Podcasts about adcs

Welcome to the Oncology Brothers podcast! In this episode, we dived into the key highlights from the SABCS 2025 conference, focusing on metastatic hormone receptor-positive breast cancer. Join us as we discussed: • The role of CDK4-6 inhibitors in frontline therapy, featuring updates from the AMBRE and MONALEESA-3 studies • Insights into second-line treatment options, including the VIKTORIA-1, evERA, EMBER-3, SERENA-6 trials • A critical look at the ASCENT-07 study, exploring the role of antibody-drug conjugates (ADCs) in endocrine-resistant disease We were thrilled to have Dr. Hope Rugo, a world-renowned breast medical oncologist from City of Hope, share her expertise and insights on these pivotal studies. Tune in for an informative discussion that unpacks the latest advancements in treatment options for metastatic hormone receptor-positive breast cancer, and learn how these findings may impact clinical practice. 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 check out our other episodes for more insights on treatment algorithms, recent approvals, and conference highlights! #SABCS2025 #MBC #HRpositive #CDK46 #ADCs #OncologyBrothers

Featuring perspectives from Dr Lisa A Carey and Dr Rita Nanda, including the following topics:  Overview: Molecular basis of antibody-drug conjugate (ADC) toxicities — Sequencing of ADCs and mechanisms of resistance (0:00) Case: A woman in her late 60s with localized triple-negative breast cancer develops myocarditis during neoadjuvant therapy with chemotherapy/pembrolizumab — Richard Zelkowitz, MD (8:22) Case: A woman in her mid 70s with recurrent ER-negative, HER2-low, PD-L1-positive metastatic breast cancer (mBC) who experiences disease progression on nab paclitaxel/atezolizumab responds to sacituzumab govitecan — Ranju Gupta, MD (26:43) Case: A woman in her early 80s with recurrent ER-positive, HER2-low (IHC 1+) mBC experiences disease progression on trastuzumab deruxtecan (T-DXd), then receives datopotamab deruxtecan and develops pulmonary symptoms — Laila Agrawal, MD (32:11) Data Review: T-DXd (37:51) Case: A woman in her early 70s with recurrent ER-positive, HER2-low (IHC 1+) mBC, including bladder metastases, experiences disease progression after palbociclib/letrozole, then capivasertib/fulvestrant, then nab paclitaxel — Justin Favaro, MD, PhD (44:02) Case: A woman in her late 70s with ER-positive, HER2-low mBC who experiences disease progression after 1 year of ribociclib/letrozole receives sacituzumab govitecan — Erik Rupard, MD (55:19) CME information and select publications

Good morning from Pharma Daily: the podcast that brings you the most important developments in the pharmaceutical and biotech world.In a dynamic landscape marked by both advancements and challenges, the pharmaceutical and biotech sectors continue to evolve with notable scientific, regulatory, and strategic updates. Ipsen's recent $1 billion acquisition of Simcere's preclinical LRRC15-targeting asset underscores a growing focus on antibody-drug conjugates (ADCs). These conjugates leverage the targeted action of antibodies combined with the cytotoxic effects of drugs, representing a promising approach to cancer treatment by potentially minimizing systemic toxicity. Ipsen's strategic move reflects its commitment to expanding its oncology portfolio and staying competitive within the rapidly advancing ADC landscape.AstraZeneca has been active in its pursuit of innovative cancer treatments. The company has invested $100 million in Jacobio's clinical-stage pan-KRAS inhibitor, a promising development targeting KRAS mutations prevalent in various cancers. This investment aligns with AstraZeneca's strategy to tackle challenging oncogenic targets. However, their efforts faced a setback as their Phase 3 trial for ceralasertib, an ATR inhibitor for lung cancer, failed to meet its primary endpoint. Despite this setback, AstraZeneca maintains confidence by investing significantly in promising areas like KRAS inhibitors, highlighting the inherent risks involved in pioneering novel therapeutic strategies, particularly those aiming to overcome resistance mechanisms in immuno-oncology.BioMarin has quietly discontinued its liver disease candidate amid a $4.8 billion deal with Amicus. This decision points to the complex nature of pipeline prioritization and resource allocation within high-stakes financial environments. The company's strategic shifts reflect ongoing evaluations of their development priorities in light of evolving market demands.Boehringer Ingelheim has demonstrated a commitment to renal therapeutics with a $448 million investment in Rectify Pharmaceuticals for a preclinical chronic kidney disease program. This partnership seeks to address significant unmet medical needs within kidney disease treatment. Meanwhile, Gilead Sciences has entered into a $35 million licensing agreement with Assembly Biosciences for herpes simplex virus (HSV) assets, diversifying its infectious disease portfolio and expanding its reach within antiviral therapies.Novo Holdings-backed Windward Bio's acquisition of rights to Qyun's clinical-stage immunology bispecifics for $700 million highlights robust activity in the immunology space. Bispecific antibodies are gaining traction due to their ability to target two antigens simultaneously, offering enhanced therapeutic efficacy. This acquisition illustrates ongoing interest in this area as companies seek innovative solutions to complex immunological challenges.The broader industry is also witnessing strategic partnerships such as Aditum Bio's launch of a new biotech venture with Fosun Pharma. This collaboration aims to foster novel therapies through a synergistic blend of biotechnology innovation and pharmaceutical expertise. These alliances reflect an industry trend towards collaborative efforts that leverage diverse strengths to advance therapeutic development.In regulatory news, nine major pharmaceutical companies have reached agreements with the U.S. government to lower certain drug prices in exchange for tariff relief. This development signals ongoing negotiations aimed at balancing drug affordability with industry sustainability amid growing scrutiny over pricing practices.In December 2025, significant developments emerged, impacting scientific innovation, regulatory approvals, mergers, and strategic partnerships across the industry. Notably, the U.S. Food and Drug Administration (FDA) granted early approval to Cytokinetics' MyqorzSupport the show

In this episode of the Oncology Brothers podcast, we are joined by Dr. Komal Jhaveri, a breast medical oncologist at Memorial Sloan Kettering, to discuss the evolving landscape of metastatic hormone receptor positive breast cancer, particularly focusing on low and ultra-low HER2 expression. Key topics include: • The significance of the DESTINY Breast-04 and DESTINY Breast-06 studies and their impact on treatment options. • The definition and implications of low and ultra-low HER2 expression in clinical practice. • The importance of HER2 testing and the dynamic nature of HER2 expression in tumors. • Treatment sequencing strategies, including the use of antibody-drug conjugates (ADCs) like trastuzumab deruxtecan (TDXd) and sasituzumab govitecan. • Management of treatment-related toxicities, including ILD, nausea, and alopecia. Join us for an insightful discussion that aims to keep healthcare professionals updated on the latest advancements in cancer care. Follow us on social media: •⁠  ⁠X/Twitter: https://twitter.com/oncbrothers •⁠  ⁠Instagram: https://www.instagram.com/oncbrothers •⁠  Website: https://oncbrothers.com/ Don't forget to subscribe for more episodes and insights!

JCO PO author Dr. Shilpa Gupta at Cleveland Clinic Children's Hospital shares insights into her article, "Fibroblast Growth Factor Receptor 3 (FGFR3) Alteration Status and Outcomes on Immune Checkpoint Inhibitors (ICPI) in Patients with Metastatic Urothelial Carcinoma". Host Dr. Rafeh Naqash and Dr. Gupta discuss how FGFR3 combined with TMB emerged as a biomarker that may be predictive for response to ICPI in mUC. TRANSCRIPT Dr. Rafeh Naqash: Hello and welcome to JCO Precision Oncology Conversations, where we bring you engaging conversations with authors of clinically relevant and highly significant JCO PO articles. I'm your host, Dr. Rafeh Naqash, podcast editor for JCO Precision Oncology and Associate Professor at the OU Health Stephenson Cancer Center. Today I am excited to be joined by Dr. Shilpa Gupta, Director of Genitourinary Medical Oncology at the Cancer Institute and co-leader of the GU Oncology Program at the Cleveland Clinic, and also lead author of the JCO PO article titled "Fibroblast Growth Factor Receptor 3 Alteration Status and Outcomes on Immune Checkpoint Inhibitors in Patients With Metastatic Urothelial Carcinoma." At the time of this recording, our guest's disclosures will be linked in the transcript. Shilpa, welcome again to the podcast. Thank you for joining us today. Dr. Shilpa Gupta: Thank you, Rafeh. Honor to be here with you again. Dr. Rafeh Naqash: It is nice to connect with you again after two years, approximately. I think we were in our infancy of our JCO PO podcast when we had you first time, and it has been an interesting journey since then. Dr. Shilpa Gupta: Absolutely. Dr. Rafeh Naqash: Well, excited to talk to you about this article that you published. Wanted to first understand what is the genomic landscape of urothelial cancer in general, and why should we be interested in FGFR3 alterations specifically? Dr. Shilpa Gupta: Bladder cancer or urothelial cancer is a very heterogeneous cancer. And while we find there is a lot of mutations can be there, you know, like BRCA1, 2, in HER2, in FGFR, we never really understood what is driving the cancer. Like a lot of old studies with targeted therapies did not really work. For example, we think VEGF can be upregulated, but VEGF inhibitors have not really shown definite promise so far. Now, FGFR3 receptor is the only therapeutic target so far that has an FDA approved therapy for treating metastatic urothelial cancer patients, and erdafitinib was approved in 2019 for patients whose tumors overexpressed FGFR3 mutations, alterations, or fusions. And in the landscape of bladder cancer, it is important because in patients with non-muscle invasive bladder cancer, about 70 to 80% patients can have this FGFR3. But as patients become metastatic, the alterations are seen in, you know, only about 10% of patients. So the clinical trials that got the erdafitinib approved actually used archival tumor from local cancer. So when in the real world, we don't see a lot of patients if we are trying to do metastatic lesion biopsies. And why it is important to know this is because that is the only targeted therapy available for our patients right now. Dr. Rafeh Naqash: Thank you for giving us that overview. Now, on the clinical side, there is obviously some interesting data for FGFR3 on the mutation side and the fusion side. In your clinical practice, do you tend to approach these patients differently when you have a mutation versus when you have a fusion? Dr. Shilpa Gupta: We can use the treatment regardless of that. Dr. Rafeh Naqash: I recently remember I had a patient with lung cancer, squamous lung cancer, who also had a synchronous bladder mass. And the first thought from multiple colleagues was that this is metastatic lung. And interestingly, the liquid biopsy ended up showing an FGFR3-TACC fusion, which we generally don't see in squamous lung cancers. And then eventually, I was able to convince our GU colleagues, urologists, to get a biopsy. They did a transurethral resection of this tumor, ended up being primary urothelial and synchronous lung, which again, going back to the FGFR3 story, I saw in your paper there is a mention of FGFR3-TACC fusions. Anything interesting that you find with these fusions as far as biology or tumor behavior is concerned? Dr. Shilpa Gupta: We found in our paper of all the patients that were sequenced that 20% had the pathognomonic FGFR3 alteration, and the most common were the S249C, and the FGFR3-TACC3 fusion was in 45 patients. And basically I will say that we didn't want to generate too much as to fusion or the differences in that. The key aspect of this paper was that historically there were these anecdotal reports saying that patients who have FGFR alterations or mutations, they may not respond well to checkpoint inhibitors because they have the luminal subtype. And these were backed by some preclinical data and small anecdotal reports. But since then, we have seen that, and that's why a lot of people would say that if somebody's tumor has FGFR3, don't give them immunotherapy, give them erdafitinib first, right? So then we had this Phase 3 trial called the THOR trial, which actually showed that giving erdafitinib before pembrolizumab was not better. That debunked that myth, and we are actually reiterating that because in our work we found that patients who had FGFR3 alterations or fusions, and if they also have TMB-high, they actually respond very well to single agent immunotherapy. And that is, I think, very important because it tells us that we are not really seeing that so-called potential of resistance to immunotherapy in these patients. So to answer your question, yeah, we did see those differences, but I wouldn't say that any one marker is more prominent. Dr. Rafeh Naqash: The analogy is kind of similar to what we see in lung cancer with these mutations called STK11/KEAP1, which are also present in some other tumors. And one of the questions that I don't think has been answered is when you have in lung cancer, if you extrapolate this, where doublet or single agent immunotherapy doesn't do as well in tumors that are STK11 mutated. But then if you have a high TMB, question is does that TMB supersede or trump the actual mutation? Could that be one reason why you see the TMB-high but FGFR3 altered tumors in your dataset responding or having better outcomes to immunotherapy where potentially there is just more neoantigens and that results in a more durable or perhaps better response to checkpoint therapy? Dr. Shilpa Gupta: It could be. But you know, the patients who have FGFR alterations are not that many, right? So we have already seen that just patients with TMB-high respond very well to immunotherapy. Our last podcast was actually on that, regardless of PD-L1 that was a better predictor of response to immunotherapy. So I think it's not clear if this is adding more chances of response or not, because either way they would respond. But what we didn't see, which was good, that if they had FGFR3, it's not really downplaying the fact that they have TMB-high and that patients are not responding to immunotherapy. So we saw that regardless, and that was very reassuring. Dr. Rafeh Naqash: So if tomorrow in your clinic you had an individual with an FGFR3 alteration but TMB-high, I guess one could be comfortable just going ahead with immunotherapy, which is what the THOR trial as you mentioned. Dr. Shilpa Gupta: Yes, absolutely. And you know, when you look at the toxicity profiles of pembrolizumab and erdafitinib, really patients really struggle with using the FGFR3 inhibitors. And of course, if they have to use it, we have to, and we reserve it for patients. But it's not an easy drug to tolerate. Currently the landscape is such that, you know, frontline therapy has now evolved with an ADC and immunotherapy combinations. So really if patients progress and have FGFR3 alterations, we are using erdafitinib. But let's say if there were a situation where a patient has had chemotherapy, no immunotherapy, and they have FGFR3 upregulation and TMB-high, yes, I would be comfortable with using only pembrolizumab. And that really ties well together what we saw in the THOR trial as well. Dr. Rafeh Naqash: Going to the clinical applications, you mentioned a little bit of this in the manuscript, is combination therapies. You alluded to it a second back. Everything tends to get combined with checkpoint therapy these days, as you've seen with the frontline urothelial, pembrolizumab with an ADC. What is the landscape like as far as some of these FGFR alterations are concerned? Is it reasonable to combine some of those drugs with immune checkpoint therapy? And what are some of the toxicity patterns that you've potentially seen in your experience? Dr. Shilpa Gupta: So there was indeed a trial called the NORSE trial. It was a randomized trial but not a comparative cohort, where they looked at FGFR altered patients. And when they combined erdafitinib plus cetrelimab, that did numerically the response rates were much higher than those who got just erdafitinib. So yeah, the combination is definitely doable. There is no overlapping toxicities. But unfortunately that combination has not really moved forward to a Phase 3 trial because it's so challenging to enroll patients with such kind of rare mutations on large trials, especially to do registration trials. And since then the frontline therapy has evolved to enfortumab vedotin and pembrolizumab. I know there is an early phase trial looking at a next generation FGFR inhibitor. There is a triplet combination looking in Phase 1 setting with a next generation FGFR inhibitor with EV-pembro. However, it's not a randomized trial. So you know, I worry about such kinds of combinations where we don't have a path for registration. And in the four patients that have been treated, four or five patients in the early phase as a part of basket trial, the toxicities were a lot, you know, when you combine the EV-pembro and an FGFR3 inhibitor, we see more and more toxicity. So the big question is do we really need the "kitchen sink" approach when we have a very good doublet, or unless the bar is so high with the doublet, like what are we trying to add at the expense of patient toxicity and quality of life is the big question in my mind. Dr. Rafeh Naqash: Going back to your manuscript specifically, there could be a composite biomarker. You point out like FGFR in addition to FGFR TMB ends up being predictive prognostic there. So that could potentially be used as an approach to stratify patients as far as treatment, whether it's a single agent versus combination. Maybe the TMB-low/FGFR3 mutated require a combination, but the TMB-high/FGFR mutated don't require a combination, right? Dr. Shilpa Gupta: No, that's a great point, yeah. Dr. Rafeh Naqash: But again, very interesting, intriguing concepts that you've alluded to and described in this manuscript. Now, a quick take on how things have changed in the bladder cancer space in the last two years. We did a podcast with you regarding some biomarkers as you mentioned two years back. So I really would like to spend the next minute to two to understand how have things changed in the bladder cancer space? What are some of the exciting things that were not there two years back that are in practice now? And how do you anticipate the next two years to be like? Maybe we'll have another podcast with you in another two years when the space will have changed even more. Dr. Shilpa Gupta: Certainly a lot has happened in the two years, you know. EV-pembro became the universal frontline standard, right? We have really moved away from cisplatin eligibility in metastatic setting because anybody would benefit from EV-pembro regardless of whether they are candidates for cisplatin or not, which historically was relevant. And just two days ago, we saw that EV-pembro has now been approved for localized bladder cancer for patients who are cisplatin ineligible or refusing. So, you know, this very effective regimen moving into earlier setting, we now have to really think of good treatment options in the metastatic setting, right? So I think that's where a lot of these novel combinations may come up. And what else we've seen is in a tumor agnostic trial called the DESTINY-PanTumor trial, patients who had HER2 3+ on immunohistochemistry, we saw the drug approval for T-DXd, and I think that has kind of reinvigorated the interest in HER2 in bladder cancer, because in the past targeting HER2 really didn't work. And we still don't know if HER2 is a driver or not. And at ESMO this year, we saw an excellent study coming out of China with DV which is targeting HER2, and toripalimab, which is a Chinese checkpoint inhibitor, showing pretty much similar results to what we saw with EV-pembro. Now, you know, not to do cross-trial comparisons, but that was really an amazing, amazing study. It was in the presidential session. And I think the big question is: does that really tell us that HER2-low patients will not benefit? Because that included 1+, 2+, 3+. So that part we really don't know, and I think we want to study from the EV-302 how the HER2 positive patients did with EV and pembro. So that's an additional option, at least in China, and hopefully if it gets approved here, there is a trial going on with DV and pembro. And lastly, we've seen a very promising biomarker, like ctDNA, for the first time in bladder cancer in the adjuvant setting guiding treatment with adjuvant atezolizumab. So patients who were ctDNA positive derived overall survival and recurrence-free survival benefit. So that could help us select moving forward with more studies. We can spare unnecessary checkpoint inhibitors in patients who are not going to benefit. So I think there is a lot happening in our field, and this will help do more studies because we already have the next generation FGFR inhibitors which don't have the toxicities that erdafitinib comes with. And combining those with these novel ADCs and checkpoint inhibitors, you know, using maybe TMB as a biomarker, because we really need to move away from PD-L1 in bladder cancer. It's shown no utility whatsoever, but TMB has. Dr. Rafeh Naqash: Well, thank you so much, Shilpa, for that tour de force of how things have changed in bladder cancer. There used to be a time when lung and melanoma used to lead this space in terms of the number of approvals, the biomarker development. It looks like bladder cancer is shifting the trend at this stage. So definitely exciting to see all the new changes that are coming up. I'd like to spend another minute and a half on your career. You've obviously been a leader and example for many people in the GU space and beyond. Could you, for the sake of our early career especially, the trainees and other listeners, describe how you focused on things that you're currently leading as a leader, and how you shaped your career trajectory over the last 10 years? Dr. Shilpa Gupta: That's a really important question, Rafeh, and you and I have had these discussions before, you know, being an IMG on visas like you, and being in different places. I think I try to make the most of it, you know, instead of focusing on the setbacks or the negative things. Like tried to grab the opportunities that came along. When I was at Moffitt, got to get involved with the Phase 1 trial of pembrolizumab in different tumor types. And just keeping my options open, you know, getting into the bladder cancer at that time when I wanted to really do only prostate, but it was a good idea for me to keep my options open and got all these opportunities that I made use of. I think an important thing is to, like you said, you know, have a focus. So I am trying to focus more on biomarkers that, you know, we know that 70% patients will respond to EV-pembro, right? But what about the remaining 30%? Like, so I'm really trying to understand what determines hyperprogressors with such effective regimens who we really struggle with in the clinic. They really don't do well with anything we give them after that. So we are doing some work with that and also trying to focus on PROs and kind of patient-reported outcomes. And a special interest that I've now developed and working on it is young-onset bladder cancer. You know, the colorectal cancer world has made a lot of progress and we are really far behind. And bladder cancer has historically been a disease of the elderly, which is not the case anymore. We are seeing patients in their 30s and 40s. So we launched this young-onset bladder cancer initiative at a Bladder Cancer Advocacy Network meeting and now looking at more deep dive and creating a working group around that. But yeah, you know, I would say that my philosophy has been to just take the best out of the situation I'm in, no matter where I am. And it has just helped shape my career where I am, despite everything. Dr. Rafeh Naqash: Well, thank you again. It is always a pleasure to learn from your experiences and things that you have helped lead. Appreciate all your insights, and thank you for publishing with JCO PO. Hopefully we will see more of your biomarker work being published and perhaps bring you for another podcast in a couple of years. Dr. Shilpa Gupta: Yeah, thank you, Rafeh, for the opportunity. And thanks to JCO PO for making these podcasts for our readers. So thanks a lot. Dr. Rafeh Naqash: 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. DISCLOSURES Dr. Shilpa Gupta Stock and Other Ownership Interests: Company: BioNTech SE,  Nektar Consulting or Advisory Role: Company: Gilead Sciences, Pfizer, Merck, Foundation Medicine, Bristol-Myers Squibb/Medarex, Natera, Astellas Pharma, AstraZeneca, Novartis, Johnson & Johnson/Janssen Research Funding: Recipient: Your Institution Company: Bristol Myers Squibb Foundation, Merck, Roche/Genentech, EMD Serono, Exelixis, Novartis, Tyra Biosciences, Pfizer, Convergent Therapeutics, Acrivon Therapeutics, Flare Therapeutics, Amgen Travel, Accommodations, Expenses: Company: Pfizer, Astellas Pharma, Merck    

