Podcasts about pd l1

In today's episode, we sat down with Sarah Sammons, MD. Dr Sammons is associate director of the Metastatic Breast Cancer Program and a senior physician at Dana-Farber Cancer Institute, as well as an assistant professor of medicine at Harvard Medical School, both in Boston, Massachusetts.In our exclusive interview, Dr Sammons discussed the rationale for and findings from a phase 2 study (NCT06449222) evaluating the PD-L1– and VEGF-A–directed bispecific antibody pumitamig (BNT327/BMS986545) in patients with locally advanced or metastatic triple-negative breast cancer (TNBC), as well as what these data may mean for the TNBC treatment paradigm.

In today's episode, we spoke with David Carbone, MD, PhD. Dr Carbone is a professor of internal medicine at The Ohio State University, co-leader of the Translational Therapeutics Program and director of the Thoracic Oncology Center at the Ohio State University Comprehensive Cancer Center–James, as well as the Barbara J. Bonner Chair in Lung Cancer Research in Columbus.In our exclusive interview, Dr Carbone discussed the 6-year data from the phase 3 CheckMate 9LA trial (NCT03215706), which not only reaffirmed the durability of benefit with nivolumab (Opdivo) plus ipilimumab (Yervoy) and chemotherapy but also highlighted particularly strong outcomes in historically poor-prognosis subgroups, including patients with PD-L1–negative tumors and those with squamous histology. Carbone also underscored the safety and tolerability of the regimen. Although dual immunotherapy carries higher toxicity than monotherapy, no new safety signals emerged at 6 years. Carbone also addressed the limitations of current biomarkers. Although PD-L1 remains the primary tool guiding immunotherapy decisions, it is an imperfect predictor. 

Dr. Lakshmi Rajdev and Dr. Manish Shah join the podcast to discuss the updated guideline on immunotherapy and targeted therapy in unresectable locally advanced, advanced, or metastatic gastroesophageal cancer. They share first-line and subsequent-line recommendations for both gastroesophageal adenocarcinoma and esophageal squamous cell carcinoma based on actionable biomarkers including PD-L1 expression, MMR and/or MSI, CLDN18.2 expression, and HER2 status. They note the importance of the algorithms and tables in the guidelines that provide visual illustrations and quick reference guides of the evidence-based recommendations. They also comment on ongoing and recently presented trials that may impact future guidelines in this space. Read the full guideline, "Immunotherapy and Targeted Therapy for Advanced Gastroesophageal Cancer: ASCO Guideline Update" at www.asco.org/gastrointestinal-cancer-guidelines" TRANSCRIPT This guideline, clinical tools and resources are available at www.asco.org/gastrointestinal-cancer-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology,  https://ascopubs.org/doi/10.1200/JCO-25-02958      Timestamps ·       00:00 – 02:15 Introduction and Overview ·       02:16 - 08:20 First-line treatment for patients with pMMR/MSS, HER2-negative gastroesophageal adenocarcinoma ·       08:21 –10:29 First-line treatment for patients with pMMR/MSS, HER2-positive gastroesophageal adenocarcinoma ·       10:30 – 14:39 First-line treatment for patients with dMMR/MSI-H, gastroesophageal adenocarcinoma ·       14:40 – 18:03 First-line treatment for ESCC ·       18:04 – 22:04 Second- and third-line therapy for gastroesophageal adenocarcinoma and ESCC ·       22:05 – 24:38 Importance of guideline ·       24:39 – 27:45 Outstanding questions and future research   Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one, at asco.org/podcasts.   My name is Brittany Harvey, and today I am interviewing Dr. Lakshmi Rajdev from the Icahn School of Medicine at Mount Sinai and Dr. Manish Shah from Weill Cornell Medicine, co-chairs on "Immunotherapy and Targeted Therapy for Advanced Gastroesophageal Cancer: ASCO Guideline Update." Thank you for being here today, Dr. Rajdev and Dr. Shah. Dr. Lakshmi Rajdev: Thank you. Dr. Manish Shah: Thank you for having us. It is wonderful. Brittany Harvey: And then just before we discuss this guideline, I would like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Rajdev and Dr. Shah, who have joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes. So then to dive into what we are here today to talk about, Dr. Shah, I would like to start first with what prompted the update to this guideline, which was previously published in 2023, and what is the scope of this updated guideline? Dr. Manish Shah: Yes, terrific. So even in the last few years, the pace of drug development in gastroesophageal cancers has just been astounding. So, what prompted this guideline is actually the practice-changing results for a new biomarker, CLDN18.2 hat was based on the GLOW and SPOTLIGHT studies, as well as a practice-changing study in HER2-positive disease where we added pembrolizumab to trastuzumab and chemotherapy for tumors that are HER2-positive and PD-L1 CPS 1 or greater. And then there were also new studies and new approvals in esophageal squamous cell cancer that you will hear about as well. So there were several studies, overall more than 5,000 patients were reported on, and that led to several new therapies, new indications, and it really necessitated this guideline. Brittany Harvey: Excellent. It is great to hear about all of these exciting updates in this space. So then to next review the key recommendations of this guideline by clinical question that the expert panel addressed. So, Dr. Rajdev, what is the recommended first-line treatment for patients with proficient mismatch repair, microsatellite stable, HER2-negative gastroesophageal adenocarcinoma? Dr. Lakshmi Rajdev: Thank you for that question. So historically, we have sort of used fluoropyrimidine and platinum doublets, which yielded a survival of about one year. More recently, immunotherapy and targeted therapy options have improved outcomes in patients with advanced esophageal and gastric adenocarcinoma, as well as squamous cell carcinoma. Patients with gastric and GE junction adenocarcinoma have a high rate of actionable alterations, so it is imperative that physicians test the following biomarkers upfront so that it can help guide therapy. The markers recommended by the ASCO panel are HER2, MMR or MSI, CLDN18.2, and PD-L1. And also, it was recommended to use NGS if feasible in this patient population. HER2, as we know, is expressed in about 15% to 25% of patients; PD-L1 expression occurs in about 80% of patients; MSI-high, deficient MMR is present in about 5% to 8% of patients; and CLDN18.2 expression is present in about 40% of patients. There is, of course, biomarker overlap. About 13% to 22% of CLDN18.2 patients are also PD-L1 positive. For patients with pMMR or microsatellite stable HER2-negative disease with PD-L1 expression greater than 1 and absence of CLDN18.2, the panel recommended a first-line therapy with fluoropyrimidine and platinum-based therapy in combination with immunotherapy. These recommendations stem from large phase 3 trials, and the agents approved in the United States are pembrolizumab, nivolumab, and tislelizumab. It has been shown that immunotherapy benefit is greater in patients with higher PD-L1 expression, and it is not possible to comment on the individual PD-L1 cutoff scores and sort of identify the optimal PD-L1 cutoff score that sort of balances benefits and harms. But what is recommended is that immunotherapy-based treatments can be offered in patients with a CPS score of greater than 1. With regard to the choice of immunotherapy agents, that is pembrolizumab, nivolumab, or tislelizumab, these agents are considered to have similar efficacy, and the selection of an agent could be based on dosing schedule, cost considerations, toxicity, and the method of administration. Typically, clinicians should avoid withholding the start of chemotherapy while awaiting biomarker testing, depending on the clinical scenario. Now, for patients with pMMR microsatellite stable disease that is HER2-negative with PD-L1 expression less than 1 and positive CLDN18.2 expression, zolbetuximab-based treatments or in combination with chemotherapy is recommended, and this is based on two global phase III randomized controlled trials, the GLOW and the SPOTLIGHT. And across both studies, the hazard ratio for the overall survival was 0.78, and similarly, there was also an improvement in progression-free survival favoring the zolbetuximab group compared to the chemotherapy group alone. An important note is that nausea, vomiting is commonly associated with zolbetuximab-based treatments, and the panel recommended prophylactic antiemetics, adjusting zolbetuximab infusion rates, pausing infusion temporarily, using non-prophylactic antiemetics, and hydration intravenously prior to discontinuation of zolbetuximab-based chemotherapy. So effective handling of the GI-related symptoms with zolbetuximab is recommended prior to discontinuation of therapy. Now, for patients with pMMR microsatellite stable HER2-negative gastric, GE junction adenocarcinoma with PD-L1 expression greater than 1 and CLDN18.2 positivity, the ones with the dual expression with CLDN18.2 as well as PD-L1 chemotherapy, the choice of therapy can be based on the degree of PD-L1 expression, the toxicity profile, the burden of symptoms, and the anticipated improvement in symptoms associated with response to treatment, the patient comorbidities, the prior medical and treatment history. So this decision needs to be made on a case-by-case basis, and these are some of the factors that we suggested that could potentially influence the choice of therapy. For patients with pMMR microsatellite stable disease that is HER2-negative and a PD-L1 expression less than 1 and an absence of CLDN18.2 expression, first-line therapy with fluoropyrimidine and platinum-based chemotherapy is recommended. So you can see we have segmented out patients based on PD-L1 expression, pMMR and microsatellite stable disease expression, and also based on CLDN expression. Brittany Harvey: Absolutely. And that first point you noted, I think is really important, that biomarker testing is really critical for treatment decision-making in this space. So then the next subgroup of patients that the panel looked at, Dr. Shah, what first-line therapy is recommended for patients with proficient mismatch repair, microsatellite stable, HER2-positive gastroesophageal adenocarcinoma? Dr. Manish Shah: So this was an update from a few years ago. So we have known for 15 years now that if you are HER2-positive, you should get trastuzumab plus chemotherapy. That was based on the ToGA trial. And the update now is based on a trial called KEYNOTE-811, where it examined the addition of pembrolizumab to trastuzumab and chemotherapy versus trastuzumab and chemotherapy, and there was a progression-free and overall survival benefit. And again, here, the biomarkers are important. If your CPS PD-L1 is less than 1, we would not recommend Pembrolizumab in that setting, so you would still get trastuzumab and chemotherapy. But if it is 1 or greater, the PD-L1 CPS score, then we do recommend pembrolizumab unless there is a contraindication to immunotherapy. The take-home message really is from the onset of diagnosis, please check your biomarkers. And I will just, it is worth repeating, it is important to check your PD-L1 status, HER2 status, mismatch repair status, and CLDN18.2 status. And then the optimal therapy, and it is outlined in the publication, is really biomarker-driven. We know that if we are able to hit the target that is overexpressed, we are going to have a better outcome. And Dr. Rajdev did mention where there is overlap, there can be a lack of data, and that is where we are with both PD-L1 positive and CLDN positive. Here we do have data in HER2-positive cases where if you are both HER2-positive and PD-L1 positive, you would combine trastuzumab and pembrolizumab for the best outcomes. Brittany Harvey: Understood. I really appreciate you detailing what is most important for each individual biomarker combination that patients may have. So then following that, Dr. Rajdev, what does the expert panel recommend for first-line treatment for patients with esophageal squamous cell carcinoma that is not amenable to definitive chemoradiation? Dr. Lakshmi Rajdev: There are three phase III randomized clinical trials that have influenced practice in patients with esophageal squamous cell carcinoma examining the benefit of immunotherapy in this patient population. The RATIONALE-306 was a randomized trial of tislelizumab plus chemotherapy with platinum and fluoropyrimidine or paclitaxel versus placebo with chemotherapy. And then you have the KEYNOTE-590, which compared pembrolizumab plus chemotherapy versus chemotherapy alone. And then you have CheckMate-648, which included comparisons of nivolumab plus chemotherapy versus nivolumab plus ipilimumab or chemotherapy. And the primary endpoints for these studies were overall survival, and they did look at subgroups with PD-L1 expression. They used TPS score greater than 1% in CheckMate-648 and PD-L1 CPS greater than 10 in KEYNOTE-590. The bottom line is that the overall hazard ratio for overall survival across this patient population was 0.72. So clearly, there is benefit in patients that express PD-L1 CPS greater than 1 for benefit for the addition of immunotherapy. Now, the benefit again in patients with a PD-L1 expression less than 1 remains limited, and so the panel has made a recommendation for using immunotherapy in combination with platinum-based chemotherapy in patients with a PD-L1 greater than 1. Again, we know that it is hard to make recommendations on what PD-L1 cutoffs are recommended in this patient population, meaning that should it be limited to patients with a PD-L1 of 1 to 4 or greater than 10? I think that the general consensus that has been gleaned from the data is that the higher the PD-L1 expression, the greater the benefit. I do want to comment on another option that is available in patients with squamous cell carcinoma compared to adenocarcinoma, and that is the combination of nivolumab and ipilimumab. Now, in CheckMate-648, nivolumab with ipilimumab was also recommended as a treatment option in patients that have a PD-L1 score of greater than 1. There was a survival benefit demonstrated with this combination compared to chemotherapy alone. And an important observation in this study is that, although there was a slightly increased rate in early death, but there was really no significant difference in PFS and OS compared to chemotherapy alone. Importantly, the treatment appeared to be pretty well tolerated by the study population. There was a notable difference in the objective response rate, which was 35% in the nivolumab plus ipilimumab group compared to patients receiving nivolumab and chemotherapy, where it was 53%. So superiority is, so the importance of chemotherapy in patients with esophageal squamous cell carcinoma is to be noted. However, there is no difference in overall survival and progression-free survival when using the combination of nivolumab and ipilimumab, and thus it affords a chemotherapy-free option for this patient population with esophageal squamous cell carcinoma and a CPS with a score of greater than 1. Brittany Harvey: Understood. I appreciate you reviewing the evidence underpinning those recommendations as well. So then the next patient population that the guideline panel addressed, what first-line therapy is recommended for patients with deficient mismatch repair, microsatellite instability-high, gastroesophageal adenocarcinoma or esophageal squamous cell carcinoma? Dr. Lakshmi Rajdev: The rate of MSI-high expression is about 3% to 7% across different studies. Now, the KEYNOTE-158 was a tumor-agnostic study in patients with non-colorectal cancers, and again, the problem with the MSI-high population, given that it is so rare, the numbers in the individual studies are fairly small. But consistent outcomes do emerge, indicating high response to immunotherapy. So in KEYNOTE-158, a response rate of about 46% was noted. The number of patients was small, it was about 24. In CheckMate-649, which is a study of chemotherapy plus or minus nivolumab in patients with advanced gastric adenocarcinoma, there was again a very small number of patients, and patients that were MSI-high or deficient MMR did experience substantial benefits with the addition of immunotherapy, with hazard ratios in the order of about 0.38. In KEYNOTE-062, again, it was a very small number of patients, again about 6% or so, and similar to CheckMate-649, a substantial benefit was noted in combination with chemotherapy, but also there were benefits noted with pembrolizumab alone. The RATIONALE-305 again was a study of tislelizumab in combination with chemotherapy and similarly showed benefits to the combination of chemotherapy plus immunotherapy in this patient population. I think that we are all aware of the dramatic benefits of immunotherapy in this particular subset of patients, deficient MMR MSI-high, and also we have seen in CheckMate-649 they did have a subset of patients that received nivolumab and ipilimumab. And in this patient population, they noted unstratified hazard ratio of 0.28. So I think that the overall consensus is that immunotherapy is a very important treatment modality in patients with deficient MMR MSI-high disease, given that a lot of the trials in gastroesophageal adenocarcinoma have utilized chemotherapy-based options, that is certainly a recommendation of the panel to use chemotherapy in combination with immunotherapy. However, on a case-by-case basis, the panel recommended immunotherapy alone as well, and given the high response rates noted in trials across different diseases as well as noted in this disease as well. Brittany Harvey: Certainly. And I appreciate you both for reviewing these first-line recommendations. So moving to later lines of therapy, Dr. Rajdev, what recommendations did the expert panel make for second or third-line therapy for gastroesophageal adenocarcinoma and esophageal squamous cell carcinoma? Dr. Lakshmi Rajdev: So, I think that the RAINBOW trial that investigated the utility of the addition of ramucirumab as second-line therapy has been around since 2014, and those results have led to the addition of ramucirumab to taxane-based therapy in the second-line setting. Based on the utilization of oxaliplatin and platinum-based therapy in the front-line setting, there may be patients that have an underlying neuropathy, and so we wanted to really include treatment options for this patient population so that an agent that is less neurotoxic could also be recommended in combination with ramucirumab. The RAMIRIS trial is one such trial where ramucirumab was combined with FOLFIRI, and it demonstrated benefit in combination with ramucirumab. So we have listed that as a potential treatment option for patients in the second-line setting who may have an underlying neuropathy or even for whatever reason that based on the toxicity profile, that needs to be the preferred option by a physician, that recommendation is new from the older guidelines that we have. With regard to the utility of PD-1 inhibitors, there really has been no benefit noted in the second-line setting with regard to overall survival or progression-free survival, so no recommendation is made for that option. I think an important study that has been recently presented is the DESTINY-Gastric04 trial, which really has been practice-changing and has led to the recommendation for trastuzumab deruxtecan in patients that have HER2-positive metastatic gastric or GE junction adenocarcinoma. Now, this is a phase III trial in patients who retained HER2-positive disease after progressing on front-line trastuzumab-based treatments, and the comparator for this trial was trastuzumab deruxtecan versus ramucirumab plus paclitaxel. There was significant improvement and progression-free survival in patients that received trastuzumab deruxtecan. The patients that were excluded from the trial are patients that have pulmonary problems, interstitial lung disease; that is one of the toxicities of this particular agent, and close monitoring and prompt initiation of therapy such as glucocorticoid treatment in patients who develop this toxicity was also highlighted by the panel. So to summarize, the new guidelines highlight the possibility of FOLFIRI plus ramucirumab as a second-line option and then trastuzumab deruxtecan as a later-line option in patients that still retain HER2 expression. And that is very important because the trial did retest patients whether they expressed HER2. As we know, in a substantial number of patients, there is downregulation of HER2, and there is emerging data that the benefit for subsequent HER2-directed therapies is best noted in patients that still retain HER2 expression. Brittany Harvey: Great. So as our listeners have heard, there are many recommendations and new treatment options for advanced gastroesophageal cancer. Dr. Shah, earlier you highlighted the importance of biomarker testing, but I would like to hear in your view, what is the importance of this guideline and how will it impact both clinicians and patients with gastroesophageal carcinoma? Dr. Manish Shah: So as we have discussed throughout this podcast, the treatment for gastroesophageal cancer, both adenocarcinoma and squamous cell cancer, is increasingly complex, increasingly biomarker-driven. And I think the value of the guideline is to place all of that into context. So it provides the data for why certain biomarkers are important, what therapies should be indicated. Not only that, but if you are able to review the guideline, it provides the details of each of these studies and summarizes them in a meta-analysis fashion to sort of give you the context, because sometimes the individual studies can be maybe a little bit discordant or confusing and the guideline attempts to harmonize all that. And then also, I think the tables are very, very interesting because they give you actual numbers in terms of how many patients over a thousand would this benefit or how many patients over a thousand would this cause harm in terms of nausea, vomiting, or other things like that. So it gives you context for helping clinicians and patients weigh the potential benefits of the novel treatment strategies against the potential adverse events. And then finally, the guideline does also provide an algorithm that you are able to follow based on the biomarkers, and those are in figures 4 and 5. So I think overall, it is a very comprehensive guideline. It intends to make more manageable a very complex subject, and you know, I really encourage our listeners to review it after listening to the podcast. Dr. Lakshmi Rajdev: If I can add to that, I think that what is also really good about the guidelines is there are quick summaries. So if someone is busy in the clinic, of course, there is the opportunity to review the data supporting the guidelines in great depth in the manuscript, but what is also really good is that there are good summaries. In the event that you are very busy, you can easily identify what the recommendations should be for that particular patient based on these summaries. Brittany Harvey: Absolutely. Listeners are encouraged to review the full guideline, including those tables and figures that may be more helpful when they are looking for something quick to look at in the clinic as well. So, as you both mentioned, there have been a number of recent practice-changing trials in this area. So I imagine there is still a lot of ongoing research as well. So Dr. Shah, what are the outstanding questions regarding treatment options for patients with locally advanced unresectable, advanced, or metastatic gastroesophageal carcinoma? Dr. Manish Shah: I think we touched upon it a little bit. The guidelines are based on the data available, and they are primarily examining one novel therapy with chemotherapy in a specific biomarker population. But as you know, the biomarkers are not either/or; you are not either CLDN18.2 positive or PD-L1 positive. A portion of patients could have dual biomarkers, and you know, I think that we are generating data on how to manage those patients. At the recent GI Symposium in January this year, the ILUSTRO trial was presented by Dr. Shitara, which looked at combining zolbetuximab and chemotherapy with immunotherapy for dual-positive biomarkers, and that is leading to a phase III study that has begun to enroll. So unanswered questions are: how do we manage dual-positive biomarkers? The other thing that was mentioned is that the current data for mismatch repair deficiency involve chemotherapy plus immunotherapy. Only squamous cell cancer is there a study with a positive non-chemotherapy kind of backbone, that is CheckMate-648 that Dr. Rajdev mentioned. As we move forward, it will be good to get data on non-chemotherapy options in certain biomarker-positive populations. And then finally, another update, which is likely to be practice-changing, is the HERIZON-GEA-01 study that looked at zanidatamab, which is another biparatopic antibody that targets HER2, and that is likely to change practice. And as that data gets published, we may look to even do a rapid update for the current immunotherapy and targeted therapy guideline that is just being published. Dr. Lakshmi Rajdev: So, if I can add to that, there are numerous ADCs that look very interesting. There are bispecific antibodies; in fact, the zanidatamab is a bispecific antibody showing improved activity in patients with HER2-positive disease. So I think there are studies from Asia looking at CLDN CAR T-based therapies. So, I think that there are a lot of novel agents and a lot of excitement in the field. We know that the bemarituzumab study, unfortunately, the FGFR2 inhibitor failed to demonstrate any benefit, but I think that there are other agents that are being explored, so there are newer targets, newer agents, ADCs, bispecifics that could potentially change the field in the future. Brittany Harvey: Yes, we will look forward to the data to address these unanswered questions and new agents and inform future guideline updates. So, I would like to thank you both for all of your work to review the evidence here and update this important guideline, and for your time today, Dr. Rajdev and Dr. Shah. Dr. Lakshmi Rajdev: Thank you. Dr. Manish Shah: Thank you. Brittany Harvey: And finally, thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/gastrointestinal-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, which is available in the Apple App Store or the Google Play Store. If you have enjoyed what you have heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

