients with metastatic prostate cancer also undergo somatic next-generation sequencing testing. We recognize that at this point in time it's only those with metastatic castration-resistant prostate cancer or hormone-resistant prostate cancer, which is a later disease state where there are drugs that may target those mutations, for instance, like PARP inhibitors, but that early identification for a patient population that's fit and that can benefit from these therapies makes sense so that you know it's in place already and you have your treatments outlined and mapped out for the future. So we recommend it for everybody - somatic testing also for everyone with metastatic prostate cancer. Brittany Harvey: Understood. And then when patients are receiving that somatic testing, what is recommended for somatic testing? Primary tumor archival tissue? Fresh metastatic biopsy tissue? Or circulating tumor DNA testing? Dr. Evan Yu: We recommend that in the initial setting when you're first diagnosed, that archival tissue samples are fine and preferred. But circulating tumor DNA is good when there's no accessible archival tissue, or if the archival tissue, let's say, is very old and it's been sitting around for a long time, or you can't get it anymore because it's many years back when maybe a patient had a prostate needle biopsy. So if it's not accessible, then we recommend ctDNA. We believe that is preferred and also that ctDNA is recommended in a situation where you can't easily biopsy a metastatic site. Sometimes it's just not in a safe area to go after. Sometimes it's just a small lesion. So in general, we recommend tissue when available, and when we think that the tissue sample will yield clean results, if not, then we recommend doing ctDNA at that point in time. Brittany Harvey: So you have described who should get germline and somatic genomic testing. But what are the therapeutic impacts of this germline or somatic testing for single gene genetic variants? Dr. Evan Yu: We pulled this panel together and we met like every single month for like 12 months straight, and part of it was to review the literature. And as part of this literature review, we were able to pull a whole bunch of different trials. I think there was like 1713 papers we identified in the literature search. Eventually, we narrowed it down because with ASCO, we want to present the data with the highest level evidence, level 1 evidence, randomized controlled prospective data. And after reviewing 1713 papers, we narrowed it down to 14 papers. With those 14 papers, if you look at it, there are a lot of things that we think may have implications for treatment or prognosis, but we didn't feel was the highest level of evidence that we could support. So the things that have the highest level of evidence that we can support are certain DNA repair gene alterations, especially BRCA2, and treatment with PARP inhibitors because there are many PARP inhibitor prospective trials that show progression-free survival benefit and even overall survival benefit. And so that's the type of study that achieved the level of evidence that we could include. So I would say BRCA1 and BRCA2 highest level of evidence and PARP inhibitor use also is included in that. Brittany Harvey: Understood. I appreciate you reviewing those therapeutic options. So then, the last clinical question, which you just touched on briefly, but what are the prognostic impacts of germline and/or somatic testing? Dr. Evan Yu: Whenever you do testing, especially if you use panel testing, you find a lot of information. There's a lot of different mutations and some of which are VUSs (variants of unknown significance) where we don't quite know what it means yet, but we can track that, especially if it's germline. But with somatic, we find lots of things that have implications, but maybe just not treatment implications. A perfect example is p53. p53 is one of the most common tumor suppressor gene mutations on all cancers, but in prostate cancer they can occur and they can usually occur late, although there can even be germline inherited p53 alterations. There's no treatment that targets p53 right now, but we know that if you have a p53 mutation that those patients may have more aggressive disease and that prognostic information is important to give to the patient. And I think it's important for future clinical trial design and direction. So we do not recommend making treatment recommendations or changes based on these prognostic only biomarkers at this point in time. But we do recommend that, based on this, we can design intensification trials for those patients who have these poor risk biomarkers and de-intensification trials for patients who may have a good risk biomarker. So for instance, SPOP is a gene where we think these patients may have better outcomes, they might respond better to certain hormonal therapies like abiraterone. I say might because the level of evidence isn't quite there. But what I would say is that these prognostic only biomarkers, we just don't think they cut the mustard yet to be able to make treatment decisions. But we do think that they can drive counseling for the patient and potential selection and trial design for the future to say, “Okay. This is a patient population that has a more aggressive cancer. We need to be more aggressive in treating these patients.” “This patient population might have a less aggressive cancer. Maybe we can de-intensify and say side effects and quality of life may be better for the patients.” Brittany Harvey: Definitely. It's important for thinking through how to personalize care for these patients. So then you've talked about this a little bit in talking through the recommendations, but could you expand on what is the importance of this guideline and how it will impact both clinicians and patients with metastatic prostate cancer? Dr. Evan Yu: Yeah, I think the number one thing is awareness. I think the data's out there and people that are in my field, they know this. But by evidence of the fact that it's not first-line presentation lingo that everyone's talking about things like BRCA status, it means it hasn't necessarily disseminated all the way through. So it's increasing awareness of the fact that both germline and somatic alterations can occur and that these may have impacts on the patient for their treatment and their prognosis, and basically to increase testing for the future. I really think that in the future, there'll be other reasons that we may want to serially even retest and we may find that there may be mutations that develop as mechanisms of resistance that might guide therapy down the road. So we need to get people to start doing this for everyone with metastatic prostate cancer, because someday we might be doing it not just once, but over and over again. Brittany Harvey. Absolutely. We hope this guideline reaches a wide audience and that these recommendations can be put into practice. Finally, you've talked about how not all the data in the field has yet risen to the level of evidence that made it into the guidelines. So what are the outstanding questions in future research areas for both germline and somatic genomic testing for metastatic prostate cancer? Dr. Evan Yu: It was in our discussion, but it clearly- it's not common enough for there to be randomized prospective trials that would reach that level of evidence to make it in this guideline recommendation. But we all know that for any solid tumor, you can get mismatched repair deficiency, microsatellite instability leading to hypermutation or high tumor mutational burden. And that happens in maybe 3 to 5% of patients with metastatic prostate cancer as well. There is evidence and data that these patients can potentially benefit from immunotherapies like pembrolizumab. But again, it's just not common enough for there to be those randomized prospective controlled trials out there. But we mention it because we know it's FDA-approved across all the tumor types, so we felt like we have to mention it because that's something that has treatment implications for the patient. But also, I alluded to this earlier, I think an area of active investigation is the tried and true number one driver of prostate cancer, which is androgen receptor. Testosterone binds to androgen receptors, stimulates it. That's how androgen deprivation therapy works. That's how abiraterone and the amides like enzalutamide, apalutamide, darolutamide, that's how they all work. But even beyond that, we're starting to identify that maybe 15%, 20% of patients with metastatic castration resistant prostate cancer have androgen receptor mutations. And there are newer classes of therapies like androgen receptor degraders like CYP11A1 antagonist that lead to complete adrenal annihilation of other steroid hormones that might promiscuously stimulate these androgen receptor mutants. These things develop as mechanisms of resistance, and in the future, we might want to serially test- and that's an active area of investigation in the future, to say you've been treated, let's say, with androgen deprivation therapy and abiraterone for years. There are certain mutations that might develop as a resistance mechanism. We might need to serially test somebody because you didn't have that mutation earlier on, but later in the disease course you might. And then there might be a new drug X out there that we would want to use. Again, we need the data, we need the randomized prospective controlled trials, but they're happening out there. And somewhere down the road we may rewrite this guideline and have a lot more recommendations to add to it. Brittany Harvey: Yes, we'll look forward to more research in this field to better provide targeted therapies for patients with metastatic prostate cancer across the treatment paradigm. And we'll look forward to report outs from those trials that you mentioned. So I want to thank you so much for your work to develop this guideline and thank you for your time today, Dr. Yu. Dr. Evan Yu: Thank you so much. It's wonderful to be here today. 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/genitourinary-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, which is 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 the second installment of our two-part series on lung cancer, Brig (Dr) J Muthukrishnan continues his engaging discussion with Col (Dr) G.S. Chaudhary, a leading medical oncologist from AFMC, Pune. This episode dives into the critical aspects of lung cancer management, covering: The current standards of care, including surgery, chemotherapy, radiation, and immunotherapy. The role of targeted therapies and the impact of genetic mutations like EGFR, ALK, and ROS1 on treatment decisions. Strategies for managing advanced-stage lung cancer and improving patient outcomes. The importance of multidisciplinary care and palliative support in holistic cancer management. Dr. Chaudhary also shares valuable insights into emerging therapies and ongoing research that hold promise for the future of lung cancer treatment.

La Dra. Tannia Soria, oncóloga clínica adscrita al Hospital de Solca en Quito, Ecuador, en conjunto con el Dr. Carlos Cabrera, oncólogo médico adscrito al UOMi Cancer Center en Barcelona, España nos presentan un resumen de los estudios que consideran más relevantes en el ámbito del cáncer de pulmón expuestos durante el Congreso de ESMO 2024. ALKOVE-1: estudio fase I/II el cual evalúa NVL-655, un inhibidor de tirosina quinasa de cuarta generación específico para ALK en pacientes con cáncer de pulmón de células no pequeñas avanzado y otros tumores sólidos. ARROS-1: estudio fase I/II del inhibidor altamente selectivo ROS1, se evalúa NVL-520 en pacientes con cáncer de pulmón de células no pequeñas avanzado y otros tumores sólidos. MARIPOSA-2: estudio fase III, abierto y aleatorizado de amivantamab y lazertinib en combinación con quimioterapia basada en platino en comparación con quimioterapia basada en platino en pacientes con cáncer de pulmón de células no pequeñas localmente avanzado o metastásico con mutación de EGFR que han progresado tras tratamiento con osimertinib. MARIPOSA: estudio fase III, el cual tiene como objetivo evaluar la eficacia de la combinación de amivantamab y lazertinib vs. osimertinib, en pacientes con cáncer de pulmón de células no pequeñas localmente avanzado o metastásico con mutación EGFR. RELATIVITY-104: estudio fase III, aleatorizado y doble ciego de quimioterapia neoadyuvante más nivolumab vs. quimioterapia neoadyuvante más placebo, seguida de resección quirúrgica y tratamiento adyuvante con nivolumab o placebo para participantes con cáncer de pulmón de células no pequeñas resecable en estadio II-IIIB. BR.31: estudio fase III, prospectivo, doble ciego, controlado con placebo, en el cual no se demostró mejoras en la supervivencia libre de enfermedad con el uso de durvalumab adyuvante en pacientes con cáncer de pulmón de células no pequeñas que se sometieron a una resección quirúrgica completa y quimioterapia opcional.     Fecha de grabación: 07 de octubre de 2024.                               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 perspectives from Dr Ibiayi Dagogo-Jack and Dr Corey J Langer, including the following topics: Introduction: A Model for Targeted Treatment in Non-Small Cell Lung Cancer (NSCLC) (0:00) NSCLC with ALK, ROS1 and NTRK Rearrangements — Dr Langer (9:10) Current and Future Treatment of Metastatic NSCLC with RET, MET, HER2 and KRAS Alterations — Dr Dagogo-Jack (34:22) CME information and select publications

El Dr. Fred Hirsch, oncólogo médico con PhD, Doctorado en Ciencias por la Universidad de Copenhague en Dinamarca, y  Director Ejecutivo del Centro de Oncología Torácica en The Tisch Cancer Institute del Hospital Mount Sinai en Nueva York, discute sobre la evolución del tratamiento del cáncer de pulmón en los últimos años. El experto comienza explorando el impacto de la medicina de precisión y las terapias dirigidas, que han revolucionado el manejo del cáncer de pulmón de células no pequeñas (CPCNP). Afirma que estas terapias han demostrado mayor eficacia y menor toxicidad comparadas con la quimioterapia tradicional, gracias a la identificación de mutaciones accionables como EGFR, ALK, ROS1, BRAF y NTRK. Además, la inmunoterapia ha representado otro avance crucial en el tratamiento de esta enfermedad. Este panorama subraya la creciente importancia de las pruebas de biomarcadores, recomendadas por las guías NCCN, para optimizar la selección del tratamiento desde el momento del diagnóstico. El Dr. Hirsch pasa a discutir sobre las etapas tempranas de la enfermedad, aclarando que la detección con tomografías de baja dosis ha reducido la mortalidad al identificar cánceres tratables, mientras que técnicas quirúrgicas mínimamente invasivas como VATS y cirugía asistida por robot han mejorado la recuperación postoperatoria. También, estudios más recientes sobre la terapia sistémica adyuvante y perioperatoria, ya sea terapia dirigida o inmunoterapia, han demostrado beneficios en esta población. Por otro lado, en pacientes con CPCNP en estadios avanzados, la radioterapia estereotáctica ha ofrecido excelente control local con mínima toxicidad en aquellos que no son candidatos para cirugía. De igual forma, la integración de terapias dirigidas e inmunoterapias ha revolucionado las opciones de tratamiento de consolidación, incluso con resultados positivos en pacientes con cáncer de pulmón de células pequeñas. En el contexto metastásico, la combinación de quimioterapia con inmunoterapia o terapias dirigidas ha redefinido el estándar de tratamiento. Estudios recientes han mostrado mejoras en la supervivencia global y respuestas duraderas, abriendo nuevas esperanzas para estos pacientes. En resumen, estos avances permiten personalizar el tratamiento del cáncer de pulmón y mejorar la supervivencia. El experto invita a fomentar la colaboración y la adaptabilidad, ya que son la clave para continuar innovando y alcanzar nuevos logros en el cuidado de estos pacientes. Gracias al apoyo educativo de AstraZeneca México. Videograbado: 27 de junio de 2024                           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 mexicanos exclusivamente.

En esta cápsula de ESMO 2024 EXPRESS, el Dr. Santiago Viteri, oncólogo médico en UOMI Cancer Center de Barcelona, España, nos comenta brevemente las novedades presentadas durante el congreso que, a su parecer, son las más representativas en cáncer de pulmón. Estudio ALKOVE-1: Este estudio evalúa NVL-655. NVL-655 es un inhibidor de tirosina quinasa de cuarta generación específico para ALK, diseñado para evitar la inhibición de TRK, lo que mejora su tolerabilidad, especialmente en pacientes con metástasis cerebrales. El estudio mostró una tasa de respuesta objetiva del 38% en pacientes previamente tratados, destacándose una duración de respuesta de 14.4 meses en aquellos con mutaciones de resistencia ALK​. Estudio ARROS-1: Este estudio fase I-II evaluó zidesamtinib, un inhibidor específico para tumores con fusiones ROS1. Se observó una tasa de respuesta objetiva del 44% en pacientes con mutaciones de resistencia y metástasis cerebrales, mostrando respuestas intracraneales del 50% en los pacientes evaluados​. Estudio MARIPOSA-2: Este estudio fase III combina amivantamab con quimioterapia para pacientes con mutaciones de EGFR que han progresado tras tratamiento con osimertinib. Los datos preliminares sugieren una mejora en el tiempo hasta el siguiente tratamiento, aunque aún no hay significancia estadística en la supervivencia global​. Estudio REZILIENT1: Este ensayo evalúa zipalertinib, un inhibidor de EGFR específico para mutaciones del exón 20. Los resultados muestran una buena tasa de respuesta, con una mayor tolerabilidad comparada con otros inhibidores previos​. Fecha de grabación: 15 de septiembre de 2024

In this episode, listen to Alice T. Shaw, MD, PhD, and Jessica J. Lin, MD, share their thoughts on the available and emerging clinical data for second-line and beyond treatments in patients with recurrent ROS1-altered advanced NSCLC including:Assessing ROS1-TKI resistance mutations with tumor and liquid biopsies in patients with ROS1-altered advanced NSCLCPrevious TKI-treated cohort from the TRIDENT-1 study: efficacy of repotrectinib in patients with recurrent ROS1-altered NSCLC and measurable baseline brain metastases   Phase II TRUST-1 trial of taletrectinib: activity in patients with known ROS1 G2032R resistance mutation ROS1-altered advanced NSCLCThe global phase I/II ARROS-1 study of zidesamtinib (NVL-520): safety summary in patients with ROS1-altered advanced NSCLC  Program faculty:Jessica J. Lin, MDAttending PhysicianMassachusetts General HospitalAssociate Professor of MedicineHarvard Medical SchoolBoston, MassachusettsAlice T. Shaw, MD, PhDChief, Strategic PartnershipsAttending Physician, Thoracic OncologyDana-Farber Cancer InstituteHarvard Medical SchoolBoston, MassachusettsResources:To download the slides associated with this podcast discussion, please visit the program page.