Please visit answersincme.com/860/99120473-replay to participate, download slides and supporting materials, complete the post test, and get a certificate. In this activity, experts in oncology discuss the latest advances in HER2- and TROP2-directed ADCs for the management of advanced NSCLC, and how these approved and emerging ADCs may impact patients' treatment algorithms. Upon completion of this activity, participants should be better able to: Identify the rationale for targeting HER2 and TROP2 in the treatment of non-small cell lung cancer (NSCLC; Discuss the clinical impact of approved and emerging HER2- and TROP2-directed antibody-drug conjugates (ADCs) in NSCLC; and Formulate evidence-based strategies for the individualized management of patients with NSCLC using HER2- and TROP2-directed ADCs.

“Twenty years ago, who knew that ADCs and next-generation bioconjugates were going to be so exciting, so successful?”Campbell Bunce, Chief Scientific Officer at Abzena, reflects on the strategic positioning that has placed his company at the forefront of one of pharma's fastest-growing segments.Campbell leads a global team spanning discovery, development, and GMP manufacturing at Abzena, where he has spent nearly a decade building the company's capabilities in complex modalities. His background as an immunologist, combined with 18 years in biotech before joining Abzena, gives him a unique perspective on translating scientific innovation into commercial manufacturing reality.In this conversation on the PharmaSource podcast, Campbell discusses Abzena's strategic focus on antibody-drug conjugates (ADCs) and bioconjugates, the company's approach to proprietary platform development, and how the CDMO is responding to increased demand driven by geopolitical manufacturing shifts and clinical successes in the space.Read more.

In this episode of the Oncology Brothers podcast, we dived deep into the world of antibody drug conjugates (ADCs) in non-small cell lung cancer (NSCLC). We welcomed Dr. Jacob Sands from the Dana-Farber Cancer Institute to discuss the latest ADCs approved for NSCLC, including Trastuzumab deruxtecan (TDXd), Datopotamab deruxtecan (Dato-DXd), and Telisotuzumab Vedotin (Teliso-V). We explored the side effect profiles of these therapies, focusing on critical toxicities such as interstitial lung disease (ILD), mucositis, and peripheral neuropathy. Dr. Sands shared valuable clinical pearls on managing these adverse events, emphasized the importance of proactive monitoring and patient education. Key topics covered in this episode: • Overview of ADCs and their role in NSCLC treatment • TDXd: alopecia, ILD, fatigue, nausea/vomiting • Dato-DXd:  cytopenias, mucositis, dry eyes • Teliso-V: peripheral neuropathy, fatigue, peripheral edema • The evolving landscape of ADCs and future directions in lung cancer treatment Whether you're a healthcare professional or someone interested in oncology, this episode provides essential insights into the management of side effects associated with these innovative therapies. Tune in for practical advice and expert opinions that can enhance patient care in the community setting. 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 episodes on practice-changing discussions in oncology! #ADC #NSCLC #TDXd #DatoDXD #TelisoV #ToxicityManagement #OncologyBrothers

"I'll go back to the backpack analogy. When your kids come home with a backpack, all of a sudden their homework is not on the desk where it's supposed to be. It's in the kitchen; it kind of spreads all over the place, but it's still in the house. When we give antibody–drug conjugates (ADCs), the chemotherapy does go in, but then it can kind of permeate out of the cell membrane and something right next to it—another cancer cell that might not look exactly like the cancer cell that the chemotherapy was delivered into—is affected and the chemotherapy goes over to that cancer cell and kills it," ONS member Marisha Pasteris, OCN®, office practice nurse in the breast medicine service at Memorial Sloan Kettering Cancer Center in New York, NY, told Jaime Weimer, MSN, RN, AGCNS-BS, AOCNS®, manager of oncology nursing practice at ONS, during a conversation about ADCs in metastatic breast cancer. Music Credit: "Fireflies and Stardust" by Kevin MacLeod Licensed under Creative Commons by Attribution 3.0  This podcast is sponsored by Gilead and is not eligible for NCPD contact hours. ONS is solely responsible for the criteria, objectives, content, quality, and scientific integrity of its programs and publications.  Episode Notes  This episode is not eligible for NCPD. ONS Podcast™ episodes: Episode 391: Pharmacology 101: Antibody–Drug Conjugates Episode 378: Considerations for Adolescent and Young Adult Patients With Metastatic Breast Cancer Episode 368: Best Practices for Challenging Patient Conversations in Metastatic Breast Cancer Episode 350: Breast Cancer Treatment Considerations for Nurses Episode 303: Cancer Symptom Management Basics: Ocular Toxicities ONS Voice articles: An Oncology Nurse's Guide to Cancer-Related Ocular Toxicities Black Patients With Metastatic Breast Cancer Are Less Informed About Their Clinical Trial Options Communication Case Study: Talking to Patients About Progressive Metastatic Breast Cancer What Is HER2-Low Breast Cancer? ONS Voice drug reference sheets: Belantamab mafodotin-blmf Datopotamab deruxtecan-dlnk Enfortumab vedotin-ejfv Fam-trastuzumab deruxtecan-nxki ONS books: Chemotherapy and Immunotherapy Guidelines and Recommendations for Practice (second edition) Guide to Breast Care for Oncology Nurses Guide to Cancer Immunotherapy (second edition) ONS courses: ONS Fundamentals of Chemotherapy and Immunotherapy Administration™ ONS/ONCC® Chemotherapy Immunotherapy Certificate™ Clinical Journal of Oncology Nursing article: Antibody–Drug Conjugates and Ocular Toxicity: Nursing, Patient, and Organizational Implications for Care The Association Between Hormone Receptor Status and End-of-Life Care Among Patients With Metastatic Breast Cancer Oncology Nursing Forum article: Impact of Race and Area Deprivation on Triple-Negative Metastatic Breast Cancer Outcomes ONS huddle cards: Altered Body Image Huddle Card Chemotherapy Huddle Card Targeted Therapy Huddle Card Foundations of Antibody–Drug Conjugate Use in Metastatic Breast Cancer: A Case Study ONS Biomarker Database (refine by breast cancer) ONS Breast Cancer Learning Library American Society of Clinical Oncology (ASCO) homepage Drugs@FDA package inserts National Comprehensive Cancer Network homepage Susan G. Komen metastatic breast cancer page To discuss the information in this episode with other oncology nurses, visit the ONS Communities.  To find resources for creating an ONS Podcast club in your chapter or nursing community, visit the ONS Podcast Library. To provide feedback or otherwise reach ONS about the podcast, email pubONSVoice@ons.org. Highlights From This Episode "What an ADC is doing is taking the antibody and linking it to a cytotoxic chemotherapy with the idea of delivering it directly into the cell. How I explain this to new nurses or patients is a backpack analogy. If we think of it as a HER2 molecule wearing a chemo backpack, it's going to find the HER2 receptor attached to it and then drop the chemotherapy into the cell via the backpack. Similar to how we come home from work, we open the key to our door, we're carrying all of our items, and then we drop our own personal items in our house." TS 2:30 "The reason that so many patients with metastatic breast cancer are able to receive ADC therapy is because they are targeting two very common antibodies that we see in breast cancer. One is HER2 and the other is trophoblast cell surface antigen 2 (TROP2). These are seen across the board. We see these on triple-negative breast cancers, hormone receptor–positive cancers, and HER2-positive breast cancers. And now we have a new way to talk about HER2, which is a HER2-low. ... Recently, we have found that patients who express low levels of HER2 are able to receive ADC therapy, specifically fam-trastuzumab deruxtecan." TS 4:21 "Another [ADC] that has just been approved is datopotamab deruxtecan. This is another ADC that targets the TROP2 receptor on a cancer cell. This one carries a lot of side effects. I mentioned earlier that you need an ophthalmology clearance because there is a lot of ocular toxicity around this one. We see a lot of blepharitis, conjunctivitis, there can be blurred vision. Another thing we monitor on this one is mucositis. In the package insert, there's a recommendation for using ice chips while receiving the treatment. ... Then in the HER2-positive and HER2-low space is the big one, which is fam-trastuzumab deruxtecan. This was approved in 2019 for the HER2-positive patients, then more recently in the HER2-low [patients]. The big [side effect] with this one is interstitial lung disease." TS 10:11 "Interstitial lung disease is an inflammation or a little bit of fibrosis within the lung that causes an impaired exchange between the oxygen and carbon dioxide. This was seen in the clinical trials, specifically around fam-trastuzumab deruxtecan. During the trials, they had a very small percentage, I think it was 1%, that died due to interstitial lung disease. So, this is a very important side effect for us as nurses to be aware of. It typically presents in patients like a dyspnea. A lot of times, it's like, 'Well, I used to be able to walk my kid to the bus stop, but now when I walk there, I feel really short of breath.' Or 'I've had this dry cough for the past couple weeks and I've tried medications, but haven't had that relieved.' So, we really need to be aware of that because early intervention in interstitial lung disease is key." TS 12:57 "ADCs are toxic drugs. They have the benefit of being targeted, but we know that they carry a lot of side effects. ... Their specificity makes them so wonderful and we've seen amazing responses to these drugs. But also, we want patients to be safe. We want to give these drugs safely. So, we have to assess our patients and make sure that this is an appropriate patient to give this therapy to. I think that's an open conversation that clinicians need to have with patients regarding these drugs." TS 18:08

Please visit answersincme.com/860/99097105-replay to participate, download slides and supporting materials, complete the post test, and get a certificate. In this activity, experts in small cell lung cancer (SCLC) discuss the pathophysiologic rationale, emerging clinical evidence, and potential future role for B7-H3–directed antibody-drug conjugates in extensive-stage SCLC. Upon completion of this activity, participants should be better able to: Recognize the rationale for investigating B7-H3–directed antibody-drug conjugates (ADCs) in the treatment of patients with extensive-stage small cell lung cancer (ES-SCLC); Analyze recent clinical trial findings on B7-H3–directed ADCs in patients with previously treated ES-SCLC; and Formulate evidence-based, multidisciplinary team strategies for incorporating B7-H3–directed ADCs into treatment plans for patients with ES-SCLC, as they become available.

Did you know that, while well established in the metastatic setting, second-generation antibody-drug conjugates are now moving into the early setting? Credit available for this activity expires: 12/10/26 Earn Credit / Learning Objectives & Disclosures: https://www.medscape.org/viewarticle/how-are-adcs-shaping-future-early-breast-cancer-care-latest-2025a1000yca?ecd=bdc_podcast_libsyn_mscpedu

Please visit answersincme.com/860/IME-69386-replay1 to participate, download slides and supporting materials, complete the post test, and get a certificate. In this activity, experts in NSCLC discuss how to harness targeted ADCs with practical, case-based insights to personalize care and improve outcomes in advanced lung cancer. Upon completion of this activity, participants should be better able to: Interpret the latest clinical trial data for approved and emerging antibody-drug conjugates (ADCs) in NSCLC; Recognize biomarker-driven strategies to guide treatment management in patients with NSCLC; and Apply evidence-based strategies for the individualized management of patients with NSCLC receiving ADC therapy.

This content has been developed for healthcare professionals only. Patients who seek health information should consult with their physician or relevant patient advocacy groups.For the full presentation, downloadable Practice Aids, slides, and complete EBAC/CME information, and to apply for credit, please visit us at PeerView.com/WMS865. EBAC/CME credit will be available until December 2, 2026.Putting the Puzzle Together in Advanced Ovarian and Cervical Cancers: Translating Evidence Into Practice for Approved and Emerging ADCs In support of improving patient care, PVI, PeerView Institute for Medical Education, is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.SupportThis activity is supported by an independent educational grant from Genmab.Disclosure information is available at the beginning of the video presentation.

This content has been developed for healthcare professionals only. Patients who seek health information should consult with their physician or relevant patient advocacy groups.For the full presentation, downloadable Practice Aids, slides, and complete EBAC/CME information, and to apply for credit, please visit us at PeerView.com/WMS865. EBAC/CME credit will be available until December 2, 2026.Putting the Puzzle Together in Advanced Ovarian and Cervical Cancers: Translating Evidence Into Practice for Approved and Emerging ADCs In support of improving patient care, PVI, PeerView Institute for Medical Education, is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.SupportThis activity is supported by an independent educational grant from Genmab.Disclosure information is available at the beginning of the video presentation.

This content has been developed for healthcare professionals only. Patients who seek health information should consult with their physician or relevant patient advocacy groups.For the full presentation, downloadable Practice Aids, slides, and complete CME/MOC/AAPA information, and to apply for credit, please visit us at PeerView.com/UAD865. CME/MOC/AAPA credit will be available until November 20, 2026.Harnessing the Power of ADCs in Gynecologic Cancers: Expert Insights for Practice Integration In support of improving patient care, PVI, PeerView Institute for Medical Education, is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.SupportThis activity is supported by independent educational grants from AstraZeneca, Daiichi Sankyo, Inc., and Gilead Sciences, Inc.Disclosure information is available at the beginning of the video presentation.

This content has been developed for healthcare professionals only. Patients who seek health information should consult with their physician or relevant patient advocacy groups.For the full presentation, downloadable Practice Aids, slides, and complete CME/MOC/AAPA information, and to apply for credit, please visit us at PeerView.com/UAD865. CME/MOC/AAPA credit will be available until November 20, 2026.Harnessing the Power of ADCs in Gynecologic Cancers: Expert Insights for Practice Integration In support of improving patient care, PVI, PeerView Institute for Medical Education, is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.SupportThis activity is supported by independent educational grants from AstraZeneca, Daiichi Sankyo, Inc., and Gilead Sciences, Inc.Disclosure information is available at the beginning of the video presentation.