In this episode of JCO Article Insights, host Dr. Melis Canturk summarizes the article, "Atezolizumab With Bevacizumab and Nonplatinum Chemotherapy for Recurrent Ovarian Cancer: Final Results From the Placebo-Controlled AGO-OVAR 2.29/ENGOT-ov34 Phase III Trial," by Harter et al. TRANSCRIPT Melis Canturk: Hello, and welcome to the JCO Article Insight. I'm your host, Melis Canturk, and today we will be discussing the JCO article, "Atezolizumab With Bevacizumab and Nonplatinum Chemotherapy for Recurrent Ovarian Cancer: Final Results From the Placebo-Controlled AGO-OVAR 2.29/ENGOT-ov34 Phase III Trial." While integrating immune checkpoint inhibitors has revolutionized the treatment of various gynecologic cancers, these agents have historically shown limited single agent activity in ovarian cancer. Despite a strong biological rationale for combining immunotherapy with chemotherapy and bevacizumab to enhance T-cell infiltration and normalized tumor vasculature, several phase III trials have failed to demonstrate a significant survival benefit in this setting. The AGO-OVAR 2.29/ENGOT-ov34 trial was launched to definitely evaluate whether adding the PD-L1 inhibitor atezolizumab to this combination could improve long-term outcomes for patients experiencing early relapse. This international, double-blind, randomized phase III trial enrolled 574 patients with epithelial ovarian, fallopian tube, or peritoneal cancer. Eligible participants had to be in their first or second relapse within 6 months of completing platinum therapy or in their third relapse regardless of the treatment-free interval. All patients received bevacizumab and an investigator selected chemotherapy backbone, either paclitaxel or doxorubicin. They were randomly assigned to receive either 840 mg of atezolizumab or a placebo every 2 weeks until disease progression or for a maximum of 2 years. The study population was an all-comer group, though patients were stratified by their PD-L1 status, previous bevacizumab use, and the number of prior treatment lines. The trial did not meet its primary end points, as the addition of atezolizumab failed to significantly improve overall survival or progression-free survival in the intention-to-treat population. For the primary end point of overall survival, the median was 14.2 months with atezolizumab compared to 13 months with the placebo. Progression-free survival was similarly insignificant, with a median of 6.4 months in the experimental arm versus 6.7 months in the control arm. Furthermore, the objective response rates were nearly identical between the groups, recorded at 40% for atezolizumab and 44% for the placebo. Interestingly, exploratory subgroup analyses revealed potential signals of benefit in specific populations, even though the overall trial was negative. Patients who had been previously treated with bevacizumab appeared to derive a greater benefit from the addition of atezolizumab than those who were bevacizumab-naïve. Additionally, outcomes seemed more favorable for patients receiving a paclitaxel chemotherapy backbone compared to those receiving doxorubicin. However, PD-L1 status did not appear to be a predictive marker for success, as hazard ratios for survival were similar regardless of whether the tumor was PD-L1 positive or negative. The safety profile of the triple combination was consistent with the known toxicities of the individual drugs. Grade 3 or higher adverse events occurred in 73% of the atezolizumab group and 70% of the placebo group. While the experimental arm saw higher incidences of immune-mediated events, such as thyroid-related issues, these were generally manageable. Serious adverse events were more frequent in the atezolizumab arm than in the placebo arm, but discontinuation rates due to toxicity were relatively low and comparable between the two groups. In conclusion, the AGO-OVAR 2.29 trial confirms that adding atezolizumab to bevacizumab and nonplatinum chemotherapy does not provide a statistically significant survival advantage for patients who receive nonplatinum chemotherapy for recurrent ovarian cancer. This study contributes to the growing body of evidence showing that immune checkpoint inhibitors have yet to find a definitive role in the standard treatment of recurrent ovarian cancer. Future research will likely focus on more sophisticated molecular stratification and the use of novel agents, such as bispecific antibodies, to overcome the challenging tumor microenvironment of low-grade serous ovarian cancer. Thank you for tuning into JCO Article Insights. Don't forget to subscribe and join us next time as we explore more groundbreaking research shaping the future of oncology. 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.  

Sarah Poland, MD, lead author of a recently published article in the journal ONCOLOGY titled Advances in Immunotherapy for Breast Cancer, highlighted key findings from her review in a conversation with CancerNetwork®.1 Throughout the discussion, she spoke about: Shifting Perspectives on Immunogenicity: Historically, breast cancer was considered a “cold,” poorly immunogenic tumor due to low tumor mutational burden (TMB) and few tumor-infiltrating lymphocytes (TILs). Poland highlighted how clinical research has shifted this perspective, particularly through the study of triple-negative breast cancer (TNBC), which often exhibits higher PD-L1 expression and immune infiltration.Key Clinical Milestones: The review highlighted foundational data that established immunotherapy as a standard of care: Early-Stage TNBC: The phase 3 KEYNOTE-522 trial (NCT03036488) established pembrolizumab (Keytruda) plus chemotherapy as a standard neoadjuvant treatment for stage II to III TNBC.2 Metastatic TNBC: The phase 3 KEYNOTE-355 trial (NCT02819518) demonstrated the benefit of pembrolizumab in PD-L1–positive metastatic disease.3 Managing Toxicity and Rechallenge: Poland addressed the feasibility of pembrolizumab rechallenge after an immune-related adverse effect (irAE), emphasizing that while possible, it requires a highly individualized approach based on the severity and timing of the initial toxicity.The Future Landscape: Beyond PD-1/PD-L1 inhibitors, the discussion covered emerging technologies that are poised to redefine treatment: Antibody-Drug Conjugates (ADCs): Exploration of novel combinations of ADCs with immunotherapy. Emerging Modalities: The potential role of bispecific antibodies and vaccine trials utilizing tumor antigens. Subtype Expansion: Emerging evidence supporting the efficacy of immunotherapy in hormone receptor–positive and HER2-positive subtypes, moving beyond the traditional focus on TNBC. Unmet Educational Needs: Poland emphasized the importance of resources that connect providers and patients, particularly in translating complex trial data into clinical practice and addressing patient concerns regarding the newest therapies and trials.Poland is from the Department of Medicine in the Section of Hematology/Oncology at The University of Chicago.References1.        Poland S, de Oliveira Andrade M, Nanda R. Advances in immunotherapy for breast cancer. Oncology (Williston Park). 2026;40(1):8-15. doi:10.46883/2026.259210612.        Schmid P, Cortes J, Pusztai L, et al. Pembrolizumab for early triple-negative breast cancer. N Engl J Med. 2020;382(9):810-821. doi:10.1056/NEJMoa19105493.        Cortes J, Rugo HS, Cescon DW, et al. Pembrolizumab plus chemotherapy in advanced triple-negative breast cancer. N Engl J Med. 2022;387(3):217-226. doi:10.1056/NEJMoa2202809

Send a textWhat actually needs to be in place before digital pathology can replace the microscope?In this episode of DigiPath Digest, I walk through the 2026 Polish Society of Pathologists guidelines and translate them into practical steps for real pathology labs. This isn't theory. It's about hardware fidelity, data integrity, validation, and AI integration — and what each of these actually requires in daily workflow.We talk about scanner resolution standards (≤0.26 μm per pixel), 4K monitor calibration, visually lossless compression (20:1), scalable storage, pathologist-driven validation, and what “non-inferiority” truly means.Digital pathology is not just a change of medium. It's an operational shift.Episode Highlights[00:02] Community & growth 1,600+ new newsletter subscribers, 10,000+ Facebook members, and free Digital Pathology 101 book access.[07:20] The 4 pillars of adoption Hardware fidelity · Data integrity · Clinical validation · Future integration.[08:30] Hardware requirements 40x equivalent scanning (≤0.26 μm/px), 4K monitors, >300 cd/m² luminance, 10-bit color depth.[12:00] Workflow & throughput 200–300 slides/day per scanner, automated focus control, urgent case prioritization.[17:25] Storage & archiving ~1 GB per slide. Active archive (6–24 months). Long-term retention (10–20 years). GDPR compliance & TLS encryption.[23:09] Validation philosophy Pathologist-centered validation. Two phases: • Familiarization (~20 retrospective cases) • Dual review with discrepancy tracking Goal: digital must be non-inferior to glass.[29:03] AI in digital pathology AI supports quantification (Ki-67, HER2, ER/PR, PD-L1), tumor detection, and future multimodal predictions — but pathologists remain central.[33:26] Intraoperative telepathology

Send a textJoin us for a special Kidney Cancer treat!!!A Must Listen episode!!We discuss the role of biomarkers in advanced kidney cancer with the wonderful Professor Laurence Albiges from the Gustave Roussy Institute of Oncology in Paris.No Kidney Cancer talk is complete without the question -" Where are we with biomarkers?"This is part 1 of a 2 part walkthrough of the biomarker story so far in kidney cancer.Laurence is unequalled in her clear delivery on this subject.As lead for the CARE-1 study Laurence is examining the role of PDL1 as a biomarker in 1st line treatment of mRCC.We also discuss the;- IMDC criteria- Clusters- KIM-1- PDL1- Sarcomatoid featuresRecorded before Christmas this is a gift that keeps on giving.We hope you enjoy!!Check the Transcript for more details.

Is it time to trade your scrubs for a corporate career? In this episode, we sit down with Sydney Gramuglia, a Registered Nurse who successfully transitioned from bedside burnout to a high-impact, 6-figure role as an Oncology Clinical Educator at Eversana partnering with Sun Pharma. Sydney didn't have prior sales experience, and the job she landed wasn't even listed in her state—but she beat out veteran candidates anyway. Today, we're pulling back the curtain on the "Medical Sales U" blueprint she used to master a grueling 5-round interview process and land her dream job in the pharmaceutical industry.INSIDE THIS EPISODE:*The "Experience" Myth: Why "not enough experience" is usually a cover for "not enough preparation."*The LinkedIn Transformation: How Sydney went from 20 connections to 500+ and got headhunted by hiring managers.*The Mock Presentation: The exact 40-step rehearsal strategy Sydney used to master complex MOA (Mechanism of Action) and PD-L1 pathways.*Clinical Educator vs. Sales: Understanding the different paths for nurses in pharma.*The Contract Partnership: How the Eversana and Sun Pharma collaboration works.CHAPTERS:0:00 – Meet Sydney: From Bedside Nurse to Pharma Pro2:15 – The "Depressing" Reality of Nursing during COVID5:00 – Finding a Passion for Oncology7:30 – Why Your LinkedIn Profile Is Your New Resume9:15 – Breaking Down the Sun Pharma Offer13:45 – Clinical Educator vs. Sales: Which is right for you?16:10 – The Brutal Rejection that changed everything23:50 – Preparing for the 5-Round Interview Gauntlet25:30 – How to Ace a Mock Clinical Presentation31:00 – The Power of the Medical Sales U Community36:45 – Lifestyle Design: The perks of a corporate clinical role39:30 – Exploring Charleston: Best food & dog-friendly spotsCONNECT WITH Sydney Gramuglia - https://www.linkedin.com/in/sydney-gramuglia/READY TO BREAK INTO MEDICAL SALES? We help professionals transition into top-tier medical sales roles: medicalsalesu.com/#MedicalSales #NurseCareerChange #PharmaJobs #ClinicalNurseEducator #MedicalSalesU #NursingBurnout #CareerPivot #SunPharma #Eversana #MedicalDeviceSales #HealthcareInnovation