In this episode, listen to Alice T. Shaw, MD, PhD, and Jessica J. Lin, MD, share their thoughts on the available clinical data in support of frontline treatments for ROS1-altered NSCLC including:Efficacy and safety data for crizotinib, entrectinib, and repotrectinib in patients with ROS1-altered advanced NSCLCLong-term safety observations for crizotinib and entrectinib CNS activity of entrectinib and repotrectinib in patients with brain metastasesRepotrectinib activity in ROS1-TKI resistance mutations  Program faculty:Jessica J. Lin, MDAttending PhysicianMassachusetts General HospitalAssociate Professor of MedicineHarvard Medical SchoolBoston, MassachusettsAlice T. Shaw, MD, PhDChief, Strategic PartnershipsAttending Physician, Thoracic OncologyDana-Farber Cancer InstituteHarvard Medical SchoolBoston, MassachusettsResources:To download the slides associated with this podcast discussion, please visit the program page.

Today we are joined by Dr. Rajat Thawani. He discusses why biomarker testing is crucial in guiding treatment decisions for patients with ROS1 mutations in NSCLC. He also highlights how specialized biomarker testing teams enhance the identification and management of patients with ROS1-positive NSCLC by providing knowledge about resistance mechanisms and helping select appropriate therapies. Let us know what you thought of this week's episode on Twitter: @physicianswkly Want to share your medical expertise, research, or unique experience in medicine on the PW podcast? Email us at editorial@physweekly.com! Thanks for listening!

In this episode, listen to Alice T. Shaw, MD, PhD, and Jessica J. Lin, MD, share their thoughts on the current understanding of ROS1 rearrangements in non-small-cell lung cancer tumor biology and its implications for molecular testing and treatment selection including:ROS1-gene fusions in advanced lung cancerROS1 testing recommendations with DNA NGS, RNA NGS, FISH break apart assay, and IHCComparative specificity of ROS1 and ALK targeting tyrosine kinase inhibitorsAdvantages of RNA- vs DNA-based next-generation sequencing Program faculty:Jessica J. Lin, MDAttending PhysicianMassachusetts General HospitalAssociate Professor of MedicineHarvard Medical SchoolBoston, MassachusettsAlice T. Shaw, MD, PhDChief, Strategic PartnershipsAttending Physician, Thoracic OncologyDana-Farber Cancer InstituteHarvard Medical SchoolBoston, MassachusettsResources:To download the slides associated with this podcast discussion, please visit the program page

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  

Welcome to the Oncology Brothers Podcast! Join Drs. Rahul & Rohit Gosain in this episode as they welcome Dr. Balazs Halmos, a thoracic medical oncologist from Montefiore-Einstein Comprehensive Cancer Center, to discuss the current landscape of metastatic non-small cell lung cancer with actionable mutations in first-line settings. In this informative episode, they cover a wide range of topics including the importance of NGS testing, treatment options for various actionable mutations such as EGFR, ALK, ROS1, RET rearrangements, and more. Dr. Halmos provides valuable insights into decision-making processes, sequencing treatments, and managing toxicities associated with targeted therapies. Don't miss out on this insightful discussion that sheds light on the rapidly evolving space of precision medicine in lung cancer treatment. Stay informed and learn how identifying and targeting specific mutations can optimize treatment outcomes and improve patient quality of life. Tune in to the Oncology Brothers Podcast for expert insights and discussions on the latest developments in oncology. Subscribe now to stay updated on their informative episodes!

Trend Micro Incorporated ( TYO: 4704 ; TSE: 4704 ), a global cybersecurity leader, announced plans to demo a new data center solution, using NVIDIA technology, for security-conscious business and government customers harnessing the power of AI. This is just one of multiple AI security solutions being shown for the first time at COMPUTEX 2024. Innovent Biologics, Inc. (HKEX: 01801), a world-class biopharmaceutical company announced that results from the pivotal Phase 2 TRUST-I study conducted in China evaluating taletrectinib, next-generation ROS1 tyrosine kinase inhibitor (TKI), were published in the Journal of Clinical Oncology (JCO) and will be highlighted in an oral presentation at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting. For more information, please visit StockDayMedia.com

Dr. Jyoti Patel discusses the latest update to the stage IV NSCLC with driver alterations living guideline, specifically for patients with EGFR or ROS1 alterations. She shares the latest recommendations based on recently published evidence, such as the FLAURA2, MARIPOSA-2, and TRIDENT-1 trials. Dr. Patel talks about how to choose between these new options and the impact for patients living with stage IV NSCLC, as well as novel drugs the panel is monitoring for future guideline updates. Read the full living guideline update “Therapy for Stage IV Non-Small Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, Version 2024.1” at www.asco.org/living-guidelines. TRANSCRIPT This guideline, clinical tools, and resources are available at 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.24.00762  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. Jyoti Patel from Northwestern University, co-chair on, “Therapy for Stage IV Non-Small Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, Version 2024.1.”  Thank you for being here today, Dr. Patel. Dr. Jyoti Patel: Thanks so much.   Brittany Harvey: 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 in the Journal of Clinical Oncology, which is linked in the show notes.  So then to dive into the content of why we're here today, Dr. Patel, this living clinical practice guideline for systemic therapy for patients with stage four non-small cell lung cancer with driver alterations is being updated on a regular basis. So what prompted the update to the recommendations in this latest update?  Dr. Jyoti Patel: This recent update, I think, absolutely reflects how quickly the science is changing. The landscape of treatment options for patients with advanced non-small cell lung cancer is evolving so rapidly, and guidelines from even six months ago don't address some of the newest approvals and newest data and the newest clinical scenarios that we're presented with when we see patients. I think it's harder because before there was usually a single answer, and now there are a number of scenarios, and we hope that the guideline addresses this. Brittany Harvey: Absolutely. The panel's had a lot of data to review as you keep this guideline up to date.  So then this latest update addresses updates to both EGFR and ROS1 alterations. So starting with EGFR, what are the updated recommendations for patients with stage four non-small cell lung cancer and an EGFR exon 19 deletion or exon 21 L858R substitution?  Dr. Jyoti Patel: So for patients with classical driver mutations in EGFR, our recommendation remains that patients should be offered osimertinib. We now also have data to support intensification of therapy with osimertinib and chemotherapy. The FLAURA2 trial was a global randomized study in which patients with classical mutations were assigned to receive either osimertinib or osimertinib with doublet chemotherapy. The trial showed that progression free survival was longer with osimertinib plus chemotherapy with a hazard ratio that was pretty profound, 0.62. In patients who had CNS metastasis as well as patients with L858R mutations, this benefit remained and was perhaps even greater. Now the study remains immature in terms of OS. What we can say is that chemotherapy adds toxicity, so the inconvenience of 13 weekly infusions, expected toxicities from chemotherapy of myelosuppression and fatigue. I think this- we'll continue to watch as the study matures to really see the OS benefit, but certainly intensification in the frontline setting is an option for patients.  The other major update was for second and subsequent line therapy for these patients with EGFR mutations. Another important trial, a study called MARIPOSA-2, was published in the interim, and this was for patients who had received osimertinib in the frontline setting. Patients were randomized to one of three arms. The two arms that are most relevant for us to discuss are chemotherapy with amivantamab or chemotherapy alone. Chemotherapy with amivantamab was associated with an improvement in progression free survival with a hazard ratio of 0.48 as well as improvements in response rate with almost a doubling of response rate to the mid 60%. There was certainly an increase in AEs associated with amivantamab, primarily rash and lower extremity edema and importantly infusion reaction. Based on this data, though in the superior PFS and response rate, we've said that patients after osimertinib should be offered chemotherapy plus amivantamab. Patients may opt for chemotherapy alone because of the toxicity profile, but this recent update is reflective of that data. Brittany Harvey: Excellent. Thank you for reviewing those updated recommendations and the supporting evidence behind those recommendations. I think that's important to the nuance and the toxicity associated with these new recommendations as well.   So then, following those recommendations, what are the updated recommendations for patients with stage four non-small cell lung cancer and a ROS1 rearrangement? Dr. Jyoti Patel: ROS1 fusions have been noted in a small but important subset of patients. We now reflect multiple new options for patients. Traditionally, crizotinib was the primary drug that was recommended, but we now have two very active drugs, repotrectinib, and entrectinib, that have both been FDA approved. Repotrectinib was approved based on a study called the TRIDENT-1 trial. In this study, patients who were treatment naive, who had not received a prior TKI, had a response rate of 79% and a long duration of response over 34 months. For patients who had received prior TKIs, so primarily crizotinib, the response rate was lower at 38%. But again, very clinically meaningful. Repotrectinib has known CNS activity, so it would be the favored drug over crizotinib, which doesn't have CNS penetration. The decision between entrectinib and repotrectinib is one, I think, based on toxicity. Repotrectinib can cause things like dizziness and hypotension. Entrectinib can cause weight gain, and also has CNS effects. Brittany Harvey: Appreciate you reviewing those recommendations as well.  So then you've already talked a little bit about this in terms of deciding between some of the options. But in your view, what should clinicians know as they implement these new recommendations, and how do these new recommendations fit into the previous recommendations? Dr. Jyoti Patel: So there's an onslaught of new data, and certainly many of us want to remain at the front of our fields and prescribe the newest drug, our most effective drug, to all of our patients. But for the person living with cancer and in the practice of medicine, I think it's much more nuanced than that. For example, for a patient with an EGFR mutation exon deletion 19, the expectation is that osimertinib will have a deep and durable response. Certainly a patient will eventually have progression. I think the decision about intensification of therapy and chemotherapy on the onset really has to do with how much the patient is willing to deal with the inconvenience of ongoing chemotherapy, the uncertainty about what comes next after progression on chemotherapy. It may be, though, that a patient may very much fear progressive disease, and so that inconvenience is lessened because anxiety around feeling like they're doing everything for their cancer is diminished by intensification of therapy. Others who may have a large volume of disease or profoundly symptomatic, or who have L858R or brain metastasis it may make sense to give chemotherapy again, we're improving the time until progression significantly by combination therapy. Brittany Harvey: Definitely those nuances are important as we think about which options that patients should receive, along with shared decision making as well.  So then what do these new options mean for patients with EGFR or ROS1 alterations? Dr. Jyoti Patel: It's fantastic for patients that there are multiple options. It's also really hard for patients that there are multiple options, because then again, we have to really clarify aims of therapy, identify what's really important in patient experience and the lived importance of treatment delivery and the burden of treatment delivery. Now more than ever, oncologists have to know what's new and exciting. But patients have to be willing to ask and participate in the shared decision making - understanding their cancer and understanding that their options are absolutely important. As patients start making their decisions, we have the data just in terms of trial outcomes. I think we're now trying to understand the burden of treatment for patients. And so that piece of communicating financial toxicity, long term cumulative lower grade toxicity is going to be more important than ever. Brittany Harvey: Absolutely. It's great to have these new options, and those elements of communication are key to ensuring that patients meet their goals of care.  So then finally, as this is a living guideline, what ongoing research is the panel monitoring for future updates to these recommendations for patients with stage four non-small cell lung cancer with driver alterations? Dr. Jyoti Patel: It's certainly been an exciting time, and that's primarily because we've been able to build on years of foundational science and we have new drugs. Patients have been willing to volunteer to go on clinical trials and to think about what treatment options may be best. Now, the work really comes on seeing the longer term outcomes from these trials. So looking at these trials for overall survival, we want to also better identify which patients will benefit the most from these treatments and so that might be additional biomarker analysis. So it may be that we can identify patients that may need intensification of therapy based on tumor factors as well as patient factors as well in those patients in whom we can de-escalate treatment. I think there are a number of new compounds that are in the pipeline. So fourth generation EGFR TKIs are certainly interesting. They may be able to overcome resistance for a subset of patients who progress on osimertinib. We also think about novel drugs such as antibody drug conjugates and how they'll fit into our paradigm with osimertinib or after carboplatin-based doublets. Brittany Harvey: Definitely. We'll look forward to both longer term readouts from the current trials and new trials in this field to look at additional options for patients.  So I want to thank you so much for your time today, Dr. Patel, and thank you for all of your work to keep this living guideline up to date. Dr. Jyoti Patel: Great. Thanks so much, Brittany. It really is an exciting time for people who treat lung cancer and for patients who have lung cancer. We certainly have a long way to go, but certainly the rapid uptake of these guidelines reflect the progress that's being made.  Brittany Harvey: Absolutely. And just a final 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, which is 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.      

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 

CME credits: 1.00 Valid until: 01-03-2025 Claim your CME credit at https://reachmd.com/programs/cme/the-role-of-chemotherapy-and-immunotherapy-in-ros1-rearranged-nsclc/18159/ This program aims to raise awareness of approved and emerging targeted therapies and practice guidelines for ROS1+ NSCLC. It is critical to create a greater understanding of the limitations existing agents have with acquired resistance mutations and intracranial penetration and the potential advantage new and emerging agents offer to resolve and evade these challenges.

CME credits: 1.00 Valid until: 01-03-2025 Claim your CME credit at https://reachmd.com/programs/cme/case-treatment-selection-for-ros1-rearranged-nsclc-patient-with-brain-metastases/18162/ This program aims to raise awareness of approved and emerging targeted therapies and practice guidelines for ROS1+ NSCLC. It is critical to create a greater understanding of the limitations existing agents have with acquired resistance mutations and intracranial penetration and the potential advantage new and emerging agents offer to resolve and evade these challenges.

CME credits: 1.00 Valid until: 01-03-2025 Claim your CME credit at https://reachmd.com/programs/cme/overcoming-acquired-tki-resistance-with-next-generation-ros1-tki-agents/18161/ This program aims to raise awareness of approved and emerging targeted therapies and practice guidelines for ROS1+ NSCLC. It is critical to create a greater understanding of the limitations existing agents have with acquired resistance mutations and intracranial penetration and the potential advantage new and emerging agents offer to resolve and evade these challenges.

CME credits: 1.00 Valid until: 01-03-2025 Claim your CME credit at https://reachmd.com/programs/cme/treatment-strategy-of-ros1-rearranged-nsclc-in-tki-naive-patient/18160/ This program aims to raise awareness of approved and emerging targeted therapies and practice guidelines for ROS1+ NSCLC. It is critical to create a greater understanding of the limitations existing agents have with acquired resistance mutations and intracranial penetration and the potential advantage new and emerging agents offer to resolve and evade these challenges.

CME credits: 1.00 Valid until: 01-03-2025 Claim your CME credit at https://reachmd.com/programs/cme/safety-and-tolerability-of-ros1-tyrosine-kinase-inhibitors/18158/ This program aims to raise awareness of approved and emerging targeted therapies and practice guidelines for ROS1+ NSCLC. It is critical to create a greater understanding of the limitations existing agents have with acquired resistance mutations and intracranial penetration and the potential advantage new and emerging agents offer to resolve and evade these challenges.

CME credits: 1.00 Valid until: 01-03-2025 Claim your CME credit at https://reachmd.com/programs/cme/later-line-targeted-therapies-for-ros1-fusion-positive-lung-cancers/18156/ This program aims to raise awareness of approved and emerging targeted therapies and practice guidelines for ROS1+ NSCLC. It is critical to create a greater understanding of the limitations existing agents have with acquired resistance mutations and intracranial penetration and the potential advantage new and emerging agents offer to resolve and evade these challenges.

CME credits: 1.00 Valid until: 01-03-2025 Claim your CME credit at https://reachmd.com/programs/cme/first-line-targeted-therapies-for-ros1-fusion-positive-lung-cancers/18155/ This program aims to raise awareness of approved and emerging targeted therapies and practice guidelines for ROS1+ NSCLC. It is critical to create a greater understanding of the limitations existing agents have with acquired resistance mutations and intracranial penetration and the potential advantage new and emerging agents offer to resolve and evade these challenges.

CME credits: 1.00 Valid until: 01-03-2025 Claim your CME credit at https://reachmd.com/programs/cme/current-guidelines-and-real-world-evidence-for-ros1-testing-in-nsclc/18154/ This program aims to raise awareness of approved and emerging targeted therapies and practice guidelines for ROS1+ NSCLC. It is critical to create a greater understanding of the limitations existing agents have with acquired resistance mutations and intracranial penetration and the potential advantage new and emerging agents offer to resolve and evade these challenges.

CME credits: 1.00 Valid until: 01-03-2025 Claim your CME credit at https://reachmd.com/programs/cme/intracranial-activity-of-ros1-tkis/18157/ This program aims to raise awareness of approved and emerging targeted therapies and practice guidelines for ROS1+ NSCLC. It is critical to create a greater understanding of the limitations existing agents have with acquired resistance mutations and intracranial penetration and the potential advantage new and emerging agents offer to resolve and evade these challenges.

