Treatment Landscape in Gastric Cancers Pre-ESMO 2020



Johanna Bendell, MD: Yesterday at European Society for Medical Oncology, they tried to figure out howwe’re going to approach treating these patients, so maybe we start with where we are before yesterday or where we were before yesterday in terms of how we would approach the treatment of an advanced metastatic gastric cancer patients, and we’ll also talk about esophageal and gastroesophageal [GE]- junction adenocarcinoma. Dan, can you set the stage for us on where we were just 48 hours ago?

Daniel Catenacci, MD: Forty-eight hours ago, from an immunotherapy standpoint, we had a number of studies that were monotherapy checkpoint inhibitor with nivolumab, pembrolizumab [PEMBRO], and others like nivolumab [NIVO].

We had only 1 study with in combination with chemotherapy. Briefly, to just set the stage of the background, we had the ATTRACTION-2 study (NCT02267343), which was a third-line study of nivolumab versus placebo in Asian patients that was positive and led to approval in all-comers, not elsewhere outside of Asia. One way I check is the KEYNOTE-059 study (NCT02335411), which was a single-arm study, third line and higher. That study showed benefit and enriched for PD-L1 status by combined positivity score of 1 or higher with pembrolizumab, and it was led to an accelerated approval for patients in the United States in the third-line setting or higher with combined positive score of 1 or higher.

We also had a pan-solid tumor approval in the United States based on microsatellite instability [MSI]-high in the second-line setting for this disease. That was the status in the United States 48 hours ago based on the gastric and GE-junction cancers. In Europe, Ian can say that none of these led to approvals based on that.

The other thing to mention is moving it into earlier lines of treatment. In the second-line setting, we had the KEYNOTE-061 (NCT02370498) study which was pembrolizumab versus paclitaxel. Overall, it was a negative study but showed some promise and certainly higher PD-L1, CPS 10 or higher, not leading to any approvals.

Then we had the KEYNOTE-062 (NCT02494583) study which was the first-line study, a 3-arm study of chemotherapy with or without pembrolizumab, placebo-controlled, and an open-label third on the PEMBRO alone. The PEMBRO-alone arm was again showing some signs and high PD-L1 scores; PD-L1 CPS 10 or higher, but there was still sort of a detriment in a subgroup of those patients. Overall, the claim was noninferiority, and there was a group of patients not benefiting. The chemotherapy arm showed a trend to improvement with PEMBRO, but with a hazard ratio of 0.85; this was not statistically significant and was considered negative.

Then we have the esophageal part of this story which the studies that are pertinent are the KEYNOTE-181 study (NCT02564263), which allowed squamous cell and adenocarcinoma and that was comparing PEMBRO versus taxane. The study was looking at a number of primary end points, but overall led to approvals in the United States only for squamous cell cancers that were CPS 10 or higher. When you looked at the forest plots of that study, that’s where the benefit was being driven from. The other ones were really not driving much benefit. That’s what led to the approval.

Shortly thereafter, the ATTRACTION-3 study (NCT02569242), which was a 95% Asian study in all-comers, showed benefit with nivolumab versus chemotherapy, and led to approvals in Asia and in the United States for NIVO in the second line for esophagus cancer.That’s where we are as of 2 days ago. Then we’ll talk about how that might change.

Ian Chau, MD: If I may add and highlight 1 point about getting approvals in Asia and United States and not in Europe; it actually leads to a very important point about why some of these studies that we are about to discuss is of great importance in global studies. Europe would not accept studies which included a patient population with a vast majority being Asians. They still feel within the European Union countries that they, there are practical variations, maybe different treatment patterns. Therefore they would not approve, would not give the drug approval, on studies which are predominant based in Asia or nonrandomized studies. I think it really gives importance of the study that we are, in the past 24 hours, are really, truly global studies, and how that hopefully will change practice globally.

Johanna Bendell, MD: It is interesting because I think we’re going to break this down, too. As Dan was alluding to, the squamous population, certainly potentially driving studies that are not only global in geography but also global in the types of tumors that they’re accepted in histology that it accepts, I think we’re going to definitely break that down. I think, Ken, I would love to hear your perspective from Japan in terms of how you are approaching the treatments of these patients in Japan and utilization of checkpoint inhibitors.

Ken Kato, MD, PhD: Yeah. As Daniel mentioned, the immune checkpoint inhibitor is already approved for the second-line and the third-line patient for the gastric cancer. Of course, it had squamous cell carcinoma patient with it being very dominant in Asian countries, but recently the first-line treatment was studied in a phase 3 study for the esophageal cancer. The study included many patients, but they’re not from the European countries.

The phase 3 trial should be held globally, and of course maybe the same histology type, the same results. Global studies should be done, not only Asian trials.

Daniel Catenacci, MD: I’ll just summarize my thoughts based on these studies that were previously, before yesterday, just coming into this and how I was thinking about it. The monotherapy checkpoint inhibitor in all of these studies seemed to be optimized with a higher PD-L1 score, certainly MSI-high. Asian patients tend to do better on the forest plots; squamous cells always tend to do better than adenocarcinoma, and gastric cancers tend to do better than GE junctions and esophageal adenocarcinomas; that’s with monotherapy. That’s sort of what the principles how I would think about in later lines, and even in the first line.

Johanna Bendell, MD: I think that’s a fantastic summary, and I think also it’s going to help us shape how we’re thinking about what happened yesterday.

Transcript Edited for Clarity

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