Dr. Joshua Reuss is back on the podcast to discuss the full update to the living guideline on stage IV NSCLC without driver alterations. He discusses the new evidence and how this impacts the latest recommendations on first-line and subsequent therapeutic options. Dr. Reuss emphasizes the need for shared decision-making between clinicians and patients. He shares ongoing research that the panel will review in the future for further updates to this living guideline, and puts the updated recommendations into context for clinicians treating patients with stage IV NSCLC. Read the full living guideline update "Therapy for Stage IV Non-Small Cell Lung Cancer Without Driver Alterations: ASCO Living Guideline, Version 2026.3.0" at www.asco.org/thoracic-cancer-guidelines" TRANSCRIPT This guideline, clinical tools and resources are available at www.asco.org/thoracic-cancer-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology,  https://ascopubs.org/doi/10.1200/JCO-25-02825    Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one, at asco.org/podcasts. My name is Brittany Harvey, and today I am interviewing Dr. Joshua Reuss from Georgetown University, co-chair on "Therapy for Stage IV Non-Small Cell Lung Cancer Without Driver Alterations: ASCO Living Guideline, Version 2026.3.0." It is great to have you back on the show today, Dr. Reuss. Dr. Joshua Reuss: Happy to be here, Brittany. Brittany Harvey: Just before we discuss this guideline, I would like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest Policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Reuss who has joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes. Dr. Reuss, this living clinical practice guideline for systemic therapy for patients with stage IV non-small cell lung cancer without driver alterations is updated on an ongoing basis. So, what prompted this latest update to the recommendations? Dr. Joshua Reuss: Our committee is tasked with making routine updates to the living guidelines and really keeping them living, right? So, evaluating new data as it is coming in to see, is this practice changing? Is this data that should inform and potentially alter our guideline recommendations so that practitioners and other care providers could really make the best treatment decisions for their patients? So that is something that happens on a more routine basis, but periodically, we are tasked with performing a more comprehensive update of our guideline where we really evaluate every one of our point recommendations, the data associated with these recommendations, to be sure that these are up to date, these are comprehensive, and to see if we need to alter anything in the language of these updates. Brittany Harvey: Excellent. Thank you for providing that background. And yes, this is truly a comprehensive update that goes through all the latest literature. Given that, I would like to review what has changed and what is new in the recommendations. So, what are the updated recommendations on first-line therapy for patients with stage IV non-small cell lung cancer without driver alterations? Dr. Joshua Reuss: So there are two main guidelines that we recommend from this panel. One is a driver mutation-positive guideline and the other is a driver mutation-negative guideline. And I think on first blush, one might look at kind of the recent flurry of approvals and new data and say, well, all the excitement, you know, is in the driver mutation-positive guideline. But I would say that the driver mutation-negative guideline is equally as important and really has several unique challenges associated with it. You know, first and foremost is that there are really a multitude of regimens that can be considered for any one patient. And how to choose between one can be quite difficult and a stressful challenge that clinicians can have, particularly since there are really no randomized studies comparing these regimens in a head-to-head fashion. In addition, you know, these guidelines are really broken down by two key factors. One is disease histology, so namely squamous versus non-squamous histology. And the other is PD-L1 status, broken down into one of three tertiles: PD-L1 high, which is greater than or equal to 50% expression; PD-L1 low, which is 1% to 49% expression; and then PD-L1 negative or unknown. So what you are really looking at, if you do that math, is really six unique patient subpopulations where we need to make a recommendation on one of the multitude of treatment regimens that is approved. And what that means is you are oftentimes really looking at subset and sub-subset level data to help inform clinicians in their treatment decision making, which can be quite challenging because as those small subsets of data is more and more parsed, there are many confounders that can be interjected there. And so I think the committee is tasked with really quite a challenge in terms of how to really communicate and broadcast that data in a way that informs clinicians in making a decision on what is the right treatment for their patient. Brittany Harvey: Absolutely. It can be challenging to interpret that subgroup data across several different studies that are reporting on different regimens and different outcomes. And I appreciate you mentioning the driver mutation-positive guideline as well. Listeners can check out the companion episode with Dr. Puri for more information on what is changed in the driver mutation-positive guideline. Based on that primer, what is new for first-line therapy for patients with stage IV non-small cell lung cancer without driver alterations? Dr. Joshua Reuss: Even though I will say there is not a lot of new trial data that was incorporated into this guideline, there were some updates and just some meaningful long-term data that we incorporated. I think first and foremost, there is a new top-level recommendation in this guideline pertaining to molecular testing, which is absolutely critical in both the driver mutation-positive and driver mutation-negative space. I think we tend to think that, oh, well, molecular testing really only pertains to then finding a driver mutation. But the lack of a mutation is absolutely critical as well, right? Because that is what leads us down the mutation-negative pathway. We also need this molecular testing to assess PD-L1 status. We are seeing emerging data on molecular mutations that might confer resistance to certain immunotherapy-based strategies. So the committee felt strongly that a recommendation on molecular testing is critical to include in both the driver mutation-positive guideline and the driver mutation-negative guideline. I will also say that we are now seeing five and six-year updates from some of the landmark trials of immunotherapy in driver mutation-negative non-small cell lung cancer. It is really incredible to see that in some of these trials, we are seeing very impressive durability of the treatment in the patient subsets that we are commenting on. In others, perhaps that durability is less clear, and I think that leads to challenges in making a recommendation on any one particular regimen. And I think that is nowhere more clear than in the squamous subset. I think that was one perhaps subtle change that is in this guideline where, particularly in the PD-L1 negative squamous population, the committee felt that no one regimen really was worthy of standing above the others. Sometimes I think it is important to really champion one unique regimen if we feel that the data is there to support it. But I think it is equally important to list multiple regimens where the data is less clear. I think another point is that while perhaps there were no new regimens that we have added or that led to other clear changes in the prioritization of one regimen over another, there are other unique data subsets that I think come into play in making a decision and that really are important when looking at the discussion on any one recommendation from this guideline. For example, we know there is emerging data on perhaps the significance of molecular alterations in KEAP1 or STK11 and how that might influence frontline decision-making. You know, there is not a prospective phase III trial in this population, but I think we still need to use that data in certain scenarios to make recommendations for a particular patient. Another example of a trial that, again, did not change our recommendations, but I think one can incorporate in their decision making is the KEYNOTE-598 trial. Now, this is not a new study, but what it studied was pembrolizumab versus pembrolizumab plus ipilimumab in a PD-L1 high subset, and found that the addition of ipilimumab to pembrolizumab in the PD-L1 high population did not significantly improve clinical efficacy. And so while pembrolizumab plus ipilimumab is not an approved regimen, it is hard to extrapolate that to our combination treatments that are approved. I think some clinicians might find that data valuable when making a frontline treatment decision on a patient who has PD-L1 high status. So a bit of a whirlwind tour, but I think there are still multiple factors that went into this guideline that are important to review when making treatment decisions for any one patient. Brittany Harvey: Absolutely. I think what you just mentioned in having that upfront molecular testing is really key for individualized patient care. And the evidence summaries that you provide in addition to the recommendations are really important for clinicians to be able to refer to as they are making decisions in their clinic. So then beyond those changes for first-line therapy, what is updated for second-line and subsequent therapies? Dr. Joshua Reuss: For second-line and subsequent therapies, we did see one new treatment recommendation join these ranks, and that was telisotuzumab vedotin. Telisotuzumab vedotin, quite a mouthful. That is an antibody-drug conjugate. I like to think of that as smart chemotherapy, targeted chemotherapy, where you are trying to utilize some aspect of a marker that is selectively expressed or overexpressed on the cancer surface to then shepherd in the anticancer molecule, a highly potent chemotherapeutic in the case of currently approved antibody-drug conjugates, to exert antitumor killing effect. So in this case, the antibody-drug conjugate telisotuzumab vedotin targets MET overexpression. So telisotuzumab is an antibody targeting MET, and that is conjugated to an MMAE highly potent chemotherapeutic payload called vedotin. So we know MET can be selectively expressed and overexpressed in non-small cell lung cancer in both driver mutation-positive and mutation-negative subsets. The data that led to this approval was from the phase II LUMINOSITY trial which evaluated telisotuzumab vedotin, or Teliso-V, in many subsets. But the subset that really showed promise and was expanded was the EGFR wild-type, non-squamous, non-small cell lung cancer population with MET overexpression. And so in 78 patients with high levels of expression, the response rate here was 34.6%, median progression-free survival of 5.5 months, and a median overall survival of 14.6 months. With an overall acceptable safety profile; grade 3 or higher adverse events, neuropathy was perhaps the most common at 7%, also increased ALT at 3.5%, and pneumonitis at 2.9%. Now this was phase II data that led to an accelerated approval. There is an ongoing phase III study randomizing patients with high expression to Teliso-V versus docetaxel. That is the phase III TeliMET study. But it is nice that we now have another option for patients, perhaps a more biomarker-directed option with, again, this MET overexpression. And again, it further reinforces the importance of molecular testing in patients with traditionally driver mutation-negative non-small cell lung cancer, whether that is upfront or at progression, and in particular utilizing immunohistochemistry to assess MET expression in these patients. And this does join another ADC that we had previously made an update in our recommendation, which is trastuzumab deruxtecan, which is approved for those patients with HER2-overexpressing non-small cell lung cancer. So just again to reiterate the importance of molecular testing in patients both at the outset of their treatment and upon progression on frontline therapy. Brittany Harvey: Definitely. It is great to have this new antibody-drug conjugate join the treatment options, and as you mentioned, very important in this case to have that molecular testing done at the outset and at progression. So then in your view, what should clinicians know as they implement this living guideline, and how do these changes impact patients with non-small cell lung cancer? Dr. Joshua Reuss: Because there are so many different regimens that one can consider for any one patient, I think it is easy to become overwhelmed and stress on, "Am I making the right choice for my patient?" And I think one of the key take home points is that in many cases, there is no one right regimen. And I think one has to weigh several factors. It is the treatment schedule. It is the toxicity profile. It is the molecular profile of the patient. It is the patient preference. You know, there are so many factors here. And I would like to draw the reader and viewer's attention to an important section of these guidelines, particularly the Patient and Clinician Communication section, where we have a box focused on discussion points between patients and clinicians, which I think focuses on several of the high-level points that one can emphasize in making these decisions, ranging on things from: what are the goals of the treatment? What are the risks and benefits to any one approach? What are comorbidities that should be factored in? Common concerns, toxicity management, clinical trial consideration. All of these factors that I think are incredibly important in making that frontline treatment decision and implementing a regimen that both the clinician and, more importantly, the patient feels comfortable with. Brittany Harvey: It is really important that there is shared decision-making in these scenarios. And I think that patient-clinician communication section can tease out some of those preferences from the patient end and talk through the risks and benefits of different regimens as well. As we mentioned at the top of this episode, this guideline is a living guideline and updated on an ongoing basis. So what is the panel examining and keeping an eye on for future updates to this guideline? Dr. Joshua Reuss: So I think there are a lot of exciting new therapies and more up-to-date trials that we are anxiously awaiting the results of on our committee, and I think the oncology community in general is awaiting the results of. When we will have these results, I think, is a bit of an open-ended question, but I can give some insight on several of the trials that our committee is really keeping a close eye on. One that we have mentioned for several guideline iterations is the ECOG-ACRIN INSIGNA trial. This is a phase III clinical trial comparing pembrolizumab versus pembrolizumab plus carboplatin and pemetrexed chemotherapy in PD-L1 positive, non-squamous, non-small cell lung cancer. We talk about there being different regimens that can be considered in PD-L1 positive and PD-L1 high subsets, namely immunotherapy alone or immunotherapy plus chemotherapy, but there is no direct head-to-head comparison here. So this trial hopefully will answer that question. It has now finished accrual. There are other very interesting molecules and trials. I think another interesting compound is ivonescimab. This is a PD-1/VEGF bispecific antibody that is currently approved in China as monotherapy in patients with PD-L1 positive non-small cell lung cancer based off of the HARMONi-2 trial, where the progression-free survival of this bispecific antibody, ivonescimab, appeared superior to pembrolizumab. And we are looking closely at ongoing trials to see if these results will be replicated in an ex-China population. And if so, I think it could have a real impact and change on our guidelines. Still other very interesting things. There are obviously confirmatory studies for antibody-drug conjugates, such as the TeliMET study that I alluded to earlier, and many promising antibody-drug conjugates, both bispecific and trispecific antibody-drug conjugates, that hopefully can inform practice. And then there are several unique subsets of populations that I think we now are utilizing data on to make decisions, but a lot of that is retrospective in small subsets where we do not have that prospective data. And there are several trials ongoing in some of these subsets to try to gain clarity on what regimen may be the best for patients. One example is the phase III TRITON trial, which is looking at comparing CTLA-4 containing regimen, particularly the POSEIDON regimen of durvalumab plus tremelimumab and chemotherapy, versus the KEYNOTE-189 regimen, which is pembrolizumab plus carboplatin and pemetrexed, in patients with non-squamous, non-small cell lung cancer that have alterations in either KRAS, KEAP1, and/or STK11. There is a lot of both preclinical and clinical data to suggest that patients with these alterations in STK11 and KEAP1 may be more resistant to a PD-1 based treatment approach, and perhaps the incorporation of CTLA-4 can lead to a more meaningful response in this unique subset. Obviously, that data, it is retrospective, it is in small subsets. And when you add in a CTLA-4 molecule, you are also introducing greater risk for toxicity. So this trial is going to be very important in elucidating: is there a benefit in that unique subset? Does that data that we see retrospectively in this small subset hold true when evaluated in a prospective fashion? So while our guideline, our most recent comprehensive panel update, may not have had a lot of new data in it that has influenced frontline treatment decision-making, I think the future is bright and there are a lot of novel studies and novel treatments on the horizon that will hopefully improve the outcomes for our patients. Brittany Harvey: Absolutely. We will look forward to the results of those ongoing trials to provide more options and particularly clarity for patients with non-small cell lung cancer and to inform this guideline and its many updates to come. So I want to thank you so much for your work to rapidly and continuously update this guideline, and thank you for your time today, Dr. Reuss. Dr. Joshua Reuss: Thank you so much. Brittany Harvey: And finally, thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/thoracic-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines App available in the Apple App Store or the Google Play Store. If you have enjoyed what you have heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  

Dr. Sonam Puri discusses the full update to the living guideline on stage IV NSCLC with driver alterations. She shares a new overarching recommendation on biomarking testing and explains the new recommendations and the supporting evidence for first-line and subsequent therapies for patients with stage IV NSCLC and driver alterations including EGFR, MET, ROS1, and HER2. Dr. Puri talks about the importance of this guideline and rapidly evolving areas of research that will impact future updates. Read the full living guideline update "Therapy for Stage IV Non-Small Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, Version 2026.3.0" at www.asco.org/thoracic-cancer-guidelines TRANSCRIPT This guideline, clinical tools and resources are available at www.asco.org/thoracic-cancer-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology,  https://ascopubs.org/doi/10.1200/JCO-25-02822    Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one, at asco.org/podcasts. My name is Brittany Harvey, and today I'm interviewing Dr. Sonam Puri from Moffitt Cancer Center, co-chair on "Therapy for Stage IV Non-Small Cell Lung Cancer with Driver Alterations: ASCO Living Guideline, Version 2026.3.0." It's great to have you here today, Dr. Puri. Dr. Sonam Puri: Thanks, Brittany. Brittany Harvey: And then just before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest Policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Puri, who has joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes. So then, to dive into the content that we're here today to talk about, Dr. Puri, this living clinical practice guideline for systemic therapy for patients with stage IV non-small cell lung cancer with driver alterations is updated on an ongoing basis. So, what data prompted this latest update to the recommendations? Dr. Sonam Puri: So Brittany, non-small cell lung cancer is one of the fastest-moving areas in oncology right now, particularly when it comes to targeted therapy for driver alterations. New data are emerging continuously from clinical trials, regulatory approvals, real-world experience, which is exactly why these are living guidelines. The goal is to rapidly integrate important advances as they happen, rather than waiting for years for a traditional update. Since the last full update of the ASCO Stage IV Non-small Cell Lung Cancer Guideline with Driver Alterations published in 2024, there have been seven new regulatory approvals and changes in first-line therapy for some driver alterations. [This version] of the "Stage IV Non-small Cell Lung Cancer Guidelines with Driver Alterations" represents a full update, which means that the panel reviewed and refreshed every applicable section of the guideline to reflect the most current evidence across therapies including sequencing and clinical decision-making. This is to ensure that clinicians have up-to-date practical guidelines that keep pace with how quickly the field is evolving. Brittany Harvey: Absolutely. As you mentioned, this is a very fast-moving space and this full update helps condense all of those versions that the panel reviewed before into one document, along with additional approvals and new trials that you reviewed during this time period. So then, the first aspect of the guideline is there's a new overarching recommendation on biomarker testing. Could you speak a little bit to that updated recommendation? Dr. Sonam Puri: Yeah, definitely. So the panel has discussed and provided recommendations on comprehensive biomarker testing and its importance in all patients diagnosed with non-small cell lung cancer. Ideally, biomarker testing should include a broad-based next-generation sequencing panel, rather than single-gene tests, along with immunohistochemistry for important markers such as PD-L1, HER2, and MET. These results really drive treatment decisions, both in frontline settings for all patients diagnosed with non-small cell lung cancer and in subsequent line settings for patients with non-small cell lung cancer harboring certain targetable alterations. Specifically in the frontline setting, it helps determine whether a patient should receive upfront targeted therapy or immunotherapy-based approach. We now have strong data that shows that complete molecular profiling results before starting first-line therapy is associated with better overall survival and actually more cost-effective care. Using both tissue and blood-based testing can improve likelihood of getting actionable results in a timely way, and we've also provided guidance on platforms that include RNA sequencing, which are specifically helpful for identifying gene fusions that might be otherwise missed with other platforms. On the flip side, outside of a truly resource-limited setting, single-gene PCR testing really should not be routine anymore. This is what the panel recommends. It's less sensitive and inefficient and increases the risk of missing important actionable alterations. Brittany Harvey: Understood. I appreciate you reviewing that recommendation. It really helps identify critical individual factors to match the best treatment option to each individual patient. So then, following that recommendation, what are the updated recommendations on first-line therapy for patients with stage IV non-small cell lung cancer with a driver alteration? Dr. Sonam Puri: Since the last full update in 2024, there have been four additional interim updates which were published across 2024 and 2025. Compared to the last version, there have been several updates which have been included in this full update. One of the most important shifts has been in first-line treatment of patients with non-small cell lung cancer harboring the classical, or what we call as typical, EGFR mutation. The current version of the recommendation is based on the updated survival data from the phase III FLAURA2 and MARIPOSA studies, based on which the panel recommended to offer either osimertinib combined with platinum-pemetrexed chemotherapy or the combination of amivantamab plus lazertinib in the first-line treatment of classical EGFR mutations. And these recommendations, as I mentioned, are grounded in the results of the FLAURA2 and MARIPOSA trials, both of which demonstrated improvement in progression-free survival and overall survival compared to osimertinib alone in patients with common EGFR mutations. That being said, the panel actually spent significant time discussing the toxicities associated with these treatments as well. These combination approaches come with higher toxicity, longer infusion time, increased treatment frequency. So while combination therapy is now recommended as preferred, the panel has recommended that osimertinib monotherapy remains a reasonable option, particularly for patients with poor performance status and for those who are not interested in treatment intensification after knowing the risks and benefits. Brittany Harvey: Absolutely. It's important to consider both those benefits and risks of those adverse events that you mentioned to match appropriately individualized patient care. So then, beyond those recommendations for first-line therapy, what is new for second-line and subsequent therapies? Dr. Sonam Puri: So this is a section that saw several major updates, particularly again in the EGFR space. The first was an update on treatment after progression on osimertinib for patients with classical EGFR mutation. Here the panel recommends the combination of amivantamab plus chemotherapy, and this recommendation was based on the phase III MARIPOSA-2 trial, which compared amivantamab plus chemotherapy with chemotherapy alone with progression-free survival as the primary endpoint. The study met its primary endpoint, showing an improvement in median PFS with the combination of amivantamab plus chemotherapy compared to chemotherapy alone. And as expected, the combination was associated with higher toxicity. So, although the panel recommends this regimen, the panel emphasizes that patients should be counseled on the side effects which may be moderate to severe with the combination therapy approach. In addition, a new recommendation was added for patients who are not candidates for amivantamab plus chemotherapy. In those cases, platinum-based chemotherapy with or without continuation of osimertinib may be offered, and the option of continuing osimertinib with chemotherapy was recommended and supported by data from a recently presented phase III COMPEL study, which randomized 98 patients with EGFR exon 19 deletion or L858R-mutated advanced non-small cell lung cancer who had experienced no CNS progression on first-line osimertinib, and these patients were randomized to receive platinum-pemetrexed chemotherapy with osimertinib or placebo. Although this study was small, it demonstrated a PFS benefit with continuation of osimertinib with chemotherapy, and this approach may be appropriate for patients without CNS progression who prefer or require alternatives to more intensive treatment strategies. Next was an update on options for patients with EGFR-mutated lung cancer after progression on osimertinib and platinum-based chemotherapy. Here the panel recommended that for patients whose disease has progressed after both osimertinib and platinum-based chemotherapy, a new drug known as datopotamab deruxtecan can be offered as a treatment option. And this treatment recommendation was based on evaluation of pooled data from the TROPION-Lung01 and TROPION-Lung05 study, in which in the pooled analysis about 114 patients with EGFR-mutant non-small cell lung cancer were treated with Dato-DXd, 57% of whom had received three or more prior lines of treatment, and what was observed was an overall response rate of 45% with a median duration of response of 6.5 months. So definitely promising results. Next, we focused on updates to subsequent therapy options for patients with another type of EGFR mutation known as EGFR exon 20 insertion mutations. In this section, the panel added sunvozertinib as a subsequent line option after progression on platinum-based chemotherapy with or without amivantamab. Sunvozertinib is an oral, irreversible, and selective EGFR tyrosine kinase inhibitor with efficacy demonstrated in the phase II WU-KONG6 study conducted in Chinese patient population. In this study, amongst 104 patients with platinum-pretreated EGFR exon 20 mutated non-small cell lung cancer, the observed response rate was 61%. Staying in the EGFR space, the panel added a recommendation for patients with acquired MET amplification following progression on EGFR TKI therapy. In these situations, the panel recommended that treatment may be offered with osimertinib in combination with either tepotinib or savolitinib. As our listeners may know, MET amplification occurs in approximately 10% to 15% of patients with EGFR-mutated non-small cell lung cancer when they progress on third-generation EGFR TKIs, and detection of MET amplification is done with various methods, such as tissue-based methods like FISH, NGS, and IHC, as well as ctDNA-based NGS with variable cut-offs. Over the last few years, several studies have informed this recommendation. I'm going to be discussing some of them. In the phase II ORCHARD trial, 32 patients with MET-amplified non-small cell lung cancer after progression on first-line osimertinib were evaluated, where the combination of osimertinib plus savolitinib achieved an overall response rate of 47% with a duration of response of 14.5 months. More recently, the phase II SAVANNAH trial reported outcomes in 80 patients with MET-amplified tumors after progression on osimertinib, and in this patient population, the combination of savolitinib and osimertinib achieved an overall response rate of 56% with a median PFS of 7.4 months. And lastly, the phase II single-arm INSIGHT 2 trial assessed the efficacy of osimertinib plus tepotinib in patients with advanced EGFR-mutant non-small cell lung cancer who had disease progression following first-line osimertinib therapy. And in this study, in a cohort of 98 patients with MET-amplified tumors confirmed by central testing, the overall response rate with the combination was 50% with a duration of response of 8.5 months. So definitely informing this guideline recommendation. Next, we had an update on recommendation in patients with ROS1-rearranged non-small cell lung cancer. For patients with ROS1-rearranged non-small cell lung cancer, the panel recommended specifically for patients who progressed after first-line ROS1 TKIs, the addition of taletrectinib as a new option alongside repotrectinib. And this recommendation was based on analysis of the results of the TRUST-I and TRUST-II studies, which showed that amongst 113 tyrosine kinase inhibitor-pretreated patients, taletrectinib achieved a confirmed overall response rate of 55.8% with a median duration of response of 16.6 months and a median PFS of 9.7 months, a very promising agent. Finally, for patients with HER2 exon 20 mutated non-small cell lung cancer, the panel added two new oral HER2 tyrosine kinase inhibitors, zongertinib and sevabertinib, as options in addition to T-DXd and after exposure to T-DXd. These recommendations are based on early phase data from two trials: the phase I Beamion LUNG-01 study, which evaluated zongertinib, and the phase I/II SOHO-01 study that evaluated sevabertinib. In this study, zongertinib demonstrated an overall response rate of 71% in previously treated patients, with an overall response rate of 48% amongst patients who had received prior HER2-directed ADCs including T-DXd. Sevabertinib in its early phase study showed an overall response rate of 64% in previously treated but HER2 therapy-naive patients, and an overall response rate of 38% in patients previously exposed to HER2-directed therapy. The panel believes that both agents had manageable toxicity profile and represent meaningful new options for this patient population. Brittany Harvey: Certainly, it's an active space of research, and I appreciate you reviewing the evidence underpinning all of these recommendations for our listeners. So, it's great to have these new options for patients in the later-line settings. And given all of these updates in both the first and the later-line settings, what should clinicians know as they implement this latest living guideline update, and how do these changes impact patients with non-small cell lung cancer? Dr. Sonam Puri: Some great questions, Brittany. I think for clinicians when implementing this update, I think about two practical steps. First is reiterating the importance of comprehensive biomarker testing. That is the only way to identify key drivers and resistance mechanisms that we are now targeting. And second, picking a first-line strategy that balances efficacy and toxicity and patient preference for your specific patient. I think informed decision-making, shared decision-making is more important than any time right now. It has always been important, but definitely very important now. For patients, this guideline brings recommendations on more personalized treatment options for both first-line and post-progression settings, which potentially means better outcomes. But it is also very important for our patients to continue to have informed conversations about side effects, time commitment, and what matters most to them with their providers. The panel in this version of the guideline specifically acknowledges the real-world barriers that prevent patients from receiving guideline-concordant therapy, including challenges with access to comprehensive molecular testing and treatment availability, and the panel emphasizes on the importance of shared decision-making, and we provide practical discussion points to help clinicians navigate these conversations with the patient. In addition, the panel has also addressed common real-world clinical complexities, such as treating elderly or frail patients, managing multiple chronic conditions, considerations around pregnancy and fertility, and certain disease scenarios such as oligoprogression or oligometastatic disease. And where available, the guideline summarizes this existing data to support informed individual decision-making in these complex situations. Brittany Harvey: Shared decision-making is really paramount, especially with all of the options and weighing the risks and benefits and considering the individual circumstances of each patient that comes before a clinician. We've talked a lot about all of the new studies that the panel has reviewed, but what other studies or areas of research is the panel examining for future updates to this living guideline as it continues to be updated on an ongoing basis? Dr. Sonam Puri: Yes, definitely, so much to look forward to, right? Looking ahead, the panel is closely monitoring several rapidly evolving areas that are likely to shape future updates of the guideline. This includes emerging data from ongoing later-phase studies, particularly the studies that are evaluating these new targeted agents moving to earlier lines of therapy, alongside studies evaluating additional combination strategies or more refined approaches to treatment sequencing. We're also closely watching advances in biomarker testing, the evolving understanding of resistance mechanisms, development of new targets, and promising therapeutic agents. I think ultimately the living guideline exists to help clinicians and patients navigate this rapidly evolving field, and we would like to ensure that scientific advances are rapidly translated into better, more personalized patient care. Brittany Harvey: Definitely. We'll look forward to those updates from those ongoing trials and future areas of research that you mentioned to provide better options for patients with non-small cell lung cancer and a driver alteration. So I want to thank you so much for your work to rapidly and continuously update this guideline, and thank you for your time today, Dr. Puri. Dr. Sonam Puri: Thanks so much. Thanks so much for the opportunity. Brittany Harvey: And finally, thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/thoracic-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in the Apple App Store or the Google Play Store. There's also a companion episode with Dr. Reuss on the related living guideline on stage IV non-small cell lung cancer without driver alterations that listeners can find in their feeds as well. And if you've enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  