Dr. Natash Leighl and Dr. Jyoti Patel are back on the podcast to discuss the update to the living guideline on stage IV NSCLC with driver alterations. This guideline includes recommendations for first-, second-, and subsequent-line therapy for patients with driver alterations including: EGFR, ALK, ROS1, BRAFV600E, MET exon skipping mutation, RET rearrangement, NTRK rearrangement, HER2, and KRAS G12C. They highlight the key changes to the recommendations, addition of recent trials, the importance of biomarker testing, and the impact of this guideline for clinicians and patients living with advanced NSCLC. Stay tuned for future updates to this continuously updated guideline. Read the full update, “Therapy for Stage IV Non-Small-Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, Version 2023.3” 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.23.02744.    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 am interviewing Dr. Jyoti Patel and Dr. Natasha Leighl, co-chairs on “Therapy for Stage IV Non-Small-Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, Version 2023.3.” Thank you for being here, Dr. Patel and Dr. Leighl.  And before we discuss this guideline, I would 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 and Dr. Leighl, who have joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes. So, to start us off on this living clinical practice guideline, Dr. Leighl, this guideline for systemic therapy for patients with stage four non-small cell lung cancer with driver alterations is being routinely updated. What new data was reviewed in this full update to the living guideline? Dr. Natasha Leighl: Thanks so much, Brittany. So, we looked through the literature for publications between February and the end of October 2023, and also any novel agents that were approved, in particular by the United States FDA, to really incorporate this update in the current guidelines. In particular, we had updates in EGFR-driven tumors, BRAF and RET-driven tumors. And we also worked very hard to make this more digestible. In particular, it was turning into a bit of a laundry list of all of the things that we had ever recommended. So we really wanted to shorten things, pare them down, and really make them helpful and very, very current for the treatment of people with lung cancer in 2023 and 2024. Brittany Harvey: Excellent. Thank you for providing that overview of the evidence reviewed and the key updates that we will address in this guideline. So then I would like to talk about some of those key updated recommendations from the expert panel. You mentioned both EGFR, BRAF, and RET. So starting with patients with stage IV non-small cell lung cancer with EGFR alterations, Dr. Leighl, what are the key changes to those recommendations? Dr. Natasha Leighl: So, as I said, we really started to get quite a long list of things we recommended, including drugs that, to be honest, we no longer think are what we should lead with first-line. So we updated the recommendation to recommend first-line osimertinib in patients with sensitizing mutations. We were also able to capture in this update for patients with EGFR exon 20 insertion mutant lung cancer, the data from the randomized PAPILLON trial, recommending amivantamab plus chemotherapy for progression-free survival benefit. Not yet an overall survival benefit, but we will see how these data mature.  The other thing that we did was we moved all of the- I don't want to call them "legacy agents" because, in many countries, these are still very important. But older agents such as gefitinib, approaches such as gefitinib plus chemotherapy, and drugs like dacomitinib and other agents where we truly believe as an international panel that we would prefer a third-generation kinase inhibitor like osimertinib. We moved all of those to our discussion, just to recognize that, around the world, not everybody may have access. And we also specified that things are different in different countries. So, for example, in China, there are other third-generation kinase inhibitors with randomized data to support their use. And those are approved and used in China. And also, for example, in Korea, there are other agents that are used. So, we have really tried to be both inclusive and yet keep things simple at the same time. And hopefully, we have succeeded.  One of the challenges was that, with all of the updates that we made, we did not have all of the publications out yet at the end of October to make recommendations about moving beyond osimertinib in the first-line setting. So, please stay tuned for the next guideline update, where we're going to tackle whether we should give osimertinib alone or combination therapy. Brittany Harvey: Excellent. Thank you for providing those updates and clarifications for those patients with non-small cell lung cancer and an EGFR alteration. And we will look forward to the guideline panel's review of that evidence and future updates as well. So then, Dr. Leighl, you had previously mentioned that additional recommendations were updated, such as those for patients with BRAF alterations and RET alterations. So, Dr. Patel, what are the other key updated recommendations from the expert panel? Dr. Jyoti Patel: Thanks so much, Brittany. So certainly, I think we have seen many of these trials mature over time, which has been fantastic. I think one remarkable achievement was the reporting of a phase III selpercatinib trial. This was a trial in the front-line setting, in which patients who were RET-positive were randomized to selpercatinib versus carboplatin-based chemotherapy. And the selpercatinib significantly outperformed platinum-based chemotherapy, and I think really demonstrated a significant improvement in progression-free survival. So, based on that phase III trial, the recommendation for selpercatinib was elevated. Many of these agents that are used in clinical practice are approved initially on smaller phase I or phase II trials. And so, seeing the maturity of these phase III trials gives clinicians and patients greater certainty that these agents are really effective. And so, the evidence was increased for that, and that's now a preferred agent over another TKI, pralsetinib, in which there is only phase II data. So, certainly, those kinds of real things that we can explain to patients are important in these guidelines.  Another thing that we were able to update was another doublet for BRAF V600E non-small cell lung cancer. So, the combination of the two TKIs, encorafenib and binimetinib, was also included in the guidelines.  One thing that we tried to help was really identifying the best therapy post-progression on these first-generation TKIs. And again, there is a paucity of data, but often we went back to carboplatin-based doublets, and there is some data regarding whether or not patients with driver alterations should get immunotherapy in the second-line setting. And so, certainly, I think we have a number of randomized studies for patients with classical EGFR mutations, and our recommendation is generally avoidance of immunotherapy for these patients and treating many of these patients with carboplatin and pemetrexed when appropriate. I do not think we have the data for a lot of other subsets of patients. So, again, stay tuned as these data evolve. Brittany Harvey: Thank you for reviewing those updated recommendations and the supporting evidence. I think it's helpful for our listeners to understand the level of evidence behind these recommendations as well.  So then, Dr. Leighl, what should clinicians know as they implement these new and updated recommendations? Dr. Natasha Leighl: It's really important, first of all, to make sure that you have the information that you need to get your patients to these great new treatments as part of the shared decision-making process. So your patients need biomarker testing. You need to get that as quickly as you can. As Dr. Patel has highlighted, you really want to get that before they start their first-line therapy, if at all possible. We also really tried to bring out in this guideline that when things are delayed, I mean, this is the real world that we live in, just to be very cautious of immunotherapy with chemotherapy for that first cycle. That obviously, again, is a discussion with your patient, but this concept that the approach of a cycle of chemotherapy while you wait for the next-generation sequencing testing. And then if the patient does not have a driver alteration, adding any other therapy as appropriate is okay. It's something that people do. We believe it's important as we talk about the balance between benefits and harms. And so I think that's in there for clinicians, and I hope that they and patients can really benefit from that to avoid toxicity and also to really improve the ability to get molecular testing results first line.  Also, I think it's really important that when people read the wording of the guidelines, that this really follows GRADE, which is a type of system that we use to develop our recommendations. And so things like "may" do not mean that you shouldn't do it. So sometimes we'll hear back from clinicians and say, "Well, you said that they may use alectinib or lorlatinib, for example, with ALK, and I can only get coverage for one or the other." And so I think it's really important that clinicians and patients recognize that all of the things that we do recommend, even if we do use the word "may" or the recommendation is more conditional, we do think that these agents should be available for patients and clinicians, and that they go through this shared decision-making process together.  And so I think that's something that clinicians, we hope, can help take forward as they advocate for their patients to get access to these different and new and emerging treatments that have clearly shown benefit. Even when we say patients and clinicians may use this or that, there may be excellent reasons for using something newer, that's emerged, perhaps for toxicity benefits or benefits in terms of efficacy, even though we can't compare directly. And so we really want clinicians and patients to be empowered to access these new compounds and these new exciting agents that are in our guidelines. Brittany Harvey: Absolutely. Thank you for reviewing those key points. And, yes, that's a great comment that the level of obligation in the recommendations may be based on the evidence quality, but that doesn't mean that clinicians and patients shouldn't have access to all of the recommended treatment options to offer patients based off their individual patient and clinical characteristics.  So then, Dr. Patel, in your view, how will these changes affect patients with non-small cell lung cancer, with driver alterations?  Dr. Jyoti Patel: A lot of this echoes the points made by Dr. Leighl. I think there are opportunities for patients to assess toxicity or what it means for intensification of therapy. So, particularly for EGFR patients, for example, we have data that chemotherapy with osimertinib can improve progression-free survival, or the incorporation of a bispecific antibody, amivantamab, can improve progression-free survival over the TKI alone. It certainly comes with increased toxicity. And so how we weigh this in the absence of a known survival benefit at this juncture is one that, again, really gives patients the opportunity to prioritize what's important for them. And so I think this guideline affects patients and that we have multiple options, we help with the weight of the evidence so they may be able to better discern what treatment makes sense for them. Brittany Harvey: Understood. Yes, this guideline provides lots of options for different patients based off their driver alterations. So it's helpful to have that information for shared decision-making with their clinicians.  So then finally, to wrap us up, Dr. Leighl, what current research is the living guideline expert panel monitoring for updates to the guideline recommendations? Dr. Natasha Leighl: This process of the living guidelines has really been to help us stay on top of the amazing and incredibly rapid progress that we're making in lung cancer and other cancers. And even with this process, where we're trying to stay up-to-the-minute, there have already been some changes in the literature between the start of November and now. And so we're already working on some additional commentary and options for the first-line treatment of patients with EGFR-mutant lung cancer. Also, the subsequent treatment of patients with EGFR-mutant lung cancer, depending on what they've had before. Also, a great new study in patients with ROS1 fusion-driven lung cancer. And so these are some of the things that we're looking at.   Also, a bit more discussion about the importance of molecular testing. In our companion article, the Journal of Oncology Practice, along with Dr. Patel, we're going to be talking a bit more about new ways to genotype, for example, using both liquid biopsy and tumor tissue at the same time, and some of the support for that and how it gets us with our patients to the answers that they need faster.  Brittany Harvey: Absolutely. The pace of research in non-small cell lung cancer has moved quite quickly. So we definitely appreciate the panel's efforts to review all of this evidence on a continuous basis and take the time to develop these guideline recommendations for both clinicians and patients with non-small cell lung cancer.  So I want to thank you so much for your work to update these guidelines, and thank you for your time today, Dr. Patel and Dr. Leighl. Dr. Natasha Leighl: Thanks so much. It's a real pleasure to be here. Dr. Jyoti Patel: Thank you.  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 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 this Hope With Answers episode, host Diane Mulligan interviews Dr. Tejas Patil, an oncologist specializing in lung cancer, about ROS1-positive lung cancer. As Dr. Patil explains, "ROS1 is a type of mutation that we see in patients who have lung cancer. It's one of many but it's an important one because there is targeted treatments available to these patients that really are not like chemotherapy." A ROS1-positive lung cancer, also known as a ROS1 rearrangement in lung cancer, refers to any lung cancer that tests positive for a fusion in the ROS1 gene. ROS1 rearrangements occur in approximately 1-2% of non-small cell lung cancer (NSCLC) patients. ROS1-positive lung cancer tends to be aggressive and can spread to the brain and the bones. The hosts also speak with Lysa Buonanno, a 12-year lung cancer survivor and patient advocate living with ROS1-positive lung cancer. Lysa stresses the importance of self-advocacy.  "You have to keep advocating for yourself. Throughout this entire process I think that is so critically important."  She describes her excitement at being able to join a clinical trial for a new targeted therapy when her cancer progressed. Overall, the episode provides critical information about this rare form of lung cancer, highlights new research and treatments, and offers inspiration through Lysa's story. As Diane says, not only do Dr. Patil and Lysa help us understand ROS1 lung cancer, but they also give hope to anyone living with lung cancer. Guests Tejas Patil, MD, Assistant Professor, Medicine-Medical Oncology, University of Colorado Anschutz Medical Campus  Lysa Buonanno, Lung Cancer survivor, a mother of two, who has ROS1 mutation and is being treated with the targeted therapy. Show Notes | Transcript | Watch video

Featuring articles on apixaban for stroke prevention in subclinical atrial fibrillation, repotrectinib for ROS1 fusion–positive lung cancer, acoramidis in transthyretin amyloid cardiomyopathy, low-dose calcium supplementation in pregnancy, and the financialization of health in the United States; a review article on peripartum cardiomyopathy; a case report of a woman with bleeding after a snakebite; and Perspective articles on the overdose crisis among U.S. adolescents, on accuracy and equity in clinical risk prediction, on centering women of color in academic medicine, and on the buddy system.

FDA D.I.S.C.O. Burst Edition: FDA approval of Augtyro (repotrectinib) for locally advanced or metastatic ROS1-positive non-small cell lung cancer

How confident are you in managing patients your patients on ROS1 inhibitor therapy? Credit available for this activity expires: 11/30/24 Earn Credit / Learning Objectives & Disclosures: https://www.medscape.org/viewarticle/998606?ecd=bdc_podcast_libsyn_mscpedu

Lung Cancer Considered host Dr. Stephen Liu moderates a discussion on the November 15, 2023, US FDA approval of repotrectinib for advanced NSCLC with a ROS1 gene fusion based on the single-arm, multi-cohort TRIDENT-1 trial.

The end of the year typically brings a number of FDA approvals, and 2023 is no different. Last week, the Food and Drug Administration approved a new drug, Augyro (repotrectinib) for the treatment of patients with ROS1-positive non-small cell lung cancer.  Also making oncology headlines this week, is an expert update on the cancer drug shortage, research about how the severity of diabetes can impact colorectal cancer outcomes and how vitamin D may be able to mitigate the severity of chemotherapy-induced peripheral neuropathy.   FDA Approves Augtyro for Patients With NSCLC Subset Another week, another FDA approval. This time, the agency approved Augtyro for the treatment of patients with locally advanced or metastatic ROS1-positive non-small cell lung cancer.  The drug works by targeting ROS1 oncogene fusions, which can be responsible for the growth of cancer. The approval was based off findings from the phase 1/2 TRIDENT-1 clinical trial, which showed that 79% of patients responded to therapy with the drug, including 6% who experienced a complete response, which is when all signs of cancer disappear.  Bristol Myers Squibb, the pharmaceutical company that manufacturers Augtyro, expects the drug to be available to patients in mid-December.  FDA Approves Keytruda plus Chemo for Advanced HER2-Negative Gastric, GEJ Cancers Also in FDA news last week, the agency approved the immunotherapy drug, Keytruda, in combination with chemotherapy for the treatment of patients with advanced unresectable or metastatic HER2-negative gastric or gastroesophageal junction adenocarcinoma.  The approval came after findings from the KEYNOTE-859 trial showed that the immunotherapy-chemo combination improved overall survival) that's time from treatment until death of any cause); progression-free survival (time from treatment until death or disease worsening) and response rate compared to a group that received placebo plus chemotherapy.  FDA Approves Truqap Plus Chemo for Some With HR-Positive, HER-Negative Breast Cancer Additionally, the FDA has approved Truqap with chemotherapy fulvestrant for the treatment of adults with HR-positive or HER2-negative locally advanced or metastatic breast cancer with one or more PIK3CA/AKT1/PTEN-alterations and who have progressed on at least one endocrine-based regimen in the metastatic setting or recurred at or within one year of completing adjuvant therapy. And now this approval was based on the results of the CAPItello-291 trial where among patients with these altered tumors, the median progression free survival was 7.3 months in the Truqap and chemotherapy cohort and 3.1 months in the placebo and chemotherapy cohort. FDA Approves Xtandi for High-Risk Prostate Cancer And the FDA approved Xtandi for the treatment of patients with non-metastatic castration-sensitive prostate cancer, with a high risk of biochemical recurrence, meaning a recurrence that is determined by rising prostate specific antigen levels. According to Pfizer, the manufacturer of the drug, and notably, this marks the first approval of an androgen receptor signaling inhibitor that is FDA approved for this patient population.  The approval is based on findings from the randomized phase 3 EMBARK clinical trial were five-year metastasis free survival, which is the time from treatment until metastatic disease was 87.3% in the Xtandi arm, compared with 71.4% and the leuprolide-only group and 80% in the monotherapy group, according to findings that were published in the New England Journal of Medicine.  Drug Shortages Continue to Be a ‘Serious Problem' in Oncology While the shortage of the chemotherapy drugs, cisplatin and carboplatin, seems to be improving, drug shortages, in general, are not a new problem and likely are not going anywhere soon, according to Corey McEwen, the director of oncology pharmacy services at Massachusetts General Hospital in Bostin.   McEwen explained that most of these drugs are manufactured outside of the United States. The FDA will approve certain locations to make the drugs, which then are shipped to the wholesaler, then the cancer treatment center or clinic and finally, to the patients. However, at no point during that process is there an obligation to be transparent about drugs that are in shortage or at risk to be in shortage.  Additionally, with increased demand and decreased supply, the price of these therapies can go up. At Mass. General, McEwen said that the institution will oftentimes take on the financial burden of the increased cost, because they are mainly focused on getting the drugs in the first place. However, that may not be the case in all cancer treatment centers, leading to more disparities and financial burdens from cancer care.  Diabetes Severity Associated With Poor Colorectal Cancer Survival Research published in the journal, Cancer, analyzed outcomes for patients with diabetes and colorectal cancer who underwent surgery for their cancer. Findings showed that patients with more severe diabetes tended to have poorer survival outcomes. This was particularly the case for patients who were female or in their earlier stages of cancer.  The researchers theorized that the relationship between diabetic severity and cancer prognosis may be explained by three mechanisms:  ·      Diabetes can lead to increased levels of insulin-like growth, which can accelerate tumor growth  ·      High blood sugar levels may result in poor response to chemotherapy  ·      The potential increased accumulation of genetic mutations that result from the high inflammatory burden caused by diabetes  Vitamin D May Help Prevent Chemo-Induced Neuropathy Once again, vitamin D made oncology headlines last week. This time, findings published in the Journal of the National Comprehensive Cancer Network found that patients who were deficient in vitamin D before starting treatment with paclitaxel had higher rates of chemotherapy-induced peripheral neuropathy than patients with sufficient vitamin D levels.  Peripheral neuropathy is a common side effect from certain types of chemotherapy drugs that presents as numbness, tingling or a stabbing feeling in the hands and/or feet. Eventually if the neuropathy gets so bad, patients can have a higher risk of falls or become unable to perform some essential everyday tasks, such as preparing food or getting dressed. There is currently no cure for the condition, so potential prevention or mitigation strategies — like getting enough vitamin D — are particularly important.  I spoke with study author Dr. Dan Hertz who said that while more research is needed in this space, it is worth it for patients to check their vitamin D levels and take a supplement, if needed. 