This content has been developed for healthcare professionals only. Patients who seek health information should consult with their physician or relevant patient advocacy groups.For the full presentation, downloadable Practice Aids, slides, and complete CME/MOC/AAPA information, and to apply for credit, please visit us at PeerView.com/UAD865. CME/MOC/AAPA credit will be available until November 20, 2026.Harnessing the Power of ADCs in Gynecologic Cancers: Expert Insights for Practice Integration In support of improving patient care, PVI, PeerView Institute for Medical Education, is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.SupportThis activity is supported by independent educational grants from AstraZeneca, Daiichi Sankyo, Inc., and Gilead Sciences, Inc.Disclosure information is available at the beginning of the video presentation.

This content has been developed for healthcare professionals only. Patients who seek health information should consult with their physician or relevant patient advocacy groups.For the full presentation, downloadable Practice Aids, slides, and complete CME/MOC/AAPA information, and to apply for credit, please visit us at PeerView.com/UAD865. CME/MOC/AAPA credit will be available until November 20, 2026.Harnessing the Power of ADCs in Gynecologic Cancers: Expert Insights for Practice Integration In support of improving patient care, PVI, PeerView Institute for Medical Education, is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.SupportThis activity is supported by independent educational grants from AstraZeneca, Daiichi Sankyo, Inc., and Gilead Sciences, Inc.Disclosure information is available at the beginning of the video presentation.

This content has been developed for healthcare professionals only. Patients who seek health information should consult with their physician or relevant patient advocacy groups.For the full presentation, downloadable Practice Aids, slides, and complete CME/MOC/AAPA information, and to apply for credit, please visit us at PeerView.com/UAD865. CME/MOC/AAPA credit will be available until November 20, 2026.Harnessing the Power of ADCs in Gynecologic Cancers: Expert Insights for Practice Integration In support of improving patient care, PVI, PeerView Institute for Medical Education, is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.SupportThis activity is supported by independent educational grants from AstraZeneca, Daiichi Sankyo, Inc., and Gilead Sciences, Inc.Disclosure information is available at the beginning of the video presentation.

This content has been developed for healthcare professionals only. Patients who seek health information should consult with their physician or relevant patient advocacy groups.For the full presentation, downloadable Practice Aids, slides, and complete CME/MOC/AAPA information, and to apply for credit, please visit us at PeerView.com/UAD865. CME/MOC/AAPA credit will be available until November 20, 2026.Harnessing the Power of ADCs in Gynecologic Cancers: Expert Insights for Practice Integration In support of improving patient care, PVI, PeerView Institute for Medical Education, is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.SupportThis activity is supported by independent educational grants from AstraZeneca, Daiichi Sankyo, Inc., and Gilead Sciences, Inc.Disclosure information is available at the beginning of the video presentation.

In this episode of Lung Cancer Considered, host Dr. Stephen Liu speaks with Prof. Li Zhang and Dr. Elaine Shum about recent progress in antibody–drug conjugates (ADCs) for EGFR-mutant non-small cell lung cancer (NSCLC). They discuss new approvals of datopotamab deruxtecan (in the United States) and sacituzumab tirumotecan (in China), key findings from the TROPION and OptiTROP trials, and emerging agents. The conversation highlights the advances in efficacy, safety, and combination strategies that are shaping the evolving treatment landscape for patients with EGFR-mutant NSCLC. Guest: Li Zhang, MD Professor, Medical Oncology Department Sun Yat-Sen University Cancer Center No Social Guest: Elaine Shum, MD Assistant Professor Director of Cancer Screening Programs New York University Perlmutter Cancer Center

Please visit answersincme.com/860/99224979-replay1 to participate, download slides and supporting materials, complete the post test, and obtain credit. In this activity, experts in oncology discuss the latest data on emerging B7-H3–directed antibody–drug conjugates (ADCs) for the treatment previously treated extensive-stage small-cell lung cancer (ES-SCLC). Upon completion of this activity, participants should be better able to: Specify how B7-H3 overexpression is relevant to ES-SCLC prognosis and treatment; Interpret the clinical evidence for emerging B7H3–directed ADCs in patients with previously treated ES-SCLC; and Translate current evidence and clinical considerations for B7-H3–targeted ADCs into treatment algorithms for patients with ES-SCLC.

"Antibody–drug conjugates (ADCs) have three basic parts: the antibody part, the cytotoxic chemo, and the linker that connects the two. First, the antibody part binds to the target on the surface of the cell. Antibodies can be designed to bind to proteins with a very high level of specificity. That's what gives it the targeted portion. Then the whole thing gets taken up by the cell and broken down, which releases the chemotherapy part. Some sources will call this the 'payload' or the 'warhead.'  That's the part that's attached to the 'heat-seeking' part, and that's what causes the cell death," Kenneth Tham, PharmD, BCOP, clinical pharmacist in general oncology at the University of Washington Medicine and Fred Hutchinson Cancer Center in Seattle, WA, told Jaime Weimer, MSN, RN, AGCNS-BS, AOCNS®, manager of oncology nursing practice at ONS, during a conversation about antibody–drug conjugates. Music Credit: "Fireflies and Stardust" by Kevin MacLeod Licensed under Creative Commons by Attribution 3.0  Earn 0.5 contact hours of nursing continuing professional development (NCPD) by listening to the full recording and completing an evaluation at courses.ons.org by November 28, 2026. The planners and faculty for this episode have no relevant financial relationships with ineligible companies to disclose. ONS is accredited as a provider of nursing continuing professional development by the American Nurses Credentialing Center's Commission on Accreditation. Learning outcome: Learners will report an increase in knowledge related to the mechanism of action of antibody–drug conjugates. Episode Notes  Complete this evaluation for free NCPD. ONS Podcast™ episodes: Pharmacology 101 series Episode 303: Cancer Symptom Management Basics: Ocular Toxicities Episode 283: Desensitization Strategies to Reintroduce Treatment After an Infusion-Related Reaction ONS Voice articles: An Oncology Nurse's Guide to Cancer-Related Ocular Toxicities Antibody–Drug Conjugates Join the Best of Two Worlds Into One New Treatment Nursing Management of Adverse Events From Enfortumab Vedotin Therapy for Urothelial Cancer Oncology Nurses' Role in Translating Biomarker Testing Results The Pharmacist's Role in Combination Cancer Treatments ONS Voice drug reference sheets: Belantamab mafodotin-blmf Datopotamab deruxtecan-dlnk Enfortumab vedotin Fam-trastuzumab deruxtecan-nxki ONS book: Chemotherapy and Immunotherapy Guidelines and Recommendations for Practice (second edition) ONS course: ONS Fundamentals of Chemotherapy and Immunotherapy Administration™ Clinical Journal of Oncology Nursing articles: Antibody–Drug Conjugates and Ocular Toxicity: Nursing, Patient, and Organizational Implications for Care Nurse-Led Grading of Antineoplastic Infusion-Related Reactions: A Call to Action Other ONS resources: Antineoplastic Administration Huddle Card Biomarker Database Chemotherapy Huddle Card Monoclonal Antibodies Huddle Card Association of Cancer Care Centers (ACCC) antibody–drug conjugates page Drugs@FDA Hematology/Oncology Pharmacy Association (HOPA) National Cancer Institute cancer drugs page Network for Collaborative Oncology Development and Advancement (NCODA) clinical resource library ACCC/HOPA/NCODA/ONS Patient Education Sheets website To discuss the information in this episode with other oncology nurses, visit the ONS Communities.  To find resources for creating an ONS Podcast club in your chapter or nursing community, visit the ONS Podcast Library. To provide feedback or otherwise reach ONS about the podcast, email pubONSVoice@ons.org Highlights From This Episode "The mechanism of action of the chemo itself depends on what agent or what 'warhead' is attached. Generally, [ADCs] have some kind of cytotoxic mechanism related to many of the chemotherapies that we use in practice, without attachment to the antibody. Some of them can be microtubule inhibitors, vinca alkaloids like vincristine. Some of them can be topoisomerase I (TOP1) inhibitors like irinotecan. Some can be alkylating agents that cause DNA breaks. So, again, looking back at the arsenal we have of cytotoxic chemo, these can all be incorporated into the ADCs." TS 5:54 "I want to talk about a case where the biomarker is being tested, but the biomarker isn't the target that you're looking for. One good case of this is a newer agent that was approved called datopotamab deruxtecan. The datopotamab portion is specific to a target called 'trophoblast cell surface antigen 2' (TROP2), which is expressed on the surface of many epithelial cancers. This agent was first approved in hormone receptor-positive, HER2-negative breast cancer, and received accelerated approval in patients with non-small cell lung cancer (NSCLC) with an EGFR mutation. ... The antibody looks for a target, TROP2. But in both of these cases—in the breast cancer and the NSCLC—you're testing for expression of different mutations or lack thereof. You're not looking for expression of TROP2. There's more research that needs to be done about the relationship between TROP2 expression and the presence or absence of these other biomarkers, but until we know more, we're actually testing for biomarkers that aren't the target of the ADC." TS 10:22 "There are common adverse advents to antibodies and chemo in general. Because we have both of these components, we want to watch out for the adverse effects of both of them. Antibodies, as with most proteins, can trigger an immune response or an infusion reaction. So, many ADCs can also cause hypersensitivity or infusion reactions. The rates of that are really variable and depend on the actual antibodies themselves. Then you have the cytotoxic component, the chemotherapy component, which has its own characteristic side effects. So, if we think of general chemo side effects—fatigue, nausea, bone marrow suppression, alopecia—these can [occur] with a lot of ADCs as well." TS 15:34 "The rate of ocular toxicity in [mirvetuximab soravtansine] is quite high. The manufacturer reports that this can occur in up to 60% of patients. With rates so high, the manufacturer recommends a preventive strategy. For this particular agent, [they] recommend patients have required eyecare. ... This ocular toxicity is something we do see in other ADCs that don't have the same target and don't necessarily have the same payload component. For example, tisotumab vedotin and again, datopotamab deruxtecan, can both cause ocular toxicities and both would have required ocular supportive care." TS 20:08 "Overall, I feel like the future is incredibly bright for these agents. There have only been around a dozen therapies approved by the U.S. Food and Drug Administration (FDA) despite this idea—the first agent came out in 2000. So, 25 years later, there are only around a dozen FDA-approved treatments. But there are so many more that are coming through the pipeline. And as we're discovering more biomarkers and developing more specialized antibodies, it's only natural that more ADCs will follow." TS 26:50

Please visit answersincme.com/CAZ860 to participate, download slides and supporting materials, complete the post test, and obtain credit. In this activity, an expert in hematology-oncology answers the most commonly asked questions from clinicians about the management of relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) with antibody–drug conjugates (ADCs). Upon completion of this activity, participants should be better able to: Identify patients with R/R DLBCL who may benefit from ADC therapy in the third-line or later setting; Interpret current evidence to inform selection of ADC therapies for patients with R/R DLBCL in the third-line or later setting; and Discuss strategies to optimize the use of ADC therapies for patients with R/R DLBCL, particularly in the community setting.

In today's episode,filmed live at the 43rd Annual CFS Chemotherapy Foundation Symposium, lung cancer expert Benjamin P. Levy, MD, hosted a cross-specialty discussion with breast cancer experts Kamel Abou Hussein, MD, and Victoria Rizk, MD, about the rapidly evolving therapeutic landscape in breast cancer. Dr Levy is the clinical director of medical oncology at the Johns Hopkins Sidney Kimmel Cancer Center at Sibley Memorial Hospital and an associate professor of oncology at the Johns Hopkins University School of Medicine in Washington, DC. Dr Abou Hussein is co-director of the Janet Knowles Breast Cancer, director of Breast Medical Oncology, and director of Breast Cancer Clinical Trials at Cooper University Health Care; as well as an assistant professor of medicine at Cooper Medical School of Rowan University in Camden, New Jersey. Dr Rizk is a medical oncologist at Tampa General Hospital Cancer Institute in Florida.

In this episode, Dr. Paul Wheatley-Price is back for our annual recap of the IASLC 2025 World Conference on Lung Cancer (WCLC), which took place in Barcelona, Spain in early September. He is joined by two special guests, Dr. Barbara Melosky, Professor of Medicine at UBC and Medical Oncologist at BC Cancer, and Dr. Peter Ellis, Professor of Oncology at McMaster University and Medical Oncologist at Juravinski Cancer Center. They chat about all the updates for treatments like osimertinib for EGFR+ lung cancer, immunotherapy for small-cell lung cancer, and promising new treatments like for HER2 and ADCs coming down the pipeline.