From Discovery to Delivery: Charting Progress in Gynecologic Oncology, hosted by Ursula A. Matulonis, MD, brings expert insights into the most recent breakthroughs, evolving standards, and emerging therapies across gynecologic cancers. Dr Matulonis is chief of the Division of Gynecologic Oncology and the Brock-Wilcon Family Chair at the Dana-Farber Cancer Institute, as well as a professor of medicine at Harvard Medical School, both in Boston, Massachusetts.In this episode, Dr Matulonis sat down with guest Rebecca Porter, MD, PhD. Dr Porter is a physician at Dana-Farber Cancer Institute and an assistant professor of medicine at Harvard Medical School.Drs Matulonis and Porter discussed the evolving role of immunotherapy in gynecologic cancer management, focusing on recent clinical breakthroughs and future directions. They noted that although high-grade serous ovarian cancer has historically been refractory to immunotherapy, the phase 3 KEYNOTE-B96 trial (NCT05116189) demonstrated an efficacy benefit with the addition of pembrolizumab to weekly paclitaxel for patients with platinum-resistant disease. In particular, improvements in overall survival were noted in the PD-L1–positive patient population. Dr Porter attributed this success to the metronomic weekly dosing of paclitaxel, which may increase neoantigen levels and favorably alter the tumor microenvironment (TME).Moreover, the experts highlighted how immunotherapy has already become the standard of care for patients with mismatch repair–deficient advanced or recurrent endometrial cancer. However, they explained that for the mismatch repair–proficient population, this benefit is less clear and appears most significant in patients with measurable disease or specific molecular subtypes. They added that although circulating tumor DNA (ctDNA) assay results correlate with treatment outcomes, ctDNA is currently not an actionable biomarker for determining treatment duration or selection.Lastly, Drs Matulonis and Porter reported that the field of gynecologic oncology is shifting toward combination therapies and novel platforms beyond standard checkpoint inhibitors. Treatment advances include bispecific and trispecific antibodies that engage multiple cell types or signals; as well as adoptive cellular therapies, such as CAR T-cell and CAR natural killer–cell therapies. Ultimately, the experts concluded that the goal of managing challenging-to-treat diseases like ovarian cancer is to use combinatorial approaches—incorporating vaccines, anti-angiogenic therapies, and chemotherapy—to overcome the immunosuppressive nature of the TME.

In this episode of the Oncology Brothers podcast, we dived into the current treatment landscape for head and neck cancer. We welcomed Dr. Fangdi Sun, a head and neck medical oncologist from Stanford University, to discuss key topics including: • The importance of initial workup and the role of biomarkers, including HPV and EBV testing. • Treatment paradigm for early-stage and locally advanced head and neck cancers, focusing on the differences between HPV-positive and HPV-negative disease. • The evolving role of immunotherapy and the new perioperative approaches in treatment. • Insights into managing metastatic disease, including the use of PD-L1 scores and systemic therapy options. • The significance of multidisciplinary collaboration in optimizing patient care. Whether you're a healthcare professional or simply interested in oncology, this episode provides valuable insights into the complexities of head and neck cancer treatment. Don't miss out on this informative discussion! Follow us on social media: •⁠  ⁠X/Twitter: https://twitter.com/oncbrothers •⁠  ⁠Instagram: https://www.instagram.com/oncbrothers •⁠  Website: https://oncbrothers.com/ Subscribe to our channel for more episodes as we continue to bridge the gap in oncology! #HeadAndNeckCancer, #HPV, #Immunotherapy, #MultidisciplinaryCare, #OncologyBrothers

What if inflammation—not genetics, not aging, not bad luck—was the common thread behind most chronic disease?In this expansive and thought-provoking conversation, physicist, inventor, and engineer Samuel Shepherd shares his extraordinary personal journey after being diagnosed with a rare, terminal bone marrow cancer in 2003. Given no viable medical options, Sam turned to decades of scientific expertise to investigate inflammation, free radicals, and cellular breakdown—ultimately leading him to study astaxanthin, one of the most powerful antioxidants found in nature.We explore the science of oxidative stress, PD-L1 immune signaling, cellular transport, and why conventional antioxidant delivery often fails. Sam explains how he developed a patented glycosidic form of astaxanthin designed to improve absorption and target inflammation more effectively—and how this work reshaped not only his health, but his entire understanding of disease, aging, and resilience.This episode also dives into:Why inflammation may be the root driver of many chronic and neurodegenerative conditionsThe role of free radicals in cancer, Parkinson's, Alzheimer's, and metabolic diseaseHow modern diets—especially fructose exposure—impact inflammation over timeWhat HS-CRP can reveal about long-term health riskWhy curiosity, self-trust, and asking better questions matter more than blind complianceThis is not medical advice. It is an invitation into inquiry, responsibility, and deeper self-education—especially for those who sense that healing requires more than symptom management.If you're someone who values science, autonomy, and understanding your body rather than outsourcing it, this conversation will expand how you think about health, inflammation, and what's truly possible.Connect with Samuel: Website: https://valasta.net/ Youtube: https://www.youtube.com/@ValAsta Facebook: https://www.facebook.com/ValastaHome Connect with Kelly:⁠⁠⁠drkellykessler.com⁠⁠⁠Free Guide: Sacred Boundaries: ⁠⁠⁠http://drkellykessler.com/sacredboundaries⁠⁠Self-Respect Reset is a guided, body-based experience for women who struggle to set boundaries—not because they don't know what they need, but because it hasn't felt safe to honor it.Inside, you'll learn how to rebuild inner safety, strengthen self-trust, and create boundaries that actually protect your peace—without guilt, over-explaining, or self-abandonment.

Featuring perspectives from Dr Javier Cortés, Dr Rita Nanda, Prof Peter Schmid and Dr Priyanka Sharma, including the following topics:  Introduction (0:00) Case: A woman in her early 80s with multiple comorbidities and triple-negative breast cancer (TNBC) develops bone-only metastases 4 months after declining capecitabine for post-neoadjuvant residual disease — Justin Favaro, MD, PhD (1:50) Case: A woman in her mid 70s with ER-negative, HER2-low (IHC 1+), PIK3CA-mutated, PD-L1-positive metastatic breast cancer (mBC) after receiving 3 cycles of neoadjuvant paclitaxel/carboplatin/pembrolizumab, which was discontinued — Alan Astrow, MD (6:47) Previously Untreated Metastatic TNBC (mTNBC) — Prof Schmid (10:47)  Case: A woman in her early 80s with multiregimen-recurrent ER-positive, HER2-low (IHC 1+) ESR1-mutant mBC receives sacituzumab govitecan — Jennifer Yannucci, MD (27:19) Case: The role of datopotamab deruxtecan (Dato-DXd) for patients with ER-positive, HER2-low mBC who experienced disease progression on prior trastuzumab deruxtecan (T-DXd) — Ranju Gupta, MD; Case: A woman in her late 70s with bilateral recurrence in the lungs of ER-negative, HER2-low (IHC 1+) breast cancer (PD-L1 TPS 20%) receives Dato-DXd with durvalumab on protocol — Yanjun Ma, MD, PhD (31:35) Integrating Antibody-Drug Conjugates (ADCs) into the Management of Endocrine-Resistant Hormone Receptor-Positive mBC — Dr Sharma (36:31) Case: A woman in her early 70s with recurrent ER-negative, HER2-low (IHC 2+) mBC receives sacituzumab govitecan and achieves complete remission — Dr Gupta; Case: Management of neutropenia associated with sacituzumab govitecan — Gigi Chen, MD (50:30) Case: A woman in her late 60s with recurrent ER-negative, HER2-low (IHC 1+) mBC (HER2 V69L mutation) receives T-DXd and achieves a complete response but develops Grade 1 interstitial lung disease — Dr Gupta; Case: Management of T-DXd-related side effects — Laila Agrawal, MD (54:10) Selection and Sequencing of Therapy for Relapsed/Refractory mTNBC — Dr Nanda (58:59) Case: A woman in her early 40s with multiregimen-recurrent ER-positive, HER2-low mBC who has experienced severe nausea with past treatments is about to initiate T-DXd — Atif M Hussein, MD, MMM (1:12:40) Tolerability and Other Practical Considerations with ADCs and Other Cytotoxic Agents for mBC — Dr Cortés (1:18:10) CME information and select publications

