Spotlight on GI Cancers: Learning From the CheckMate-648 & KEYNOTE-811 Trials

Dr. Pamela Kunz, associate professor of medicine and director of the Center for Gastrointestinal Cancers at the Yale School of Medicine, discusses promising advances in metastatic esophageal squamous cell carcinoma, and HER2-positive metastatic gastric or gastroesophageal junction cancer featured at the 2021 ASCO Annual Meeting.   Transcript:  ASCO Daily News: Welcome to the ASCO Daily News Podcast. I'm Geraldine Carroll, a reporter for the ASCO Daily News. My guest today is Dr. Pamela Kunz, associate professor of medicine in the Division of Oncology at the Yale School of Medicine, where she also serves as the director of the Center for Gastrointestinal Cancers. Dr. Kunz will highlight promising advances in metastatic esophageal squamous cell carcinoma and HER2-positive metastatic gastric or gastroesophageal (GE) junction cancer featured at the 2021 ASCO Annual Meeting. Dr. Kunz has served in a consulting or advisory role for Acrotech Biopharma, Advanced Accelerator Applications, and Ipsen, among other organizations. Her full disclosures and those relating to all episodes of the podcast are available on our transcripts at ASCO.org/podcasts. Dr. Kunz, it's great to have you on the podcast today. Dr. Pamela Kunz: Thank you so much, my pleasure to be here. ASCO Daily News: Let's start with the KEYNOTE-811 study. That's Abstract 4013. This ongoing global study is assessing whether adding pembrolizumab to standard of care improves efficacy for HER2-positive metastatic gastric or GE junction cancer. There's very promising data in this study. What are your takeaways from KEYNOTE-811? Dr. Pamela Kunz: Thank you. I think this was an exciting interim analysis of this study. And as you said, it's really one of our first assessments of adding pembrolizumab plus trastuzumab in the first line setting for treatment of HER2-positive metastatic gastric or GE junction cancer, and I think that's why it's really exciting. We don't have an immuno-oncology (IO) agent approved in the first line setting for HER2-positive disease, so I think we are eagerly awaiting the final results. And Dr. Janjigian presented some early efficacy results of this study. So, just to review for our audience the design of the study, so we know exactly what interim data were presented. This is a study, it's a two-arm study, randomized 1 to 1 of patients with advanced gastric or GE junction adenocarcinoma, no prior therapy, and are HER2-positive. And patients are randomly assigned to receive pembrolizumab plus trastuzumab and fluoropyrimidne or capecitabine/oxaliplatin versus placebo plus trastuzumab and the same chemotherapy backbone. And in this interim analysis, about 260 patients out of the planned a total of 692 were presented. And this was a planned analysis. It was really based on these 260 participants enrolling for about 8--and it was about 8 1/2 months of follow-up. And the authors presented objective response rate. We do not yet have overall survival or progression-free survival, but the objective response rate was quite promising. So in the pembrolizumab containing arm, there was a 74% objective response rate compared to 51% in the placebo arm. And this absolute difference was about 22%. This was statistically significant. And I think other key take-homes--but I know our audience does not have the visuals of the waterfall plot--but suffice it to say that in the pembrolizumab waterfall plot, we had deeper responses, so meaning higher level of objective responses. About 30% of this population had decreases of 80% or more by RECIST criteria. And the duration of response was longer in the pembrolizumab arm compared to the placebo arm, 10.6 months median duration of response compared to 9.5 months in placebo. I think that the adverse events were as one would expect with adding pembrolizumab to this arm--I'm sorry, to this regimen. So I think it's very promising. It did, in fact, lead to accelerated approval of this combination, but we are of course awaiting the primary endpoint. ASCO Daily News: Excellent. Well, let's turn our attention to the CheckMate-648 study. This is LBA 4001. This is the first global phase III study to evaluate both a chemoimmunotherapy combination and an immunotherapy combination in advanced esophageal squamous cell carcinoma. Can you tell us about potential new treatment options to emerge from this study? Dr. Pamela Kunz: Sure. I think this study, similarly, is really important because it's the first immunotherapy in the first line setting for squamous cell carcinoma. We had already nivolumab and pembrolizumab approved in the second line setting, but no IO agent in the first line setting. So, this study was a three-arm study to evaluate, as you'd mentioned before, first line squamous cell carcinoma that's advanced or metastatic. And