Dr. Linda Duska and Dr. Kathleen Moore discuss key studies in the evolving controversy over radical upfront surgery versus neoadjuvant chemotherapy in advanced ovarian cancer. TRANSCRIPT Dr. Linda Duska: Hello, and welcome to the ASCO Daily News Podcast. I am your guest host, Dr. Linda Duska. I am a professor of obstetrics and gynecology at the University of Virginia School of Medicine.  On today's episode, we will explore the management of advanced ovarian cancer, specifically with respect to a question that has really stirred some controversy over time, going all the way back more than 20 years: Should we be doing radical upfront surgery in advanced ovarian cancer, or should we be doing neoadjuvant chemotherapy? So, there was a lot of hype about the TRUST study, also called ENGOT ov33/AGO-OVAR OP7, a Phase 3 randomized study that compares upfront surgery with neoadjuvant chemotherapy followed by interval surgery. So, I want to talk about that study today. And joining me for the discussion is Dr. Kathleen Moore, a professor also of obstetrics and gynecology at the University of Oklahoma and the deputy director of the Stephenson Cancer Center, also at the University of Oklahoma Health Sciences.  Dr. Moore, it is so great to be speaking with you today. Thanks for doing this. Dr. Kathleen Moore: Yeah, it's fun to be here. This is going to be fun. Dr. Linda Duska: FYI for our listeners, both of our full disclosures are available in the transcript of this episode.  So let's just jump right in. We already alluded to the fact that the TRUST study addresses a question we have been grappling with in our field. Here's the thing, we have four prior randomized trials on this exact same topic. So, share with me why we needed another one and what maybe was different about this one? Dr. Kathleen Moore: That is, I think, the key question. So we have to level-set kind of our history. Let's start with, why is this even a question? Like, why are we even talking about this today? When we are taking care of a patient with newly diagnosed ovarian cancer, the aim of surgery in advanced ovarian cancer ideally is to prolong a patient's likelihood of disease-free survival, or if you want to use the term "remission," you can use the term "remission." And I think we can all agree that our objective is to improve overall survival in a way that also does not compromise her quality of life through surgical complications, which can have a big effect. The standard for many decades, certainly my entire career, which is now over 20 years, has been to pursue what we call primary cytoreductive surgery, meaning you get a diagnosis and we go right to the operating room with a goal of achieving what we call "no gross residual." That is very different – in the olden days, you would say "optimal" and get down to some predefined small amount of tumor. Now, the goal is you remove everything you can see.  The alternative strategy to that is neoadjuvant chemotherapy followed by interval cytoreductive surgery, and that has been the, quote-unquote, "safer" route because you chemically cytoreduce the cancer, and so, the resulting surgery, I will tell you, is not necessarily easy at all. It can still be very radical surgeries, but they tend to be less radical, less need for bowel resections, splenectomy, radical procedures, and in a short-term look, would be considered safer from a postoperative consideration. Dr. Linda Duska: Well, and also maybe more likely to be successful, right? Because there's less disease, maybe, theoretically. Dr. Kathleen Moore: More likely to be successful in getting to no gross residual. Dr. Linda Duska: Right. Yeah, exactly. Dr. Kathleen Moore: I agree with that. And so, so if the end game, regardless of timing, is you get to no gross residual and you help a patient and there's no difference in overall survival, then it's a no-brainer. We would not be having this conversation. But there remains a question around, while it may be more likely to get to no gross residual, it may be, and I think we can all agree, a less radical, safer surgery, do you lose survival in the long term by this approach? This has become an increasing concern because of the increase in rates of use of neoadjuvant, not only in this country, but abroad. And so, you mentioned the four prior studies. We will not be able to go through them completely. Dr. Linda Duska: Let's talk about the two modern ones, the two from 2020 because neither one of them showed a difference in overall survival, which I think we can agree is, at the end of the day, yes, PFS would be great, but OS is what we're looking for. Dr. Kathleen Moore: OS is definitely what we're looking for. I do think a marked improvement in PFS, like a real prolongation in disease-free survival, for me would be also enough. A modest improvement does not really cut it, but if you are really, really prolonging PFS, you should see that-  Dr. Linda Duska: -manifest in OS. Dr. Kathleen Moore: Yeah, yeah. Okay. So let's talk about the two modern ones. The older ones are EORTC and CHORUS, which I think we've talked about. The two more modern ones are SCORPION and JCOG0602. So, SCORPION was interesting. SCORPION was a very small study, though. So one could say it's underpowered. 170 patients. And they looked at only patients that were incredibly high risk. So, they had to have a Fagotti score, I believe, of over 9, but they were not looking at just low volume disease. Like, those patients were not enrolled in SCORPION. It was patients where you really were questioning, "Should I go to the OR or should I do neoadjuvant? Like, what's the better thing?" It is easy when it's low volume. You're like, "We're going." These were the patients who were like, "Hm, you know, what should I do?" High volume. Patients were young, about 55. The criticism of the older studies, there are many criticisms, but one of them is that, the criticism that is lobbied is that they did not really try. Whatever surgery you got, they did not really try with median operative times of 180 minutes for primary cytoreduction, 120 for neoadjuvant. Like, you and I both know, if you're in a big primary debulking, you're there all day. It's 6 hours. Dr. Linda Duska: Right, and there was no quality control for those studies, either. Dr. Kathleen Moore: No quality control. So, SCORPION, they went 451-minute median for surgery. Like, they really went for it versus four hours and then 253 for the interval, 4 hours. They really went for it on both arms. Complete gross resection was achieved in 50% of the primary cytoreduced. So even though they went for it with these very long surgeries, they only got to the goal half the time. It was almost 80% in the interval group. So they were more successful there. And there was absolutely no difference in PFS or OS. They were right about 15 months PFS, right about 40 months OS.  JCOG0602, of course, done in Japan, a big study, 300 patients, a little bit older population. Surprisingly more stage IV disease in this study than were in SCORPION. SCORPION did not have a lot of stage IV, despite being very bulky tumors. So a third of patients were stage IV. They also had relatively shorter operative times, I would say, 240 minutes for primary, 302 for interval. So still kind of short. Complete gross resection was not achieved very often. 30% of primary cytoreduction. That is not acceptable. Dr. Linda Duska: Well, so let's talk about TRUST. What was different about TRUST? Why was this an important study for us to see? Dr. Kathleen Moore: So the criticism of all of these, and I am not trying to throw shade at anyone, but the criticism of all of these is if you are putting surgery to the test, you are putting the surgeon to the test. And you are assuming that all surgeons are trained equally and are willing to do what it takes to get someone to no gross residual. Dr. Linda Duska: And are in a center that can support the post-op care for those patients. Dr. Kathleen Moore: Which can be ICU care, prolonged time. Absolutely. So when you just open these broadly, you're assuming everyone has the surgical skills and is comfortable doing that and has backup. Everybody has an ICU. Everyone has a blood bank, and you are willing to do that. And that assumption could be wrong. And so what TRUST said is, "Okay, we are only going to open this at centers that have shown they can achieve a certain level of primary cytoreduction to no gross residual disease." And so there was quality criteria. It was based on – it was mostly a European study – so ESGO criteria were used to only allow certified centers to participate. They had to have a surgical volume of over 36 cytoreductive surgeries per year. So you could not be a low volume surgeon. Your complete resection rates that were reported had to be greater than 50% in the upfront setting. I told you on the JCOG, it was 30%. Dr. Linda Duska: Right. So these were the best of the best. This was the best possible surgical situation you could put these patients in, right? Dr. Kathleen Moore: Absolutely. And you support all the things so you could mitigate postoperative complications as well. Dr. Linda Duska: So we are asking the question now again in the ideal situation, right? Dr. Kathleen Moore: Right. Dr. Linda Duska: Which, we can talk about, may or may not be generalizable to real life, but that's a separate issue because we certainly don't have those conditions everywhere where people get cared for with ovarian cancer. But how would you interpret the results of this study? Did it show us anything different? Dr. Kathleen Moore: I am going to say how we should interpret it and then what I am thinking about. It is a negative study. It was designed to show improvement in overall survival in these ideal settings in patients with FIGO stage IIIB and C, they excluded A, these low volume tumors that should absolutely be getting surgery. So FIGO stage IIIB and C and IVA and B that were fit enough to undergo radical surgery randomized to primary cytoreduction or neoadjuvant with interval, and were all given the correct chemo. Dr. Linda Duska: And they were allowed bevacizumab and PARP, also. They could have bevacizumab and PARP. Dr. Kathleen Moore: They were allowed bevacizumab and PARP. Not many of them got PARP, but it was distributed equally, so that would not be a confounder. And so that was important. Overall survival is the endpoint. It was a big study. You know, it was almost 600 patients. So appropriately powered. So let's look at what they reported. When they looked at the patients who were enrolled, this is a large study, almost 600 patients, 345 in the primary cytoreductive arm and 343 in the neoadjuvant arm. Complete resection in these patients was 70% in the primary cytoreductive arm and 85% in the neoadjuvant arm. So in both arms, it was very high. So your selection of site and surgeon worked. You got people to their optimal outcome. So that is very different than any other study that has been reported to date. But what we saw when we looked at overall survival was no statistical difference. The median was, and I know we do not like to talk about medians, but the median in the primary cytoreductive arm was 54 months versus 48 months in the neoadjuvant arm with a hazard ratio of 0.89 and, of course, the confidence interval crossed one. So this is not statistically significant. And that was the primary endpoint. Dr. Linda Duska: I know you are getting to this. They did look at PFS, and that was statistically significant, but to your point about what are we looking for for a reasonable PFS difference? It was about two months difference. When I think about this study, and I know you are coming to this, what I thought was most interesting about this trial, besides the fact that the OS, the primary endpoint was negative, was the subgroup analyses that they did. And, of course, these are hypothesis-generating only. But if you look at, for example, specifically only the stage III group, that group did seem to potentially, again, hypothesis generating, but they did seem to benefit from upfront surgery.  And then one other thing that I want to touch on before we run out of time is, do we think it matters if the patient is BRCA germline positive? Do we think it matters if there is something in particular about that patient from a biomarker standpoint that is different? I am hopeful that more data will be coming out of this study that will help inform this. Of course, unpowered, hypothesis-generating only, but it's just really interesting. What do you think of their subset analysis? Dr. Kathleen Moore: Yeah, I think the subsets are what we are going to be talking about, but we have to emphasize that this was a negative trial as designed. Dr. Linda Duska: Absolutely. Yes. Dr. Kathleen Moore: So we cannot be apologists and be like, "But this or that." It was a negative trial as designed. Now, I am a human and a clinician, and I want what is best for my patients. So I am going to, like, go down the path of subset analyses. So if you look at the stage III tumors that got complete cytoreduction, which was 70% of the cases, your PFS was almost 28 months versus 21.8 months. Dr. Linda Duska: Yes, it becomes more significant. Dr. Kathleen Moore: Yeah, that hazard ratio is 0.69. Again, it is a subset. So even though the P value here is statistically significant, it actually should not have a P value because it is an exploratory analysis. So we have to be very careful. But the hazard ratio is 0.69. So the hypothesis is in this setting, if you're stage III and you go for it and you get someone to no gross residual versus an interval cytoreduction, you could potentially have a 31% reduction in the rate of progression for that patient who got primary cytoreduction. And you see a similar trend in the stage III patients, if you look at overall survival, although the post-progression survival is so long, it's a little bit narrow of a margin.  But I do think there are some nuggets here that, one of our colleagues who is really one of the experts in surgical studies, Dr. Mario Leitao, posted this on X, and I think it really resonated after this because we were all saying, "But what about the subsets?" He is like, "It's a negative study." But at the end of the day, you are going to sit with your patient. The patient should be seen by a GYN oncologist or surgical oncologist with specialty in cytoreduction and a medical oncologist, you know, if that person does not give chemo, and the decision should be made about what to do for that individual patient in that setting. Dr. Linda Duska: Agreed. And along those lines, if you look carefully at their data, the patients who had an upfront cytoreduction had almost twice the risk of having a stoma than the patients who had an interval cytoreduction. And they also had a higher risk of needing to have a bowel resection. The numbers were small, but still, when you look at the surgical complications, as you've already said, they're higher in the upfront group than they are in the interval group. That needs to be taken into account as well when counseling a patient, right? When you have a patient in front of you who says to you, "Dr. Moore, you can take out whatever you want, but whatever you do, don't make me a bag." As long as the patient understands what that means and what they're asking us to do, I think that we need to think about that. Dr. Kathleen Moore: I think that is a great point. And I have definitely seen in our practice, patients who say, "I absolutely would not want an ostomy. It's a nonstarter for me." And we do make different decisions. And you have to just say, "That's the decision we've made," and you kind of move on, and you can't look back and say, "Well, I wish I would have, could have, should have done something else." That is what the patient wants. Ultimately, that patient, her family, autonomous beings, they need to be fully counseled, and you need to counsel that patient as to the site that you are in, her volume of disease, and what you think you can achieve. In my opinion, a patient with stage III cancer who you have the site and the capabilities to get to no gross residual should go to the OR first. That is what I believe. I do not anymore think that for stage IV. I think that this is pretty convincing to me that that is probably a harmful thing. However, I want you to react to this. I think I am going to be a little unpopular in saying this, but for me, one of the biggest take-homes from TRUST was that whether or not, and we can talk about the subsets and the stage III looked better, and I think it did, but both groups did really well. Like, really well. And these were patients with large volume disease. This was not cherry-picked small volume stage IIIs that you could have done an optimal just by doing a hysterectomy. You know, these were patients that needed radical surgery. And both did well. And so what it speaks to me is that anytime you are going to operate on someone with ovary, whether it be frontline, whether it be a primary or interval, you need a high-volume surgeon. That is what I think this means to me. Like, I would want high volume surgeon at a center that could do these surgeries, getting that patient, my family member, me, to no gross residual. That is important. And you and I are both in training centers. I think we ought to take a really strong look at, are we preparing people to do the surgeries that are necessary to get someone to no gross residual 70% and 85% of the time? Dr. Linda Duska: We are going to run out of time, but I want to address that and ask you a provocative question. So, I completely agree with what you said, that surgery is important. But I also think one of the reasons these patients in this study did so well is because all of the incredible new therapies that we have for patients. Because OS is not just about surgery. It is about surgery, but it is also about all of the amazing new therapies we have that you and others have helped us to get through clinical research. And so, how much of that do you think, like, for example, if you look at the PFS and OS rates from CHORUS and EORTC, I get it that they're, that they're not the same. It's different patients, different populations, can't do cross-trial comparisons. But the OS, as you said, in this study was 54 months and 48 months, which is, compared to 2010, we're doing much, much better. It is not just the surgery, it is also all the amazing treatment options we have for these patients, including PARP, including MIRV, including lots of other new therapies. How do you fit that into thinking about all of this? Dr. Kathleen Moore: I do think we are seeing, and we know this just from epidemiologic data that the prevalence of ovarian cancer in many of the countries where the study was done is increasing, despite a decrease in incidence. And why is that? Because people are living longer. Dr. Linda Duska: People are living longer, yeah. Dr. Kathleen Moore: Which is phenomenal. That is what we want. And we do have, I think, better supportive care now. PARP inhibitors in the frontline, which not many of these patients had. Now some of them, this is mainly in Europe, will have gotten them in the first maintenance setting, and I do think that impacts outcome. We do not have that data yet, you know, to kind of see what, I would be really interested to see. We do not do this well because in ovarian cancer, post-progression survival can be so long, we do not do well of tracking what people get when they come off a clinical trial to see how that could impact – you know, how many of them got another surgery? How many of them got a PARP? I think this group probably missed the ADC wave for the most part, because this, mirvetuximab is just very recently available in Europe. Dr. Linda Duska: Unless they were on trial. Dr. Kathleen Moore: Unless they were on trial. But I mean, I think we will have to see. 600 patients, I would bet a lot of them missed the ADC wave. So, I do not know that we can say we know what drove these phenomenal – these are some of the best curves we've seen outside of BRCA. And then coming back to your point about the BRCA population here, that is a really critical question that I do not know that we're ever going to answer. There have been hypotheses around a tumor that is driven by BRCA, if you surgically cytoreduced it, and then chemically cytoreduced it with chemo, and so you're starting PARP with nothing visible and likely still homogeneous clones. Is that the group we cured? And then if you give chemo first before surgery, it allows more rapid development of heterogeneity and more clonal evolution that those are patients who are less likely to be cured, even if they do get cytoreduced to nothing at interval with use of PARP inhibitor in the front line. That is a question that many have brought up as something we would like to understand better. Like, if you are BRCA, should you always just go for it or not? I do not know that we're ever going to really get to that. We are trying to look at some of the other studies and just see if you got neoadjuvant and you had BRCA, was anyone cured? I think that is a question on SOLO1 I would like to know the answer to, and I don't yet, that may help us get to that. But that's sort of something we do think about. You should have a fair number of them in TRUST. It wasn't a stratification factor, as I remember. Dr. Linda Duska: No, it wasn't. They stratified by center, age, and ECOG status Dr. Kathleen Moore: So you would hope with randomization that you would have an equal number in each arm. And they may be able to pull that out and do a very exploratory look. But I would be interested to see just completely hypothesis-generating what this looks like for the patients with BRCA, and I hope that they will present that. I know they're busy at work. They have translational work. They have a lot pending with TRUST. It's an incredibly rich resource that I think is going to teach us a lot, and I am excited to see what they do next. Dr. Linda Duska: So, outside of TRUST, we are out of time. I just want to give you a moment if there were any other messages that you want to share with our listeners before we wrap up. Dr. Kathleen Moore: It's an exciting time to be in GYN oncology. For so long, it was just chemo, and then the PARP inhibitors nudged us along quite a bit. We did move more patients, I believe, to the cure fraction. When we ultimately see OS, I think we'll be able to say that definitively, and that is exciting. But, you know, that is the minority of our patients. And while HRD positive benefits tremendously from PARP, I am not as sure we've moved as many to the cure fraction. Time will tell. But 50% of our patients have these tumors that are less HRD. They have a worse prognosis. I think we can say that and recur more quickly. And so the advent of these antibody-drug conjugates, and we could name 20 of them in development in GYN right now, targeting tumor-associated antigens because we're not really driven by mutations other than BRCA. We do not have a lot of things to come after. We're not lung cancer. We are not breast cancer. But we do have a lot of proteins on the surface of our cancers, and we are finally able to leverage that with some very active regimens. And we're in the early phases, I would say, of really understanding how best to use those, how best to position them, and which one to select for whom in a setting where there is going to be obvious overlap of the targets. So we're going to be really working this problem. It is a good problem. A lot of drugs that work pretty well. How do you individualize for a patient, the patient in front of you with three different markers? How do you optimize it? Where do you put them to really prolong survival? And then we finally have cell surface. We saw at ASCO, CDK2 come into play here for the first time, we've got a cell cycle inhibitor. We've been working on WEE1 and ATR for a long time. CDK2s may hit. Response rates were respectable in a resistant population that was cyclin E overexpressing. We've been working on that biomarker for a long time with a toxicity profile that was surprisingly clean, which I like to see for our patients. So that is a different platform. I think we have got bispecifics on the rise. So there is a pipeline of things behind the ADCs, which is important because we need more than one thing, that makes me feel like in the future, I am probably not going to be using doxil ever for platinum-resistant disease. So, I am going to be excited to retire some of those things. We will say, "Remember when we used to use doxil for platinum-resistant disease?" Dr. Linda Duska: I will be retired by then, but thanks for that thought. Dr. Kathleen Moore: I will remind you. Dr. Linda Duska: You are right. It is such an incredibly exciting time to be taking care of ovarian cancer patients with all the opportunities.  And I want to thank you for sharing your valuable insights with us on this podcast today and for your great work to advance care for patients with GYN cancers. Dr. Kathleen Moore: Likewise. Thanks for having me. Dr. Linda Duska: And thank you to our listeners for your time today. You will find links to the TRUST study and other studies discussed today in the transcript of this episode. Finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. More on today's speakers:   Dr. Linda Duska  @Lduska Dr. Kathleen Moore Follow ASCO on social media:     @ASCO on X (formerly Twitter) ASCO on Bluesky   ASCO on Facebook     ASCO on LinkedIn     Disclosures of Potential Conflicts of Interest:    Dr. Linda Duska:   Consulting or Advisory Role: Regeneron, Inovio Pharmaceuticals, Merck, Ellipses Pharma  Research Funding (Inst.): GlaxoSmithKline, Millenium, Bristol-Myers Squibb, Aeterna Zentaris, Novartis, Abbvie, Tesaro, Cerulean Pharma, Aduro Biotech, Advaxis, Ludwig Institute for Cancer Research, Leap Therapeutics  Patents, Royalties, Other Intellectual Property: UptToDate, Editor, British Journal of Ob/Gyn  Dr. Kathleen Moore: Leadership: GOG Partners, NRG Ovarian Committee Chair Honoraria: Astellas Medivation, Clearity Foundation, IDEOlogy Health, Medscape, Great Debates and Updates, OncLive/MJH Life Sciences, MD Outlook, Curio Science, Plexus, University of Florida, University of Arkansas for Medical Sciences, Congress Chanel, BIOPHARM, CEA/CCO, Physician Education Resource (PER), Research to Practice, Med Learning Group, Peerview, Peerview, PeerVoice, CME Outfitters, Virtual Incision Consulting/Advisory Role: Genentech/Roche, Immunogen, AstraZeneca, Merck, Eisai, Verastem/Pharmacyclics, AADi, Caris Life Sciences, Iovance Biotherapeutics, Janssen Oncology, Regeneron, zentalis, Daiichi Sankyo Europe GmbH, BioNTech SE, Immunocore, Seagen, Takeda Science Foundation, Zymeworks, Profound Bio, ADC Therapeutics, Third Arc, Loxo/Lilly, Bristol Myers Squibb Foundation, Tango Therapeutics, Abbvie, T Knife, F Hoffman La Roche, Tubulis GmbH, Clovis Oncology, Kivu, Genmab/Seagen, Kivu, Genmab/Seagen, Whitehawk, OnCusp Therapeutics, Natera, BeiGene, Karyopharm Therapeutics, Day One Biopharmaceuticals, Debiopharm Group, Foundation Medicine, Novocure Research Funding (Inst.): Mersana, GSK/Tesaro, Duality Biologics, Mersana, GSK/Tesaro, Duality Biologics, Merck, Regeneron, Verasatem, AstraZeneca, Immunogen, Daiichi Sankyo/Lilly, Immunocore, Torl Biotherapeutics, Allarity Therapeutics, IDEAYA Biosciences, Zymeworks, Schrodinger Other Relationship (Inst.): GOG Partners