Check out our free downloads at nascentmc.com: Implementing AMA Style – 8 Things to Get Right in Your Next Project Needs Assessments – 7 Essentials for Getting Funded Working With Your Medical Writer – 8 Ways to Get the Most out of Them See the full write ups for today's episode at nascentmc.com/podcast   Here are the highlights: ·       Capivasertib (Truqap) has been FDA-approved for the treatment of hormone receptor-positive/HER2-negative breast cancer with AKT pathway alterations, showing improved progression-free survival in clinical trials. ·       Repotrectinib (Augtyro) has received FDA approval for ROS1-positive non-small cell lung cancer (NSCLC), demonstrating high response rates in patients who had not received a prior tyrosine kinase inhibitor. ·       Enzalutamide (Xtandi) has gained FDA approval for nonmetastatic castration-sensitive prostate cancer (nmCSPC) in high-risk patients with biochemical recurrence, expanding its use in prostate cancer treatment. ·       Pembrolizumab (Keytruda) has received supplemental approval for the first-line treatment of HER2-negative stomach cancer when combined with chemotherapy, showing improved overall survival compared to chemotherapy alone. ·       The Symplicity Spyral™ renal denervation (RDN) system has been approved by the FDA for treating hypertension through a minimally invasive procedure targeting overactive nerves near the kidneys.  ·       A combination of taurolidine and heparin catheter lock solution (DefenCath) has been approved for preventing catheter-related bloodstream infections in hemodialysis patients, demonstrating a significant reduction in infection risk in clinical trials.     Intro and outro music Garden Of Love by Pk jazz Collective

Good morning from Pharma and Biotech Daily: the podcast that gives you only what's important to hear in the Pharma and Biotech world. ## The world's first CRISPR medicine, Casgevy, developed by Vertex Pharmaceuticals and CRISPR Therapeutics, has been approved in the UK for the treatment of sickle cell disease and beta thalassemia. However, a gene editing therapy like CRISPR may not be as simple as it seems. While Casgevy can mute the damaging symptoms of sickle cell disease, treatment may not be straightforward. Red Tree Venture Capital plans to expand into San Diego's biotech pipeline and build a competitor to Boston-area investors. The FDA has approved Augtyro, a new drug developed by Bristol Myers, for the treatment of lung cancer. Astellas has published a paper detailing a gene therapy study that led to patient deaths. The company is working with regulators to lift a clinical hold on the treatment.## The Biden administration has finalized a rule requiring nursing homes to disclose their ownership. CommonSpirit, a nonprofit operator, has started its 2024 fiscal year with a $738 million loss. CMS has proposed stricter network adequacy standards for plans sold in state-run ACA exchanges. Centene, a health insurer, has named Susan Smith as its new Chief Operating Executive. UnitedHealth is being sued for using an algorithm to deny care for Medicare Advantage members. There is an increasing trend of electronic health record (EHR) adoption, which has facilitated the rise of big data in healthcare.## The UK's Medicines and Healthcare Products Regulatory Agency (MHRA) has granted conditional marketing authorization for gene-edited therapy ExA-Cel, developed by Vertex Pharmaceuticals and CRISPR Therapeutics. This marks the world's first approval for a CRISPR-edited therapy. Bristol Myers Squibb's (BMS) drug Augtyro has received FDA approval to treat ROS1-positive non-small cell lung cancer (NSCLC). Astellas sees a path forward for its gene therapy AT132 despite four patient deaths in a clinical trial.## The traditional approach to health marketing is becoming inadequate and less effective compared to biotech and pharmaceutical marketers' expectations. Quad offers next-generation solutions that aim to deliver superior results at a lower cost. The text mentions that Quad has a downloadable resource called "next-gen solutions for health marketing" that covers various topics. Quad also offers advertising opportunities to reach over 96,000 biopharma industry executives.## Influencer marketing is growing at a faster rate than traditional paid social media and is projected to reach $21.2 billion worldwide by 2023. Top retailers are taking note of this trend and using it to shape their strategies for the future. The trendline highlights several examples of how brands are leveraging influencer marketing.## Cognizant's Life Sciences Manufacturing Practice offers resources such as web content, whitepapers, videos, and thought leadership articles on their website. They specialize in creating connected GMP manufacturing and lab systems using digital technology adoption and support.## An infographic discusses the factors and macro-trends that different types of medical device companies need to consider when developing a location strategy. The infographic highlights several macro-trends that companies should take into account when developing their manufacturing strategies.## Finance and procurement professionals in the healthcare industry are encouraged to stay ahead by embracing change and utilizing automation. There is an e-book available that provides tools for success and offers a custom demo for transforming operations management in healthcare organizations.## Novo Nordisk plans to invest $6 billion in expanding its manufacturing capabilities in Denmark. Valneva has received regulatory approval from the FDA for its chikungunya vaccine. The American Medical Association (AMA) has called for broader health insurance coverage f