the arms are as follows. So, it was nivolumab plus chemotherapy, versus nivolumab plus ipilimumab, versus chemotherapy. And the chemotherapy was a fluorouracil plus cisplatin backbone. Over 900 patients were enrolled to this phase III study. The randomization was 1 to 1 to 1. And statistically, the comparison, the way the study team designed the study, was to compare nivolumab plus chemotherapy versus chemotherapy and nivolumab plus ipilimumab versus chemotherapy. And so this was--the analysis was conducted in that manner. I think it's also important to note that PD-L1 status was collected and was balanced between the arms, as were other standard baseline characteristics. So, when we're looking at the data, I'll first just describe the nivolumab plus chemotherapy versus chemotherapy. And perhaps, maybe, we'll just take a big kind of 30,000-foot view of what these results say. So really, what were the take-home is that both ipilimumab and nivolumab and nivolumab plus chemotherapy were better than chemotherapy alone. So, I think that what we will see is that--I'm hopeful--these are not U.S. Food and Drug Administration approved yet. But I think that in a large phase III study, we're hopeful to see these become available for the first-line treatment for advanced squamous cell carcinoma. So we saw an improvement in overall survival of nivolumab plus chemotherapy versus chemotherapy alone. This was seen in both the PD-L1 greater than or equal to 1% and all patients, regardless of PD-L1 status. And in terms of the overall survival (OS) difference, the median OS for nivolumab plus chemotherapy was 15.4 months versus 9.1 for chemotherapy alone. This was a hazard ratio of 0.54, so a very clinically significant difference. And we also saw a statistically significant and clinically significant difference for all randomized patients, regardless of their PD-L1 status. So that's overall survival with the nivolumab plus chemotherapy. We also saw a benefit in terms of progression-free survival for that same arm, so the nivolumab plus chemotherapy arm. And then moving to the nivolumab plus ipilimumab arm.  And I want to just comment that I think it's really important for our patients to have a chemo-free option. Some of these patients are quite sick. The cytotoxic chemotherapy can have a different set of side effects compared to our immunotherapy agents. And I think it's important to be able to tailor these treatments to the patient that you see in front of you. So, some patients may better tolerate cytotoxic chemotherapy, and some may better tolerate IO. So, I think that that's important. So, this nivolumab plus ipilimumab also showed a statistically significant difference in median overall survival. So, the median OS for the nivolumab/ipilimumab arm was 13.7 months compared to chemotherapy alone of 9.1 months, with a hazard ratio of 0.64. And we also saw a difference for all randomly assigned patients, regardless of their PD-L1 status. So, the difference, really, for both of the IO containing arms was higher for the PD-L1 greater than or equal to 1%, but the benefit was maintained regardless of the PD-L1 status. Similarly, progression-free survival, we saw a benefit compared of nivolumab plus ipilimumab versus chemotherapy alone. So, I think we are hopeful to see an ability to use this for our patients in the first line setting. I think what's really remarkable is that in the last, really, three to four months, we have seen an explosion of U.S. Food and Drug Administration approvals and phase III results for esophageal, GE junction, and gastric cancers with IO. So, it's exciting. It's frankly hard to keep track of. ASCO Daily News: Absolutely. Dr. Kunz, thanks very much for joining us today to highlight these key abstracts in the gastrointestinal cancer field. Dr. Pamela Kunz: Thank you so much. ASCO Daily News: Well, before we go, I'd like to tell our listeners about an upcoming episode of the podcast that will feature another interesting discussion with Dr. Kunz. She'll tell us about an interesting session from the ASCO Annual Meeting that looked at ways to dismantle gender disparities in the global oncology workforce. Dr. Kunz will also tell us about a new study on sexual harassment of oncologists. And finally, thank you to our listeners for joining us today. If you enjoyed this episode, please take a moment to rate, review, and subscribe wherever you get your podcasts.   Disclosures: Dr. Pamela Kunz Stock and Other Ownership Interests: Guardant Health Consulting or Advisory Role: Ipsen, Lexicon, SunPharma, Acrotech Biopharma, Novartis (Advanced Accelerator Applications) Research Funding (institution): Lexicon, Ipsen, Xencor, Brahms (Thermo Fisher Scientific), Novartis (Advanced Accelerator Applications) 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. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.