Authors Drs. Jessica Ross and Alissa Cooper share insights into their JCO PO article, "Clinical and Pathologic Landscapes of Delta-Like Ligand 3 and Seizure-Related Homolog Protein 6 Expression in Neuroendocrine Carcinomas"  Host Dr. Rafeh Naqash and Drs. Ross and Cooper discuss the landscape of Delta-like ligand 3 (DLL3) and seizure-related homolog protein 6 (SEZ6) across NECs from eight different primary sites. TRANSCRIPT Dr. Rafeh Naqash: Hello and welcome to JCO Precision Oncology Conversations, where we bring you engaging conversations with authors of clinically relevant and highly significant JCO PO articles. I'm your host, Dr. Rafeh Naqash, podcast editor for JCO PO and an Associate Professor at the OU Health Stephenson Cancer Center. Today, I'm excited to be joined by Dr. Jessica Ross, third-year medical oncology fellow at the Memorial Sloan Kettering Cancer Center, as well as Dr. Alissa Cooper, thoracic medical oncologist at the Dana-Farber Cancer Institute and instructor in medicine at Harvard Medical School. Both are first and last authors of the JCO Precision Oncology article entitled "Clinical and Pathologic Landscapes of Delta-like Ligand 3 and Seizure-Related Homolog Protein 6 or SEZ6 Protein Expression in Neuroendocrine Carcinomas." At the time of this recording, our guest disclosures will be linked in the transcript. Jessica and Alissa, welcome to our podcast, and thank you for joining us today. Dr. Jessica Ross: Thanks very much for having us. Dr. Alissa Cooper: Thank you. Excited to be here. Dr. Rafeh Naqash: It's interesting, a couple of days before I decided to choose this article, one of my GI oncology colleagues actually asked me two questions. He said, "Rafeh, do you know how you define DLL3 positivity? And what is the status of DLL3 positivity in GI cancers, GI neuroendocrine carcinomas?" The first thing I looked up was this JCO article from Martin Wermke. You might have seen it as well, on obrixtamig, a phase 1 study, a DLL3 bi-specific T-cell engager. And they had some definitions there, and then this article came along, and I was really excited that it kind of fell right in place of trying to understand the IHC landscape of two very interesting targets. Since we have a very broad and diverse audience, especially community oncologists, trainees, and of course academic clinicians and some people who are very interested in genomics, we'll try to make things easy to understand. So my first question for you, Jessica, is: what is DLL3 and SEZ6 and why are they important in neuroendocrine carcinomas? Dr. Jessica Ross: Yeah, good question. So, DLL3, or delta-like ligand 3, is a protein that is expressed preferentially on the tumor cell surface of neuroendocrine carcinomas as opposed to normal tissue. It is a downstream target of ASCL1, and it's involved in neuroendocrine differentiation, and it's an appealing drug target because it is preferentially expressed on tumor cell surfaces. And so, it's a protein, and there are several drugs in development targeting this protein, and then Tarlatamab is an approved bi-specific T-cell engager for the treatment of extensive-stage small cell lung cancer in the second line. SEZ6, or seizure-like homolog protein 6, is a protein also expressed on neuroendocrine carcinoma cell surface. Interestingly, so it's expressed on neuronal cells, but its exact role in neuroendocrine carcinomas and oncogenesis is actually pretty poorly understood, but it was identified as an appealing drug target because, similarly to DLL3, it's preferentially expressed on the tumor cell surface. And so this has also emerged as an appealing drug target, and there are drugs in development, including antibody-drug conjugates, targeting this protein for that reason. Dr. Alissa Cooper: Over the last 10 to 15 years or so, there's been an increasing focus on precision oncology, finding specific targets that actually drive the cancer to grow, not just within lung cancer but in multiple other primary cancers. But specifically, at least speaking from a thoracic oncology perspective, the field of non-small cell lung cancer has completely exploded over the past 15 years with the discovery of driver oncogenes and then matched targeted therapies. Within the field of neuroendocrine carcinomas, including small cell lung cancer but also other high-grade neuroendocrine carcinomas, there has not been the same sort of progress in terms of identifying targets with matched therapies. And up until recently, we've sort of been treating these neuroendocrine malignancies kind of as a monolithic disease process. And so recently, there's been sort of an explosion of research across the country and multiple laboratories, multiple people converging on the same open questions about why might patients with specific tumor biologies have different kind of responses to different therapies. And so first this came from, you know, why some patients might have a good response to chemo and immunotherapy, which is the first-line approved therapy for small cell lung cancer, and we also sort of extrapolate that to other high-grade neuroendocrine carcinomas. What's the characteristic of that tumor biology? And at the same time, what are other targets that might be identifiable? Just as Jesse was saying, they're expressed on the cell surface, they're not necessarily expressed in normal tissue. Might this be a strategy to sort of move forward and create smarter therapies for our patients and therefore move really into a personalized era for treatment for each patient? And that's really driving, I think, a lot of the synthesis of this work of not only the development of multiple new therapies, but really understanding which tumor might be the best fit for which therapy. Dr. Rafeh Naqash: Thank you for that explanation, Alissa. And as you mentioned, these are emerging targets, some more further along in the process with approved drugs, especially Tarlatamab. And obviously, DLL3 was something identified several years back, but drug development does take time, and readout for clinical trials takes time. Could you, for the sake of our audience, try to talk briefly about the excitement around Tarlatamab in small cell lung cancer, especially data that has led to the FDA approval in the last year, year and a half? Dr. Alissa Cooper: Sure. Yeah, it's really been an explosion of excitement over, as you're saying, the last couple of years, and work really led by our mentor, Charlie Rudin, had identified DLL3 as an exciting target for small cell lung cancer specifically but also potentially other high-grade neuroendocrine malignancies. Tarlatamab is a DLL3-targeting bi-specific T-cell engager, which targets DLL3 on the small cell lung cancer cells as well as CD3 on T cells. And the idea is to sort of introduce the cancer to the immune system, circumventing the need for MHC class antigen presentation, which that machinery is typically not functional in small cell lung cancer, and so really allowing for an immunomodulatory response, which had not really been possible for most patients with small cell lung cancer prior to this. Tarlatamab was tested in a phase 2 registrational trial of about 100 patients and demonstrated a response rate of 40%, which was very exciting, especially compared with other standard therapies which were available for small cell lung cancer, which are typically cytotoxic therapies. But most excitingly, more than even the response rate, I think, in our minds was the durability of response. So patients whose disease did have a response to Tarlatamab could potentially have a durable response lasting a number of months or even over a year, which had previously not ever been seen in this in the relapsed/refractory setting for these patients. I think the challenge with small cell lung cancer and other high-grade neuroendocrine malignancies is that a response to therapy might be a bit easier to achieve, but it's that durability. The patient's tumors really come roaring back quite aggressively pretty quickly. And so this was sort of the most exciting prospect is that durability of response, that long potential overall survival tail of the curve really being lifted up. And then most recently at ASCO this year, Dr. Rudin presented the phase 3 randomized controlled trial which compared Tarlatamab to physician's choice of chemotherapy in a global study. And the choice of chemotherapy did vary depending on the part of the world that the patients were enrolled in, but in general, it was a really markedly positive study for response rate, for progression-free survival, and for overall survival. Really exciting results which really cemented Tarlatamab's place as the standard second-line therapy for patients with small cell lung cancer whose disease has progressed on first-line chemo-immunotherapy. So that has been very exciting. This drug was FDA approved in May of 2024, and so has been used extensively since then. I think the adoption has been pretty widespread, at least in the US, but now in this global trial that was just presented, and there was a corresponding New England Journal paper, I think really confirms that this is something we really hopefully can offer to most of our patients. And I think, as we all know, that this therapy or other therapies like it are also being tested potentially in the first-line setting. So there was data presented with Tarlatamab incorporated into the maintenance setting, which also showed exciting results, albeit in a phase 1 trial, but longer overall survival than we're used to seeing in this patient population. And we await results of the study that is incorporating Tarlatamab into the induction phase with chemotherapy as well. So all of this is extraordinarily exciting for our patients to sort of move the needle of how many patients we can keep alive, feeling functional, feeling well, for as long as possible. Dr. Rafeh Naqash: Very exciting session at ASCO. I was luckily one of the co-chairs for the session that Dr. Rudin presented it, and I remember somebody mentioning there was more progress seen in that session for small cell lung cancer than the last 30, 35 years for small cell, very exciting space and time to be in as far as small cell lung cancer. Now going to this project, Jessica, since you're the first author and Alissa's the last, I'm assuming there was a background conversation that you had with Alissa before you embarked on this project as an idea. So could you, again, for other trainees who are interested in doing research, and it's never easy to do research as a resident and a fellow when you have certain added responsibilities. Could you give us a little bit of a background on how this started and why you wanted to look at this question? Dr. Jessica Ross: Yeah, sure. So, as with many exciting research concepts, I think a lot of them are derived from the clinic. And so I think Alissa and I both see a good number of patients with small cell, large cell lung cancer, and then high-grade neuroendocrine carcinomas. And so I think this was really born out of a basic conversation of we have these drugs in development targeting these two proteins, DLL3 and SEZ6, but really what is the landscape of cancers that express these proteins and who are the patients that really might benefit from these exciting new therapies. And of course, there was some data out there, but sort of less than one would imagine in terms of, you know, neuroendocrine carcinomas can really come from anywhere in the body. And so when you're seeing a patient with small cell of the cervix, for example, like what are the chances that their cancer expresses DLL3 or expresses SEZ6? So it was really derived from this pragmatic, clinically oriented question that we had both found ourselves thinking about, and we were lucky enough at MSK, we had started systematically staining patients' tumors for DLL3, tumors that are high-grade neuroendocrine carcinomas, and then we had also more recently started staining for SEZ6 as well. And so we had this nice prospectively collected dataset with which to answer this question. Dr. Rafeh Naqash: Excellent. And Alissa, could you try to go into some of the details around which patients you chose, how many patients, what was the approach that you selected to collect the data for this project? Dr. Alissa Cooper: This is perhaps a strength but also maybe a limitation of this dataset is, as Jesse alluded to, our pathology colleagues are really the stars of this paper here because we were lucky enough at MSK that they were really forethinking. They are absolute experts in the field and really forward-thinking people in terms of what information might be needed in the future to drive treatment decision-making. And so, as Jesse had said, small cell lung cancer tumor samples reflexively are stained for DLL3 and SEZ6 at MSK if there's enough tumor tissue. The other high-grade neuroendocrine carcinomas, those stains are performed upon physician request. And so that is a bit of a mixed bag in terms of the tumor samples we were able to include in this dataset because, you know, upon physician request depends on a number of factors, but actually at MSK, a number of physicians were requesting these stains to be done on their patients with high-grade neuroendocrine cancers of of other histologies. So we looked at all tumor samples with a diagnosis of high-grade neuroendocrine carcinoma of any histology that were stained for these two stains of interest. You know, I can let Jesse talk a bit more about the methodology. She was really the driver of this project. Dr. Jessica Ross: Yeah, sure. So we had 124 tumor samples total. All of those were stained for DLL3, and then a little less than half, 53, were stained for SEZ6. As Alissa said, they were from any primary site. So about half of them were of lung origin, that was the most common primary site, but we included GI tract, head and neck, GU, GYN, even a few tumors of unknown origin. And again, that's because I think a lot of these trials are basket trials that are including different high-grade neuroendocrine carcinomas no matter the primary site. And so we really felt like it was important to be more comprehensive and inclusive in this study. And then, methodologically, we also defined positivity in terms of staining of these two proteins as anything greater than or equal to 1% staining. There's really not a defined consensus of positivity when it comes to these two novel targets and staining for these two proteins. But in the Tarlatamab trials, for some of the correlative work that's been done, they use that 1% cutoff, and we just felt like being consistent with that and also using a sort of more pragmatic yes/no cutoff would be more helpful for this analysis. Dr. Alissa Cooper: And that was a point of discussion, actually. We had contemplated multiple different schemas, actually, for how to define thresholds of positivity. And I know you brought up that question before, what does it mean to be DLL3 positive or DLL3 high? I think you were alluding to prior that there was a presentation of obrixtamig looking at extra-pulmonary neuroendocrine carcinomas, and they actually divvied up the results between DLL3 50% or greater versus DLL3 low under 50%. And they actually did demonstrate differential efficacy certainly, but also some differential safety as well, which is very provocative and that kind of analysis has not been presented for other novel therapies as far as I'm aware. I could be wrong, but as far as I'm aware, that was sort of the first time that we saw a systematic presentation of considering patients to be, quote unquote, "high" or "low" in these sort of novel targets. I think it is important because the label for Tarlatamab does not require any DLL3 expression at all, actually. So it's not hinging upon DLL3 expression. They depend on the fact that the vast majority of small cell lung cancer tumors do express DLL3, 85% to 90% is what's been demonstrated in a few studies. And so, there's not prerequisite testing needed in that regard, but maybe for these extra-pulmonary, other histology neuroendocrine carcinomas, maybe it does matter to some degree. Dr. Rafeh Naqash: Definitely agree that this evolving landscape of trying to understand whether an expression for something actually really does correlate with, whether it's an immune cell engager or an antibody-drug conjugate is a very evolving and dynamically moving space. And one of the questions that I was discussing with one of my friends was whether IHC positivity and the level of IHC positivity, as you've shown in one of those plots where you have double positive here on the right upper corner, you have the double negative towards the left lower, whether that somehow determines mRNA expression for DLL3. Obviously, that was not the question here that you were looking at, but it does kind of bring into question certain other aspects of correlations, expression versus IHC. Now going to the figures in this manuscript, very nicely done figures, very easy to understand because I've done the podcast for quite a bit now, and usually what I try to do first is go through the figures before I read the text, and and a lot of times it's hard to understand the figures without reading the text, but in your case, specifically the figures were very, very well done. Could you give us an overview, a quick overview of some of the important results, Jessica, as far as what you've highlighted in the manuscript? Dr. Jessica Ross: Sure. So I think the key takeaway is that, of the tumors in our cohort, the majority were positive for DLL3 and positive for SEZ6. So about 80% of them were positive for DLL3 and 80% were positive for SEZ6. About half of the tumors were stained for both proteins, and about 65% of those were positive as well. So I think if there's sort of one major takeaway, it's that when you're seeing a patient with a high-grade neuroendocrine carcinoma, the odds are that their tumor will express both of these proteins. And so that can sort of get your head thinking about what therapies they might be eligible for. And then we also did an analysis of some populations of interest. So for example, we know that non-neuroendocrine pathologies can transform into neuroendocrine tumors. And so we specifically looked at that subset of patients with transformed tumors, and those were also- the majority of them were positive, about three-quarters of them were positive for both of these two proteins. We looked at patients with brain met samples, again, about 70% were positive. And then I'd say the last sort of population of interest was we had a subset of 10 patients who had serial biopsies stained for either DLL3 or SEZ6 or both. In between the two samples, these patients were treated with chemotherapy. They were not treated with targeted therapy, but interestingly, in the majority of cases, the testing results were concordant, meaning if it was DLL3 positive to begin with, it tended to remain DLL3 positive after treatment. And so I think that's important as well as we think about, you know, a patient who maybe had DLL3 testing done before they received their induction chemo-IO, we can somewhat confidently say that they're probably still DLL3 positive after that treatment. And then finally, we did do a survival analysis among specifically the patients with lung neuroendocrine carcinomas. We looked at whether DLL3 expression affected progression-free survival on first-line platinum-etoposide, and then we looked at did it affect overall survival. And we found that it did not have an impact or the median progression-free survival was similar whether you were DLL3 positive or negative. But interestingly, with overall survival, we found that DLL3 positivity actually correlated with slightly improved overall survival. These were small numbers, and so, you know, I think we have to interpret this with caution, for sure, but it is interesting. I think there may be something to the fact that five of the patients who were DLL3 positive were treated with DLL3-targeting treatments. And so this made me think of, like in the breast cancer world, for example, if you have a patient with HER2-positive disease, it initially portended worse prognosis, more aggressive disease biology, but on the other hand, it opens the door for targeted treatments that actually now, at least with HER2-positive breast cancer, are associated with improved outcomes. And so I think that's one finding of interest as well. Dr. Rafeh Naqash: Definitely proof-of-concept findings here that you guys have in the manuscript. Alissa, if I may ask you, what is the next important step for a project like this in your mind? Dr. Alissa Cooper: Jesse has highlighted a couple of key findings that we hope to move forward with future investigative studies, not necessarily in a real-world setting, but maybe even in clinical trial settings or in collaboration with sponsors. Are these biomarkers predictive? Are they prognostic? You know, those are still- we have some nascent data, data has been brewing, but I think that we we still don't have the answers to those open questions, which I think are critically important for determining not only clinical treatment decision-making, but also our ability to understand sequencing of therapies, prioritization of therapies. I think a prospective, forward-looking project, piggybacking on that paired biopsy, you know, we had a very small subset of patients with paired biopsies, but a larger subset or cohort looking at paired biopsies where we can see is there evolution of these IHC expression, even mRNA expression, as you're saying, is there differential there? Are there selection pressures to targeted therapies? Is there upregulation or downregulation of targets in response not just to chemotherapy, but for example, for other sort of ADCs or bi-specific T-cell engagers? I think those are going to be critically important future studies which are going to be a bit challenging to do, but really important to figure out this key clinical question of sequencing, which we're all contemplating in our clinics day in and day out. If you have a patient, and these patients often can be sick quite quickly, they might have one shot of what's the next treatment that you're going to pick. We can't guarantee that every patient is going to get to see every therapy. How can you help to sort of answer the question of like what should you offer? So I think that's the key question sort of underlying any future work is how predictive or prognostic are these biomarkers? What translational or correlative studies can we do on the tissue to understand clinical treatment decision-making? I think those are the key things that will unfold in the next couple of years. Dr. Rafeh Naqash: The last question for you, Alissa, that I have is, you are fairly early in your career, and you've accomplished quite a lot. One of the most important things that comes out from this manuscript is your mentorship for somebody who is a fellow and who led this project. For other junior investigators, early-career investigators, how did you do this? How did you manage to do this, and how did you mentor Jessica on this project with some of the lessons that you learned along the way, the good and other things that would perhaps help other listeners as they try to mentor residents, trainees, which is one of the important things of what we do in our daily routine? Dr. Alissa Cooper: I appreciate you calling me accomplished. Um, I'm not sure how true that is, but I appreciate that. I didn't have to do a whole lot with this project because Jesse is an extraordinarily smart, driven, talented fellow who came up with a lot of the clinical questions and a lot of the research questions as well. And so this project was definitely a collaborative project on both of our ends. But I think what was helpful from both of our perspectives is from my perspective, I could kind of see that this was a gap in the literature that really, I think, from my work leading clinical trials and from treating patients with these kinds of cancers that I really hoped to answer. And so when I came to Jessica with this idea as sort of a project to complete, she was very eager to take it and run with it and also make it her own. You know, in terms of early mentorship, I have to admit this was the first project that I mentored, so it was a great learning experience for me as well because as an early-career clinician and researcher, you're used to having someone else looking over your shoulder to tell you, "Yes, this is a good journal target, here's what we can anticipate reviewers are going to say, here are other key collaborators we should include." Those kind of things about a project that don't always occur to you as you're sort of first starting out. And so all of that experience for me to be identifying those more upper-level management sort of questions was a really good learning experience for me. And of course, I was fantastically lucky to have a partner in Jesse, who is just a rising star. Dr. Jessica Ross: Thank you. Dr. Rafeh Naqash: Well, excellent. It sounds like the first of many other mentorship opportunities to come for you, Alissa. And Jessica, congratulations on your next step of joining and being faculty, hopefully, where you're training. Thank you again, both of you. This was very insightful. I definitely learned a lot after I reviewed the manuscript and read the manuscript. Hopefully, our listeners will feel the same. Perhaps we'll have more of your work being published in JCO PO subsequently. Dr. Alissa Cooper: Hope so. Thank you very much for the opportunity to chat today. Dr. Jessica Ross: Yes, thank you. This was great. Dr. Rafeh Naqash: 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 as you never miss an episode. You can find all ASCO shows at asco.org/podcasts. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Disclosures: Dr. Alissa Jamie Cooper Honoraria Company: MJH Life Scienes, Ideology Health, Intellisphere LLC, MedStar Health, Physician's Education Resource, LLC,  Gilead Sciences, Regeneron, Daiichi Sankyo/Astra Zeneca, Novartis,  Research Funding: Merck, Roche, Monte Rosa Therapeutics, Abbvie, Amgen, Daiichi Sankyo/Astra Zeneca Travel, Accommodations, Expenses: Gilead Sciences