ASCO: You're listening to a podcast from Cancer.Net. This cancer information website is produced by the American Society of Clinical Oncology, known as ASCO, the voice of the world's oncology professionals.  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. Guests' statements on this 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. Cancer research discussed in this podcast is ongoing, so data described here may change as research progresses. In this podcast, Cancer.Net Associate Editor for Lung Cancer, Dr. Charu Aggarwal, and Cancer.Net Specialty Editor for Thymoma, Dr. Ryan Gentzler, discuss what people with early-stage non-small cell lung cancer should know about their treatment options before and after surgery, called neoadjuvant therapy and adjuvant therapy, respectively. Dr. Aggarwal is the Leslye Heisler Associate Professor of Medicine in the Hematology-Oncology Division at the University of Pennsylvania's Perelman School of Medicine. Dr. Gentzler is a thoracic medical oncologist and Associate Professor of Medicine in the Division of Hematology/Oncology at the University of Virginia (UVA) Comprehensive Cancer Center. View disclosures for Dr. Aggarwal and Dr. Gentzler at Cancer.Net.  To begin, Dr. Gentzler will discuss what people with early-stage non-small cell lung cancer should know about neoadjuvant treatment options before lung surgery. Welcome, Dr. Gentzler. Dr. Gentzler: Hi, this is Ryan Gentzler from the University of Virginia. We're here to discuss the role of neoadjuvant chemotherapy and immunotherapy for the treatment of locally advanced non-small cell lung cancer. So first, I thought I'd address some of the data and definition of what is neoadjuvant treatment. So when we think about treating lung cancer that is not metastatic, that is earlier stage disease, there typically involves multimodality treatment. Sometimes these lesions or tumors can be very small and can be stage I and treated with surgery alone or perhaps radiation alone and no further treatment is needed. But the vast majority of lung cancers that are considered early stage are in fact either larger tumors, involve lymph nodes, and typically fall into the category of stage II or III lung cancers. And these are cancers that often require multiple treatments beyond the local surgery approach alone. When we think about how we deliver that treatment, it can either be given before surgery or after a surgery. If we give treatment before a surgery, we call that neoadjuvant. If it is given after the surgery, we call that adjuvant. And most of the data that we have today in lung cancer uses one or the other of these approaches, and we don't typically give treatments both before and after, at least in terms of the chemotherapy part of that treatment. Historically, most of the data exists in the adjuvant treatment of lung cancer going back several decades that showed that the benefit of chemotherapy after a surgery, particularly for those with stage II and stage III lung cancer, derived a clear benefit of survival by giving chemotherapy after surgery. More recently, with the advent of immune therapy, which we have used in patients with stage IV lung cancer as well as those with stage III lung cancer who cannot undergo surgery, those immunotherapy drugs have been shown to improve overall survival and improve clinical outcomes for a wide range of patients with more advanced disease. And so in the last 4 or 5 years, we have really looked at new trials that have added immunotherapy in what we call perioperative space, either before surgery or after surgery for those that have surgically resectable disease. I'm going to focus on the neoadjuvant approaches that we have seen today, and this largely all started with data from Patrick Forde out of Johns Hopkins and Jamie Chaft from Memorial Sloan Kettering looking at single agent treatment with nivolumab immunotherapy. This was no chemotherapy given for 3 treatments prior to or three cycles prior to surgery. And that trial demonstrated a high degree of patients with tumor reduction and more importantly, we saw that the pathologic response, meaning how much tumor was left under the microscope at the time of surgery, was higher than what anyone anticipated with just immunotherapy alone. That launched a whole series of larger randomized prospective trials evaluating largely the combination of chemotherapy and immune therapy prior to surgery. Now, before we get into some of the results of these trials, I really wanted to emphasize some of the theoretical advantages to neoadjuvant approach. Now, the first potential advantage of giving neoadjuvant treatment is that we know when you start with immunotherapy and chemotherapy regimens and that's the first type of treatment, everyone is guaranteed to get that treatment. And we know that the completion rate prior to surgery is higher than it is after surgery. These patients can get all of the prescribed treatment and will be more likely to get it than if they get it after surgery. So this is one advantage. The other is potentially starting these medications which go throughout the body and treat the cancer, wherever it may be, earlier. We know that one of the risks of all cancers, but lung cancer in particular, is that even with good surgery and removing all of that cancer, there is a chance that there are cancer cells left behind, which leads to risk of recurrence in the years to come after surgery. Naturally, if we start the treatment that can eliminate those cancer cells, wherever they may be, and do that first, perhaps we catch this earlier with fewer cells that have escaped and have a more likely chance of success of eliminating the cancer and resulting in a cure. The third, I think, is one that we still have yet to learn more about, but if we give immunotherapy in particular, these are medications that activate the immune system, particularly the type of immune system cell called a T cell. If that T cell is able to recognize tumor cells, it is more likely to be able to continue to attack those tumor cells. And if we give that treatment prior to removal of the tumor, perhaps that activates the immune system in a more robust way that it can go after these cancer cells and eliminate those that are left behind after the surgery. If you give the immunotherapy after a surgery and the bulk of the tumor, most of the cancer cells have been removed, it may be harder to find those antigens or foreign proteins that are expressed in cancer cells. So the immune system may not be as robustly able to go after cancer if you give it solely after a surgery. Another potential advantage of neoadjuvant approaches is that it really helps us learn as oncologists how well a cancer is responding to a treatment. If we give these treatments for 4 cycles after a surgery, we don't know whether it's eliminating those residual cancer cells or whether it is totally ineffective. If we give it before a surgery and we see that there is tumor reduction or that there is a complete elimination of the cancer, we know that that treatment was an effective treatment at attacking the cancer cells and eliminating them. We know that the cancer was sensitive to that treatment. We can then better prognosticate how well the patients are going to do after surgery. We know based on the latest data that if you achieve what we call a pathologic complete response with chemotherapy and immunotherapy prior to surgery, meaning there are no cancer cells left when we look at that surgical specimen under the microscope, we know that those patients have a much better likelihood of surviving for longer periods of time than those who have active cancer at the time of surgery after prior treatment. And so neoadjuvant approaches allow us in a 2-month time frame to get a great sense of how well our treatments are working and able to prognosticate outcomes based on how well those cancer cells have been eliminated at the time of surgery. One large phase 3 trial called the CheckMate 816 trial was a randomized phase 3 trial and that enrolled patients with stage IB through IIIA non-small cell lung cancer using the old staging system of the 7th edition. These would all now be categorized as stage II and stage III non-small cell lung cancer patients. And it randomized these patients to 3 cycles of chemotherapy plus nivolumab, which is an immunotherapy drug, and compared that to patients treated with chemotherapy alone for 3 cycles. After these 3 cycles of chemotherapy, which is about a 9-week time frame, patients had surgical resection of their tumors. And then after surgery, patients received no further treatment, although treating physicians were allowed to give additional treatments like chemotherapy or radiation if they thought it would be beneficial for these patients, although it was not mandated by the study. One of the first results we saw from this study was that there was a much higher rate of pathologic complete response of 24% of patients achieving a path CR [pathologic complete response] with the nivolumab plus chemotherapy combination compared to only 2.2% with chemotherapy alone. This was highly statistically significant and demonstrated a clear benefit for those receiving the immunotherapy. The other main endpoint of this study was event-free survival, meaning that the time that the patients were alive and without any significant event like cancer progression or death after the enrollment of the trial. And in this analysis, the median event-free survival was significantly longer in those who have received the immunotherapy plus chemotherapy combination prior to surgery. One of the potential concerns about neoadjuvant treatment is that it may render patients unfit for surgery who otherwise could have had their cancer removed. When we look at the outcomes from this CheckMate 816 trial, it actually did not appear to be the case to a large degree. In fact, those that got the nivolumab plus chemotherapy combination were more likely to proceed on with surgery, and the majority did; 83% received the planned surgery. There were patients who were unable to receive surgery due to adverse events of their treatment, but that was only 1% of patients enrolled in the trial. Other reasons for canceling the surgery included disease progression, meaning the cancer got worse to the point where they could not undergo surgery, or other reasons, such as the patient declined surgery, or it was found to be unresectable at the time the surgeon wanted to remove the cancer, or poor lung function.   One of the insights we got from the surgical data from this trial were that those who received the combination of chemotherapy and immunotherapy had slightly higher rates of smaller surgeries like a lobectomy compared to a pneumonectomy for those who had received [chemotherapy alone.] There were also fewer numbers of patients who required a conversion from a minimally invasive surgical procedure to an open surgical procedure if they were getting the immunotherapy combination. A higher number of patients also were able to have complete resection of their tumor if they received the immunotherapy/chemotherapy combination. The length of hospitalization was slightly lower, and the rates of pain were slightly lower in those who received the combination as well. These comparisons were not statistically significantly different, but numerically, there seems to be at least a trend toward benefit in surgical outcomes in this neoadjuvant chemotherapy/immunotherapy approach. And I think this makes sense. We know that this combination is more able to eliminate a cancer and make it a pathologic complete response when we look at it under the microscope, and therefore, if there is shrinking the tumor to a higher degree, naturally, it seems there would be more likely of completely removing the tumor, using a smaller incision to remove that tumor, shortening the length of stay in the hospital and recovery time and pain control. All makes sense if we know that the treatment itself is able to reduce that size of the tumor. There are many other phase 3 trials ongoing studying the impact of immunotherapy plus chemotherapy in the neoadjuvant setting. The AEGEAN trial has recently reported data at the AACR meeting this year in 2023 with similar results that we saw with the CheckMate 816 trial. There are 3 other phase 3 trials that are ongoing, one of which we will see later this summer called the KEYNOTE-671 trial evaluating pembrolizumab plus chemotherapy in the neoadjuvant setting and then 2 other trials evaluating nivolumab, the CheckMate 77T trial, or atezolizumab in the IMpower030 trial. Each of these more recent trials typically have used 4 cycles of chemotherapy plus immunotherapy prior to surgery and also continued the immunotherapy after surgery for a period of time, most commonly approximately 1 year. From the data we have seen so far, it remains uncertain whether additional immunotherapy beyond the 3 or 4 cycles given in the neoadjuvant setting provides any additional benefit. We still do not understand what to do with patients who did not achieve a pathologic response whether further treatment would be of any additional benefit. We do not know if there will be further benefit even in those that achieved a pathologic complete response whether a slightly longer duration of immunotherapy would further improve outcomes in that group. We suspect with longer-term follow-up over the years of all of these phase 3 trials that some of these questions will be answered. So what are some key questions that patients should ask when considering a neoadjuvant chemotherapy/immunotherapy approach? I think the first question that's key is what is my tumor stage? We know that the trials that enrolled patients with a neoadjuvant approach enrolled patients using our current staging system would be a stage II or stage III lung cancer. And this is where it gets really tricky is, what subdivision of stage III is it? We tend to think of stage IIIA's as being one that it would be surgically resectable, with a smaller number of stage IIIBs, and then stage IIIC, one that we would not typically recommend surgery for. I think the next question within the tumor stage is, is this based on imaging or based on the biopsies? And we know that biopsies are really the best way to stage locally advanced cancers, particularly getting samples of lymph nodes in the mediastinum. Sometimes what looks like a stage I or stage II on imaging is, in fact, a stage III based on biopsies that are done at the time of surgery. It's ideal to know that information prior to making the decision about surgery so that that surgery is not futile.   On the opposite side, sometimes there is imaging suggestive of lymph nodes that are enlarged in the mediastinum, and it's presumed that this is a more advanced stage III and is not surgically resectable. However, if you go and biopsy those lymph nodes, sometimes they are benign. Sometimes they are inflammation related to infection or cancer but do not actually contain cancer cells. And so we typically advise that getting biopsies of lymph nodes in the mediastinum, at least any that are particularly suspicious, is highly recommended for these locally advanced cancers. I think the next question that's key to ask is, what are my tumor biomarkers? And there are multiple biomarkers that we look at in non-small cell lung cancer that help us decide what is the best treatment. What is the best approach? What is the best medicine to treat the cancer? We know that one of these biomarkers that is a key is a mutation. So multiple different mutations can occur in lung cancers, particularly those that are adenocarcinoma subtypes. And these mutations may be less likely to benefit from immunotherapy and we may want to take a different approach with surgery, chemotherapy, and potentially targeted therapies that specifically target that mutation that exists in the tumor. The other key biomarker here is PD-L1. We know that tumors with a higher level of PD-L1 are more likely to respond and benefit from immunotherapy. As of right now, that PD-L1 status plays a more important role in the adjuvant setting. All of the chemotherapy plus immunotherapy combinations in the neoadjuvant setting seem to benefit the group as a whole regardless of that PD-L1 status. But still, an important biomarker that we should have prior to making all final decisions on treatment. I think another question that should be asked any time you have an earlier stage cancer is, is my tumor surgically resectable? And there can be many reasons why cancers are not resectable, perhaps due to the anatomy of where the tumor is located, if it invades into the mediastinum, for example, or is near large blood vessels, or perhaps because there are too many lymph nodes and this is a more advanced stage. And so I think the main reasons for not being surgically resectable would be the tumor is too large, if the stage is too high, or is it more of a function of fitness for surgery and that can be because of other underlying lung disease. Perhaps removing part or all of a lung would not be safe due to impaired lung function to begin with. And I think it's important to understand that sometimes stage III lung cancers are resectable and sometimes they are not, and understanding the reason why they are not, I think, is important. And then I think lastly and ultimately when we're talking about a neoadjuvant approach, you want to ask your treating oncologist, "Would it be better to give my treatment before surgery or after surgery?" And really discuss the pros and cons with the physician and have them incorporate all of the factors that go into these treatment decisions. How well you'll tolerate chemotherapy, other medical conditions that may play a role in the likeliness of getting through those treatments safely, perhaps underlying diseases that may increase the risk of immune-related side effects with immunotherapy. You really want to factor in all of these things and discuss the pros and cons of a systemic treatment first versus surgery first before making final decisions on how to treat locally advanced lung cancer. All right. Thank you. ASCO: Thank you, Dr. Gentzler. Next, Dr. Aggarwal will discuss what people with early-stage non-small cell lung cancer should know about their adjuvant treatment options for after lung surgery.   Dr. Aggarwal: This is Dr. Charu Aggarwal. I'm the Leslye Heisler Associate Professor for Lung Cancer Excellence at University of Pennsylvania's Abramson Cancer Center. And today I will talk to you about the use of adjuvant immunotherapy in the setting of early-stage non-small cell lung cancer. We'll start by discussing what adjuvant therapy is, what types of options we have for adjuvant therapy, what kind of testing is important, and what options there may be in terms of adjuvant immunotherapy. So let's get started. Early-stage lung cancer comprises of stages between stage I to stage III. These stages vary by the size of the tumor as well as the level of lymph node involvement. In the setting of very early-stage lung cancer, such as stage I and stage II, as well as some select stage III lung cancers, we recommend surgical resection. And in these patients, the use of additional treatment is recommended based upon the pathological determination of the tumor size as well as the lymph node status. If usually lymph nodes are involved, we recommend adjuvant chemotherapy, and also, many experts will deliver adjuvant chemotherapy for tumors that may be larger than 4 centimeters even in the absence of lymph node involvement. The data for adjuvant chemotherapy comes from several large clinical trials that were conducted about a couple of decades ago now that demonstrated not only an improvement in preventing recurrence of the cancer but also a modest improvement in overall survival, really laying the ground for improvement and therefore becoming the gold standard. Four cycles of chemotherapy are usually administered about 6 to 12 weeks following surgical resection, and this is really the basis of our treatment in the early-stage setting. In today's time and age, we now have several other options. We have treatment options that include molecular therapy, which is biomarker driven, as well as the use of immunotherapy. So it's actually very important for us in the adjuvant setting--or in the post-surgical setting--to test for mutations such as EGFR. It's also important for us to test PD-L1 status. So let's dive into why each of these may be important. Patients with EGFR mutations, especially those with sensitizing mutations in EGFR exon 19 or 21, now have the opportunity to receive a targeted therapy in the form of osimertinib, which is an oral drug, very targeted and specific for the EGFR mutation that has been studied in a clinical trial setting in patients with early-stage non-small cell lung cancer. In patients with stage IB to IIIA non-small cell lung cancer with EGFR mutation, use of osimertinib was associated with a significant improvement in our ability to delay the recurrence of cancer. Based on this significant improvement, FDA approved therapy with osimertinib, and it is currently available and ready to use. We usually recommend it for 3 years, so daily therapy for 3 years, and patients are monitored with routine CAT scans and lab work. For patients who don't have an EGFR mutation, we do recommend broad panel testing. Of course, this is not the standard, but I think it's important for us to identify patients who may not benefit from immunotherapy. Patients that have an ALK mutation, for example, or ROS1 translocation, may not have the best chances of responding to adjuvant immunotherapy, and therefore, I think testing should be performed to make sure that we are having a shared decision-making conversation with our patients about the use of the correct adjuvant options. In terms of adjuvant immunotherapy, we now have 2 approved agents. One of them is atezolizumab, and the other one that was just recently approved is pembrolizumab. Atezolizumab was approved on the basis of a large clinical trial called the IMpower010 study, which randomized 1,280 patients with stage IB to IIIA non-small cell lung cancer to either 1 year of atezolizumab or best supportive care. Of note, all of these patients had to have had adjuvant chemotherapy that included a cisplatin platinum chemotherapy. In the first analysis, we found that the disease-free survival or the probability of the patients remaining cancer-free was significantly improved in those patients that had a tumor expression of PD-L1 greater than or equal to 1% and received atezolizumab compared to patients who did not receive atezolizumab. On the basis of this positive primary endpoint, the U.S. FDA approved the use of adjuvant atezolizumab for patients with stage II to IIIA resected non-small cell lung cancer after surgical resection and adjuvant chemotherapy. Recently, we heard that this does lead to small but significant improvement in overall survival. There is a trend towards improvement in overall survival. However, the data are quite immature at this point, and we do need longer follow-up to be able to follow this trend. The greatest magnitude of overall survival benefit was found in patients who had the PD-L1 greater than or equal to 50%. So it's important to know what the PD-L1 level of a patient may be when I'm thinking about adjuvant immunotherapy because adjuvant immunotherapy is most likely to benefit those that don't have an actionable mutation, such as EGFR, and those that have the highest PD-L1 staining, at least in the IMpower trial. Secondly, the PEARLS clinical trial is a clinical trial that evaluated the use of pembrolizumab, which is another immunotherapy agent, again, in the adjuvant setting. For this clinical trial as well, there was a small but significant improvement in disease-free survival, again preventing the probability of recurrence in all patients that received pembrolizumab compared to the best supportive care. And basically, this led to also an approval by the FDA for the use of pembrolizumab. Again, now we have 2 options. Both of these are administered for 1 year. What should patients know about therapy? These drugs are usually administered once every 3 weeks. They are given intravenously. Sometimes, we can change the treatment schedule to be either once every 4 weeks in the case of atezolizumab or every 6 weeks in the case of pembrolizumab. These may be associated with some side effects. Immunotherapy side effects that are most common are fatigue, chills, myalgias, or basically a feeling of pains in the body or joints. But also, some serious life-threatening reactions can occur such as activation of the immune system to such an extent that the immune system may start to attack the body's organs. So this may lead to swelling or inflammation in the organs that may manifest itself as colitis if the gut gets inflamed, or pneumonitis if the lungs were to get inflamed, or pancreatitis if the pancreas were to get inflamed. Any organ in the body can really get inflamed. We've certainly seen cases of thyroiditis. We've seen cases of polyarthritis. We've seen cases where the brain may also get inflamed or the pituitary may get inflamed. So there are definitely some life-threatening reactions or side effects that can occur with the use of immunotherapy that should be closely monitored. The benefit of having used immunotherapy in the metastatic setting is that now we have a lot of experience managing these side effects. And if recognized early, these side effects can be managed appropriately with the use of steroids as well as holding therapy. Many of the times, we can even reinstitute immunotherapy without significant harm to the patients. However, I think immunotherapy benefits as well as side effects should be discussed in detail with the provider, especially in the adjuvant setting. Patients may ask if neoadjuvant immunotherapy along with chemotherapy is a better approach compared to adjuvant immunotherapy. At this time, we don't have a clinical trial that is comparing neoadjuvant chemoimmunotherapy followed by surgery to an approach that is surgery followed by adjuvant immunotherapy. In general, I would say that if the decision by a multidisciplinary team has been made to proceed with surgery, careful discussion should be had about adjuvant chemotherapy as well as the use of adjuvant immunotherapy, and molecular testing should be performed. All patients with early-stage disease should have a multidisciplinary tumor board discussion, which includes engagement with surgeons, radiation oncologists, pulmonologists, pathologists, and medical oncologists so that they can ensure that many experts have had the chance to weigh into their case as well as come to the right conclusion on whether or not to use new adjuvant chemoimmunotherapy or just to proceed with surgical resection. ASCO: Thank you, Dr. Aggarwal. You can learn more about neoadjuvant and adjuvant treatment options for early-stage non-small cell lung cancer at www.cancer.net/lung. Cancer.Net Podcasts feature trusted, timely, and compassionate information for people with cancer, survivors, and their families and loved ones. Subscribe wherever you listen to podcasts for expert information and tips on coping with cancer, recaps of the latest research advances, and thoughtful discussions on cancer care.   And check out other ASCO Podcasts to hear the latest interviews and insights from thought leaders, innovators, experts, and pioneers in oncology.  Cancer.Net is supported by Conquer Cancer, the ASCO Foundation, which funds lifesaving research for every type of cancer, helping people with cancer everywhere. To help fund Cancer.Net and programs like it, donate at CONQUER.ORG/Donate. 

