Johanna Bendell, MD: This is a great general first discussion, and we’re lucky to have Ken here as the first author. Maybe what we could do is break this down. Let’s attack esophageal cancer first and make our way down the line. Ken, you presented some incredible data that are going to change how we treat esophageal cancers with checkpoint inhibitors. Can you tell us a little about your trial and what that’s probably going to lead to.
Ken Kato, MD, PhD: According to the results of the KEYNOTE-590 study, this is a comparison of the standard of care of the 5-FU [5-fluorouracil] and cisplatin. The standard of care was not changed for esophageal squamous cell carcinoma and adenocarcinoma.
Indeed, from the results of the KEYNOTE-590 study, the effect of the pembrolizumab through the 5-FU–cisplatin is observed. Of course, the KEYNOTE-590 trial contained a mixed histologic type. Indeed, the CPS [combined positive score] is mixed. The 70% of the squamous cell carcinoma is enrolled to the KEYNOTE-590 study.
The prevalent point of this study is PFS [progression-free survival] and OS [overall survival] for the squamous cell carcinoma and with CPS 10. When the primary end point is shown, they move through the analysis to the patients. The same tendency and efficacy was seen, not only for patients with esophageal squamous cell carcinoma but for all patients, including adenocarcinoma. The standard of care of esophageal cancer is changing to the chemotherapy-nivolumab combination, according to the results of the KEYNOTE-590 trial.
Johanna Bendell, MD: Ian, for esophageal cancer in the West, how do you break that down? Also, we know that there was a population of the patients with esophageal cancer who were included in the nivolumab first-line setting, which we saw yesterday as well. How do you put that together?
Ian Chau, MD: If you think about esophageal cancer, as we heard many times, we really need to separate squamous cell cancer from adenocarcinoma. Certainly, with squamous cell cancer, with KEYNOTE-590, the majority of patients had squamous cell cancer. Chemotherapy plus pembrolizumab should be considered 1 of the new standards. There are other data coming through. Those are the first data that we heard with pembrolizumab. CheckMate 648, which is chemotherapy plus or minus nivolumab with the third-arm nivolumab-ipilimumab—that study has also finished recruitment, and we will hopefully hear the results in the next 12 months. If that is anything to go by, we hope that will also show a positive outcome.
Moving forward with squamous cell cancer, checkpoint inhibitors will be part of the treatment when it’s first line or second line. Obviously, we will need to discuss later how to sequence it. Once we use it first line, what do you do second line? We’ll have a chat about that later.
With adenocarcinoma, I agree with both Yelena Janjigian and Dan. You know, from a molecular point of view, adenocarcinoma of the esophagus and the junction are really the same disease. To be fair, it’s difficult for oncologists to tell the difference: Where does the esophagus stop and the OG [oesophago-gastro] junction start? Gastroenterologists, we say this, but we just need to treat it the same.
To me the CheckMate649 study is the defining trial for what we do in the future. An oxaliplatin-based chemotherapy plus nivolumab to me would be how we should be looking forward, and we still need to discuss the different benefits according to the PD-L1 expression. Certainly, for those who are CPS 5 or more, adenocarcinoma of esophagus junction and gastric stomach origin, we really should use an oxaliplatin-based chemotherapy plus nivolumab. That’s how I would view the data given so far. I still find it very difficult, and I’m very interested to hear my colleagues’ view about the junctional adenocarcinoma, with the really conflicted evidence between KEYNOTE-590 and KEYNOTE-062. There are obviously both of those 2 studies that do include a proportion of esophagogastric junction adenocarcinoma. One you would say is a negative study; the other is a positive study. To me, that is still really a gray area that is quite confusing. That’s why I said before, if in doubt, CheckMate 649 is clearer to me, so I’ll probably use the data to guide my future patient management.
Johanna Bendell, MD: Ian, your vote is we’ve changed the standard of care for squamous, so squamous in the first line will be fluorouracil plus platinum with pembrolizumab. For the adeno esophageal, that’s a little more controversial, probably CPS greater than or equal to 5.
Ian Chau, MD: Yes.
Johanna Bendell, MD: What does the group think?
Daniel Catenacci, MD: I’ll comment on some of this stuff as it pertains to KEYNOTE-590. To me, when you look at the forest plot of that presentation, it looks almost identical to the KEYNOTE-181 breakdown. When you look at it, really what’s driving the outcome is CPS more than 10 and squamous. When you look at CPS less than 10, including squamous and adenocarcinoma, it’s right on the line. I would reiterate what Ian was saying. For me, for squamous that are above 10, chemotherapy, probably folinic acid, fluorouracil, oxaliplatin plus immuno-oncology. For those less than 10, I would like to see the actual data before I bite at that. For adenocarcinoma, I would really like to see the data broken down in the Kaplan-Meier curves to really see the benefits there, if there are any. I suspect that those above 10 are going to be at least trending toward benefit, and I might give them the benefit of the doubt, and that would be very consistent with what CheckMate649 is showing. We’ll talk about the gastric, but the CheckMate649 forest plot also shows that the benefit derived in the GE [gastroesophageal] junction esophagus is much less, and they’re overlapping. When we see the breakdown by expression of PD-L1 and by histology, it’s not surprising what we’re seeing in these studies. It’s exactly as would be expected. The differences are that CheckMate649 is a much larger study, so it has the power to find the differences that are smaller, that are “statistically significant.”
In general, for me, it’s squamous for sure, GE junction esophagus, probably in the higher PD-L1 levels, whether it’s CPS 5 or 10. There are different biomarker assays that we should point out. There are different antibodies. The incidence, for example, of PD-L1 CPS 1 or higher with the 22C3 antibodies is about 60%, but the incidence of CPS 5 or higher by the other antibody that we just saw in CheckMate649 is 60% at 5. They’re clearly different biomarkers giving us different incidences of who’s actually being called positive, and that’s going to add some confusion in how we’re testing our patients and which assay we are going to use. It’s all good news about these studies, but we need to be critical, and look at the subsets. From the perspective of academics, we need to be an advocate for our patients to ensure they’re getting therapy that’s actually helping them.
Transcript Edited for Clarity