Send us a textGood morning from Pharma Daily: the podcast that brings you the most important developments in the pharmaceutical and biotech world. Today, we delve into a host of transformative events reshaping the landscape, from strategic acquisitions and funding infusions to regulatory maneuvers and scientific breakthroughs.Johnson & Johnson has taken a decisive step in its oncology strategy with the $3 billion acquisition of Halda's cell death technology. This acquisition, focusing on the "hold and kill" bifunctional small molecule platform, is poised to enhance J&J's prostate cancer pipeline significantly. It underscores J&J's commitment to expanding its oncology portfolio through innovative platforms designed to improve therapeutic outcomes. The move highlights a broader industry trend toward personalized medicine and targeted cancer therapies, which are becoming pivotal in improving patient care.In another domain of cancer treatment, Nuvalent has unveiled promising Phase 1/2 data for its candidate neladalkib, which could position the company as a formidable competitor to Pfizer's established lung cancer drug, Lorbrena. The promising data might expedite regulatory discussions with the FDA, potentially leading to an accelerated approval process. This development illustrates the competitive landscape in oncology, where firms strive to introduce novel therapies with improved efficacy and safety profiles.The field of antibody-drug conjugates (ADCs) is also experiencing significant advancements. A San Diego-based biotech has secured $120 million in funding to develop a best-in-class ADC formula, with support from Merck & Co. This initiative aims to refine the precision and efficacy of ADCs by delivering cytotoxic agents directly to cancer cells while minimizing collateral damage to healthy tissues. Such innovations are crucial as they represent a new frontier in targeted cancer therapy.In terms of financial activities, Artios Pharma's successful $115 million Series D funding round is set to bolster its clinical efforts in exploring DNA damage response inhibitors for cancer treatment. These inhibitors target cancer cells' ability to repair DNA damage, holding potential for more effective therapies against resistant cancer types. Meanwhile, Sofinnova Partners' €650 million raise for biotech and medtech investments amid a volatile economic environment underscores continued investor confidence in life sciences despite market uncertainties.Bayer is making strategic moves in China by opening an incubator in Beijing. This facility will host local biopharma companies such as Suzhou Puhe Biopharma and Beijing Youngen Technology, fostering innovation and collaboration within China's burgeoning biotech landscape. Such initiatives reflect global efforts to leverage regional strengths and foster cross-border collaborations.On the operational side, Nxera Pharma is restructuring its workforce by laying off 15% of its staff as part of a strategic pivot towards profitability. This decision mirrors broader industry trends where companies refocus resources on core projects to streamline operations and enhance financial stability.A recent study has highlighted the impact of NIH grant cuts on clinical trials across the United States. Over 383 trials involving more than 74,000 patients have been disrupted due to funding terminations under the current administration. This situation raises concerns about the sustainability of clinical research funding and its implications for ongoing medical advancements.Jazz Pharmaceuticals has reported practice-changing Phase 3 results for its HER2-targeted drug Ziihera for gastroesophageal adenocarcinoma. These findings reaffirm Jazz's confidence in positioning Ziihera as a preferred first-line treatment option for HER2-positive cancers, poSupport the show

In this episode, Benjamin Levy, MD, FASCO, and Alex Spira, MD, PhD, FASCO, discuss the latest developments in targeting TROP2 and TIGIT for the treatment of lung cancer, including:TROP2-targeting ADCs: datopotamab deruxtecan, sacituzumab govitecan, sacituzumab tirumotecan TROP2 ADCS for patients with EGFR-mutated NSCLCTIGIT-targeting agents: domvanalimab, rilvegostomigPresenters:Benjamin Levy, MD, FASCOAssociate ProfessorJohns Hopkins School of MedicineClinical DirectorJohns Hopkins Kimmel Cancer Center, National Capitol Region (NCR)Washington, DCAlex Spira, MD, PhD, FASCODirector Clinical ResearchVirginia Cancer SpecialistsCEO NEXT Oncology VirginiaFairfax, VirginiaContent based on an online CME program supported by an independent educational grant from Gilead Sciences, Inc.Link to full program:https://bit.ly/4qZLR6B Hosted by Simplecast, an AdsWizz company. See pcm.adswizz.com for information about our collection and use of personal data for advertising.

ADCs as first-line treatment? ESR1 monitoring before progression? Local therapy for CNS disease? Experts tackle today's toughest decisions. Credit available for this activity expires: 11/14/2026 Earn Credit / Learning Objectives & Disclosures: https://www.medscape.org/viewarticle/charting-course-metastatic-breast-cancer-care-optimizing-2025a1000v4s?ecd=bdc_podcast_libsyn_mscpedu

Hay vida más allá de EV Pembro. Los Dres Durán, Gómez de Liaño y Coca Membribes repasan el estudio de DV-Toripalimab presentado recientemente en ESMO. Más similitudes que diferencias con EV302 aunque quedan algunas preguntas por responder. Necesitamos más ensayos para entender cuándo hay que interrumpir el tratamiento, así como un mayor seguimiento de los pacientes. También repasaremos el arsenal de nuevos ADCs en marcha que seguirán aportando evidencia en esta población.

Tom moderates Jun Guo, Matt Galsky, Michiel Van der Heidjen and Shilpa Gupta as they discuss this ever-expanding class of agents in bladder cancer.

Good morning from Pharma Daily: the podcast that brings you the most important developments in the pharmaceutical and biotech world. Today, we explore a series of groundbreaking advancements and strategic collaborations that promise to transform drug development and patient care.In the autoimmune space, Boehringer Ingelheim has made a significant move by securing a $570 million agreement with CDR-Life. This deal centers on a trispecific antibody, a novel therapeutic approach that targets multiple pathways simultaneously, potentially revolutionizing treatments for autoimmune diseases. Boehringer's commitment to these cutting-edge modalities highlights their strategy to leverage novel technologies for more effective therapeutic solutions.Similarly, Celltrion has entered a $744 million collaboration with Kaigene, focusing on two preclinical autoimmune drugs. This partnership marks Celltrion's strategic shift from biosimilars to novel biologics, positioning the company at the forefront of biologic therapeutics. By investing in early-stage research, Celltrion aims to introduce transformative therapies for autoimmune conditions, showcasing the industry's willingness to bet on groundbreaking scientific advancements.In gene editing, Azalea Therapeutics is gaining attention with its focus on permanent genome editing using a dual-vector approach. Backed by $82 million in funding and support from CRISPR pioneer Jennifer Doudna, Azalea is poised to develop potentially curative solutions through single-dose treatments. The credibility lent by a Nobel laureate adds anticipation to their research outcomes, with the potential to significantly impact gene therapy.Shifting focus to clinical trials, Sarepta Therapeutics faces challenges after missing the primary endpoint in its confirmatory trial for Duchenne muscular dystrophy drugs. Despite this setback, Sarepta is pursuing full FDA approval, emphasizing the complex interplay between clinical data and regulatory strategies. This situation underscores the critical importance of robust confirmatory trials in securing drug approvals and ensuring patient access to new therapies.Merck is making strategic moves in oncology by regaining full control over an early-phase asset and securing $700 million from Blackstone for its oncology pipeline. This dual focus on asset acquisition and financial fortification reflects Merck's aggressive growth strategy aimed at expanding its cancer treatment offerings.Emerging from stealth mode, Neok Bio has secured a $75 million investment to advance bispecific antibody-drug conjugates into clinical trials. These bispecific ADCs represent the forefront of targeted cancer therapies, aiming for precision targeting of cancer cells while minimizing off-target effects. Neok Bio's progress could significantly enhance oncology treatment paradigms through improved therapeutic indices.Turning to regulatory landscapes, Teva's recall of over half-a-million bottles of prazosin hydrochloride due to potential carcinogenic impurities highlights ongoing challenges in ensuring drug safety and quality control within manufacturing processes. Such recalls underscore the critical importance of maintaining high standards in pharmaceutical production.In broader industry developments, we see dynamic trends where scientific innovation meets strategic business decisions and regulatory considerations. The potential impact on patient care is profound, with breakthroughs in autoimmune treatments, gene editing technologies, and targeted cancer therapies poised to alter therapeutic landscapes significantly.UCB has achieved another milestone with FDA approval for Kygevvi, an ultra-rare disease medication marking their third approval in rare conditions within three years. This success underscores UCB's strategic focus on niche markets that offer less competition but significant patient impact. Advancements in genetic research aSupport the show

In this episode, Kathleen N. Moore, MD, MS, FASCO, and Isabelle Ray-Coquard, MD, PhD, discuss the emerging role of CDH6-targeting antibody–drug conjugates (ADCs) for ovarian cancer, including:Results of the phase I trial of raludotatug deruxtecan (R-DXd) in ovarian cancerResults of the phase II REJOICE-Ovarian01 study in patients with platinum-resistant diseaseHow R-DXd may be incorporated into the treatment paradigmOther investigational CDH6-targeting ADCs: CUSP06, SIM0505Presenters:Kathleen N. Moore, MD, MS, FASCO Deputy Director and Cancer Therapeutics Co-LeadStephenson Cancer Center at the University of OklahomaProfessorDepartment of OB/GynASCO BODOklahoma City, OklahomaIsabelle Ray-Coquard, MD, PhD President of the Gineco GroupCentre Leon BérardReshape Lab Inserm u1290Université Claude Bernard Lyon EstLyon, FranceContent based on an online CME program supported by an independent educational grant from Boehringer Ingelheim Pharmaceuticals, Inc.Link to full program: https://bit.ly/43PXoeP Hosted by Simplecast, an AdsWizz company. See pcm.adswizz.com for information about our collection and use of personal data for advertising.

As we near the end of 2025, the CDMO industry finds itself at a pivotal financial and strategic juncture — shaped by constrained funding, shifting demand, and renewed investor scrutiny.  In this episode of Off Script, we speak with Brian Scanlan, Advisor of Life Sciences at Edgewater Capital Partners, to examine how the year's market and investment trends align with his predictions from an earlier CPHI Annual Report. Brian shares his perspective on: How accurately his forecast of stability and growth for clinical CROs and CDMOs has held up amid tighter capital markets; The ongoing softness among early-stage pharma service providers and what it reveals about funding flows across the sector; and Where investor interest is gravitating — from ADCs and small molecules to biologics — and what this signals for the next phase of CDMO evolution.

“We were able to show multiple datasets that actually deliver against this vision that antibody drug conjugates can improve on and therefore displace chemotherapy” says Dr. Susan Galbraith, AstraZeneca’s EVP of oncology R&D. Galbraith joins Bloomberg Intelligence analyst Sam Fazeli to break down key findings from ESMO — from early-line HER2 breast cancer data to progress in bladder and lung cancer. She details the promise of Enhertu and Datopotamab, AstraZeneca’s antibody-drug conjugates (ADCs), and how their work may transform cancer treatment in curative settings.See omnystudio.com/listener for privacy information.

As part of the European Society for Medical Oncology (ESMO) Congress 2025, CancerNetwork® spoke with a variety of experts about key takeaways from different late-breaking abstracts, oral presentations, and other sessions focused on potential advancements across cancer care. Presenting investigators highlighted updated results from clinical trials evaluating novel therapeutic strategies across different cancer populations, including breast cancer and lung cancer.  Phase 3 VIKTORIA-1 Trial Sara A. Hurvitz, MD, FACP, the Smith Family Endowed Chair in Women's Health and senior vice president and director of the Clinical Research Division at the Fred Hutch Cancer Center, and tumor chair in breast oncology for the ONCOLOGY® editorial advisory board, first discussed findings from the phase 3 VIKTORIA-1 trial (NCT05501886). Her presentation highlighted how VIKTORIA-1 was “the first study to demonstrate a statistically significant and clinically meaningful improvement in progression-free survival [PFS] with PAM inhibition” for patients with PIK3CA wild-type advanced breast cancer. Data from the trial showed that gedatolisib plus fulvestrant (Faslodex) and palbociclib (Ibrance) produced a median PFS of 9.3 months (95% CI, 7.2-16.6) vs 2.0 months (95% CI, 1.8-2.3) with fulvestrant alone (HR, 0.24; 95% CI, 0.17-0.35; P

Good morning from Pharma Daily: the podcast that brings you the most important developments in the pharmaceutical and biotech world. Today, we're diving into some of the most significant shifts occurring in these industries, touching on strategic restructuring, regulatory milestones, and groundbreaking scientific advancements that are shaping the future of drug development and patient care.Let's begin with a major corporate shakeup at Novo Nordisk. The company has announced a significant leadership transition as former CEO Lars Rebien Sorensen is set to become the new chairman of the board. This change follows the resignation of seven board members and indicates a strategic realignment within the company. The Novo Foundation's involvement suggests a deeper strategic shift, potentially aligning with new organizational objectives and innovations. Such moves are pivotal as they could influence Novo Nordisk's market position and future product development.Turning to scientific breakthroughs, Merck's collaboration with Kelun-Biotech has yielded promising results with their Trop2 antibody-drug conjugate, sacituzumab-tmt. This ADC has shown success in two Phase 3 trials targeting lung and breast cancers, underscoring the therapeutic potential of ADCs in oncology. By selectively targeting cancer cells while minimizing damage to healthy tissues, ADCs could significantly improve patient outcomes and represent a powerful modality in cancer treatment.In regulatory affairs, Kenvue is challenging the FDA over proposed safety warnings for Tylenol linked to autism during pregnancy. This dispute highlights the ongoing debates surrounding drug safety and regulatory oversight. The outcome could have significant implications for labeling practices and consumer trust in over-the-counter medications. Meanwhile, Summit Therapeutics plans to file for FDA approval of ivonescimab, highlighting ongoing innovation in drug development pipelines. Similarly, Novo Nordisk's semaglutide pill Rybelsus has received FDA expansion approval to reduce major adverse cardiovascular events. This sets a new benchmark for oral metabolism drugs by demonstrating their potential beyond glycemic control to positively impact cardiovascular health.As we explore industry trends, there's growing interest in direct-to-consumer drug sales. While this approach offers patients access to medications at reduced costs, it raises concerns about privacy and the quality of care without traditional healthcare provider interactions. Additionally, a notable decline in pharmaceutical TV ad spending by 19% in Q3 suggests a shift towards digital engagement strategies. Amidst these narratives, the Biotechnology Innovation Organization (BIO) has launched an awareness campaign to combat misinformation about vaccines. This effort underscores the importance of immunizations in public health and aims to reinforce trust amid rising disinformation.In another scientific advancement, GSK has released positive Phase 3 data for Spero Therapeutics' oral antibiotic candidate. The oral formulation's efficacy comparable to intravenous options could lead to broader use and improved patient adherence—critical advancements as antibiotic resistance remains a global health challenge.Investment activities reflect strategic shifts within the industry as well. Curewell Capital's investment in Wilmington PharmaTech aims to enhance U.S. active pharmaceutical ingredient production capacity—a crucial step given recent global supply chain disruptions. Similarly, India's ACG is making a $200 million investment in its first U.S. empty-capsule production facility, highlighting the strategic importance of manufacturing capabilities on American soil.Galapagos' decision to wind down its cell therapy unit marks a significant strategic pivot from its previous focus on this modality. This shift reflects broader industry trends where companies reassess priorSupport the show