JCO PO author Dr. Apar K. Ganti shares insights into his JCO PO article, “Pertuzumab Plus Trastuzumab in Patients With Lung Cancer With ERBB2 Mutation or Amplification: Results From the Targeted Agent and Profiling Utilization Registry Study.” Host Dr. Rafeh Naqash and Dr. Ganti discuss clinical decision-making regarding biopsy; HER2 amplification, mutation, and targeted therapy; drug combinations; and aspects of the TAPUR and DESTINY-Lung studies. Click here to read the article!   TRANSCRIPT Dr. Abdul Rafeh Naqash: Hello and welcome to JCO Precision Oncology Conversations, where we bring you engaging conversations with authors of clinically relevant and highly significant JCO PO articles. I'm your host, Dr. Abdul Rafeh Naqash, Social Media Editor for JCO Precision Oncology, and Assistant Professor at the University of Oklahoma Stephenson Cancer Center.  Today we are joined by Dr. Apar Kishor Ganti. Dr. Ganti is a Professor of Medicine and associate director of clinical research at the Fred and Pamela Buffett Cancer Center at the University of Nebraska Medical Center. He's also a staff physician at the VA Nebraska Western Iowa Healthcare System. Dr. Ganti is the lead author of the JCO Precision Oncology article titled "Pertuzumab Plus Trastuzumab in Patients With Lung Cancer With ERBB2 Mutation or Amplification: Results From the Targeted Agent and Profiling Utilization Registry Study," which is also the TAPUR Study.  Dr. Ganti, thank you so much for joining us today. Dr. Apar Kishor Ganti: Thank you for having me. I'm happy to be here. Dr. Abdul Rafeh Naqash: For starters, Dr. Ganti, this is one of the trials from the TAPUR Basket study. So I wanted to take this opportunity since this is an ASCO initiative that has been there for a few years now. Could you tell us a little bit of background about the TAPUR initiative, what kind of trials are being run or have been run, and how it all started, basically?  Dr. Apar Kishor Ganti: The TAPUR Study or the Targeted Agent and Profiling Utilization Registry Study is a pragmatic basket trial which evaluates the anti-tumor activity of commercially available targeted agents in patients with advanced cancers and tumors that have potentially actionable genomic alterations, like mutations, amplifications, etc. And this has multiple arms in multiple malignancies, using drugs that are currently approved in different indications and not necessarily approved for the indication that's being studied. But there's preclinical data that suggests that that particular drug may potentially be active in patients whose tumors harbor those mutations. For example, this present study that we conducted utilized a combination of pertuzumab and trastuzumab, both of which are FDA-approved for the treatment of patients with HER2-positive breast cancers. And we analyzed the efficacy of the combination of these two drugs in patients with lung cancer who had either a HER2 mutation or an amplification of HER2.  Dr. Abdul Rafeh Naqash: Thank you so much for giving us that background. Going to this study specifically, which is one of the very interesting TAPUR studies, what I'm reminded of especially is NCI-MATCH, for example, which runs on a similar premise to this study, where we've seen some successes and some not as exciting combination approach successes that is what we would have wanted to see.  For lung cancer specifically, as you and I both know and perhaps many of the listeners know, there's a lot of actionable drivers that have target therapies that are approved, could you touch on some of those to give a background on where the field currently lies and what are some of the important steps with respect to obtaining next generation sequencing, perhaps in patients. So what your practice is and what you would recommend for these individuals? Dr. Apar Kishor Ganti: Certainly, non-small cell lung cancer, or non-squamous non-small cell lung cancer, to be more precise, seems to be the poster child for next-generation sequencing. And the importance of NGS testing cannot be overemphasized in these patients. For example, right now we have multiple different drivers that have drugs approved for the management of these patients. The first among them, obviously, was EGFR or epidermal growth factor receptor. And that has been followed fairly successfully by targeting ALK, ROS1, now, more recently, RET, MET, KRAS, and HER2. So if you look at lung adenocarcinomas, almost half of the patients will have a tumor with a mutation that is targetable. And so it's very important to make sure that these patients are tested for, before initiating any therapy. What makes it more important is that the standard of care for patients with non-small cell lung cancer without driver mutations is either immunotherapy or chemoimmunotherapy. And we have found that if a patient has a driver mutation, especially EGFR or ALK, even if their PD-L1 expression is extremely high, their response to checkpoint inhibitors is negligible. And so it is important to make sure that we understand what their molecular status is before starting any treatment in these patients. And I think the key point here is that every patient with advanced non-small cell lung cancer should have next generation sequencing studies done prior to initiation of treatment. Dr. Abdul Rafeh Naqash: Absolutely. And in your practice, Dr. Ganti, do you tend to do liquid biopsies concurrently when you get a new individual with a diagnosis of lung cancer, or do you do it at some other time point?  Dr. Apar Kishor Ganti: Liquid biopsies, I tend to get them, but not as frequently as some would like. I tend to believe more in tumor biopsies, and I would get liquid biopsies only in the setting where a tumor biopsy is not feasible or if I feel that the patient needs treatment more rapidly than can be expected if I got a tissue biopsy. Liquid biopsies, in my opinion, are good, but they're very dependent on the tumor fraction that is present in the sample that you send. As you very well know, not all patients who have a driver mutation necessarily shed the mutation into the blood. And therefore, even if a patient has a driver mutation in a tumor, there is a small chance that the liquid biopsy may not detect it. So I tend to be more in favor of getting tumor biopsies for next-generation sequencing. In situations where the tumor fraction is high, the concordance between tumor biopsies and liquid biopsies is fairly good. Dr. Abdul Rafeh Naqash: Thank you so much for that very important clinical decision-making thought process. At least in my practice, when tissue is often the issue, as you very well know, where you don't either have enough tumor cells or the biopsy is just enough to tell you whether it is squamous or non-squamous and not enough for any further sequencing, I try to get liquid biopsies whenever feasible and appropriate so that at least we can rule out some of the driver alterations before I put a patient on immunotherapies, due to the concern for subsequent toxicities if there are driver alterations. But I totally agree, I think tissue is definitely the standard, gold standard. And if you have overlapping mutations in tissue and liquid, then obviously it increases your confidence of treating that individual with that targeted therapy. But in general, tissue definitely, at least we should try to emphasize, and I try to do this often when I get a call from a community oncologist. I'm pretty sure you do the same where we ask for multigene broad gene testing NGS, so that especially when you have HER2 mutations, for example, you won't necessarily capture those as you show on your study here.   Now, going to your study, Dr. Ganti, could you tell us a little bit more about HER2 mutations and amplifications? And there's different levels of evidence where amplification may not lead to expression or expression may not lead to amplification. And then there is a separate category of HER2 mutations. And a lot of what we know for HER2 is from breast cancer. And recently, in the last two to three years now, is for lung cancer also. Could you tell us about how the field is shaping from a HER2 mutational landscape, an amplification landscape, in the lung cancer field?  Dr. Apar Kishor Ganti: As you rightly said, most of our knowledge from HER2 is from the breast cancer world. And frankly, I think we've been spoiled by the data on breast cancer. So, unlike in breast cancer, lung cancer seems to have a much lower frequency of HER2 alterations. And while in breast cancer, HER2 amplification seems to be important and predictive for response to HER2-targeted agents, in lung cancer, we see a combination of mutations and amplifications. So, in a large TCGA study, mutations in HER2 seem to occur in about 2% of all lung cancers. And amplification seems to be occurring in approximately a similar proportion of different patients. So, they seem to be mutually exclusive as best as we can tell.  And, unlike in breast cancer, where HER2 amplification seems to be directly associated with protein over-expression and response to tumor, the data in lung are much less robust. And so, it is not necessarily that an amplification will translate into a prediction of response to a HER2-targeted agent. And we and certain other studies have shown that patients who have HER2 amplification may not respond as well to HER2-targeted therapy as opposed to, for example, patients with HER2 mutations. So, that seems to be the discrepancy in HER2 amplification and HER2 mutations when you look at lung cancer versus breast cancer. And that's another reason why we are doing the TAPUR study at the various arms because what works in one specific cancer with the same mutation or same abnormality may not necessarily work in other cancers. Dr. Abdul Rafeh Naqash: Absolutely. Thank you for indulging into that side of things. Now, going back to your trial, could you tell us a little bit of background on the eligibility criteria, how you chose some of the different mutations? What were the levels of evidence for some of those mutations from a pathogenicity standpoint, and then what were your endpoints, since this is a clinical trial with a Simon two-stage design?  Dr. Apar Kishor Ganti: Patients who were eligible for the trial included all patients with advanced lung cancer who did not have another FDA-approved treatment or were not candidates for another treatment. They all should have been 18 years or older at the time of diagnosis and have lung cancer with either ERBB2 amplification or we looked at 13 specific mutations, insertions, or deletions, and, if the patient had any of those abnormalities identified by any clear approved next-generation sequencing testing platform, then they would be eligible for the study. We chose these because of how frequently these specific mutations occurred in lung cancer and other cancers. And so, these 13 abnormalities were chosen from the host of HER2 mutations that you can see. Patients should not have received a previous HER2 inhibitor, obviously, and their LV ejection fraction should be normal because of the known risk of decreasing cardiac function with HER2-targeted therapy. They were treated with pertuzumab every three weeks and then combined with trastuzumab. Trastuzumab was given at a loading dose, initially of 8 milligrams per kilogram, and in subsequent cycles, we used 6 milligrams per kilogram. The dose of pertuzumab was a flat dose of 840 milligrams for the first dose and 420 milligrams for subsequent doses.  We continued the treatment till progression or excessive toxicity or patient withdrawal of consent. The endpoints were disease control, which we defined as objective response or stable disease for at least 16 weeks duration. Other endpoints were progression-free survival, overall survival, duration of response, and, of course, safety. We used a Simon two-stage design, as you said. The null hypothesis was that the disease control rate would be 15%, alternative hypothesis was 35%, the power was 85%, alpha was at 10%. So, if in the first stage, less than two out of ten patients had disease control, then the cohort would be closed for futility. If two patients or more had disease control of the first 10, then we expanded to an additional 18 patients for a total study size of 28. So, as far as safety analysis, any patient who received even a single dose of treatment was included in that safety analysis.  Dr. Abdul Rafeh Naqash: Thank you so much for giving us those details about the cohort. Going to the mutation or the amplifications, I'm looking at the cohort, so it seems like more or less, to some extent, there was an equal distribution of the mutations. 50% of individuals had mutations and then around 45%, 43% had amplifications. Did that play into your expectation of how the cohort did in terms of responses or the primary endpoints that you had set? Did you see differences based on those findings of mutations versus amplifications.  Dr. Apar Kishor Ganti: Yes, we did. The disease control rate was 37%, with an overall response rate of 11%. And when you looked at patients who had a partial response, which is three patients, all of them had ERBB2 mutation. And of the patients who had stable disease, only two patients out of seven had an amplification. Five patients had the mutation. So, again, this was similar to what we had expected, that based on previous studies, patients with mutation tend to respond better than patients with alterations. Dr. Abdul Rafeh Naqash: Definitely. And going to one of the striking figures that you have in this manuscript, of course, you have the waterfall plot, and then you have the swimmer's plot and the spider plot. I'm very intrigued personally by the spider plot, which is the Figure 3 in your paper, especially with this individual that had this long, durable partial response. I believe this was the same individual with the mutation. I believe it was this 776 insertion. Was there anything, any other aspect that could have contributed to this response, or does this mutation, does it have any strong preclinical data of why the activity offer to direct therapy might be more pronounced in this mutation that you came across?  Dr. Apar Kishor Ganti: Not to my knowledge. I don't think we found anything specific or different about this particular patient compared to the others. So, as far as the mutation itself is concerned, it's a fairly common mutation, the G776 insertion. It is one of the most common mutations seen in lung cancer, and studies have shown that patients with the mutation tend to respond. But why this patient responded so long, it's difficult to say. I wish we were able to find out, but unfortunately, we were not able to. Dr. Abdul Rafeh Naqash: Sure. Another question that I wanted to ask you since this falls into the precision medicine basket study questions. Does TAPUR have a different endpoint for different sub-studies? Because I vaguely remember coming across another paper where I believe a 16-week disease control was also the endpoint. So, is that something universal in TAPUR, or is it specific for specific tumor types and different combination approaches? Dr. Apar Kishor Ganti: I believe that this is a more generalized feature of the TAPUR study, the stable disease for 16 weeks as a marker of response. Of course, different arms have additional endpoints, but I think this is one of the more common ones. Dr. Abdul Rafeh Naqash: Now, there has been some work, as you very well pointed out in your paper as well, from others related to HER2 mutations, especially the DESTINY-Lung study. Could you tell us a little bit about that for listeners who may not be well aware of the DESTINY study with trastuzumab deruxtecan targeting the HER2 mutations? Dr. Apar Kishor Ganti: So, DESTINY-Lung01 was a study of patients with ERBB2 mutated lung cancer. That study just looked at mutation-positive patients as opposed to what we did, looking at both mutation and amplification. And that study showed an overall response rate of 55%, which was much higher and led to the approval of fam- trastuzumab-deruxtecan in this group of patients. And so, one of the differences between our study and trastuzumab deruxtecan DESTINY-Lung01 study, is that our study included patients with both mutations and amplification and our study did not include any cytotoxic drug. And I believe that was one of the big differences, which may make the results of our study intriguing and potentially useful to patients who may not be able to tolerate a cytotoxic agent. Because, as you know, fam-trastuzumab-deruxtecan has the cytotoxic binder. It's an ADC and has been known to have some toxicities. And the thing about lung cancer is that these patients are relatively frail and may not be able to tolerate it. And so, that's one of the major differences, a portion at least for this combination, even though the response rates are much smaller than what we see with fam-trastuzumab-deruxtecan. Dr. Abdul Rafeh Naqash: And from your practice, have you started using this combination from your study as a potential approach for individuals who may not be candidates for trastuzumab deruxtecan in your clinic? Dr. Apar Kishor Ganti: I have not as yet because I have not come across a patient who would be eligible for this combination. In my practice, as we have TAPUR open, we have the tucatinib-trastuzumab arm that opened after this arm closed. So my priority is to try and enroll patients onto that cohort. And so I currently have one patient on that. And as you know, this is not a very common alteration, so we don't have as many patients with this. But definitely, this would be a combination that I would put patients on if I felt that they were not a candidate for fam-trastuzumab-deruxtecan.  Dr. Abdul Rafeh Naqash: So, Dr. Ganti, what's the next step after this since your study didn't meet some of its endpoints? What are you planning, or is there a plan to expand on this through the TAPUR mechanism?   Dr. Apar Kishor Ganti: Right now, I don't think that there's a mechanism through TAPUR to expand this particular cohort because there is also another cohort that opened subsequently with tucatinib and trastuzumab. But I think it would not be unreasonable to study this combination in patients who are not candidates for fam-trastuzumab because of the differences in toxicity. So that would be where I would potentially see a role for this particular combination, and I think it should be studied in that setting. Dr. Abdul Rafeh Naqash: Excellent. Now, I try to dedicate a section of this conversation for provocative discussions that may not be addressed in your paper, but I still like to get insights from experts in the field such as yourself. So comparing it to the NCI-MATCH or some other precision medicine-based initiatives, we do often see that mutations that we think might be driving the process don't necessarily lead to really high or really promising responses to targeted therapies. So in this case, do you think, from a futuristic standpoint, a proteomic-based assay, since I think you work in the proteomic space as well, that would be an interesting way to look at whether signaling actually is altered from a mutation or an amplification, suggesting that that is driving the process, so would be a more attractive target than just looking at a mutational signature?  Dr. Apar Kishor Ganti: I think definitely that should be the way we should be looking at these kinds of studies, because even in this study, even if you look at fam-trastuzumab-deruxtecan and the DESTINY-Lung01 study, we have patients who have definite, identified drivers, and even there, only about half of the patients responded. It was much smaller in our study. But basically what I'm getting at is with the best of the drugs that we have today, only half of our patients respond with HER-2 mutations, for example. So I would definitely favor a more integrated approach to identifying those patients who would be candidates for these targeted agents and not just simply relying on a specific mutation.  Since we are being provocative, I would go one step further and say, “Hey, we have AI. And there are currently AI-based technologies which look at the entire next-generation sequencing profile and try to identify which drugs could potentially be effective in those patients based on a complete understanding of their entire tumor genetic profile, rather than just looking at one or two, or three mutations.” So that, I think, would be a much more robust approach through precision medicine. So, like you just said, that patient that we had who had a prolonged response, we don't know why he or she had a prolonged response. And maybe if we identified a pathway or pathways which were overexpressed or more active in that particular tumor setting, we would be able to identify better targets and better approaches for those patients. So I think that is the way to go in the future. Dr. Abdul Rafeh Naqash: Excellent. Thanks for indulging into that provocative discussion and hopefully maybe five years down the line when we meet again or run across each other at ASCO, we will say, “Oh, it did actually happen, that multiomics is being used in a way that is suited for the need of the patient.” So matching the right patient to the right therapy at the right time.  So, Dr. Ganti, the last section is going to be dedicated to you as an individual. So you've had a very successful, brilliant career as a clinical trialist and as a lung cancer expert. Tell us, for the sake of our listeners and perhaps some of the early career junior investigators, what your career trajectory has been briefly, and what are some of the things that you felt were successful that could provide advice and insights to people who are earlier in their careers and trying to emulate what perhaps you have done or you are doing?  Dr. Apar Kishor Ganti: Well, that is a big one. I never thought of myself as being a role model for anyone, far less someone who's at the beginning of their career. But what I have always mentioned to students and residents and fellows is basically there is no substitute for hard work. Luck plays some role in this because you need to be at the right place at the right time for some of it, but hard work definitely will pay off. And the other thing that is important is not to get disheartened if your first clinical trial gets rejected or concept gets rejected, or if your first grant gets unscored. That is part of life, and persisting is probably the best way to continue.   Also, continuing to believe in yourself. I've seen a lot of folks, especially once they get into their second or third year after fellowship when things are not going the way they want to, they start to wonder, “Am I suited for this job? Am I the right person? Am I doing this correctly? Should I be doing something else?” And I think it's just a matter of time before they will find success. And also, the other thing is, if one particular approach does not work, there are always other ways that you can look at. So, for example, if you extend a bunch of clinical trial concepts that do not work out, you could potentially look at other ways of answering questions. For example, you could do retrospective analyses, come up with provocative, hypothetical generating questions that could be answered in the future in a prospective study. So there are lots of avenues to do that. And I think I was benefited by my mentors who helped me see this relatively early in my career. Dr. Abdul Rafeh Naqash: Thank you so much, Dr. Ganti, for all those valuable insights that you've learned over your career and hopefully will help some of the listeners. Before we finish, I'm going to ask you three rapid-fire questions that hopefully will let our listeners--give them a little bit of a sneak peek into you as a person. And you get like five seconds for each question. And they're not complicated questions. My first question to you is what is your favorite food? Dr. Apar Kishor Ganti: Thai food. Dr. Abdul Rafeh Naqash: What is your favorite place to go for vacation?  Dr. Apar Kishor Ganti: South Africa.  Dr. Abdul Rafeh Naqash: And what is your favorite hobby?  Dr. Apar Kishor Ganti: Reading.  Dr. Abdul Rafeh Naqash: Well, thank you so much again, Dr. Ganti. This was a very interesting conversation and hopefully, when you or others have other TAPUR-related trial results, perhaps they will again choose JCO PO as a destination for that work.  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/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.   Guest Bio: Dr. Apar Kishor Ganti, MD, MS, is professor of medicine and Associate Director of Clinical Research, Fred & Pamela Buffett Cancer Center at the University of Nebraska Medical Center and Staff Physician at VA Nebraska Western Iowa Health Care System.   Guest COIs: Apar Kishor Ganti, MD, MS Consulting or Advisory Role: AstraZeneca, Jazz Pharmaceuticals, Flagship Biosciences, Cardinal Health, Sanofi Genzyme, Regeneron, Eisai Research Funding: Apexigen (Inst), NEKTAR Pharmaceuticals (Inst), TopAlliance BioSciences Inc (Inst), Novartis (Inst), Iovance (Inst), Mirati Therapeutics (Inst), Chimeric Therapeutics (Inst)  

Go online to PeerView.com/MVQ860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. In this activity, an expert in oncology discusses the latest advances with next-generation ROS1 and TRK inhibitors in treatment-naïve and pretreated ROS1 or NTRK fusion–positive NSCLC and other tumors, and provides practical, case-based guidance on how to incorporate these agents into management plans in the context of clinical practice and ongoing trials. Upon completion of this activity, participants should be better able to: Discuss the structure, characteristics, and mechanisms of action of novel tyrosine kinase inhibitors (TKIs) and their role in the treatment of ROS1/NTRK fusion–positive NSCLC and other solid tumors; Implement best practices for biomarker testing to identify patients with ROS1/NTRK fusion–positive NSCLC or other solid tumors who might benefit from novel TKIs; and Select optimal therapy for individual patients with newly-diagnosed or TKI-resistant ROS1/NTRK fusion–positive NSCLC or other solid tumors in the context of clinical practice or clinical trial participation.

Go online to PeerView.com/MVQ860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. In this activity, an expert in oncology discusses the latest advances with next-generation ROS1 and TRK inhibitors in treatment-naïve and pretreated ROS1 or NTRK fusion–positive NSCLC and other tumors, and provides practical, case-based guidance on how to incorporate these agents into management plans in the context of clinical practice and ongoing trials. Upon completion of this activity, participants should be better able to: Discuss the structure, characteristics, and mechanisms of action of novel tyrosine kinase inhibitors (TKIs) and their role in the treatment of ROS1/NTRK fusion–positive NSCLC and other solid tumors; Implement best practices for biomarker testing to identify patients with ROS1/NTRK fusion–positive NSCLC or other solid tumors who might benefit from novel TKIs; and Select optimal therapy for individual patients with newly-diagnosed or TKI-resistant ROS1/NTRK fusion–positive NSCLC or other solid tumors in the context of clinical practice or clinical trial participation.