Dr. Monty Pal and Dr. Hope Rugo discuss advances in antibody-drug conjugates for various breast cancer types as well as treatment strategies in the new era of oral SERDs for HR-positive breast cancer. TRANSCRIPT Dr. Monty Pal: Hello, and welcome to the ASCO Daily News Podcast. I'm your host, Dr. Monty Pal. I'm a medical oncologist and vice chair of academic affairs here at the City of Hope Comprehensive Cancer Center, Los Angeles. Today, I'm thrilled to be joined by Dr. Hope Rugo, an internationally renowned breast medical oncologist and my colleague here at City of Hope, where she leads the Women's Cancers Program and serves as division chief of breast medical oncology. Dr. Rugo is going to share with us exciting advances in antibody-drug conjugates (ADCs) that are expanding treatment options in various breast cancer types. She'll also address some of the complex questions arising in the new era of oral SERDs (selective estrogen receptor degraders) that are revolutionizing treatment in the hormone receptor-positive breast cancer space. Our full disclosures are available in the transcript of this episode.  Dr. Rugo, welcome, and thanks so much for being on the podcast today. Dr. Hope Rugo: Thank you. Pleasure to be here. Dr. Monty Pal: So, I'm going to switch to first names if you don't mind.  The first topic is actually a really exciting one, Hope, and this is antibody-drug conjugates. I don't know if I've ever shared this with you, but I actually started my training at UCLA, I was a med student and resident there, and it was in Dennis Slamon's lab. I worked very closely with Mark Pegram and a handful of others. This is right around the time I think a lot of HER2-directed therapies were really evolving initially in the clinics. Now we've got antibody-drug conjugates. Our audience is well-familiar with the mechanism there but tell us about how ADCs have really started to reshape therapy for HER2-positive breast cancer. Dr. Hope Rugo: Yeah, I mean, this is a really great place to start. I mean, we have had such major advances in breast cancer just this year, I think really changing the paradigm of treating patients. But HER2-positive disease, we've been used to having sequenced success of new agents. And I think the two biggest areas where we've made advances in HER2-positive disease, which were remarkably advanced this year in 2025, have been in antibody-drug conjugates with trastuzumab deruxtecan and with new oral tyrosine kinase inhibitors (TKIs) that have less of a target on EGFR and more on HER2, so they have an overall more tolerable toxicity profile and therefore a potentially better efficacy in the clinic. At least that's what we're seeing with these new strategies that we couldn't really pursue in the past because of toxicities of the oral TKIs. So, although our topic is ADCs, I'm going to include the TKI because it's so important in our thinking about treating HER2-positive disease. In the metastatic setting, we've seen these remarkable improvements in progression-free and overall survival in the second-line setting with T-DXd, or trastuzumab deruxtecan, compared to T-DM1. And then sequencing ADCs with giving T-DXd after T-DM1 was better than an oral tyrosine kinase or a trastuzumab combination with standard chemotherapy. That was DESTINY-Breast03 and DESTINY-Breast02. So, then we've had other trials since then, and T-DXd has moved into the early-stage setting, which I'll talk about in just a moment. But the next big trial for T-DXd in HER2-positive disease was moving it to the first-line setting to supplant what has become an established treatment for now quite a long time: the so-called CLEOPATRA regimen, which used the combined antibodies trastuzumab, pertuzumab with a taxane as first-line therapy. And then we've proceeded on with maintenance with ongoing HP for patients with responding or stable disease. And we'd seen long-term data showing, you know, at 8 years there was a group of patients whose cancers had never progressed and continued improved overall survival. So, T-DXd was studied in DESTINY-Breast09, either alone or in combination with pertuzumab compared to THP. The patient population had received a little bit more prior treatment, but interestingly, not a lot compared to CLEOPATRA. And they designed the trial to be T-DXd continued until progression with or without pertuzumab versus THP, which would go for six cycles and then stop around six cycles, and then stop and continue HP. Patients who had hormone receptor-positive disease could use hormone therapy, and this is one of the issues with this dataset because, surprisingly in this dataset and one other I'll mention, very few patients took hormone therapy. And even in the maintenance trial, the HER2CLIMB-05, less than 50% took hormone therapy as maintenance. This is kind of shocking to me and highlights an area of really important education, that outcome is improved when you add endocrine therapy for hormone receptor-positive HER2-positive metastatic disease in the maintenance phase, and it's a really important part of treatment. But suffice it to say, you know, you're kind of studying continued chemo versus stopping chemo in maintenance. And T-DXd, as we all expected, in combination with pertuzumab was superior to THP in terms of progression-free survival, really remarkably improved. And you could stop the chemo with toxicity, but most people continued it with T-DXd. Again, not a lot of people got hormone therapy, which is an issue, and you stop the chemo in the control arm. So, this has brought up a lot of interest in trying to use T-DXd as an induction and then go to maintenance, much as we do with the CLEOPATRA regimen with hormone therapy. But it brings up another issue. So first, T-DXd is superior; it's a great treatment. Not everybody needs to have it because we don't know whether it's better to give T-DXd first or second with progression - that we need a little bit longer follow-up. But just earlier this week, interestingly, the third week of December, the U.S. FDA approved T-DXd in the DESTINY-Breast09 approach with pertuzumab. So as I mentioned earlier, there was a T-DXd-alone arm; that arm has not yet reported. So very interesting, we don't know if you need pertuzumab or not. So what about the maintenance? That's the other area where we've made a huge advance here. So, we all want to stop chemo and we want to stop T-DXd. You don't want somebody being nauseated for two years while they're on treatment, and also there's a small number of patients with mostly de novo metastatic HER2-positive disease who are cured of their disease. We'd like to expand that, and I think these new drugs give us the opportunity to improve the number of patients who might be cured from metastatic disease. So the first maintenance study we saw was adding palbociclib, the CDK4/6 inhibitor, to endocrine therapy and HP, essentially. There, we had a remarkable improvement in progression-free survival difference of 15.2 months: 29 to 44 months, really huge. At San Antonio this year, we saw data with this oral tyrosine kinase inhibitor tucatinib, already showed it was great in a triplet, but as maintenance in combination with HP, it showed also a remarkable improvement in progression-free survival. But the numbers were all shifted down. So in PATINA, the control arm was in the 24-month range; here it was the tucatinib-HP arm that was in the 25 months and 16 months for control. So there was a differential benefit in ER-negative and ER-positive disease. So I think we're all thinking that our ideal approach moving forward would be to give T-DXd to most patients, we see how they do, and treat to best response. And then, stop the T-DXd, start HP, trastuzumab, pertuzumab for ER-negative, with tucatinib for ER-positive with palbociclib. We also have early data that suggests that both approaches may reduce the development of brain metastases, an issue in HER2-positive disease, and delay time to progression of brain metastases as seen in HER2CLIMB-05 in very early data - small numbers, but still quite intriguing that you might delay progression of brain metastases with tucatinib that clearly has efficacy in the brain.  So, I think that this is a hugely exciting advance for our patients, and these approaches are quickly moving into the early stage setting. T-DXd compared to standard chemo, essentially followed by THP, so a sequenced approach resulted in more pathologic complete responses than a standard THP-AC-type neoadjuvant therapy. T-DXd alone for eight cycles wasn't better, and that's interesting. We still need the sequenced non-cross-resistant chemo. But I think even more importantly, the data from DESTINY-Breast05 looking at T-DXd versus T-DM1 in patients with residual disease after neoadjuvant HER2-targeted therapy showed a remarkable improvement in invasive disease-free survival with T-DXd versus T-DM1, and quite early. It was a high-risk population, higher risk than the T-DM1 trial with KATHERINE, but earlier readout with a remarkable improvement in outcome. We expect to be FDA approved sometime in the first half of 2026. So then we'll get patients who've already had T-DXd who get metastatic disease. But my hope is that with T-DXd, maybe with tucatinib in the right group of patients or even sequenced in very high-risk disease, that we could cure many more patients with early-stage HER2-positive breast cancer and cure a subset, a greater subset of patients with de novo metastatic disease. Dr. Monty Pal: That's brilliant. And you tackled so many questions that I was going to follow up with there: brain metastases, etc. That was sort of looming in my mind. I mean, general thoughts on an ADC versus a TKI in the context of brain mets? Dr. Hope Rugo: Yeah, it's an interesting question because T-DXd has shown quite good efficacy in this setting. And tucatinib, of course, had a trial where they took patients with new brain mets, so a larger population than we've seen yet for the T-DXd trials, and saw that not only did they delay progression of brain metastases and result in shrinkage of existing untreated brain mets, but that patients who develop a new brain met, they could stay on the same assigned treatment. They got stereotactic radiation, and then the patients who were on tucatinib with trastuzumab and capecitabine had a further delay in progression of brain mets compared to those on the placebo arm, even after treatment of a new one that developed on treatment. So, I think it's hard. I think most of us for a lot of brain mets might start with the tucatinib approach, but T-DXd is also a very important treatment. You know, you're kind of trading off a diarrhea, some liver enzyme elevations with tucatinib versus nausea, which you really have to work on managing because it can be long-delayed nausea, and this risk of ILD, interstitial lung disease, that's about 12%, with most but not all trials showing a mortality rate from interstitial lung disease of just under 1 percent. In the early-stage setting, it was really interesting to see that with T-DXd getting four cycles in the neoadjuvant setting, a lot less ILD noted than the patients who got up to 14 cycles, as I think they got a median of 10 cycles in the post-surgical setting, there was a little bit more ILD. But I think we're going to be better and better at finding this earlier and preventing mortality by just stopping drug and treating earlier with steroids. Dr. Monty Pal: And this ILD issue, it always seems to resurface. There are drugs that I use in my kidney cancer clinic, everolimus, common to perhaps the breast cancer clinic as well, pembrolizumab, where I think the pattern of pneumonitis is quite different, right? What is your strategy for recognizing pneumonitis early in this context? Dr. Hope Rugo: Well, it is, and you know, having done the very early studies in everolimus where we gave it in the neoadjuvant setting and we're like, "Hmm, the patient came in with a cough. What's going on?" You know, we didn't know. And you have mouth sores, you know, we were learning about the drug as we were giving it. What we don't do with everolimus and CDK4/6 inhibitors, for example, is grade 1 changes like radiation pneumonitis, we don't stop, we don't treat it. We only treat for symptoms. But because of the mortality associated with T-DXd, albeit small, we stop drug for grade 1 imaging-only asymptomatic pneumonitis, and some of us treat with a half dose of steroids just to try and hasten recovery. We've actually now published or presented a couple of datasets from trials, a pooled analysis and a real-world analysis, that have looked at patients who were retreated after grade 1 pneumonitis or ILD and tolerated drug very well and none of them died of interstitial lung disease, which was really great to see because you can retreat safely and some of these patients stayed on for almost a year benefiting from treatment. So, there's a differential toxicity profile with these drugs and there are risk factors which clearly have identified those at higher risk: prior ILD, for example. A French group said smoking; other people haven't found that, maybe because they smoked more in France, I don't know. And being of Japanese descent is quite interesting. The studies just captured that you were treated in Japan, but I think it's probably being of Japanese descent with many drugs that increases your risk of ILD. And, you know, older patients, people who have hypoxia, those are the patients. So, how do we do this? With everolimus, we don't have specific monitoring. But for T-DXd we do; we do every nine weeks to start with and then every 12 weeks CT scans because most of the events occur relatively early. Somebody who's older and at higher risk now get the first CT at six weeks. Dr. Monty Pal: This is super helpful. And I have to tell you, a lot of these drugs are permeating the bladder cancer space which, you know, is ultimately going to be a component of my practice, so thank you for all this. We could probably stay on this topic of HER2-positive disease forever. I'm super interested in that space still. But let me shift gears a little bit and talk about triple-negative breast cancer and this evolving space of HR-positive, HER2-low breast cancer. I mean, tell us about ADCs in that very sort of other broad area. Dr. Hope Rugo: So triple-negative disease is the absolute hardest subset of disease that we have to treat because if you don't have a great response in the early stage setting, the median survival is very short, you know, under two years for the majority of TNBCs, with the exception of the small percentage of low proliferative disease subsets. The co-question is what do we do for these patients and how do we improve outcome? And sacituzumab govitecan has been one strategy in the later line setting that was shown to improve progression-free and overall survival, the Trop-2 ADC. We had recently three trials presented with the two ADCs, sacituzumab govitecan and the other Trop-2 ADC that's approved for HR-positive disease, datopotamab deruxtecan. And they were studied in the first-line setting. Two trials with SG, sacituzumab govitecan, those trials, one was PD-L1 positive, ASCENT-04. That showed that SG with a checkpoint inhibitor was superior, so pembrolizumab was superior to the standard KEYNOTE-355 type of treatment with either a taxane or gemcitabine and carboplatin with pembrolizumab for patients who have a combined positive score for PD-L1, 10 or greater. So, these are patients who are eligible for a checkpoint inhibitor, and SG resulted in an improved progression-free survival.  The interesting thing about that dataset is that few patients had received adjuvant or neoadjuvant checkpoint inhibitor, which is fascinating because we give it to everybody now. But access is an issue and timing of the study enrollment was an issue. The other thing which I think we've all really applauded Gilead for is that there was automatic crossover. So, you could get from the company, to try and overcome some of the enormous disparities worldwide in access to these life-saving drugs, you could get SG through the company for free once you had blinded independent central review confirmation of disease progression. Now, a lot of the people who got the SG got it through their insurance, they didn't bill the company, but 80 percent of patients in the control arm received SG in the second-line setting. So that impacts your ability to look at overall survival, but it's an incredibly important component of these trials. So then at ESMO, we saw the data from SG and Dato-DXd in the first-line metastatic setting for patients who either had PD-L1-negative disease or weren't eligible for an immunotherapy. For the Dato study, TROPION-Breast02, that was 10 percent of the patients who had PD-L1-positive disease but didn't get a checkpoint inhibitor, and for the ASCENT-03 trial population it was only 1 percent. Importantly, the trials allowed patients who relapsed within a year of receiving their treatment with curative intent, and the Dato study, TB-02, allowed patients who relapsed while on treatment or within the first six months, and that was 15 percent of the 20 percent of early relapsers. The ASCENT trial, ASCENT-03, had 20 percent who relapsed between 6 and 12 months. The drugs were better than standard of care chemotherapy, the ADCs in both trials, which is very nice. Different toxicity profiles, different dosing intervals, but better than standard of care chemotherapy in the disease that's hardest for us to treat. And importantly, when you looked at the subset of early relapsers, those patients also did better with the ADC versus chemotherapy, which is incredibly important. And we were really interested in that 15 percent of patients who had early relapse. I actually think that six months thing was totally contrived, invented, you know, categorization and doesn't make any sense, and we should drop it. But the early relapsers were 15 percent of TB-02 and Dato was superior to standard of care chemo. We like survival, but the ASCENT trial again allowed the crossover to an approved ADC that improved survival and 80 percent of patients crossed over. In the Dato trial, they did not allow crossover, they didn't provide Dato, which isn't approved for TNBC but is for HR-positive disease, and they didn't allow, of course, pay for SG. So very few patients actually crossed over in their post-treatment data and in that study, they were able to show a survival benefit. So actually, I think in the U.S. where we can use approved drugs already before there's a fixed FDA approval, that people are already switching to use SG or Dato in the first-line setting for metastatic TNBC that's both PD-L1 positive for SG and PD-L1 negative for both drugs. And I think understanding the toxicity profiles of the two drugs is really important as well as the dosing interval to try and figure out which drug to use. Dr. Monty Pal: Brilliant. Brilliant. Well, I'm going to shift gears a little bit. ADCs are a topic, again, just like HER2-positive disease we could stay on forever. Dr. Hope Rugo: Huge. Yes. Dr. Monty Pal: But we're going to shift gears to another massive topic, which is oral SERDs. In broad strokes, right, this utilization of CDK4/6 inhibitors in the context of HR-positive breast cancer is obviously, you know, a paradigm that's been well established at this point. Where do we sequence in oral SERDs? Where do they fit into this paradigm? Dr. Hope Rugo: Ha! This is a rapidly changing area; we keep changing what we're saying every other minute. And I think that there are three areas of great interest. So one is patients who develop ESR1 mutations that allow constitutive signaling through the estrogen receptor, even when there's not estrogen around, and that is a really important mutation that is subclonal; it develops under the pressure of treatment in about 40 percent of patients. And it doesn't happen when you first walk in the door. And what we've seen is that oral SERDs as single agents are better than standard single-agent endocrine therapy in that setting. The problem that we've had with that approach is that we're now really interested in giving targeted agents with our endocrine therapies, not just in the first-line setting where CDK4/6 inhibitors are our standard of care with survival benefit for ribociclib and, you know, survival benefit in subsets with other CDK4/6 inhibitors, and abemaciclib with a numeric improvement. So we give it first line. The question is, what do you do in the second-line setting? Because of the recent data, we now believe that oral SERDs should be really given with a targeted agent. And some datasets which were recently presented, which I think have helped us with that, have been EMBER-3 and then the most recently evERA BC, or evERA Breast Cancer, that looked at the oral SERD giredestrant with everolimus compared to standard of care endocrine therapy with everolimus, where 100 percent of patients received prior CDK4/6 inhibitor and showed a marked improvement in progression-free survival, including in the subsets of patients with a short response, 6-12 months of prior response to CDK4/6 inhibitor and in those who had a PIK3CA pathway mutation. The thing is that the benefit looks like it's much bigger in the ESR1 mutant population, although response was better, PFS wasn't better in the wild type. So, we're still trying to figure that out. We also saw EMBER-3 with imlunestrant and abemaciclib as a second line. Not everybody had had a prior CDK4/6 inhibitor; they compared it to imlunestrant alone, but still the data was quite striking and seemed to cross the need for ESR1 mutations. And then lastly, we saw data from the single arms of the ELEVATE trial looking at elacestrant with everolimus and abemaciclib and showed these really marked progression-free survival data, even though single-arm, that crossed the mutation status. At least for the everolimus combination, abemaciclib analysis is still to come in the mutated subgroups. But really remarkable PFS, much longer.  Single-agent fulvestrant after CDK4/6 inhibitor AI has a PFS in like the three-month range and in some studies, maybe close to five months. These are all at 10-plus months and really looking very good. And so those questions are, is it ESR1 mutation alone? Is it all comers? We'd like all comers, right? We believe in the combination approach and we're learning more about combinations with drugs like capivasertib and other drugs as we move forward. Everybody now wants to combine their targeted agent with an oral SERD because they're clearly here to stay with quite remarkable data. The other issue, so the second issue in the metastatic setting is, does it make a difference if we change to an oral SERD before radiographic imaging evidence of progression? And that was the question asked in the SERENA-6 trial where patients had serial monitoring for the presence of ESR1 mutations in ctDNA. And those who had them without progression on imaging could be randomized to switch to camizestrant with the same CDK4/6 inhibitor or stay on their same AI CDK4/6 inhibitor. And they showed a difference in progression-free survival that markedly favored camizestrant. But interestingly, the people who were on the standard control arm had an ESR1 mutation, we think AIs don't work, they stayed on for nine more months. The patients who were on the camizestrant stayed on for more than 16 months. And they presented some additional subset data which showed the same thing: follow-up PFS data, PFS2, all beneficial in SERENA-6 at the San Antonio [Breast Cancer Symposium]. So, we're still a little bit unclear about that. They did quality of life, and pain was markedly improved. They had a marked delayed time to progression of pain in the camizestrant arm. So this is all a work in progress, trying to understand who should we switch without progression to an oral SERD based on this development of this mutation that correlates with resistance. And, you know, it's interesting because the median time to having a mutation was 18 months and the median time to switch was almost 24 months. And then there were like more than 3,000 patients who hadn't gotten a mutation, hadn't switched, and were still okay. So screening everybody is the big question, and when you would start and who you would change on and how this affects outcome. Patients didn't have access to camizestrant in the control arm, something we can't fix but we have experimental drugs. We're actually planning a trial, I hope in collaboration with the French group Unicancer, and looking at this exact question. You know, if you switch and you change the CDK4/6 inhibitor and then you also allow crossover, what will we see? Dr. Monty Pal: We're coming right to the tail end of our time here, and I could probably go on for another couple of hours with you here. But if you could just give us maybe one or two big highlights from San Antonio, any thoughts to leave our audience with here based on this recent meeting? Dr. Hope Rugo: Yeah, I mean, I talked about a lot of those new data already from San Antonio, and the one that I'd really like to mention which I think was, you know, there were a lot of great presentations including personalized screening presented from the WISDOM trial by my colleague Laura Esserman, fascinating and really a big advance. But lidERA was the big highlight, I think, outside of the HER2CLIMB-05 which I talked about earlier in HER2-positive disease. And this study looked at giredestrant, the oral SERD versus standard of care endocrine therapy as treatment for medium and high-risk early-stage breast cancer. And what they showed, which I think was really remarkable with just about a three-year median follow-up, was an improvement in invasive disease-free survival with a hazard ratio of 0.7. I mean, really quite remarkable and so early. It looked as though this was all driven by the high-risk group, which makes sense, not the medium risk, it's too early. And also that there was a bigger benefit in patients who were on tamoxifen compared to giredestrant versus AI, but for both groups, the confidence intervals didn't cross 1. There's even a trend towards overall survival, even though it's way too early. I think that, you know, really well-tolerated oral drug that could improve outcome in early-stage disease, this is the first advance we've seen in over two decades in the treatment of early-stage hormone receptor-positive disease with just endocrine therapy. I think we think that we don't want to give up CDK4/6 inhibitors because we saw a survival benefit with abemaciclib and a trend with giving ribociclib in the NATALEE trial. So we're thinking that maybe one approach would be to give CDK4/6 inhibitors and then switch to an oral SERD or to have enough data to be able to give oral SERDs with these CDK4/6 inhibitors for early-stage disease. And that's all in the works, you know, lots of studies going on. We're going to see a lot of data with both switching 8,000 patients with an imlunestrant switching trial, an elacestrant trial going on, and safety data with giredestrant with abemaciclib and soon to come ribociclib. So, this is going to change everything for the treatment of early-stage breast cancer, and I hope cure more patients of the most common subset of the most common cancer diagnosed in women worldwide. Dr. Monty Pal: Super exciting. It's just remarkable to hear how this has evolved since 25 years ago, which is really the last time I sort of dabbled in breast cancer.  Thank you so much, Hope, for joining us today. These were fantastic insights. Appreciate you being on the ASCO Daily News Podcast and really want to thank you personally for your remarkable contribution to the field of breast cancer. Dr. Hope Rugo: Thank you very much, and thanks for talking with me today. Dr. Monty Pal: You got it. And thanks a lot to our listeners today as well. You'll find links to all the studies we discussed today in the transcript of this episode. Finally, if you value the insights that you hear today on the ASCO Daily News Podcast, please 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 opinion 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. Monty Pal @montypal Dr. Hope Rugo   @hoperugo Follow ASCO on social media:        ASCO on X  ASCO on Bluesky       ASCO on Facebook        ASCO on LinkedIn        Disclosures:     Dr. Monty Pal:    Speakers' Bureau: MJH Life Sciences, IntrisiQ, Peerview   Research Funding (Inst.): Exelixis, Merck, Osel, Genentech, Crispr Therapeutics, Adicet Bio, ArsenalBio, Xencor, Miyarsian Pharmaceutical   Travel, Accommodations, Expenses: Crispr Therapeutics, Ipsen, Exelixis   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  