Good morning from Pharma Daily: the podcast that brings you the most important developments in the pharmaceutical and biotech world. Recent developments in these industries underscore a period of significant scientific progress, regulatory maneuvers, and strategic investments.One notable event was AstraZeneca and Daiichi Sankyo's success at the European Society for Medical Oncology Congress 2025. Their antibody-drug conjugate, Datroway, demonstrated superior efficacy compared to Gilead's Trodelvy in the first global head-to-head trial involving Trop2-targeted therapies. This reflects the increasing focus on antibody-drug conjugates as precision medicine tools that offer targeted treatment options with potentially improved outcomes over traditional chemotherapy.In a move highlighting the ongoing trend of bolstering domestic production capacities, Merck is making a substantial $3 billion investment in a small molecule drug plant in Virginia. This is part of a broader $70 billion commitment to expand manufacturing and R&D capabilities in the U.S. Such strategic investments are crucial for maintaining competitive advantage and ensuring drug availability while meeting rising demands and streamlining supply chains.Turning to regulatory updates, the FDA has approved Amgen and AstraZeneca's Tezspire for chronic rhinosinusitis with nasal polyps. This marks Tezspire's second indication, following its initial approval for severe asthma in 2021. The expanded approval showcases the drug's versatility and represents a strategic push to enhance its market presence against competitors like Dupixent.In oncology, Merck's Keytruda and Astellas/Pfizer's Padcev have made headlines with compelling results in muscle-invasive bladder cancer. The combination therapy reduced the risk of death by 50%, reinforcing Keytruda's position as a cornerstone immunotherapy across multiple cancer types. This result not only augments treatment options but also signifies the potential for combination regimens to enhance patient outcomes.Roche has expanded the indication of its aging oncology drug Gazyva to treat lupus nephritis, demonstrating strategic repurposing efforts to extend the lifecycle of existing therapies. While this expansion into autoimmune diseases comes late in Gazyva's lifecycle, it highlights a growing trend of capitalizing on established drugs for new therapeutic areas.AstraZeneca and Daiichi Sankyo's Enhertu showed robust efficacy in early breast cancer treatment, potentially reshaping therapeutic strategies by offering new hope for early intervention. Similarly, Novartis' Pluvicto demonstrated promise in slowing hormone-sensitive prostate cancer progression, underscoring the potential of radioligand therapies in oncology.However, not all developments have been positive. AstraZeneca faced setbacks when its Imfinzi and Lynparza combination failed to meet survival goals in ovarian cancer, underscoring the challenges inherent in oncology drug development and the stringent benchmarks set by regulatory authorities like the FDA.The industry is also witnessing significant advancements in next-generation ADCs, as evidenced by Tubulis' 59% response rate in early clinical trials, which has attracted substantial investor interest. Additionally, Grail's Galleri cancer blood test is progressing towards FDA review with enhanced performance data, potentially revolutionizing cancer screening and early detection practices.These scientific and regulatory milestones are complemented by strategic investments in bioconjugation technologies. Cohance Life Sciences' $10 million investment in NJ Bio to enhance GMP bioconjugation capabilities exemplifies this trend. Such investments are crucial for advancing ADC development, which remains a focal point for innovative cancer therapies.Overall, these developments reflect a dynamic phase for the pharmaceutical and biotech sectors characterized by signSupport the show

This week's EYE ON NPI is as mysterious and powerful as the extra-dimensional being from Star Trek (https://en.wikipedia.org/wiki/Q_(Star_Trek)) - it's the new Arduino UNO Q (https://www.digikey.com/en/product-highlight/a/arduino/uno-q-microcontroller-board) microcontroller board, released as part of the Qualcomm/Arduino acquisition announcement (https://www.qualcomm.com/news/releases/2025/10/qualcomm-to-acquire-arduino-accelerating-developers--access-to-i). This Uno-shaped board is packed with both an STM32 microcontroller and a Qualcomm Dragonwing microprocessor so you get the best-of-both-worlds: 3.3V/5V logic compatibility with timers and ADCs, plus a full Debian install and AI support for running local vision models. We last checked in on Arduino we were reviewing their new announcements based on a partnership with Renesas: the Arduino Nano R4 SoC (https://www.youtube.com/watch?v=QLAI41ZfCfw) which is a miniaturized version of the UNO R4 (https://www.youtube.com/watch?v=uw0EU8urz5M). These boards feature an Arm microcontroller, with lots of fun on-board accessories like an LED grid, Qwiic connector, and WiFi/Bluetooth module. These boards represented a bump in capabilities over the classic UNO R3 (https://www.digikey.com/en/products/detail/arduino/A000073/3476357) but are still under-powered compared to the 'Portenta' line (https://www.digikey.com/en/products/detail/arduino/ABX00045/15294134). So, when we see the Arduino UNO Q (https://www.digikey.com/short/qc9d09fm) is a merging of three separate 'strands' of Arduino development history. One, it's shaped and has hardware-compatibility with the classic UNO which has been their mainstay for decades. Two, it has the powerful microcontroller type that the Pro line features. And three, it revives some of the Linux-based boards that Arduino had previously released like the Yun (https://www.digikey.com/en/products/detail/arduino/A000008/4486331), Tian (https://docs.arduino.cc/retired/boards/arduino-tian/) and Tre (https://docs.arduino.cc/retired/boards/arduino-tre). What sets the Q apart is that this time instead of being just a chip-supplier partnership, Arduino has been acquired as a subsidiary of Qualcomm (https://www.qualcomm.com/news/releases/2025/10/qualcomm-to-acquire-arduino-accelerating-developers--access-to-i) which means that there's going to be first-class engineering support for the onboard Dragonwing processor. Speaking of, let's take a look at the hardware included in the new Q! There's two chipsets on each board: the big processor is a Qualcomm Dragonwing™ QRB2210 (https://www.digikey.com/en/products/detail/qualcomm/QRB-2210-0-NSP752-TR-00-0/27904331) - 64-bit System-on-Chip with 4 × Arm Cortex-A53 running at 2.0 GHz and Adreno 702 GPU running at 845 MHz for 3D graphics. This chip runs mainline Debian OS with upstream support so you can configure a kernel and distribution image without needing patches. Arduino and Qualcomm distribute their own ready to go image too (https://docs.arduino.cc/tutorials/uno-q/update-image/). This chip has modern A/V support with both CSI camera and DSI MIPI display capability to match. Those high speed connects are available on the dual 60-pin bottom connects - while there isn't a sub-connect board right now, it's likely that Arduino will develop one soon. Meanwhile, you can use their documentation (https://docs.arduino.cc/hardware/uno-q/) such as STEP and Gerber files if you want to start adding a direct-plug integration into your hardware now. The second chipset is a STM32U585 Arm Cortex-M33 with 2 MB Flash, 786 kB SRAM and running at 160 MHz - it runs the Arduino Core via Zephyr OS and from the block diagram, looks like it communicates with the main core via UART and SPI. The STM is what handles GPIO, PWM, ADC, DAC, timers, etc since it is 3.3V logic and has some 5V logic-level compatibility. The main headers on the Arduino - and some of the bottom extra headers - expose the STM logic so you can connect standard sensors, OLEDs, relays etc. While there are some GPIO from the Dragonwing also available, they're 1.8V logic and are already allocated in the Linux Device tree. The Arduino UNO Q (https://www.digikey.com/short/qc9d09fm) is available for pre-order right now from DigiKey for a door-busting $44! We've already put in our order, and we'll do a project to check it out as soon as it arrives. After you get your pre-order in, check out some of the projects that have already been published to get a sense of the Q's capabilities like this MAME emulation arcade cabinet (https://projecthub.arduino.cc/jcarolinares/arduino-uno-q-arcade-cabinet-machine-39dd38) or face-recognition car (https://www.youtube.com/watch?v=EGDxAXpH_Ag). You can start dreaming of what you'll be able to do with a full computer + microcontroller board that fits where your old UNO R3 would fit, while you wait for the shipping notification.

Good morning from Pharma Daily: the podcast that brings you the most important developments in the pharmaceutical and biotech world. Today, we're delving into a series of fascinating updates that underscore a period of significant scientific advancement, strategic partnerships, and regulatory developments in the industry.Starting with Dianthus Therapeutics, which has taken a bold step by investing up to $1 billion to license a bifunctional fusion protein from Nanjing Leads Biolabs. This protein targets autoimmune disorders, a field of immense interest due to the unmet medical needs and potential for breakthrough treatments. Such substantial financial commitments highlight the ongoing trend in the biotech sector towards innovative therapies for autoimmune diseases. In parallel, Sanofi has secured a $500 million agreement with Evoq Therapeutics, continuing its strategic focus on next-generation autoimmune technologies. This partnership aligns with Sanofi's broader strategy to leverage cutting-edge science in managing autoimmune conditions more effectively. Sanofi's engagement with Evoq Therapeutics stands out as a significant step forward in conquering autoimmune diseases through nanodisc technology designed to facilitate the development of curative treatments for disorders like celiac disease and type 1 diabetes. This collaboration reflects a growing trend among pharmaceutical giants investing in advanced biotechnologies that promise transformative impacts on disease management and patient care.Meanwhile, AstraZeneca's renewed collaboration with Immunai, valued at $85 million, seeks to enhance therapies for inflammatory bowel disease through artificial intelligence. This collaboration is part of a wider industry movement towards utilizing AI in drug discovery and development, particularly for complex diseases like IBD. AI's ability to process large datasets and identify potential therapeutic targets faster and more accurately is revolutionizing how companies approach drug development.In clinical trial news, Praxis Precision Medicines has reported positive Phase 3 results for ulixacaltamide in treating essential tremor. This outcome reverses prior concerns from interim analyses and illustrates the persistent innovation in neurological disorder treatments. Similarly, AiCuris has announced successful results from its Phase 3 trial of pritelivir for refractory herpes simplex virus infections in immunocompromised patients. This success paves the way for an FDA filing, demonstrating ongoing progress in antiviral therapy development.Novartis is also making strides with favorable outcomes from its Phase 3 trial of fabhalta for IgA nephropathy. As a complement factor B inhibitor, fabhalta has shown efficacy in slowing kidney function decline, which may lead to a new standard of care for this chronic kidney disease. Novartis plans to file these findings with regulatory bodies soon, highlighting its strategic focus on diversifying into rare kidney diseases.Turning to industry trends, there is significant investment activity in antibody-drug conjugates (ADCs). French biotech company ADCytherix has raised $122 million to advance these targeted therapies into clinical trials. ADCs are gaining traction due to their precision in targeting cancer cells while minimizing damage to healthy tissues. Such advancements signal a potential shift in cancer treatment paradigms toward more targeted and less toxic therapies. Similarly, Tubulis raised an impressive Series C funding round to advance work on ADCs targeting ovarian and lung cancers, underscoring the growing interest in the potential of ADCs engineered to deliver cytotoxic drugs specifically to cancer cells.In another intriguing development, research has shown that a common diabetes drug can alleviate brain inflammation in female mice with multiple sclerosis. This finding exemplifies the growing interest in drug repurposSupport the show

What happens when the most complex molecules in biotech meet the organizational challenge of managing 300+ analytical scientists? The answer lies not just in the science, but in building systems that turn technical complexity into reliable delivery.In Part 2 of our deep dive with Amanda Hoertz, VP of Analytical and Formulation Sciences at KBI Biopharma, we shift focus from the molecular intricacies of ADCs to the operational mastery required to scale analytical development across multiple sites. Amanda reveals how her team achieves consistency across hundreds of scientists while maintaining the agility to pivot priorities in real time when critical programs need emergency support.This isn't just about managing people; it's about architecting systems that preserve institutional knowledge, accelerate method transfer, and deliver results when regulatory deadlines loom.What you'll discover:Seamless Project Handoffs Without Knowledge Loss: How KBI's stable team assignments eliminate the costly learning curves that plague most CDMO relationships, ensuring your molecule expertise stays with your program from development through commercial manufacturing.Organizational Scale Without Operational Chaos: The decision tree and layered reporting structure that allows 200+ analysts at a single site to function as a coordinated force, capable of rapid reprioritization and flood-level resource deployment when programs reach critical status.Digital Transformation That Actually Works: Beyond the automation buzzwords, Amanda walks through the practical realities of LIMS/ELN implementation, audit-compliant systems, and machine learning databases that transform raw data into defensible, actionable insights for complex biologics.Whether you're evaluating how analytical capabilities scale with program complexity, or seeking practical insights into leading technical teams through digital transformation, this episode delivers the operational intelligence that separates successful ADC programs from expensive failures.Connect with Amanda Hoertz:LinkedIn: www.linkedin.com/in/amanda-hoertz-3aba605KBI Biopharma: www.kbibiopharma.comKBI Portal: www.standalone.kbi.bioNext step:Book a 20-minute call to help you get started on any questions you may have about bioprocessing analytics: https://bruehlmann-consulting.com/call

Good morning from Pharma Daily: the podcast that brings you the most important developments in the pharmaceutical and biotech world. Today, we're diving into a series of major advancements and strategic moves that are shaping the future of healthcare.A significant development comes from AstraZeneca, which has committed a substantial $445 million investment to bolster production at its Texas facility for Lokelma, a treatment designed for hyperkalemia. Hyperkalemia is a condition characterized by elevated potassium levels in the blood, posing serious health risks if not managed properly. This investment highlights AstraZeneca's dedication to meeting growing global demand and enhancing patient access to this vital treatment. By strengthening its production capabilities, the company aims to ensure a more reliable supply chain, potentially leading to better outcomes for patients worldwide.Meanwhile, Pfizer is making noteworthy progress in the realm of oncology. Recent clinical trial results have positioned Tukysa, developed in collaboration with Seagen, as a promising candidate for first-line maintenance therapy in HER2-positive breast cancer. The potential shift from second-line to first-line treatment could significantly alter patient care by offering an effective therapeutic option earlier in the disease management process. This advancement underscores Pfizer's commitment to improving long-term outcomes for patients battling this aggressive form of cancer.In legal news, a dispute between Novo Nordisk and KBP Pharmaceuticals has underscored the critical importance of transparency and thorough due diligence in biotech transactions. The controversy involves "anomalous" phase 2 clinical trial results that Novo Nordisk claims were not adequately disclosed by KBP. Such cases highlight the necessity for rigorous investigation during mergers and acquisitions to prevent costly legal battles and ensure informed decision-making in drug development partnerships.On the HIV prevention front, GSK has released promising data for its long-acting pre-exposure prophylaxis drug, Apretude. This new data suggests Apretude holds higher acceptability compared to Gilead's competing product, Yetztugo. Improved patient adherence could shift market dynamics towards GSK's favor, potentially enhancing public health outcomes by preventing HIV infections more effectively.Manufacturing innovations are also taking center stage as Particle Dynamics collaborates with a former EuroAPI plant to introduce Codis, a new contract development and manufacturing organization (CDMO). Codis will offer comprehensive services such as spray drying and particle engineering, aligning with growing demand for specialized pharmaceutical manufacturing capabilities.Turning our attention to diabetes treatment advancements, Eli Lilly's oral GLP-1 candidate Orforglipron has demonstrated superiority over both placebo and AstraZeneca's Farxiga in phase 3 trials for type 2 diabetes. This success strengthens Eli Lilly's portfolio in a highly competitive market and could lead to regulatory approval next year. An oral treatment option could significantly enhance patient compliance compared to existing injectable GLP-1 therapies.In oncology, Boehringer Ingelheim has entered into a deal worth up to $991 million with AimedBio, focusing on antibody-drug conjugates (ADCs) that target proteins involved in tumor growth and resistance. This collaboration highlights the increasing interest in ADCs as targeted cancer therapies capable of minimizing systemic toxicity while delivering potent cytotoxic agents directly to cancer cells.The industry continues to be shaped by funding rounds and strategic acquisitions. Novo Nordisk's acquisition of Omeros' MASP-3 inhibitor Zaltenibart for $2.1 billion marks a significant move in rare disease therapeutics. Despite Omeros pausing development, Novo Nordisk sees potential in treating paroxysSupport the show

Featuring an interview with Dr Laura Huppert, including the following topics: General overview of antibody-drug conjugate (ADC) structure and function; mechanisms of resistance to ADCs (0:00) Preventing and managing toxicities associated with trastuzumab deruxtecan (5:44) Selecting between sacituzumab govitecan and datopotamab deruxtecan for patients with metastatic breast cancer; common toxicities associated with these 2 agents (9:30) Potential use of ADCs in the first line for metastatic triple-negative breast cancer (mTNBC) (16:13) Case: A woman in her mid 40s with mTNBC receives sacituzumab govitecan and pembrolizumab in the first-line setting (18:25) CNS penetration and activity of ADCs in the treatment of breast cancer (22:27) Use of trastuzumab deruxtecan for HER2-ultralow mTNBC; promising trials of ADCs and other therapies for mTNBC (24:24) Treatment options in the second line and beyond for patients with HR-positive mBC that is HER2-negative, HER2 low or HER2 ultralow (27:05) Case: A woman in her late 50s with HR-positive, HER2-low mBC experiences disease progression on multiple lines of therapy (30:51) Ongoing evaluation of ADCs in the localized disease setting (35:42) Novel therapeutic approaches for leptomeningeal disease in patients with breast cancer (38:38) CME information and select publications

What if the key to unlocking ADC manufacturing success lies in abandoning the platform mindset entirely?Antibody-drug conjugates represent biotech's most promising weapon against cancer: precision-targeted therapeutics that deliver cytotoxic payloads directly to tumor cells while sparing healthy tissue. But beneath the clinical promise lies a manufacturing reality that's rewriting the rules of bioprocess development, demanding analytical strategies that most CDMOs simply aren't equipped to handle.In this deep-dive episode, David Brühlmann sits down with Amanda Hoertz, Vice President of Analytical and Formulation Sciences at KBI Biopharma, where she oversees 300+ scientists across the mammalian network. Amanda's team has cracked the code on some of the industry's most challenging ADC programs, achieving a remarkable 93% batch success rate by rejecting cookie-cutter approaches in favor of molecule-specific development strategies.What you'll discover:The Platform Fallacy: Why treating ADCs like standard monoclonals is costing companies millions and months of development time, and the bespoke analytical framework that's changing everything.Cytotoxic Payload Management: From free drug analysis to employee safety protocols, Amanda reveals the hidden complexities of handling molecules designed to kill cells, including the specialized facilities and analytical methods required for GMP manufacturing.Charge Heterogeneity Mastery: The analytical method that "keeps Amanda up at night," and the development strategies her team uses to achieve robust separation and qualification across multiple sites and analysts.This episode delivers the technical depth and strategic insights that bioprocess engineers need to navigate ADC development successfully. Whether you're evaluating CDMO partnerships, optimizing analytical methods, or scaling complex conjugates, Amanda's proven strategies will transform your approach to these game-changing therapeutics.Ready to master the analytical complexities that make or break ADC programs?Connect with Amanda Hoertz:LinkedIn: www.linkedin.com/in/amanda-hoertz-3aba605KBI Biopharma: www.kbibiopharma.comKBI Portal: www.standalone.kbi.bioNext step:Book a 20-minute call to help you get started on any questions you may have about bioprocessing analytics: https://bruehlmann-consulting.com/call

Dr Laura Huppert from the University of California, San Francisco, discusses approved and investigational antibody-drug conjugates in the current and future management of HR-positive and triple-negative metastatic breast cancer. CME information and select publications here.