Go online to PeerView.com/MVQ860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. In this activity, an expert in oncology discusses the latest advances with next-generation ROS1 and TRK inhibitors in treatment-naïve and pretreated ROS1 or NTRK fusion–positive NSCLC and other tumors, and provides practical, case-based guidance on how to incorporate these agents into management plans in the context of clinical practice and ongoing trials. Upon completion of this activity, participants should be better able to: Discuss the structure, characteristics, and mechanisms of action of novel tyrosine kinase inhibitors (TKIs) and their role in the treatment of ROS1/NTRK fusion–positive NSCLC and other solid tumors; Implement best practices for biomarker testing to identify patients with ROS1/NTRK fusion–positive NSCLC or other solid tumors who might benefit from novel TKIs; and Select optimal therapy for individual patients with newly-diagnosed or TKI-resistant ROS1/NTRK fusion–positive NSCLC or other solid tumors in the context of clinical practice or clinical trial participation.

Go online to PeerView.com/MVQ860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. In this activity, an expert in oncology discusses the latest advances with next-generation ROS1 and TRK inhibitors in treatment-naïve and pretreated ROS1 or NTRK fusion–positive NSCLC and other tumors, and provides practical, case-based guidance on how to incorporate these agents into management plans in the context of clinical practice and ongoing trials. Upon completion of this activity, participants should be better able to: Discuss the structure, characteristics, and mechanisms of action of novel tyrosine kinase inhibitors (TKIs) and their role in the treatment of ROS1/NTRK fusion–positive NSCLC and other solid tumors; Implement best practices for biomarker testing to identify patients with ROS1/NTRK fusion–positive NSCLC or other solid tumors who might benefit from novel TKIs; and Select optimal therapy for individual patients with newly-diagnosed or TKI-resistant ROS1/NTRK fusion–positive NSCLC or other solid tumors in the context of clinical practice or clinical trial participation.

Go online to PeerView.com/MVQ860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. In this activity, an expert in oncology discusses the latest advances with next-generation ROS1 and TRK inhibitors in treatment-naïve and pretreated ROS1 or NTRK fusion–positive NSCLC and other tumors, and provides practical, case-based guidance on how to incorporate these agents into management plans in the context of clinical practice and ongoing trials. Upon completion of this activity, participants should be better able to: Discuss the structure, characteristics, and mechanisms of action of novel tyrosine kinase inhibitors (TKIs) and their role in the treatment of ROS1/NTRK fusion–positive NSCLC and other solid tumors; Implement best practices for biomarker testing to identify patients with ROS1/NTRK fusion–positive NSCLC or other solid tumors who might benefit from novel TKIs; and Select optimal therapy for individual patients with newly-diagnosed or TKI-resistant ROS1/NTRK fusion–positive NSCLC or other solid tumors in the context of clinical practice or clinical trial participation.

Go online to PeerView.com/MVQ860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. In this activity, an expert in oncology discusses the latest advances with next-generation ROS1 and TRK inhibitors in treatment-naïve and pretreated ROS1 or NTRK fusion–positive NSCLC and other tumors, and provides practical, case-based guidance on how to incorporate these agents into management plans in the context of clinical practice and ongoing trials. Upon completion of this activity, participants should be better able to: Discuss the structure, characteristics, and mechanisms of action of novel tyrosine kinase inhibitors (TKIs) and their role in the treatment of ROS1/NTRK fusion–positive NSCLC and other solid tumors; Implement best practices for biomarker testing to identify patients with ROS1/NTRK fusion–positive NSCLC or other solid tumors who might benefit from novel TKIs; and Select optimal therapy for individual patients with newly-diagnosed or TKI-resistant ROS1/NTRK fusion–positive NSCLC or other solid tumors in the context of clinical practice or clinical trial participation.

In this episode of the Epigenetics Podcast, we talked with Mary Gehring from MIT about her work on transgenerational inheritance and epigenetic imprinting in plants. Mary Gehring and her team are focusing on plant epigenetics and genetic imprinting in plants, studying DNA methylation in Arabidopsis. They have found significant differences in DNA methylation between the embryo and endosperm of plants, particularly in relation to imprinted genes. She also discusses their work on hydroxymethylcytosine (5-hmC) in Arabidopsis and the challenges of detecting and studying this epigenetic modification. Next, we discuss the regulatory circuit involving ROS1, a DNA glycosylase involved in demethylation, and its role in maintaining epigenetic homeostasis. The interview concludes with a discussion of CUT&RUN, which the lab has adapted for use in plants. Due to its low input requirements this method has been valuable in studying various plant tissues and has influenced Mary Gehring's research on imprinting in Arabidopsis endosperm.   References Gehring, M., Bubb, K. L., & Henikoff, S. (2009). Extensive demethylation of repetitive elements during seed development underlies gene imprinting. Science (New York, N.Y.), 324(5933), 1447–1451. https://doi.org/10.1126/science.1171609 Pignatta, D., Erdmann, R. M., Scheer, E., Picard, C. L., Bell, G. W., & Gehring, M. (2014). Natural epigenetic polymorphisms lead to intraspecific variation in Arabidopsis gene imprinting. eLife, 3, e03198. https://doi.org/10.7554/eLife.03198 Klosinska, M., Picard, C. L., & Gehring, M. (2016). Conserved imprinting associated with unique epigenetic signatures in the Arabidopsis genus. Nature plants, 2, 16145. https://doi.org/10.1038/nplants.2016.145 Zheng, X. Y., & Gehring, M. (2019). Low-input chromatin profiling in Arabidopsis endosperm using CUT&RUN. Plant reproduction, 32(1), 63–75. https://doi.org/10.1007/s00497-018-00358-1   Related Episodes The Role of Small RNAs in Transgenerational Inheritance in C. elegans (Oded Rechavi) Epigenetic Influence on Memory Formation and Inheritance (Isabelle Mansuy) The Epigenetics of Human Sperm Cells (Sarah Kimmins)   Contact Epigenetics Podcast on Twitter Epigenetics Podcast on Instagram Epigenetics Podcast on Mastodon Active Motif on Twitter Active Motif on LinkedIn Email: podcast@activemotif.com

Featuring perspectives from Dr Edward B Garon, Dr John V Heymach, Dr Corey J Langer, Dr Ticiana Leal, Dr David R Spigel and Dr Helena Yu, including the following topics: Incorporation of Immunotherapeutic Strategies into the Management of Nonmetastatic Non-Small Cell Lung Cancer (NSCLC) Introduction (0:00) Strategies to cope with platinum shortages (3:11) Selection of appropriate candidates for neoadjuvant chemoimmunotherapy (5:51) Current clinical role of adjuvant anti-PD-1/PD-L1 antibodies (11:03) Patient selection for and practical implementation of consolidation durvalumab (15:40) Faculty presentation: Dr Heymach (18:05) Contemporary Treatment for Localized or Metastatic NSCLC with an EGFR Mutation Adjuvant osimertinib for EGFR mutation-positive localized NSCLC (29:45) Potential implications of FLAURA2 (35:43) Promising investigational strategies for progressive EGFR-mutant disease (38:15) Sequencing of therapies for metastatic NSCLC with EGFR exon 20 insertion mutations (42:01) Faculty presentation: Dr Yu (46:07) Research Advances Shaping the Current and Future Treatment of Metastatic NSCLC with ALK Rearrangements, ROS1 Rearrangements or RET Fusions Selection of first- and later-line treatment for ALK-rearranged NSCLC (54:36) Role of RET-targeted therapy in current clinical practice (56:53) Selection of therapy for ROS1-positive NSCLC, including for patients with CNS involvement (59:30) Faculty presentation: Dr Langer (1:01:25) Targeting MET, HER2 and KRAS Alterations in NSCLC Current clinical role of trastuzumab deruxtecan in NSCLC (1:16:14) Therapeutic sequencing for NSCLC with KRAS G12C mutations (1:20:41) Management of MET exon 14 mutation-positive NSCLC (1:24:33) Faculty presentation: Dr Spigel (1:29:36) Current Management of Metastatic NSCLC without a Targetable Tumor Mutation Anti-PD-1/PD-L1 antibodies for patients for whom biomarker testing is pending (1:38:48) Selection of first-line therapy for newly diagnosed metastatic NSCLC without a targetable tumor mutation (1:41:13) Role of first-line immunotherapy in PD-L1-negative metastatic NSCLC (1:44:17) Implications of antibiotic use and autoimmune toxicity for checkpoint inhibitor efficacy (1:48:15) Faculty presentation: Dr Garon (1:53:41) Future Directions in the Management of Metastatic NSCLC Future directions in NSCLC: Tumor treating fields and datopotamab deruxtecan (2:04:14) Faculty presentation: Dr Leal (2:13:18) CME information and select publications