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

Featuring perspectives from Dr Yelena Y Janjigian, including the following topics: Introduction (0:00) Case: A man in his early 60s with a history of Barrett's esophagus presents with HER2-positive metastatic esophageal adenocarcinoma and a PD-L1 combined positive score (CPS) of 3 — Jennifer Yannucci, MD (10:20) Case: A man in his early 60s with multiregimen-recurrent HER2-positive gastroesophageal junction (GEJ) adenocarcinoma (claudin 18.2-positive, PD-L1 CPS 0) — Neil Morganstein, MD (14:53) Case: A woman in her early 80s with dementia and newly diagnosed mismatch repair-deficient, PD-L1-positive metastatic GEJ adenocarcinoma — Brian P Mulherin, MD (25:55) Case: A man in his mid 60s with localized HER2-negative GEJ cancer (PD-L1 CPS 2, claudin 18.2-positive) and residual disease after receiving neoadjuvant chemoradiation therapy and undergoing surgery — Stephen "Fred" Divers, MD (32:18) Case: A man in his early 80s with metastatic recurrence of esophageal adenocarcinoma and a PD-L1 total proportion score of 75% 2 years after resection of localized disease — Susmitha Apuri, MD (40:28) Case: A man in his mid 70s with claudin 18.2-positive metastatic esophageal adenocarcinoma who develops progressive toxicities with FOLFOX and zolbetuximab — Sean Warsch, MD (52:54) CME information and select publications

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    

Welcome to the Oncology Brothers podcast! In this episode, we were joined by Dr. Rutika Mehta, a GI medical oncologist from Weill Cornell. Together, we dived into the current treatment landscape for advanced metastatic gastroesophageal junction (GEJ) and gastrointestinal carcinoma, with a special focus on HER2-positive disease. Episode Highlights: • Overview of recent advancements in the treatment of resectable disease, including the approval of Durvalumab in perioperative settings. • Discussion on the importance of biomarker testing, including HER2, PD-L1, MMR, and Claudin 18.2, in determining treatment options. • Insights into frontline treatment strategies for HER2-positive patients, including the role of trastuzumab and the addition of pembrolizumab based on PD-L1 status. • The significance of retesting HER2 expression upon disease progression and the implications for treatment decisions. • Exploration of emerging therapies like TDXd and Zanidatamab, and their potential impact on the treatment landscape. • Considerations for managing side effects and the importance of treatment sequencing in palliative care. Join us for an informative discussion that aims to keep community oncologists up to date in this ever-evolving field of cancer treatment. 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 covering treatment algorithms, FDA approvals, and conference highlights! Accreditation/Credit Designation Physicians' Education Resource®, LLC is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. Physicians' Education Resource®, LLC designates this enduring material for a maximum of 0.25 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Acknowledgment of Commercial Support This activity is supported by an educational grant from Jazz Pharmaceuticals, Inc. Link to gain CME credits from this activity: https://www.gotoper.com/courses/biomarker-testing-in-her2-gea-diagnosis-and-treatment-implications    #HER2GastricCancer #GastricCancer #BiomarkerTesting #OncologyBrothers #GIOncology #CME

Featuring perspectives from Dr Manish A Shah, moderated by Dr Stephen "Fred" Divers, including the following topics:  Highlights and Principles of Management of Metastatic Gastric and Gastroesophageal Junction Adenocarcinoma — Dr Shah (0:00) Case: A man in his early 50s with microsatellite instability-high localized esophageal adenocarcinoma — Dr Mulherin (15:24) Case: A woman in her late 60s with HER2-positive (IHC 3+) and HER2 TKD-mutant metastatic esophageal adenocarcinoma — Dr Warsch (25:34) Case: A woman in her early 70s with HER2-positive (IHC 3+), PD-L1-negative, CLDN18.2-negative metastatic gastric cancer — Dr Mulherin (28:15) Case: A woman in her early 70s with metastatic gastroesophageal junction adenocarcinoma (PD-L1 CPS 15) who begins treatment with FOLFOX/nivolumab and subsequently is found to have CLDN18.2 overexpression — Dr Lamar (35:23) Case: A man in his mid 40s with CLDN18.2-positive metastatic esophageal adenocarcinoma (PD-L1 10%) who receives mFOLFOX6 and zolbetuximab — Dr Yannucci (42:54) CE information and select publications

Featuring an interview with Dr Priyanka Sharma, including the following topics: Endocrine therapy for hormone receptor-positive, HER2-negative high-risk localized breast cancer (0:00) Johnston SR et al. monarchE: Primary overall survival (OS) results of adjuvant abemaciclib + endocrine therapy (ET) for HR+, HER2-, high-risk early breast cancer (EBC). ESMO 2025;Abstract LBA13. Durvalumab in combination with neoadjuvant chemotherapy for localized triple-negative breast cancer (TNBC) (3:25) Loibl S et al. Durvalumab in combination with neoadjuvant chemotherapy in early triple-negative breast cancer (TNBC) – Long-term analysis from the GeparNuevo trial. ESMO 2025;Abstract 292MO.  Efficacy and safety findings with TROP2-directed antibody-drug conjugates for metastatic TNBC (5:11) Cortés JC et al. Primary results from ASCENT-03: A randomized phase III study of sacituzumab govitecan (SG) vs chemotherapy (chemo) in patients (pts) with previously untreated advanced triple-negative breast cancer (TNBC) who are unable to receive PD-(L)1 inhibitors (PD-[L]1i). ESMO 2025;Abstract LBA20.  de Azambuja E et al. Patient-reported outcomes (PROs) with sacituzumab govitecan (SG) + pembrolizumab (pembro) vs chemotherapy (chemo) + pembro in patients (pts) with previously untreated PD-L1+ metastatic triple-negative breast cancer (mTNBC) in the phase III ASCENT-04/KEYNOTE-D19 study. ESMO 2025;Abstract LBA22.  Dent R et al. First-line (1L) datopotamab deruxtecan (Dato-DXd) vs chemotherapy in patients with locally recurrent inoperable or metastatic triple-negative breast cancer (mTNBC) for whom immunotherapy was not an option: Primary results from the randomised, phase III TROPION-Breast02 trial. ESMO 2025;Abstract LBA21.  CME information and select publications

In this episode of The Oncology Brothers, we dived into the pivotal study of MATTERHORN, which explored the addition of Durvalumab to perioperative FLOT chemotherapy for patients with resectable gastric and gastroesophageal junction adenocarcinoma. Join us as we welcome Dr. Yelena Y. Janjigian, a medical oncologist from Memorial Sloan Kettering and the lead author of the MATTERHORN study. Dr. Janjigian shared insights on the study's design, findings, and the implications for clinical practice, including: • The significance of the study in the context of recent FDA approvals and treatment advancements. • Key survival data, including a three-year overall survival rate of 68.6% with Durvalumab. • The feasibility of combining immunotherapy with chemotherapy and impact on surgical outcomes. • Management of side effects and clinical pearls for practitioners. We also discussed the potential for extrapolating this data to esophageal adenocarcinoma and the role of PD-L1 status in treatment decisions. Whether you're a seasoned oncologist or just starting in the field, this episode is packed with valuable information to help you provide the best care for your patients. 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, share, and subscribe for more practice-changing updates in oncology! #MATTERHORN #GastricCancer #Immunotherapy #Durvalumab #OncologyBrothers #GIOncology

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're diving into a series of impactful events and breakthroughs that are shaping patient care and drug development.The U.S. Food and Drug Administration recently granted early approval for a combination therapy using Padcev and Keytruda for the perioperative treatment of bladder cancer, a decision made months ahead of schedule. This approval represents a significant advancement in the therapeutic landscape for this type of cancer, offering new hope to patients who have had limited treatment options. The combination of these two therapies underscores the growing trend of integrating multiple mechanisms of action to tackle complex diseases like cancer more effectively. It also highlights the potential of combination therapies to provide enhanced clinical benefits by leveraging different therapeutic targets.In another notable development, Merck's partner Kelun announced successful Phase 3 trial results for an antibody-drug conjugate combined with Keytruda in treating PD-L1-positive non-small cell lung cancer (NSCLC). The trial results demonstrated statistically significant improvements in progression-free survival compared to Keytruda alone. This finding reinforces the expanding role of antibody-drug conjugates in oncology and emphasizes the importance of biomarker-driven therapies in personalizing cancer treatment. These advancements reflect a broader industry shift towards precision medicine, which aims to improve patient outcomes by tailoring treatments based on individual patient profiles.Meanwhile, Novo Nordisk experienced setbacks as its shares fell nearly 9% following two unsuccessful Phase 3 trials of semaglutide for Alzheimer's disease. Despite these disappointing results, this outcome highlights the persistent challenges and complexities inherent in developing therapies for neurodegenerative diseases—areas where unmet needs remain substantial. The market's reaction reflects investor sensitivity to clinical trial outcomes, particularly in high-stakes areas like Alzheimer's where breakthroughs are eagerly anticipated.Switching gears to AstraZeneca, the company is making a strategic move by expanding its manufacturing capabilities with a $2 billion investment in Maryland. This expansion reflects an ongoing trend among pharmaceutical companies to enhance their production infrastructure, driven by increasing demand for biologics and complex therapeutics. Such investments are crucial for supporting large-scale production needs and ensuring robust supply chains that are essential for meeting global health demands.In regulatory news, a collective letter from biotech CEOs addressed to FDA director Marty Makary has raised concerns about regulatory stability in the U.S., with 82% of biopharma respondents expressing apprehension over the FDA's ability to function predictably. This plea underscores how regulatory volatility can hinder innovation and emphasizes the importance of consistent policies that support long-term research and development efforts.In clinical trial updates, Bayer's oral FXIa inhibitor asundexian has shown promise in reducing stroke risk during Phase 3 trials. These findings revive interest in FXIa inhibitors as potentially blockbuster drugs after previous setbacks in this class. This development illustrates ongoing efforts to identify novel anticoagulant therapies that balance efficacy and safety, offering new hope for improved therapeutic options.Now turning our attention to Johnson & Johnson's recent setback with their anti-tau antibody posdinemab in a phase 2 trial targeting Alzheimer's disease. The trial was unable to demonstrate a significant slowing of clinical decline, leading JSupport the show

"It's critical to identify those mutations found that are driving the cancer's growth and guide the personalized treatment based on those results. And important to remember, too, early testing is crucial for patients with non-small cell lung cancer (NSCLC). In studies, it has been found to be associated with improved survival outcomes and reduced mortality," ONS member Vicki Doctor, MS, BSN, BSW, RN, OCN®, precision medicine director at the City of Hope Atlanta, GA, Chicago, IL, and Phoenix, AZ, locations, told Jaime Weimer, MSN, RN, AGCNS-BS, AOCNS®, manager of oncology nursing practice at ONS, during a conversation about the oncology nurse's role in NSCLC biomarker testing. Music Credit: "Fireflies and Stardust" by Kevin MacLeod Licensed under Creative Commons by Attribution 3.0  This podcast is sponsored by Lilly Oncology 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 363: Lung Cancer Treatment Considerations for Nurses Episode 359: Lung Cancer Screening, Early Detection, and Disparities Episode 238: Cancer Genomics for Every Oncology Nurse Episode 157: Biomarker Testing Improves Outcomes for Patients With Non-Small Cell Lung Cancer ONS Voice articles: Non-Small Cell Lung Cancer Prevention, Screening, Diagnosis, Treatment, Side Effects, and Survivorship Only a Third of Patients With Advanced Cancer Get Biomarker Testing, Limiting Use of Potentially Effective Precision Therapies Precision Medicine in Lung Cancer: How Comprehensive Testing Optimizes Patient Outcomes Targeted Therapies Are Transforming the Treatment of Non-Small Cell Lung Cancer ONS book: Guide to Cancer Immunotherapy (second edition) ONS course: Genomic Foundations for Precision Oncology Clinical Journal of Oncology Nursing article: Using Nurse Navigators to Improve Timeliness of Biomarker Testing for Non-Small Cell Lung Cancer Oncology Nursing Forum article: Precision Medicine Testing and Disparities in Health Care for Individuals With Non-Small Cell Lung Cancer: A Narrative Review Other ONS resources: Best Practices for Biomarker Testing in Non-Small Cell Lung Cancer: A Case Study Genomics and Precision Oncology Learning Library Genomics Case Study: Precision Medicine in the Setting of Metastatic Non-Small Cell Lung Cancer Biomarker Database (refine by non-small cell lung cancer) Genomic Biomarkers Huddle Card Targeted Therapy Huddle Card National Comprehensive Cancer Network homepage 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 "These biomarkers are used to provide information about cancer's characteristics or behavior. In oncology precision medicine specifically, molecular tests can help with diagnosing a cancer that is maybe an unknown primary. It can help with monitoring response to therapy, detect recurrence of disease before other tests can find that, predict prognosis or how aggressive the cancer may be, and guide treatment decisions for targeted therapies." TS 3:14 "Some of the key biomarkers recommended by the National Comprehensive Cancer Network (NCCN) to be tested in patients who have NSCLC are EGFR, ALK, KRAS, BRAF, MET exon 14 skipping mutation, HER2 which is a protein expression from an ErbB protein, PD-L1 which is a protein expression that's used to guide immunotherapy choices, and then finally there are three fusions: ROS1, RET, and NTRK. [These] are pretty rare but really important to be tested for in patients who have NSCLC." TS 3:46 "Another important challenge for nurses related to this topic is that these results may not reveal a targeted mutation for the patient and that could be very disappointing. So, being able to provide that emotional support to a patient if they have that result … you can actually reinforce with them that if [they] go onto another treatment that the physician decides to put [them] on, the tumor can change. New pathogenic variants can develop based on the treatment that they're getting, and another test can be done. And maybe at that time—a new biomarker that could be targeted—we'd be seeing on the new test." TS 7:32  "Another circumstance we didn't talk about yet is that maybe the result came back saying that the quality was not sufficient. And sometimes that happens, but that doesn't mean that we're at the end of the road, necessarily. So, you could explain to the patient that that may mean that possibly, a new biopsy would be ordered by the physician. Or if a new biopsy or another tissue sample is not available, then maybe the physician would pivot to sending a blood specimen for the molecular testing. So that would definitely be a way [nurses] could support their patients." TS 11:52 "In the case of patients with NSCLC, early testing is so important. So, advocating for that prompt biomarker testing to be done, making sure that it's comprehensive, that it's actually looking for all of those—I think it was 12 biomarkers—that I mentioned earlier. That this testing is done as soon as possible after diagnosis or progression. Something that I talk about all the time—personalized care, precision medicine—really matters. So, tailoring treatments for patients based on the biology of the tumor that's driving the cancer's growth is really crucial if you're going to be working as an oncology nurse. Another crucial thing, because it's changing so quickly, is to stay informed." TS 16:23

In today's episode, filmed live at the 43rd Annual Chemotherapy Foundation Symposium, lung cancer expert Benjamin P. Levy, MD, hosted a cross-specialty discussion with genitourinary (GU) cancer expert Scott T. Tagawa, MD, MS, FACP, FASCO, about the rapidly evolving treatment paradigms for prostate and kidney 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 Tagawa is a professor of medicine and urology at Weill Cornell Medicine, as well as an attending physician at NewYork-Presbyterian – Weill Cornell Medical Center in New York, New York. Their conversation began with a focus on prostate-specific membrane antigen (PSMA)–positive prostate cancer. Dr Tagawa explained that PSMA is a cell surface protein, and that PSMA imaging agents are commonly used to assess biochemical recurrence and perform initial disease staging. He noted that therapy-related adverse effects are often site-specific, including dry mouth/change in taste, and myelosuppression from the radiation payload. For monitoring long-term safety, Dr Tagawa emphasized that renal function must be tracked. Beyond PSMA, other prostate cancer targets include TROP-2, B7-H3, and markers specific to aggressive or neuroendocrine variants, such as DLL3, he reported. In advanced GU cancers, circulating tumor DNA (ctDNA) testing is increasingly important, Dr Tagawa highlighted. In prostate cancer, ctDNA testing is used to assess homologous recombination deficiency (HRD) status and BRCA expression, he said, explaining that evidence for the use of ctDNA testing in GU cancers stems from findings with this type of assay to evaluate minimal residual disease levels in urothelial cancer. He noted that studies show that if patients with urothelial cancer become ctDNA positive within the first year of receiving neoadjuvant chemotherapy, they benefit from treatment with atezolizumab (Tecentriq). Similarly, he stated that patients with previously untreated HRD-positive metastatic prostate cancer also see a progression-free survival benefit when a PARP inhibitor is added to an androgen deprivation therapy/androgen receptor pathway inhibitor backbone. Shifting the conversation to the management of frontline advanced clear cell renal cell carcinoma (RCC), the experts reviewed standard approaches, which involve an immune-oncology (IO) agent plus either a CTLA-4 inhibitor or a VEGF TKI. Tagawa noted that IO/VEGF TKI combinations may be preferred for symptomatic patients needing a rapid response, whereas IO/IO combinations may offer greater potential for treatment cessation. He brought up a key distinction in RCC, which is that re-instituting PD-1/PD-L1 inhibition upon progression in the metastatic setting has generally shown no benefit. Dr Levy brought a broad scope to the GU cancer discussion through his lung cancer expertise, introducing parallels between the treatment paradigms. The interview provided an opportunity to show the importance of creating connections across oncology specialties to bring nuanced perspectives to future advances in clinical research and patient care.