Dr. Hope Rugo and Dr. Giuseppe Curigliano discuss recent developments in the field of bispecific antibodies for hematologic and solid tumors, including strategies to optimize the design and delivery of the immunotherapy. TRANSCRIPT Dr. Hope Rugo: Hello and welcome to By the Book, a podcast series from ASCO that features engaging conversations between editors and authors of the ASCO Educational Book. I am your host, Dr. Hope Rugo. I am the director of the Women's Cancers Program and division chief of breast medical oncology at the City of Hope Cancer Center. I am also the editor-in-chief of the Educational Book. Bispecific antibodies represent an innovative and advanced therapeutic platform in hematologic and solid tumors. And today, I am delighted to be joined by Dr. Giuseppe Curigliano to discuss the current landscape of bispecific antibodies and their potential to reshape the future of precision oncology. Dr. Curigliano was the last author of an ASCO Educational Book piece for 2025 titled, "Bispecific Antibodies in Hematologic and Solid Tumors: Current Landscape and Therapeutic Advances." Dr. Curigliano is a breast medical oncologist and the director of the Early Drug Development Division and chair of the Experimental Therapeutics Program at the European Institute of Oncology in Milan. He is also a full professor of medical oncology at the University of Milan. You can find our disclosures in the transcript of this episode. Dr. Curigliano, Giuseppe, welcome and thanks for being here. Dr. Giuseppe Curigliano: Thanks a lot for the invitation. Dr. Hope Rugo: Giuseppe, I would like to first ask you to provide some context for our listeners on how these novel therapeutics work. And then perhaps you could tell us about recent developments in the field of bispecific antibodies for oncology. We are at a time when antibody-drug conjugates (ADCs) are all the rage and, trying to improve on the targeting of specific antigens, proteins, receptors in the field of oncology is certainly a hot and emerging topic. Dr. Giuseppe Curigliano: So, thanks a lot. I believe really it was very challenging to try to summarize all the bispecific antibodies that are under development in multiple solid tumors. So, the first thing that I would like to highlight is the context and the mechanism of action of bispecific antibodies. Bispecific antibodies represent a groundbreaking advancement in cancer immunotherapy, because these engineered molecules have the unique ability to target and simultaneously bind to two distinct antigens. That is why we call them bispecific. So typically, one antigen is expressed on the tumor cell and the other one is expressed on the immune effectors, like T-cell or natural killer cells. So this dual targeting mechanism offers several key advantages over conventional monoclonal antibodies because you can target at the same time the tumor antigen, downregulating the pathway of proliferation, and you can activate the immune system. So the primary mechanism through which bispecific antibodies exert their therapeutic effects are: First, T-cell redirecting. I mean, many bispecific antibodies are designed to engage tumor-associated antigens like epidermal growth factor receptor, HER2, on the cancer cell and a costimulatory molecule on the surface of T-cell. A typical target antigen on T-cell is CD3. So what does it mean? That you activate the immune system, immune cells will reach the tumor bed, and you have a dual effect. One is downregulating cell proliferation, the other one is activation of the immune system. This is really important in hematological malignancies, where we have a lot of bispecifics already approved, like acute lymphoblastic leukemia or non-Hodgkin lymphoma.  The second, in fact, is the engagement of the tumor microenvironment. So, if you engage immune effector cells like NK cells or macrophages, usually the bispecific antibodies can exploit the immune system's ability to recognize and kill the immune cells, even if there is a lack of optimal antigen presentation.  And finally, the last mechanism of action, this may have a role in the future, maybe in the early cancer setting, is overcoming immune evasion. So bispecific antibodies can overcome some of the immune evasion mechanisms that we see in cancer. For example, bispecific antibodies can target immune checkpoint receptors, like PD-L1 and CTLA-4. Actually, there is a bispecific under development in breast cancer that has a dual targeting on vascular endothelial growth factor receptor and on PD-L1. So you have a dual effect at the same time. So, what is really important, as a comment, is we need to focus first on the optimal format of the bispecific, the optimal half-life, the stability, because of course even if they are very efficient in inducing a response, they may give also a lot of toxicities. So in clinical trials already, we have several bispecifics approved. In solid tumors, very few, specifically amivantamab for non-small cell lung cancer, but we have a pipeline of almost 40 to 50 bispecifics under development in multiple solid tumors, and some of them are in the context of prospective randomized trials. Dr. Hope Rugo: So this is really a fascinating area and it's really exciting to see the expansion of the different targets for bispecific antibodies. One area that has intrigued me also is that some of the bispecifics actually will target different parts of the same receptor or the same protein, but presumably those will be used as a different strategy. It's interesting because we have seen that, for example, in targeting HER2. Dr. Giuseppe Curigliano: Oh, yes, of course. You may consider some bispecifics like margetuximab, I suppose, in which you can target specifically two different epitopes of the same antigen. This is really an example of how a bispecific can potentially be more active and downregulating, let us say, a pathway, by targeting two different domains of a specific target antigen. This is an important point.  Of course, not all the bispecifics work this way, because some of the target antigen may dimerize, and so you have a family of target antigen; an example is epidermal growth factor receptor, in which you have HER1, HER2, HER3, and HER4. So some of them can inhibit the dimerization between one target antigen and the other one, in order to exert a more antiproliferative effect. But to be honest, the new generation of them are more targeting two different antigens, one on the tumor and one on the microenvironment, because according to the clinical data, this is a more efficient way to reduce proliferation and to activate the immune system. Dr. Hope Rugo: Really interesting, and I think it brings us to the next topic, which is really where bispecific antibodies have already shown success, and that is in hematologic malignancies where we have seen very interesting efficacy and these are being used in the clinic already. But the expansion of bispecific antibodies into solid tumors faces some key challenges. It's interesting because the challenges come in different shapes and forms. Tell us about some of those challenges and strategies to optimize bispecific antibody design, delivery, patient selection, and how we are going to use these agents in the right kind of clinical trials. Dr. Giuseppe Curigliano: This is really an excellent question because despite bispecific antibodies having shown a remarkable efficacy in hematological malignancies, their application in solid tumors may have some challenges. The first one is tumor heterogeneity. In hematological malignancy, you have a clear oncogene addiction. Let us say that 90% of the cells may express the same antigen. In solid tumors, it is not the same. Tumor heterogeneity is a typical characteristic of solid tumors, and you have high heterogeneity at the genetic, molecular, and phenotypic levels. So tumor cells can differ significantly from one another, even if within the same tumor. And this heterogeneity sometimes makes it difficult to identify a single target antigen that is universally expressed in an hematological malignancy. So furthermore, sometimes the antigen expressed on a tumor cell can be also present on the normal tissue. And so you may have a cross-targeting. So let's say, if you have a bispecific against epidermal growth factor receptor, this will target the tumor but will target also the skin with a lot of toxicity. The second challenge is the tumor microenvironment. The solid tumor microenvironment is really complex and often immunosuppressive. It is characterized by the presence of immunosuppressor cells like the T regulators, myeloid derived suppressor cells, and of course the extracellular matrix. All these factors hinder immune cell infiltration and also may reduce dramatically the effectiveness of bispecific antibodies. And as you know, there is also an hypoxic condition in the tumor. The other challenge is related to the poor tumor penetration. As you know also with antibody-drug conjugate, only 1 to 3% of the drug will arrive in the tumor bed. Unlike hematological malignancies where tumor cells are dispersed in the blood and easily accessible, the solid tumors have a lot of barriers, and so it means that tumor penetration can be very low. Finally, the vascularity also of the tumor can be different across solid tumors. That is why some bispecifics have a vascular endothelial growth factor receptor or vascular endothelial growth factor as a target. Of course, what do we have to do to overcome these challenges? First, we have to select the optimal antigen. So knowing very well the biology of cancer and the tumor-associated antigens can really select a subgroup of epitopes that are specifically overexpressed in cancer cells. And so we need to design bispecifics according to the tumor type. Second, optimize the antibody format. So there are numerous bispecific antibody formats. We can consider the dual variable domain immunoglobulin, we specified this in our paper. The single chain variable fragments, so FC variable fragments, and the diabodies that can enhance both binding affinity and stability. And finally, the last point, combination therapies. Because bispecific antibodies targeting immune checkpoint, we have many targeting PD-1 or PD-L1 or CTLA-4, combined eventually with other immune checkpoint inhibitors. And so you may have more immunostimulating effect. Dr. Hope Rugo: This is a fascinating field and it is certainly going to go far in the treatment of solid tumors. You know, I think there is some competition with what we have now for antibody-drug conjugates. Do you see that bispecifics will eventually become bispecific ADCs? Are we going to combine these bispecific antibodies with ADCs, with chemotherapy? What is the best combination strategy do you think looking forward? Dr. Giuseppe Curigliano: So, yes, we have a bispecific ADC. We have actually some bispecifics that are conjugated with a payload of chemotherapy. Some others are conjugated with immunoactivation agents like IL-2. One of the most effective strategies for enhancing bispecific activity is the combination therapy. So which type of combination can we do? First, bispecific antibodies plus checkpoint inhibitors. If you combine a bispecific with an immune checkpoint, like anti-PD-1, anti-PD-L1, or anti-CTLA-4, you have more activity because you have activation of T-cells, reduction of immunosuppressive effect, and of course, the capability of this bispecific to potentiate the activity of the immune checkpoint inhibitor. So, in my opinion, in a non-small cell lung cancer with an expression of PD-L1 more than 50%, if you give pembrolizumab plus a bispecific targeting PD-L1, you can really improve both response rate and median progression-free survival.  Another combination is chemotherapy plus bispecific antibodies. Combining chemotherapy with bispecific can enhance the cytotoxic effect because chemotherapy induces immunogenic cell death, and then you boost with a bispecific in order to activate the immune system. Bispecific and CAR T-cells, until now, we believe that these are in competition, but this is not correct. Because CAR T-cells are designed to deliver an activation of the immune system with the same lymphocytes engineered of the patients, with a long-term effect. So I really do not believe that bispecifics are in competition with CAR T-cells because when you have a complete remission induced by CAR T-cell, the effect of this complete remission can last for years. The activity of a bispecific is a little bit different. So there are some studies actually combining CAR T-cells with bispecifics. For example, bispecific antibodies can direct CAR T-cells in the tumor microenvironment, improving their specificity and enhancing their therapeutic effect.  And finally, monoclonal antibody plus bispecific is another next generation activity. Because if you use bispecific antibodies in combination with existing monoclonal antibodies like anti-HER2, you can potentially increase the immune response and enhance tumor cell targeting. In hematological malignancies, this has been already demonstrated and this approach has been particularly effective. Dr. Hope Rugo: That's just so fascinating, the whole idea that we have these monoclonal antibodies and now we are going to add them to bispecifics that we could maybe attach on different toxins to try and improve this, or even give them with different approaches. I suppose giving an ADC with a bispecific would sort of be similar to that idea of giving a monoclonal antibody with the bispecific. So it is certainly intriguing. We also will need to understand the toxicity and cost overall and how we are going to use these, the duration of treatment, the assessment of biomarkers. There are just so many different aspects that still need to be explored.  And then with that idea, can you look ahead five or ten years from now, and tell us how you think bispecific antibodies will shape our next generation cancer therapies, how they will be incorporated into precision oncology, and the new combinations and approaches as we move forward that will help us tailor treatment for patients both with solid tumors and hematologic malignancies? Are we going to be giving these in early-stage disease in solid tumors? So far, the studies are primarily focusing on the metastatic setting, but obviously one of the goals when we have successful treatments is to move them into the early stage setting as quickly as possible. Dr. Giuseppe Curigliano: Let us try to look ahead five years rather than ten years, to be more realistic. So, personally I believe some bispecifics can potentially replace current approaches in specifically T-cell selected population. As we gather more data from ongoing clinical trials and we adopt a deeper understanding of the tumor immuno microenvironment, of course we may have potentially new achievement. A few days ago, we heard that bispecifics in triple negative breast cancer targeting VEGF and PD-L1 demonstrated an improvement in median progression-free survival.  So, how to improve and to impact on clinical practice both in the metastatic and in the early breast cancer setting or solid tumor setting? First, personalized antigen selection. So we need to have the ability to tailor bispecific antibody therapy to the unique tumor profile of individual patients. So the more we understand the biology of cancers, the more we will be able to better target. Second, bispecific antibodies should be combined. I can see in the future a potential trial in which you combine a bispecific anti-PD-L1 and VEGF with immune checkpoint inhibitor selected also to the level of expression of PD-L1, because integration of antibody bispecific with a range of immunotherapies, and this cannot be only immune checkpoint inhibitors, but can be CAR T-cells, oncolytic viruses, also targeted therapy, will likely be a dominant theme in the coming years. This combination will be based on the specific molecular and immuno feature of the cancer of the patient.  Then we need an enhanced delivery system. This is really important because you know now we have a next generation antibody. An example are the bicyclic. So you use FC fragment that are very short, with a low molecular weight, and this short fragment can be bispecific, so can target at the same time a target antigen and improving the immune system. And so the development of this novel delivery system, including also nanoparticles or engineered viral vectors, can enhance the penetration in the tumor bed and the bioavailability of bispecific antibodies. Importantly, we need to reduce toxicity. Until now, bispecifics are very toxic. So the more we are efficient in delivering in the tumor bed, the more we will reduce the risk of toxicity. So it will be mandatory to reduce off-target effects and to minimize toxicity.  And finally, the expansion in new indication. So I really believe you raised an excellent point. We need to design studies in the neoadjuvant setting in order to better understand with multiple biopsies which is the effect on the tumor microenvironment and the tumor itself, and to generate hypotheses for potential trials or in the neoadjuvant setting or in those patients with residual disease.  So, in my opinion, as we refine design, optimize patient selection, and explore new combination, in the future we will have more opportunity to integrate bispecifics in the standard of care. Dr. Hope Rugo: I think it is particularly helpful to hear what we are going to be looking for as we move forward to try and improve efficacy and reduce toxicity. And the ability to engineer these new antibodies and to more specifically target the right proteins and immune effectors is going to be critical, of course, moving forward, as well as individualizing therapy based on a specific tumor biology.  Hearing your insights has been great, and it really has opened up a whole area of insight into the field of bispecifics, together with your excellent contribution to the ASCO Educational Book. Thank you so much for sharing your thoughts and background, as well as what we might see in the future on this podcast today. Dr. Giuseppe Curigliano: Thank you very much for the invitation and for this excellent interview. Dr. Hope Rugo: And thanks to our listeners for joining us today. You will find a link to the Ed Book article we discussed today in the transcript of this episode. It is also, of course, on the ASCO website, as well as on PubMed. Please join us again next month on By the Book for more insightful views on the key issues and innovations that are shaping modern oncology. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement. Follow today's speakers:       Dr. Hope Rugo  @hope.rugo  Dr. Giuseppe Curigliano @curijoey Follow ASCO on social media:       @ASCO on X (formerly Twitter)       ASCO on Bluesky      ASCO on Facebook       ASCO on LinkedIn       Disclosures:      Dr. Hope Rugo:   Honoraria: Mylan/Viatris, Chugai Pharma  Consulting/Advisory Role: Napo Pharmaceuticals, Sanofi, Bristol Myer  Research Funding (Inst.): OBI Pharma, Pfizer, Novartis, Lilly, Merck, Daiichi Sankyo, AstraZeneca, Gilead Sciences, Hoffman La-Roche AG/Genentech, In., Stemline Therapeutics, Ambryx  Dr. Giuseppe Curigliano: Leadership: European Society for Medical Oncology, European Society of Breast Cancer Specialists, ESMO Open, European Society for Medical Oncology Honoraria: Ellipses Pharma Consulting or Advisory Role: Roche/Genentech, Pfizer, Novartis, Lilly, Foundation Medicine, Bristol-Myers Squibb, Samsung, AstraZeneca, Daiichi-Sankyo, Boerigher, GSK, Seattle Genetics, Guardant Health, Veracyte, Celcuity, Hengrui Therapeutics, Menarini, Merck, Exact Sciences, Blueprint Medicines, Gilead Sciences Speakers' Bureau: Roche/Genentech, Novartis, Pfizer, Lilly, Foundation Medicine, Samsung, Daiichi Sankyo, Seagen, Menarini, Gilead Sciences, Exact Sciences Research Funding: Merck Travel, Accommodations, Expenses: Roche/Genentech, Pfizer, Daiichi Sankyo, AstraZeneca      

Featuring a slide presentation and related discussion from Dr Laura Huppert, including the following topics: Overview of approved antibody-drug conjugates (ADCs) for metastatic hormone receptor-positive HER2-negative breast cancer — trastuzumab deruxtecan, sacituzumab govitecan and datopotamab deruxtecan(0:00) Approved and investigational ADCs for metastatic triple-negative breast cancer (17:18) Sequencing of ADCs for metastatic HER2-negative breast cancer; future research directions (26:10) CME information and select publications