Dr. John Sweetenham and Dr. Neeraj Agarwal discuss advances across the spectrum of malignancies, including key studies in precision oncology and disparities in cancer care in advance of the 2023 ASCO Annual Meeting.  TRANSCRIPT Dr. John Sweetenham: Hello, I'm Dr. John Sweetenham, now the associate director for cancer network clinical affairs at UT Southwestern's Harold C. Simmons Comprehensive Cancer Center, and host of the ASCO Daily News Podcast. I'm delighted to welcome Dr. Neeraj Agarwal, director of the Genitourinary Oncology Program and a professor of medicine at the University of Utah Huntsman Cancer Institute, who is editor-in-chief of the ASCO Daily News.  Today we'll be discussing some key advances across the spectrum of malignancies, as well as novel approaches in precision medicine and cancer disparities that will be featured at the 2023 ASCO Annual Meeting.  Our full disclosures are available in the transcript of this episode, and disclosures of all guests on the podcast can be found on our transcripts at asco.org/DNpod.  Neeraj, it's great to have you back on the podcast today. Dr. Neeraj Agarwal: Thank you so much, John, for having me. Dr. John Sweetenham: Neeraj, let's begin by discussing some practice-changing phase 3 trials, starting with Abstract 5500, the KEYNOTE-826 study. This study reports the final overall survival results from a randomized, double-blind, phase 3 study of pembrolizumab plus chemotherapy versus placebo plus chemotherapy for first-line treatment of persistent, recurrent, or metastatic cervical cancer, which will be presented by Dr. Bradley Monk.  Dr. Neeraj Agarwal: I'd be happy to. The initial analysis of the KEYNOTE-826 study revealed that first-line pembrolizumab plus chemotherapy provided significant improvements in the overall survival and progression-free survival compared to placebo plus chemotherapy in patients with metastatic, persistent, or recurrent cervical cancer who had not previously received systemic chemotherapy and were not candidates for curative treatments such as surgery or radiation. In this study, patients were randomly assigned in a 1:1 ratio to receive pembrolizumab or placebo at 200 milligrams every three weeks for up to 35 cycles, along with chemotherapy with paclitaxel, plus a platinum therapy with or without bevacizumab.   From November 2018 to January 2020, 617 patients were enrolled with 308 receiving pembrolizumab plus chemotherapy and 309 patients receiving placebo plus chemotherapy. At the data cutoff of October 3, 2022, the median follow-up was 39 months. At this protocol-specified final overall survival analysis, pembrolizumab plus chemotherapy treatment continues to show a significant improvement in overall survival and progression-free survival, regardless of whether patients receive bevacizumab or not. The incidence of grade 3 or more adverse events was higher in the pembrolizumab plus chemotherapy arm than the placebo plus chemotherapy arm, with the most common adverse event being anemia, neutropenia, and hypertension. Dr. John Sweetenham: These are exciting data, Neeraj. So the main message from this trial is that pembrolizumab plus chemotherapy, with or without bevacizumab, can now be considered as standard of care for first-line treatment of persistent, recurrent, or metastatic cervical cancer. Dr. Neeraj Agarwal: Yes, I agree, John. Now, moving on to a different common type of cancer, let's discuss Abstract 1001, titled “Second-Line Endocrine Therapy with or without Palbociclib Maintenance in Patients with Hormone Receptor-Positive/HER2-Negative Advanced Breast Cancer: Results from the PALMIRA Trial,” which will be discussed by Dr. Antonio Llombart-Cussac. So, John, based on this abstract, can you please tell us about the role of palbociclib after prior progression on this drug? Dr. John Sweetenham: Yes. In this study, the authors aimed to determine if palbociclib maintenance with an alternative endocrine therapy improves the anti-tumor activity of second-line treatment in patients with endocrine-sensitive hormone receptor-positive and HER2-negative advanced breast cancer who had disease progression to first-line treatment with palbociclib in combination with endocrine therapy. After including 198 patients in the trial with a 2:1 randomization, 136 patients received palbociclib with endocrine therapy and 62 patients received endocrine therapy alone. And at a median follow-up of 8.7 months, the primary endpoint of progression-free survival was not met with a median progression-free survival of 4.2 months in the palbociclib-containing combination versus 3.6 months in the control arm. Also, higher grade 3 to 4 adverse events were reported in patients treated in the palbociclib arm. Dr. Neeraj Agarwal: Thanks, John. So you are saying that continuing the CDK4/6 inhibitor palbociclib after prior disease progression on palbociclib, even when the primary endocrine therapy has been changed, doesn't seem to be beneficial, therefore, this practice may be discouraged in the clinical setting? Dr. John Sweetenham: Yes, that's correct. Neeraj, I think that's the conclusion from this study. Dr. Neeraj Agarwal: So, John, now let's switch gears and highlight some precision oncology studies.  Dr. John Sweetenham: Well, Abstract 3602, titled “Real World Rates of FDA-Approved Targeted Therapy and Immunotherapy Prescriptions for Metastatic Colorectal Cancer Patients in the VA's National Precision Oncology Program” will be presented by Dr. Alice Nono Djosta. Can you tell us more about this abstract, Neeraj? Dr. Neeraj Agarwal: Well, comprehensive genomic profiling has the potential to guide the administration of FDA-approved biomarker-directed therapies and improve outcomes among patients with metastatic colorectal cancer. So, in this study, Abstract 3602, investigators sought to determine the rates of actionable biomarkers and prescription of associated FDA-approved therapies among veterans in the National Precision Oncology Program. Patients with metastatic colorectal cancer who had undergone comprehensive genomic profiling via tissue or liquid biopsy were included between 2019 and 2022 and had 1 of the following 5 actionable biomarker profiles including: NRAS, KRAS, BRAF wild-type, BRAF V600E mutation, MSI-high, TMB-high, NTRK fusion or rearrangements.  Prescription data for seven FDA-approved biomarker-directed therapies were extracted and rates of comprehensive genomic profiling (CGP)-directed therapy prescriptions were assessed by the investigators. A total of 908 patients with metastatic colorectal cancer underwent comprehensive genomic profiling, with 80% patients having colon adenocarcinoma and 20% with rectal adenocarcinoma. The combined rates of any actionable variants were 47% in patients with colon adenocarcinoma and 45% in patients with rectal adenocarcinoma. After including 424 eligible patients for FDA-approved biomarker therapy, only 70% patients with MSI-high, 48% patients with TMB-high, 38% patients with NRAS, KRAS, and BRAF wild-type, and only 17% of patients with BRAF V600E mutation received FDA-approved CGP-directed therapies.  Dr. John Sweetenham: Very important data, Neeraj. What's the main conclusion of this study? Dr. Neeraj Agarwal: So, in conclusion, this study found that almost 30% of patients with MSI-high metastatic colorectal cancer did not receive effective immune checkpoint inhibitors. And overall, a significant number of eligible patients did not receive FDA-approved biomarker-directed therapies. So, it is crucial that we evaluate the barriers to prescribing comprehensive genomic profiling-directed therapies in our patients with metastatic colorectal cancers.  So, John, let's move on to lung cancer, where the use of single-gene testing is still common in the community practice. Can you please tell us about Abstract 6506, titled “The Impact of Single-Gene Testing on Subsequent Comprehensive Genomic Profiling Success in Community Oncology Practice for Advanced Non–small Cell Lung Cancer”? These are results from a prospective observational reference laboratory testing program and these results will be presented by Dr. Mary Nesline. Dr. John Sweetenham: Yes, definitely. In this study, researchers aim to investigate the impact of prior single-gene testing on comprehensive genomic profiling success and therapeutic opportunities for patients with non–small cell lung cancer in community settings. They included patients who underwent at least 1 single gene testing for guideline recommending genomic variants in non–small cell lung cancer such as BRAF, EGFR, KRAS, MET exon 14 skipping mutations, ALK, RET, and ROS1 rearrangements as well as PD-L1 immunohistochemistry.  And they offered comprehensive genomic profiling either before or after receipt of a negative single gene test. Of 580 patients with non–small cell lung cancer with the comprehensive genomic profiling ordered between 2021 and 2022, around 30% of the patients had at least 1 single-gene testing ordered prior to the comprehensive testing, with a median of 5 prior single-gene tests. Compared to CGP-only cases. CGP per cases with prior negative single gene testing was canceled twice as often at tissue review, had a higher DNA extraction failure, and a lower DNA sequencing success. CGP also identified guideline-recommended variants in genes with no single-gene testing offered during the study period, such as ERBB2 mutations, or NTRK2/3 fusions, as well as variants targeted in ongoing clinical trials in 28% of patients. Dr. Neeraj Agarwal: Very interesting. So John, what is your key takeaway message from this? Dr. John Sweetenham: The main message is that in a community oncology setting, the practice of ordering single gene testing prior to comprehensive genomic profiling for patients with non–small cell lung cancer is common. Prior negative single-gene testing led to a higher rate of CGP test cancellation due to tissue insufficiency and increased CGP DNA extraction failures. The practice of single-gene testing does not align with practice guideline recommendations and may negatively impact the potential benefits of CGP testing for patients with non–small cell lung cancer.  Now, let's move on to another important abstract that our fellow clinicians should hear about. This is Abstract 1534 titled “Real-World Experience of an In-House Dihydropyrimidine Dehydrogenase Genotype Test to Guide Fluoropyrimidine Dosing at a Multi-Site Cancer Hospital” that will be presented by Dr. Jai Patel. Can you tell us more about this abstract, Neeraj? Dr. Neeraj Agarwal: Sure. Fluoropyrimidines, such as 5-fluorouracil and capecitabine, are commonly used to treat solid tumor cancers such as gastrointestinal and breast cancers. We know that severe toxicity occurs in one-third of patients, which delays the timely completion of treatments and result in prolonged hospitalization of these patients. These toxicities may be due in part to genetic variation in the DPYD gene. Five variants are known to have moderate to strong evidence according to the Clinical Pharmacogenetics Implementation Consortium. So, in this observational study, the authors describe the implementation of an in-house DPYD test and its impact on the dosing of these fluoropyrimidines, which include capecitabine and 5-fluorouracil.  From March 2020 to December 2022, 491 patients received DPYD genotyping testing, and 90% of them had gastrointestinal cancers. The median lab turnaround time was only 3 days. Pre-treatment testing was ordered in 80% of patients, and 93% of patients had results before starting cycle 1. Overall, 6% of patients were heterozygous carriers. Fluoropyrimidine dose was reduced, avoided, or discontinued in 90% of these patients. Moreover, in pre-treatment carriers, 90% of patients received an upfront dose reduction, avoidance, or they even declined chemotherapy. Dr. John Sweetenham: Thanks, Neeraj. So what do you think is the key takeaway message here? Dr. Neeraj Agarwal: So, DPYD genotype-guided dosing of fluoropyrimidine, including 5-fluorouracil and capecitabine, is logistically feasible with a rapid turnaround time and can result in treatment dose modifications for most carriers, potentially avoiding or mitigating severe toxicities, especially in those patients who received pre-treatment testing. Dr. John Sweetenham: Thanks again. Now let's transition to studies that focus on disparities in cancer care. Dr. Neeraj Agarwal: Definitely. Let's discuss Abstract 6530, titled “Impact of Free Hospital-Provided Rideshare Service on Radiation Therapy Completion Rates: A Matched Cohort Analysis.” In this study, Dr. Eric Chen and colleagues assess the potential of rideshare services in facilitating timely radiation therapy for patients facing barriers, such as limited transportation, financial constraints, and lack of adequate social support. So the authors analyzed data from about 2,900 patients who underwent radiation therapy and found that 58 of them utilized a free hospital-provided rideshare service.  These free hospital-provided rideshare service utilizers had a lower median age and were more likely to identify as Black or African American compared to those who did not utilize these services. They also had higher socioeconomic disadvantages and traveled shorter distances for treatment. Interestingly, more rideshare utilizers underwent radiation therapy with curative intent, had longer treatment course duration, and a higher number of fractions prescribed. In the matched-cohort analysis, the study found that radiation therapy completion rates were significantly higher for rideshare utilizers compared to non-rideshare utilizers, especially for patients who were undergoing radiation therapy with curative intent.  Dr. John Sweetenham: So what's the key take-home message from this abstract? Dr. Neeraj Agarwal: This study highlights the potential benefit of utilizing hospital-provided free ride-share services, particularly for patients facing barriers to timely treatment. So, using these services were associated with higher radiation therapy completion rates, especially in the curative setting.  So, John, there is another study, Abstract 1606, titled “Trends and Disparities in Oncology Telehealth after the Initial Pandemic Era” that will be presented by Dr. Michael Lee and colleagues. They evaluated whether telehealth utilization continued after the pandemic and if demographic differences in its users persist. So John, please tell us more about this abstract. Dr. John Sweetenham: Yes, the authors conducted a retrospective cohort study in 22 Kaiser Permanente Northern California hematology and oncology clinics between October 1, 2020, and June 1, 2022. The study investigated the use of office, video, and telephone visits, analyzing more than 340,000 hematology oncology visits with MD or DO providers. Of these visits, 25% were in-office, 37% were video visits, and 39% were telephone visits. Monthly telehealth visits peaked in January 2021, representing around 86% of total visits, and decreased to 69% of the total visits by June 2022. Video visits were more common for new appointments, whereas telephone visits were more common for return appointments. Moving to the post-pandemic period, telehealth visits remained popular, with video visits being the most commonly utilized. However, telehealth use varied among demographic populations. Video visits were a significantly higher proportion of all visits among individuals less than 45 years old, primary English speakers, patients with commercial insurance, non-Hispanic Whites and Asians, compared with Hispanic, Whites, and Blacks, and patients living in the deprived neighborhoods. Dr. Neeraj Agarwal: Interesting data, John. So what is the key takeaway message from this abstract? Dr. John Sweetenham: Well, overall, it's encouraging to see that even after the pandemic, telehealth continued to be widely used. However, the concerning issue is that telehealth is less utilized in patients who may need it most. The next step, in my view, will be to work on barriers to access telehealth by underprivileged populations.   And that brings our discussion to a close today. Before we wrap up the podcast, Neeraj, do you have any final thoughts to share? Dr. Neeraj Agarwal: Yes, thanks, John. I would urge our listeners to come and join us at the ASCO Annual Meeting, not only to celebrate these successes but also to help disseminate these cutting-edge data to practitioners and patients across the world. Dr. John Sweetenham: Absolutely. I'd like to thank our listeners for joining us today, and thank you, Neeraj, for sharing your insights with us as well.  You will find links to the abstracts discussed today on the transcripts of this episode. Finally, if you value the insights that you hear on 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. John Sweetenham Dr. Neeraj Agarwal @neerajaiims Follow ASCO on social media:   @ASCO on Twitter  ASCO on Facebook  ASCO on LinkedIn   Disclosures: Dr. John Sweetenham: Consulting or Advisory Role: EMA Wellness 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. Dwight Owen is back on the ASCO Guidelines podcast, discussing the latest updates to the ASCO living guidelines for stage IV NSCLC. In Part 1, Dr. Owen presents the update for stage IV NSCLC without driver alterations. He reviews new evidence from EMPOWER-Lung3 and POSEIDON and discusses new recommended options for patients with squamous cell carcinoma and non-squamous cell carcinoma, and PD-L1 tumor proportion score 0-49%. Read the update, “Therapy for Stage IV Non-Small Cell Lung Cancer Without Driver Alterations: ASCO Living Guideline, Version 2023.1” and view all recommendations at www.asco.org/living-guidelines. Listen to Part 2 for recommendations for patients with stage IV NSCLC with driver alterations. TRANSCRIPT This guideline, clinical tools, and resources are available at www.asco.org/living-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest disclosures in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO.23.00282  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 I'd like to welcome back Dr. Dwight Owen from Ohio State University in Columbus, Ohio, co-chair on ‘Therapy for Stage IV Non-Small-Cell Lung Cancer Without Driver Alterations: ASCO Living Guideline Version 2023.1'.   Thank you for being here, Dr. Owen. Dr. Dwight Owen: Thanks for having me, Brittany. Brittany Harvey: Then, before we discuss this update, 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. Owen on this episode, are available online, with a publication of the guideline in the Journal of Clinical Oncology linked in the show notes.   So then, diving into this update, this living clinical practice guideline for systemic therapy for patients with stage IV non-small cell lung cancer without driver alterations is being updated on a regular basis. What was the new evidence identified by the expert panel through routine literature searches to prompt an update to the recommendations? Dr. Dwight Owen: Yeah. Thanks, Brittany. I think it's really important to point out that these living guidelines are evidence-based. And so, we are constantly reviewing the literature to find new data to support recommendations for treatment options for clinicians to choose for their patients with metastatic non-small cell lung cancer. Clinicians these days, and physicians and oncologists are faced with so much information coming from abstracts to press releases to publications of new clinical trial results that it can be sometimes overwhelming to keep track of all the latest breakthroughs and nuances in the literature for non-small cell lung cancer.  So for this specific update, the panel and the committee reviewed two papers, including the EMPOWER Lung-3 Study and the POSEIDON Study. The EMPOWER Lung-3 study was a double-blind, placebo-controlled phase III study investigating cemiplimab plus platinum doublet chemotherapy as the first treatment for patients with either locally advanced stage III or stage IV non-small cell lung cancer without either an EGFR, ALK, or ROS1 alteration. And this is a mode of treatment that we've seen before, which is a PD-1 plus chemotherapy or PD-L1 plus chemotherapy compared to a chemotherapy control. And indeed, we did see an improvement in median overall survival in this study with the addition of cemiplimab to chemotherapy of almost 22 months versus 13 months with the placebo. This was accompanied by a higher rate of grade 3 or higher toxicities. But overall, these data were consistent with what we have seen with other studies of checkpoint inhibitor therapy plus chemotherapy in the first-line setting, which is now the current standard of care.  The second study we reviewed was the POSEIDON Study, and this was an open-label phase III study of combination checkpoint inhibitors. So this was PD-L1 plus CTLA-4, durvalumab + tremelimumab with chemotherapy versus chemotherapy alone, and these patients were metastatic non-small cell lung cancer without EGFR or ALK alterations. The interesting thing about this study is there was a cohort of patients treated with durvalumab plus chemotherapy alone. But it was really the cohort of patients treated with tremelimumab, durvalumab, and chemotherapy who had a significant improvement in median survival of 14 months versus 11.7 months with chemotherapy alone, with a hazard ratio of 0.77. In this study, the tremelimumab was only given for a total of five cycles, so it was not continued during the maintenance phase with durvalumab, which is a slight difference from other combination checkpoint inhibitor therapies, which are approved based on CheckMate 227 and CheckMate 9LA, which is nivolumab + ipilimumab.  So, overall, neither of these two studies present a new paradigm of treatment. But they present new treatment options for patients as a first-line treatment for non-small cell lung cancer in the form of either PD1/L1 plus chemotherapy or combined checkpoint inhibitor with a PD-L1 plus CTLA-4 plus chemotherapy, again showing improved survival compared to chemotherapy alone. Brittany Harvey: I appreciate you reviewing the details of those two trials. So then, based off this new data from the trials that you mentioned, EMPOWER Lung-3 and POSEIDON, what are the updated recommendations from the expert panel? Dr. Dwight Owen: So we felt it was important to update our prior recommendations for patients, especially with low to intermediate PD-L1 expression from 0% to 49%, that patients may offer cemiplimab plus chemotherapy as an additional treatment option in addition to the recommendations that have already been in place, regardless of histology. And then, based on the POSEIDON data, we felt that this was also a treatment option for those similar patients, especially with PD-L1 negative or up to 49%.  We do feel that the patients with PD-L1 TPS scores of 50% or higher still seem to benefit the most from checkpoint inhibitor monotherapy and multiple studies that have been done there. And so we did not make any changes to the recommendations for those patients with PD-L1 high non-small cell lung cancer.  Brittany Harvey: Understood. And then you just mentioned that neither of these therapies represent a paradigm change for treatment options. So what should clinicians know as they consider these new options in addition to previously recommended therapies? Dr. Dwight Owen: Yes. So I think when clinicians are looking at these studies, things to keep in mind are the size of the study, the cohorts included, the endpoints. The comparison arm, for now, remains chemotherapy alone, which again is no longer the standard of care. So we are sort of looking backwards at a historical standard of care that we no longer really confront other than for patients who have some contraindication to immunotherapy.   The other thing to keep in mind is, of course, when you add more treatments together, you expect more toxicities. And that is certainly the case when we see the dual combined checkpoint inhibitor therapies plus chemotherapy. Regardless of whether it's nivolumab + ipilimumab and chemotherapy or whether it's durvalumab + tremelimumab plus chemotherapy, we do expect a higher rate of toxicities when we do add the CTLA-4 to the PD1/L1 backbone.   And so this is a conversation that's really important to have with your patients. We don't have a head-to-head trial, so we are inferring differences in terms of response and benefit using the same comparison of chemotherapy but from different studies and also different populations. So that is probably one of the more important lessons to take from all of these studies is that we know that the toxicity rate does change depending on how you add therapies for these patients. And we also know that there are patients who may not need that additional therapy. So patient selection is key.   And I think one of the most unmet needs right now is for patients with PD-L1 negative tumors who don't seem to benefit from checkpoint inhibitor monotherapy or even in long term data when checkpoint inhibitor therapy is given just combined with chemotherapy, these patients seem to be the ones who don't benefit as much. And so I think that would be the patient population that really warrants that extra discussion where you may consider a more aggressive treatment depending on a patient's preference in terms of susceptibility, in terms of toxicity. Brittany Harvey: Absolutely. Considerations of the toxicity profiles of these agents is key for patient quality of life. That leads nicely into my next question, but what do these new recommended therapies mean for patients with stage IV non small cell lung cancer without driver alterations?  Dr. Dwight Owen: Well, I think, of course, it is beneficial to have more treatment options, but when we have more treatment options, the decision can actually become more challenging because how do you select from any of the treatment options that we have? And in the absence of direct head-to-head trials for now, we really need to look at the toxicity data, look at the outcome data, and see how the patient in front of you fits into the studies that have been done in order to make an inference and to have that informed discussion with the patient about what to expect from a specific treatment.   And I think the higher rates of immune toxicities that we see when we use combination checkpoint therapy needs to be a discussion with patients, and also the type of chemotherapy backbone and how long that chemotherapy will be continued. Whether it's two cycles like Checkmate 9LA, whether it's four cycles like POSEIDON, whether we have a non-chemotherapy option to offer patients, these are all nuances that right now lead to a really robust conversation with our patients up front. And really trying to guide patients through these discussions because the information can be so overwhelming when it's given at one time. So, really trying to have that meaningful conversation in a way that the patient can help advocate for themselves in the clinical decision-making.  Brittany Harvey: Definitely, those nuances are important for those individual discussions. So then, finally, you've mentioned that the panel is reviewing literature on an ongoing basis. So, what ongoing developments is this panel monitoring for future updates?  Dr. Dwight Owen: So, I think all of us are very excited about the announcements that we have been hearing, both in terms of press releases, in terms of abstracts at the upcoming ACR meeting, and of course, ASCO later this year, where we expect to have a wealth of new data for patients with non-small cell lung cancer, both in the metastatic setting but also in the early stage setting. And I think one of the challenges for us in this committee and for practicing oncologists every day is the speed at which this information is coming out and making sure that we have time to really review each study and give each study the time needed to understand how it can impact our treatment selection based on what's already an accepted practice and what maybe is something that we should reconsider.  And so I think it's very rewarding work to work with the committee members and the panel and ASCO. But it is also something that we take very seriously, just because data can come out so quickly at varying levels of detail. And we really want to make sure that when we make a guideline recommendation, that we are very clear that it is evidence-based and what that evidence is. Brittany Harvey: Absolutely, we appreciate the panel's evidence-based approach to developing these recommendations.  So, I want to thank you for your time working on this update and for coming on the podcast to speak with me today, Dr. Owen. Dr. Dwight Owen: Thanks very much, Brittany.  Brittany Harvey: And thank you to all of our listeners for tuning into ASCO Guidelines podcast series. To read the full guideline, go to www.asco.org/living-guidelines.  There's a companion living guideline update on therapy for stage IV non-small-cell lung cancer with driver alterations available there and in the JCO. You can also find many of our guidelines and interactive resources in the newly redesigned ASCO Guidelines app, available for free 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, experiences, 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.