Host: Jennifer Caudle, DO Guest: Samuel Klempner, MD Guest: Nataliya Uboha, MD, PhD Testing for biomarkers like PD-L1, HER2, claudin 18.2, and FGFR2b is reshaping our approach to first-line therapy in advanced gastric and gastroesophageal junction cancers. Alongside biomarker profiling, we must also weigh practical considerations around efficacy, toxicity, and patient-specific factors when selecting treatment. Joining Dr. Jennifer Caudle to explore how we can optimize our first-line treatment selection are Drs. Samuel Klempner and Dr. Nataliya Uboha. Dr. Klempner is an Associate Professor of Medicine at Harvard Medical School, and Dr. Uboha is an Associate Professor in the Division of Hematology and Oncology in the Department of Medicine at the University of Wisconsin.

Following a fruitful European Society of Medical Oncology (ESMO) Congress 2025 for gastrointestinal malignancies, CancerNetwork® organized an X Spaces discussion hosted by 3 experts. They were Nicholas J. Hornstein, MD, an assistant professor at the Donald and Barbara Zucker School of Medicine of Hofstra University and Northwell Health; Timothy Brown, MD, an assistant professor in the Department of Internal Medicine and the associate program director of the Hematology & Oncology Fellowship at UT Southwestern Medical Center; and Udhayvir S. Grewal, MD, an assistant professor in the Department of Hematology and Medical Oncology at Emory University School of Medicine. Each doctor focused on a specific disease type, highlighting the most important abstracts in colorectal cancer, pancreatic neuroendocrine tumors (NETs), and upper gastrointestinal cancers. The Phase 3 MATTERHORN Trial (NCT04592913) Results from MATTERHORN demonstrated that adding durvalumab (Imfinzi) to 5-fluorouracil, leucovorin (folinic acid), oxaliplatin, and docetaxel (FLOT) improved overall survival (OS) compared with FLOT plus placebo in patients with resectable gastric/gastroesophageal junction (GEJ) adenocarcinoma, regardless of pathological status.1 In the intention-to-treat population, the median OS was not reached in either arm, and the hazard ratio (HR) was 0.78 (95% CI, 0.63-0.96; P = .021). Notably, the improvement was observed regardless of PD-L1 status; in patients with PD-L1–positive disease, the HR was 0.79 (95% CI, 0.63-0.99), and in patients with PD-L1–negative disease, the HR was 0.79 (95% CI, 0.41-1.50). “This, I believe, will seal durvalumab plus FLOT as the standard of care for resectable [gastric/GEJ] cancers,” said Brown. The Observational ASPEN Study (NCT03084770) The ASPEN study showed that active surveillance was a safe approach for patients with low-grade, asymptomatic, nonfunctioning pancreatic neuroendocrine tumors (NETs) fewer than 2 centimeters in size.2 Of the 1000 patients enrolled in the trial, 20 patients died, of whom 18 underwent active surveillance and 2 underwent surgery. Nineteen of the deaths were unrelated to pancreatic NETs; 1 death in the surgery arm was related to a pancreatic NET. After surgery, 5 patients had disease relapse or progression. With a median follow-up of 42 months (IQR, 25-60), the OS analysis showed a P value of 0.530.  “This really settles the debate on whether or not to surgically operate on patients with a [pancreatic NET] size of [fewer] than 2 centimeters and shows that active surveillance is a safe option for these patients with pancreatic NETs [fewer] than 2 centimeters in size and non-functional NETs,” said Grewal.  Data From the Phase 2/3 FOxTROT (NCT00647530) and Phase 2 NICHE-2 (NCT03026140) Trials Neoadjuvant nivolumab (Opdivo) plus ipilimumab (Yervoy) achieved a clinically meaningful and statistically significant improvement in long-term outcomes, including responses and survival, compared with chemotherapy strategies in patients with mismatch repair deficient (dMMR) or microsatellite instability–high (MSI-H) locally advanced colon cancer.3 In NICHE-2, neoadjuvant nivolumab plus ipilimumab achieved a 3-year disease-free survival (DFS) rate of 100% compared with 80% (95% CI, 73%-85%) with all chemotherapy strategies in FOxTROT (P

CME credits: 1.00 Valid until: 31-10-2026 Claim your CME credit at https://reachmd.com/programs/cme/Evidence-and-Guideline-Based-Treatment-for-Advanced-Metastatic-Cervical-Cancer/39292/ This series features interdisciplinary discussions on the evolving management of cervical and endometrial cancers, emphasizing biomarker-driven decision-making and personalized care. Experts examine screening, biomarker testing, clinical trial evidence, and the integration of immunotherapy into guideline-driven treatment regimens, highlighting the clinical implications of PD-L1 expression. Case-based dialogues highlight diagnostic approaches, treatment planning, and toxicity management across disease stages. The program underscores the importance of coordinated care involving oncologists, nurse practitioners, and pathologists to optimize outcomes.

CME credits: 1.00 Valid until: 31-10-2026 Claim your CME credit at https://reachmd.com/programs/cme/Applications-in-Multidisciplinary-Care-for-Cervical-Cancer/39297/ This series features interdisciplinary discussions on the evolving management of cervical and endometrial cancers, emphasizing biomarker-driven decision-making and personalized care. Experts examine screening, biomarker testing, clinical trial evidence, and the integration of immunotherapy into guideline-driven treatment regimens, highlighting the clinical implications of PD-L1 expression. Case-based dialogues highlight diagnostic approaches, treatment planning, and toxicity management across disease stages. The program underscores the importance of coordinated care involving oncologists, nurse practitioners, and pathologists to optimize outcomes.

CME credits: 1.00 Valid until: 31-10-2026 Claim your CME credit at https://reachmd.com/programs/cme/Managing-Immune-Related-Adverse-Events-in-Cervical-and-Endometrial-Cancer/39296/ This series features interdisciplinary discussions on the evolving management of cervical and endometrial cancers, emphasizing biomarker-driven decision-making and personalized care. Experts examine screening, biomarker testing, clinical trial evidence, and the integration of immunotherapy into guideline-driven treatment regimens, highlighting the clinical implications of PD-L1 expression. Case-based dialogues highlight diagnostic approaches, treatment planning, and toxicity management across disease stages. The program underscores the importance of coordinated care involving oncologists, nurse practitioners, and pathologists to optimize outcomes.

CME credits: 1.00 Valid until: 31-10-2026 Claim your CME credit at https://reachmd.com/programs/cme/Evidence-Base-for-Treatment-Strategies-for-Endometrial-Cancer-After-Disease-Progression-and-Interdisciplinary-Collaboration/39295/ This series features interdisciplinary discussions on the evolving management of cervical and endometrial cancers, emphasizing biomarker-driven decision-making and personalized care. Experts examine screening, biomarker testing, clinical trial evidence, and the integration of immunotherapy into guideline-driven treatment regimens, highlighting the clinical implications of PD-L1 expression. Case-based dialogues highlight diagnostic approaches, treatment planning, and toxicity management across disease stages. The program underscores the importance of coordinated care involving oncologists, nurse practitioners, and pathologists to optimize outcomes.

CME credits: 1.00 Valid until: 31-10-2026 Claim your CME credit at https://reachmd.com/programs/cme/Evidence-Base-for-First-Line-Treatment-Strategies-for-Endometrial-Cancer-and-Delivering-Guideline-Concordant-Care/39294/ This series features interdisciplinary discussions on the evolving management of cervical and endometrial cancers, emphasizing biomarker-driven decision-making and personalized care. Experts examine screening, biomarker testing, clinical trial evidence, and the integration of immunotherapy into guideline-driven treatment regimens, highlighting the clinical implications of PD-L1 expression. Case-based dialogues highlight diagnostic approaches, treatment planning, and toxicity management across disease stages. The program underscores the importance of coordinated care involving oncologists, nurse practitioners, and pathologists to optimize outcomes.

CME credits: 1.00 Valid until: 31-10-2026 Claim your CME credit at https://reachmd.com/programs/cme/Role-of-Predictive-Biomarkers-in-Endometrial-Cancer/39293/ This series features interdisciplinary discussions on the evolving management of cervical and endometrial cancers, emphasizing biomarker-driven decision-making and personalized care. Experts examine screening, biomarker testing, clinical trial evidence, and the integration of immunotherapy into guideline-driven treatment regimens, highlighting the clinical implications of PD-L1 expression. Case-based dialogues highlight diagnostic approaches, treatment planning, and toxicity management across disease stages. The program underscores the importance of coordinated care involving oncologists, nurse practitioners, and pathologists to optimize outcomes.

CME credits: 1.00 Valid until: 31-10-2026 Claim your CME credit at https://reachmd.com/programs/cme/Case-Applications-in-Multidisciplinary-Care-for-Endometrial-Cancer/39298/ This series features interdisciplinary discussions on the evolving management of cervical and endometrial cancers, emphasizing biomarker-driven decision-making and personalized care. Experts examine screening, biomarker testing, clinical trial evidence, and the integration of immunotherapy into guideline-driven treatment regimens, highlighting the clinical implications of PD-L1 expression. Case-based dialogues highlight diagnostic approaches, treatment planning, and toxicity management across disease stages. The program underscores the importance of coordinated care involving oncologists, nurse practitioners, and pathologists to optimize outcomes.

CME credits: 1.00 Valid until: 31-10-2026 Claim your CME credit at https://reachmd.com/programs/cme/Interdisciplinary-Management-of-Gynecologic-Cancers/39286/ This series features interdisciplinary discussions on the evolving management of cervical and endometrial cancers, emphasizing biomarker-driven decision-making and personalized care. Experts examine screening, biomarker testing, clinical trial evidence, and the integration of immunotherapy into guideline-driven treatment regimens, highlighting the clinical implications of PD-L1 expression. Case-based dialogues highlight diagnostic approaches, treatment planning, and toxicity management across disease stages. The program underscores the importance of coordinated care involving oncologists, nurse practitioners, and pathologists to optimize outcomes.

CME credits: 1.00 Valid until: 31-10-2026 Claim your CME credit at https://reachmd.com/programs/cme/Screening-for-Cervical-Cancer/39290/ This series features interdisciplinary discussions on the evolving management of cervical and endometrial cancers, emphasizing biomarker-driven decision-making and personalized care. Experts examine screening, biomarker testing, clinical trial evidence, and the integration of immunotherapy into guideline-driven treatment regimens, highlighting the clinical implications of PD-L1 expression. Case-based dialogues highlight diagnostic approaches, treatment planning, and toxicity management across disease stages. The program underscores the importance of coordinated care involving oncologists, nurse practitioners, and pathologists to optimize outcomes.

Live from Berlin, Germany, Dr. Aly-Khan Lalani and Dr. Christopher Wallis review ESMO 2025's bladder cancer headlines, from the evolving role of PD-1/PD-L1 inhibitors to ctDNA-guided adjuvant therapy and antibody-drug conjugates redefining metastatic management.The View on GU with Lalani & Wallis integrates key clinical data from major conferences and high impact publications, sharing meaningful take home messages for practising clinicians in the field of genitourinary (GU) cancers. Learn more about The View on GU: theviewongu.caThis podcast has been made possible through unrestricted financial support by Novartis, Bayer, Astellas, Tolmar, Ipsen, J&J, Merck, Pfizer, Eisai and AbbVie.

TWiV explains studies showing that SARS-CoV-2 mRNA vaccines improve life span of cancer patients on checkpoint immunotherapy, and broad immunity conferred by a vaccine central in A(H5) influenza antigenic space. Hosts: Vincent Racaniello, Alan Dove, Rich Condit, and Kathy Spindler Subscribe (free): Apple Podcasts, RSS, email Become a patron of TWiV! Links for this episode Support science education at MicrobeTV Immune 100 live at the Incubator SARS-CoV-2 mRNA vaccines sensitize tumors to checkpoint immunotherapy (Nature) People with some cancers live longer after mRNA vaccines (Nature) Immune checkpoint inhibitors (NCI) Broad immunity from influenza H5 vaccine (Nature) Derek Smith on antigenic cartography (TWiV 99 at 2:53) Letters read on TWiV 1265 Timestamps by Jolene Ramsey. Thanks! Weekly Picks Kathy – Permethrin-treated baby wraps for malaria prevention and Phil Sharp and the Biotech Revolution Rich – Lydia Fairchild; Tetragametic Chimerism (NEJM) Alan – Warning Signs Vincent – radio.garden thanks to Kim! Listener Pick Jamie – SkyCards by Flightradar24 Intro music is by Ronald Jenkees Send your virology questions and comments to twiv@microbe.tv Content in this podcast should not be construed as medical advice.

Two Onc Docs, hosted by Samantha A. Armstrong, MD, and Karine Tawagi, MD, is a podcast dedicated to providing current and future oncologists and hematologists with the knowledge they need to ace their boards and deliver quality patient care. Dr Armstrong is a hematologist/oncologist and assistant professor of clinical medicine at Indiana University Health in Indianapolis. Dr Tawagi is a hematologist/oncologist and assistant professor of clinical medicine at the University of Illinois in Chicago. In this episode, OncLive On Air® partnered with Two Onc Docs to feature a comprehensive review of the current management of metastatic breast cancer, emphasizing evidence-based treatment strategies across molecular subtypes, toxicity management, and patient-centered care. Drs Armstrong and Tawagi discussed that the primary goals of metastatic breast cancer therapy include prolonging survival, controlling symptoms, minimizing toxicity, improving quality of life, and incorporating patients' goals and preferences into care decisions. Their discussion also highlighted the importance of recognizing when transitioning to best supportive care is most appropriate. For estrogen receptor–positive metastatic breast cancer, they noted that first-line therapy includes an aromatase inhibitor or fulvestrant (Faslodex) combined with a CDK4/6 inhibitor, with ovarian function suppression for premenopausal patients. PARP inhibitors are recommended for patients with BRCA1/2-positive disease. In visceral crisis, chemotherapy remains the category 1 recommendation. Second-line treatment options include therapies guided by repeat molecular testing. fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) is approved for patients with HER2-low disease. For HER2-positive metastatic breast cancer, first-line treatment consists of a taxane plus pertuzumab (Perjeta) and trastuzumab (Herceptin), followed by T-DXd in the second-line setting. For triple-negative metastatic breast cancer, therapy depends on PD-L1 status. The episode concluded by underscoring the role of bone-protective agents such as zoledronic acid, pamidronate, or denosumab (with dental clearance to prevent osteonecrosis). Key takeaways emphasize tailoring therapy to molecular subtype, recognizing drug-specific toxicities, and prioritizing patient-centered decision-making in the management of metastatic breast cancer.

Good morning from Pharma Daily: the podcast that brings you the most important developments in the pharmaceutical and biotech world. Today, we'll delve into a series of remarkable advancements and strategic movements shaping the landscape of healthcare. Let's start with a recent spotlight on the European Society for Medical Oncology Congress 2025, where key clinical trial outcomes have emerged, potentially reshaping future treatment protocols.AstraZeneca made waves with its Phase 3 trial results for Imfinzi, a PD-L1 inhibitor, in high-risk non-muscle invasive bladder cancer. The findings suggest that Imfinzi stands strong against Pfizer's PD-1 candidate, Sasanlimab. This is particularly noteworthy as bladder cancer has historically had limited non-invasive treatment options. The implications for patient care are substantial, providing hope for improved management of this form of cancer and possibly influencing treatment standards.Meanwhile, Eli Lilly's Verzenio marked another success at the ESMO Congress with its overall survival win in early breast cancer cases. This victory enhances Verzenio's standing within the CDK4/6 inhibitor class, suggesting increased adoption in clinical settings. The demonstration of extended survival benefits not only strengthens Verzenio's competitive position but also contributes to setting a new standard of care in early breast cancer treatment.On the regulatory front, Sanofi encountered mixed outcomes from the European Medicines Agency's Committee for Medicinal Products for Human Use. While Rezurock was not recommended as a third-line treatment for chronic graft-versus-host disease, this decision underscores the stringent regulatory processes companies navigate despite existing market success in other regions like the U.S.In a significant move by the FDA to expedite drug approvals, nine companies including Merck KGaA and Regeneron received priority review vouchers. These vouchers allow a shortened review timeline, reflecting an ongoing trend towards accelerating drug availability to address unmet medical needs swiftly.In terms of strategic developments, EMD Serono—Merck KGaA's U.S. branch—has unveiled a major discount initiative for its IVF treatments on the TrumpRx platform. This aligns with broader efforts to make fertility treatments more accessible amidst rising demand and economic pressures.The metabolic dysfunction-associated steatohepatitis (MASH) arena is also witnessing robust interest with over $10 billion recently reported in mergers and acquisitions. This surge indicates confidence among Big Pharma players in MASH as a lucrative therapeutic field ripe for innovation and development.In response to competitive pressures and operational challenges, Kezar Life Sciences is preparing for layoffs following the FDA's decision to cancel a critical meeting related to its R&D program. This situation illustrates the volatile dynamics within biotech firms where regulatory decisions can significantly impact corporate strategies and workforce stability.Overall, these developments reflect an industry characterized by rapid innovation, strategic realignments, and an evolving regulatory framework. The implications for patient care are substantial as these scientific advancements promise enhanced treatment options across various therapeutic areas.Switching gears to scientific developments, Bristol Myers Squibb has reported promising results from early-stage trials of its EGFRxHER3 antibody-drug conjugate. Demonstrating a 55% overall response rate, this positions BMS to potentially gain a competitive edge in the ADC market—a sector valued for targeting cancer cells while minimizing side effects on healthy tissues.Strategic partnerships continue to shape industry growth and innovation. Roche has secured a deal with Hansoh Pharmaceutical worth up to $1.45 billion for global rights to an experimental ADC outside Greater China. SimilSupport the show

