Yelena Y. Janjigian, MD: We know the majority of patients will not benefit from anti—PD-1 therapy alone. The gastric tumors, although they are immunogenic and immune visible, are not as visible as some of the other immunogenic tumors such as kidney cancer or melanoma. And therefore, in a majority of our population, we will need combination therapy to really cause a meaningful clinical response. The field is really moving toward using a combination of anti–PD-1 therapy as a backbone, because we know it has activity with combination of anti–CTLA-4 agents like IDO and other immune-targeted agents.

The CheckMate-032 study is the first to look at and publish an anti—PD-1 combination with anti–CTLA-4. This was a basket study looking at multiple solid tumor types, and it actually is in small-cell cancer, that led to FDA approval of a combination of nivolumab with a higher dose of ipilimumab.

Nivolumab 1 and ipilimumab 3 was also the winning combination, at least based on the response rate, in patients with metastatic heavily pretreated gastric cancer. With these patients, over three-quarters of them, 75% of these patients, received 3 or more lines of therapy, and some of them have gotten a fourth line of therapy. What we saw in these heavily pretreated patients, irrespective of PD-L1 status, in PD-L1—positive and negative tumors, was a 26% response rate with combination therapy. In the PD-L1–positive population, although it’s a rare subset, it was only a third of the population. The responses were 40% in the heavily pretreated population.

These responses come at a cost of toxicity. They were grade 3 or 4, so a symptomatic rise in liver function tests, adrenal insufficiency, symptomatic colitis, and other immune related adverse events were substantially higher in the combination group related to the toxicity of ipilimumab. And so, generally, this combination is used mostly only in setting of a clinical trial right now, although we know that the responses are higher. Whether or not it really translates into meaningful survival benefit will need to be determined further.

The CheckMate-649 study is a study that is exploring this combination in the first-line setting. The idea is that by the time we get to the third and fourth-line settings, these patients are quite frail and the combination therapy may not be an appropriate treatment for them. And therefore, in the first-line setting for patients with symptomatic disease who are relatively fit, combination therapy may be the best approach. The CheckMate-649 study is looking at nivolumab/ipilimumab, and it’s randomized to FOLFOX plus nivolumab—so chemotherapy plus nivolumab monotherapy—or FOLFOX as the standard of care to study against others. This is a large randomized study. It is global and is rapidly accruing, and so we are hoping for the readout from it soon. It could potentially change the landscape for this disease.

What about patients with resected but technically curable disease that is at high risk for recurrence? In patients with esophageal and GE juncture tumors, after chemoradiation and surgery, after complete resection, there is no additional therapy that has been shown to be beneficial. We try to give these patients more chemotherapy, and that has not helped. In fact, it’s poorly tolerated after all of the surgery. In regard to using immunotherapy agents early on in high-risk resected disease, these patients generally, if they have lymph node positive metastases, all recur within a year. So, why not try to suppress the metastases or even help the immune system treat it early on? This is a strategy that is also being explored with postoperative nivolumab therapy. That is a trial that’s currently ongoing.

Transcript Edited for Clarity