Yelena Y. Janjigian, MD, on Gastric/GEJ Cancer: Immunotherapy Plus FLOT

The MATTERHORN is a large phase three study and the takeaway point from our study is that addition of durvalumab plus perioperative FLOT improves event-free survival in localized gastric and esophageal adenocarcinoma. 1.2 million people will die of gastroesophageal adenocarcinoma worldwide this year and so we need to do better. We know that addition of chemotherapy plus immunotherapy works in metastatic disease, but whether or not it will help patients with early-stage disease is yet unknown. So that's the question that MATTERHORN was designed to answer. Will adding anti–PD-L1 drug durvalumab in early treatment of non-metastatic disease impact survival after surgery? So patients across the world in over 20 countries including Asia versus non-Asia with gastric and esophageal adenocarcinoma who were non-metastatic and had not had prior therapy were randomized to receive. That overall survival and disease-free survival and pathologic complete response—at ASCO this year we’re presenting the primary endpoint, which is the final analysis for event-free survival, and I am excited to report that we met the primary endpoint. Event-free survival was improved with addition of durvalumab to FLOT. We demonstrated an early and sustained separation in the survival curve. At two years, the improvement in the event-free survival was by 8%—absolute 8%—with hazard ratio of 0.71, translating to 29% reduction in risk of progression or other events, and the p-value was statistically significant and clinically meaningful. The median event-free survival for the experimental arm was not yet reached and so it's still in follow-up. What we also saw is that in each pre-specified key subgroup—by geographic location, by patient age 65 or greater or less, by nodal status, T4 stage, and others—for each pre-specified subgroup, there was a meaningful improvement in EFS. So this was a large global study, really inclusive population of patients. This was a positive study for the first time pretty much in neoadjuvant setting in gastric and esophageal adenocarcinoma. We also showed improvement in pathologic complete response. We saw improvement in, you know, in possibly improvement in overall survival, but that's too early. We still need to follow up—this analysis is not final—but in overall survival, we saw a separation of the survival curves at 12 months, which was then subsequently sustained, and the delta at two years is approximately the same, actually 8% numerically overall survival. But the way that the study was designed, we cannot formally test overall survival at this point. We also worry about toxicity and feasibility of this regimen. The good news is close to 100% of patients received neoadjuvant cycles—no problem. The likelihood that someone will have a complete resection was not impaired. 92% of patients had R0 resection in both groups, and the completion of adjuvant therapy was quite good. In fact, FLOT completion was better than what we saw in historical groups, and 52% of patients—more than half—completed all 12 cycles of immunotherapy. Overall toxicity was related to FLOT, so we saw about 60% grade 3–4 toxicity, and the common toxicities are chemotherapy-related toxicities including neutropenia, nausea, vomiting—so not anything that the doctors are not used to dealing with. And the immune-related grade 3–4 toxicities were rare. It was 7% in the durvalumab group and 4% in the placebo group. So in totality of the data, what we're seeing at ASCO is a practice-changing study. Of course, it was an ASCO plenary, and we see that event-free survival is improved with durvalumab and FLOT, which is practice-changing for us, for our patients. And it's amazing to see—of course, pathologic complete response was improved. There were no new safety signals, nothing surprising that we saw, and the overall survival data is promising, but we need to see further follow-up. And what we're seeing already is that globally this is going to be the new standard, which is exciting to see.