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      

In this JCO Precision Oncology Article Insights episode, Dr. Jiasen He summarizes JCO PO article "Synthetic Lethal Co-Mutations in DNA Damage Response Pathways Predict Response to Immunotherapy in Pan-Cancer" by Hua Zhong et al. TRANSCRIPT Jiasen He: Hello and welcome to the JCO Precision Oncology Article Insights. I am your host, Jiasen He, and today we will be discussing the JCO Precision Oncology article, "Synthetic Lethal Co-mutations in DNA Damage Response Pathway Predict Response to Immunotherapy in Pan-Cancer" by Dr. Zhang and colleagues. Immunotherapy has emerged as a groundbreaking treatment option for many types of cancer. However, the overall response rate to immunotherapy is low, around 10% to 30%. This highlights the critical need to identify which patients are most likely to benefit from immunotherapy. Two of the most extensively studied biomarkers are PD-L1 expression and tumor mutation burden (TMB). High levels of PD-L1 and TMB have been associated with better response to immune checkpoint inhibitors, which are now widely used in clinical practice. The predictive value of these markers is inconsistent across all settings. Some tumors with high PD-L1 or TMB still respond poorly to immunotherapy. One reason is that TMB reflects new antigen production, but recent studies suggest that new antigen levels do not always correlate with tumor immunogenicity. Many new antigens are not effectively recognized by T cells, limiting the immune response. Emerging evidence indicates that mutations in the DNA damage response (DDR) pathway play a critical role in moderating tumor immune interactions. Tumors harboring DDR pathways frequently exhibit increased genome instability, which may enhance their sensitivity to immune checkpoint inhibitors. While all these pathways are under active investigation, the optimal DDR pathway biomarkers for patient selection remain unclear. Notably, tumor cells with a defect in one DDR pathway may acquire greater reliance on alternative DDR pathways. Recent studies suggest that synthetic lethal co-mutations within DDR pathways are associated with immune-inflamed or hot tumor microenvironments. Based on this rationale, Dr. Zhang is investigating if synthetic lethal co-mutations in DDR pathway response pathway can serve as a treatment biomarker for immune checkpoint inhibitors. To address this question, Dr. Zhang and colleagues first utilized SynLethDB 2.0, a comprehensive database that integrated multiple data sets. Synthetic lethal (SL) gene pairs in this resource are identified through both experimental and computational approaches, with confidence scores assigned to each pair. These SL pairs were then mapped to gene sequencing results from several clinical cohorts. SL co-mutation status was defined as positive when both genes in a synthetic lethal pair were mutated. From this, SL co-mutation pairs specifically involving DDR pathway genes were selected. Patients were classified as DDR co-mutation positive if both genes in a synthetic lethal pair, each belonging to the defined DDR pathways, were mutated. In total, 431 DDR-related SL pairs were identified and matched to sequencing data from clinical cohorts. Clinical information was extracted from the cBioPortal, while further analysis of immune infiltration was performed using DNA mutation and RNA expression data from The Cancer Genome Atlas (TCGA) pan-cancer data set. The author first examined the correlation between SL co-mutation status and response to ICI therapy. They discovered that patients with SL co-mutation showed significantly improved outcome to ICI therapy across various clinical cohorts. Notably, in patients who did not receive ICI treatment, patients with SL co-mutation showed markedly compromised overall survival. Further analysis focused on the predictive value of SL co-mutation within DDR pathway genes. The author found that patients with DDR SL co-mutation had a longer overall survival compared to those with mutations in a single DDR gene, implying that SL co-mutations may be more effective biomarkers within the DDR pathway. To explore this further, in the TMB-MSKCC cohort, the author found that patients with DDR co-mutation constituted approximately 20% of various cancer types, including non-small cell lung cancer, melanoma, and bladder cancer. These patients demonstrated significantly better survival outcomes and disease control rates when treated with ICIs compared to DDR co-mutation negative patients. Notably, the TMB level was substantially higher in patients with DDR co-mutation, a finding consistent with data from the Miao-lung cohort. Furthermore, in cohorts not treated with ICIs, patients with DDR co-mutation had a shorter overall survival compared to their counterparts. Upon stratifying by PD-L1 expression, the author observed that patients with DDR co-mutation who were also PD-L1 positive derived the greatest clinical benefit from ICI therapy. Upon analyzing the frequency of co-mutation within the DDR pathway, the authors found that patients with SL co-mutation in the CPF-CPF pathway experienced remarkable survival benefit from ICIs. Within this group, one of the most common co-mutation combinations was TP53-ATM, observed in approximately 45% of cases, which was associated with a better response to ICI therapy. Further analysis of immune cell infiltration revealed that patients with TP53-ATM co-mutation exhibited a distinct tumor immune microenvironment. As the authors stated, the study's main limitation lies in the nature of retrospective analysis, which lacked the control over confounding variables and was subject to non-random sampling. For instance, patients with both SL co-mutations and DDR SL co-mutations exhibited high TMB, and TMB was known to be associated with improved response to ICI therapy itself. So, these findings require validation through prospective studies, and immune infiltration analysis needs confirmation via laboratory experiments. In conclusion, the authors found that patients with SL co-mutations in DDR pathways showed favorable clinical response and prolonged survival following ICI therapy. They also identified TP53-ATM co-mutations as a clinically relevant biomarker for predicting ICI treatment response. Thank you for tuning in to JCO Precision Oncology Article Insights. Don't forget to subscribe and join us next time as we explore more groundbreaking research shaping the future of oncology. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.   Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  

In this new installment of Tea with Dr D, host James Q. Del Rosso, DO, is joined by Karan Lal, DO, to examine 3 complex cases where clinical reasoning required moving beyond conventional pathways. This episode features visually impactful case images that bring the discussion to life. The first case centers on an elderly patient on PD-L1 immunotherapy who developed erosive plaques on the head and neck. Dr Lal reviews the diagnostic challenges of atypical presentations, the limitations of standard treatments, and his decision to carefully introduce a JAK inhibitor with oncology support, illustrating the importance of balancing risks and benefits in drug-induced BP. Next, they consider a young adult male with diffuse hair loss. A biopsy confirmed androgenetic alopecia without inflammation, prompting Dr Lal to initiate low-dose oral minoxidil with finasteride. He details why combination therapy can be advantageous in younger patients, the need for counseling about shedding phases and time to response, and how to interpret prostate screening in those taking finasteride. The final case highlights a dramatic case of rhinophyma presenting as fibrotic nodules without classic inflammatory features of rosacea. Dr Lal explains his staged management of surgical debulking followed by laser resurfacing, along with the role of isotretinoin for long-term maintenance. For patients unable to pursue surgical options, he shares alternative approaches such as combining isotretinoin with neuromodulators to shrink tissue and improve appearance. Tune in to the full episode to see striking clinical images, learn how expert dermatologists navigate diagnostic uncertainty, and gain insight into creative, patient-centered strategies for challenging presentations.

Please visit answersincme.com/860/MED-ONC-03349-replay to participate, download slides and supporting materials, complete the post test, and obtain credit. In this activity, experts discuss how the latest data for first-line immunotherapy-based regimens informs personalized approaches for advanced NSCLC and how to elevate care through patient advocate–centered approaches. Upon completion of this activity, participants should be better able to: Differentiate the clinical profiles of NCCN-preferred first-line immunotherapy-based regimens for advanced NSCLC based on the latest data for disease with no actionable mutations and PD-L1 expression 50% or greater; Identify how first-line treatment selection varies for different patient subpopulations with advanced NSCLC with no actionable mutations and PD-L1 expression 50% or greater; and Apply patient-centered strategies to optimize the integration of immunotherapy-based regimens into first-line treatment plans of patients with advanced NSCLC with no actionable mutations and PD-L1 expression 50% or greater.

Featuring an interview with Prof Peter Schmid, including the following topics: Response to immunotherapy in breast cancer subtypes (0:00) Tolerability of TROP2 antibody-drug conjugates (ADCs) for metastatic breast cancer (mBC) (3:51) Approaches to therapy for patients with HR-negative HER2-low and HER2-ultralow mBC (13:03) ADC structure and treatment-related adverse events (19:02) Available data from the Phase III ASCENT-04 trial evaluating sacituzumab govitecan with pembrolizumab as first-line therapy for patients with PD-L1-positive advanced triple-negative breast cancer (23:06) Novel ADCs and bispecific antibodies under investigation for mBC (28:30) Comparing datopotamab deruxtecan and sacituzumab govitecan for HR-positive disease (33:01) Clinical investigator perspectives on the Phase III DESTINY-Breast09 trial evaluating first-line trastuzumab deruxtecan with or without pertuzumab versus THP (docetaxel/rastuzumab/pertuzumab) for HER2-positive mBC (35:06) CME information and select publications

Featuring a slide presentation and related discussion from Prof Peter Schmid, including the following topics: Evolution of the therapeutic landscape for metastatic triple-negative breast cancer; age of immunotherapy (0:00) Case: A woman in her early 40s with no actionable mutations (7:29) Evolution of antibody-drug conjugates (ADCs) in the management of metastatic breast cancer (11:13) TROP2-directed ADCs (15:22) Case: A woman in her early 50s with PD-L1-negative, HR-negative, HER2-low de novo metastatic breast cancer (20:21) Novel strategies utilizing approved and investigational ADCs (23:28) Case: A woman in her early 60s with loss of HER2 expression on disease progression (31:39) ADCs in combination with immunotherapy (32:51) CME information and select publications

Featuring perspectives from Dr Ana C Garrido-Castro and Prof Peter Schmid, including the following topics:  Introduction: Legendary Figures in Breast Cancer Research (0:00) Case: A woman in her early 80s, a current smoker with a history of myocardial infarction and stroke, who develops recurrent triple-negative breast cancer (TNBC) — Justin Favaro, MD, PhD (6:44) Case: A woman in her late 60s with metastatic TNBC and a PD-L1 level of 20% who receives chemotherapy/pembrolizumab followed by sacituzumab govitecan — Priya Rudolph, MD, PhD (25:08) Case: A woman in her late 60s with localized TNBC who develops myocarditis while receiving neoadjuvant chemotherapy/pembrolizumab — Richard Zelkowitz, MD (33:53) Case: A woman in her mid 60s with recurrent ER-negative, HER2-low, PI3K-mutant TNBC — Ranju Gupta, MD (37:49) Case: A woman in her early 60s with recurrent TNBC confined to contralateral neck nodes — Eric H Lee, MD, PhD (42:10) Case: A woman in her early 40s with metastatic TNBC who receives sacituzumab govitecan after multiple lines of chemotherapy — Estelamari Rodriguez, MD, MPH (48:10) Case: A woman in her mid 70s with ER-negative, HER2-low breast cancer who develops an isolated brain metastasis — Dr Gupta (55:02) CME information and select publications

Immune discusses how cancer cells swap mitochondria with T cells and then digs in for a discussion of an unusual checkpoint blockade that failed for cancer but could be repurposed for autoimmune inflammation. Hosts: Vincent Racaniello, Cindy Leifer, Steph Langel, and Brianne Barker Subscribe (free): Apple Podcasts, RSS, email Become a patron of Immune! Links for this episode MicrobeTV Discord Server Cancer cells steal mitochondria from neurons for metastasis (Nature 2025) Cancer cells donate damaged mitochondria to T cells to impair them (Nature 2025) PD-L1 binding to CD80 on the same dendritic cell needed for migration (Sci Adv 2025) Time stamps by Jolene Ramsey. Thanks! Music by Tatami. Immune logo image by Blausen Medical Send your immunology questions and comments to immune@microbe.tv Information on this podcast should not be construed as medical advice.

“We're really using these in many, many types of malignancies. But you can see this class of drug, these monoclonal antibodies, the small molecule inhibitors, being used in colorectal cancer, ovarian cancer, renal cell carcinoma, brain cancers, hepatocellular, non-small cell lung cancer, gynecologic malignancies, so lots of different types of cancers where we're seeing these drugs used,” Danielle Roman, PharmD, BCOP, manager of clinical pharmacy services at the Allegheny Health Network Cancer Institute in Pittsburgh, PA, told Jaime Weimer, MSN, RN, AGCNS-BS, AOCNS®, manager of oncology nursing practice at ONS, during a conversation about the vascular endothelial growth factor (VEGF) inhibitor drug class. 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 August 8, 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: Learner will report an increase in knowledge related to the use of VEGF inhibitors in the treatment of cancer. Episode Notes  Complete this evaluation for free NCPD.  ONS Podcast™ episodes: Pharmacology 101 series Episode 303: Cancer Symptom Management Basics: Ocular Toxicities Episode 244: Cancer Symptom Management Basics: Cardiovascular Complications Episode 196: Oncologic Emergencies 101: Bleeding and Thrombosis Episode 161: Administer Bevacizumab Infusions With Confidence ONS Voice articles: Manage Afatinib's Adverse Events to Keep Patients on Treatment Oncology Drug Reference Sheet: Cabozantinib Oncology Drug Reference Sheet: Fruquintinib Patient Education Needs With Pazopanib Therapy for Soft Tissue Sarcoma ONS books: Chemotherapy and Immunotherapy Guidelines and Recommendations for Practice (second edition) Clinical Guide to Antineoplastic Therapy: A Chemotherapy Handbook (fourth edition) Safe Handling of Hazardous Drugs (fourth edition) ONS courses: Safe Handling Basics Clinical Journal of Oncology Nursing article: Safety and Adverse Event Management of VEGFR-TKIs in Patients With Metastatic Renal Cell Carcinoma Oral Anticancer Medication Care Compass: Resources for Interprofessional Navigation ONS Oral Anticancer Medication Learning Library ONS Oral Anticancer Medication Toolkit IV Cancer Treatment Education Sheets Oral Chemotherapy Education Sheets 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 “Cancer cells are known to secrete factors that cause the formation of new blood vessels, and tumors need blood vessels to supply themselves with nutrients so that they can grow and metastasize. A lot of tumors overexpress these factors, so they had more of this ability to create new blood vessels. You may hear that term somewhere neo vascularization. … And also these factors can increase the permeability of blood vessels, so making them kind of leaky blood vessels. … So the thought behind it is being able to block the ability for this new blood vessel formation and to decrease that leakiness or permeability of those blood vessels.” TS 2:07 “These are drugs that are tyrosine kinase inhibitors. These are oral, small molecule drugs that are acting intracellular, so they are working within the cell to bind and prevent that downstream signaling of producing more blood vessels. So we have a number of small molecule drugs that fall into this class. Many of them target multiple types of receptors, VEGF being included, but also a lot of these drugs have other targets.” TS 7:58 “I would really say, number one, something that we very commonly see with this drug class is hypertension. Giving you an example of bevacizumab—If we look at any grade hypertension, this can be up to 67% of patients, so very common toxicity really spanning all of these agents. So something that we need to be monitoring closely for.” TS 13:24 “With that impaired wound healing, keeping that in mind, as we are planning for this agent, for patients and even sometimes with the minor surgical procedures, maybe a need for a short hold, and even for something like a catheter placement. I know and some of the providers I work with have a preference for holding for a short period of time around that as well.” TS 20:15 “I think one big area, and we've seen some of this just recently, and particularly in the hepatocellular setting, we're seeing combinations of using the VEGF inhibitor class with immunotherapy. And so I think we're going to continue to see that evolve. Even hearing about some bispecific antibodies that are in development, where they are targeting VEGF as well as PD-L1, so getting the immunotherapy and VEGF effects.” TS 24:44

Featuring an interview with Dr Erika Hamilton, including the following topics: Optimal selection and sequencing of available antibody-drug conjugates for HR-positive metastatic breast cancer (0:00) Bardia A et al. Datopotamab deruxtecan versus chemotherapy in previously treated inoperable/metastatic hormone receptor-positive human epidermal growth factor receptor 2-negative breast cancer: Primary results from TROPION-Breast01. J Clin Oncol 2025;43(3):285-96. Abstract  Pistilli B et al. Datopotamab deruxtecan (Dato-DXd) vs chemotherapy in previously-treated inoperable or metastatic hormone receptor-positive, HER2-negative breast cancer: Final overall survival from the Phase III TROPION-Breast01 trial. ESMO Virtual Plenary 2025;Abstract VP1-2025. First-line use of sacituzumab govitecan in combination with pembrolizumab for advanced triple-negative breast cancer (8:02) Tolaney SM et al. Sacituzumab govitecan (SG) + pembrolizumab (pembro) vs chemotherapy (chemo) + pembro in previously untreated PD-L1–positive advanced triple-negative breast cancer (TNBC): Primary results from the randomized phase 3 ASCENT-04/KEYNOTE-D19 study. ASCO 2025;Abstract LBA109. Ongoing trials evaluating datopotamab deruxtecan in earlier lines of therapy (12:06) Dent RA et al. TROPION-Breast02: Datopotamab deruxtecan for locally recurrent inoperable or metastatic triple-negative breast cancer. Future Oncol 2023;19(35):2349-59. Abstract McArthur HL et al. TROPION-Breast04: A randomized phase III study of neoadjuvant datopotamab deruxtecan (Dato-DXd) plus durvalumab followed by adjuvant durvalumab versus standard of care in patients with treatment-naïve early-stage triple negative or HR-low/HER2- breast cancer. Ther Adv Med Oncol 2025;17:17588359251316176. Abstract Bardia A et al. TROPION-Breast03: A randomized phase III global trial of datopotamab deruxtecan ± durvalumab in patients with triple-negative breast cancer and residual invasive disease at surgical resection after neoadjuvant therapy. Ther Adv Med Oncol 2024;16:17588359241248336. Abstract Schmid P et al. TROPION-Breast05: A randomized phase III study of Dato-DXd with or without durvalumab versus chemotherapy plus pembrolizumab in patients with PD-L1-high locally recurrent inoperable or metastatic triple-negative breast cancer. Ther Adv Med Oncol 2025;17:17588359251327992. Abstract Available data with and ongoing trials of sacituzumab tirumotecan for HR-positive, HER2-negative and triple-negative breast cancer (16:53) Yin Y et al. Sacituzumab tirumotecan (sac-TMT) as first-line treatment for unresectable locally advanced/metastatic triple-negative breast cancer (a/mTNBC): Initial results from the phase II OptiTROP-Breast05 study. ASCO 2025;Abstract 1019. Xu B et al. Sacituzumab tirumotecan in patients with previously treated locally recurrent or metastatic triple-negative breast cancer (TNBC): Results from the Phase III Opti-TROP-Breast01 study. ASCO 2024;Abstract 104. Yin Y et al. Sacituzumab tirumotecan in previously treated metastatic triple-negative breast cancer: A randomized phase 3 trial. Nat Med 2025;31(6):1969-1975. Abstract Garrido-Castro AC et al. SACI-IO HR+: A randomized phase II trial of sacituzumab govitecan with or without pembrolizumab in patients with metastatic HR+/HER2-negative breast cancer. ASCO 2024;Abstract LBA1004. CME information and select publications