Pembrolizumab Demonstrates Potential of Immunotherapy in Gastric Cancer

Yung-Jue Bang, MD, PhD

Pembrolizumab (Keytruda) showed promising antitumor activity in patients with metastatic gastric cancer, according to updated findings from the recent KEYNOTE-012 trial.

The anti—PD-1 monoclonal antibody was investigated as part of the gastric cancer cohort of KEYNOTE-012, which included 39 patients whose tumors expressed PD-L1.

The study is ongoing, and participants in the cohort are receiving IV pembrolizumab at 10 mg/kg once every 2 weeks, and will continue to receive the drug until disease progression, death, withdrawal of consent, or up until patients have been on treatment for 2 years. Thus far, approximately 53% of patients have had some degree of tumor shrinkage. The overall response rate for patients receiving pembrolizumab is 22.2% (95% CI, 10.1-39.2) by RECIST v.1 central review and 33.3% (95% CI, 19.1-50.2) by investigator review. There were eight partial responses and stable disease was observed in another five patients.

The results demonstrate the potential of immunotherapy in treating gastric cancer, said one of the trial’s lead investigators Yung-Jue Bang, MD, PhD, professor of Medical Oncology, Seoul National University College of Medicine, president, Biomedical Research Institute, Seoul National University Hospital. OncLive spoke with Bang to learn more about this study’s findings.

OncLive: What were the most significant findings from this trial?

Dr Bang: Our study was part of the KEYNOTE-012 study, which looked at several cohorts of patients treated with the anti—PD-1 agent pembrolizumab. We focused on the gastric cancer cohort, where each patient was treated with pembrolizumab every 2 weeks. The response rate was 22%. Twenty-six percent of patients experienced progression-free survival at 6 months, and median survival was 11 months. Two-thirds of patients had received two or more lines of chemotherapy before entry. These results are quite promising; they have led to a number of other trials that we are awaiting results on.

The study also suggests that a particular immune gene signature can predict which patients will respond to this class of agents. More data is needed to validate these findings, but it is promising at this time. In patients with melanoma, it was shown that this kind of gene signature could predict the benefit of anti—PD-1 agents. Moreover, we had similar findings in our gastric cancer cohort, so it is worth investigating further.

Were these findings surprising?

Yes, they were. We knew that immunotherapy was effective in patients with melanoma. Recently, immune checkpoint inhibitors were also found to be effective in small-cell lung cancer. However, we did not expect such activity in patients with advanced gastric cancer because we did not believe the cancer was immunogenic. In this study, some patients had durable efficacy. It is quite exciting and promising. It is possible that gastric cancer treatment may be designed with more of a targeted therapy approach in the future.

What are the challenges of taking a targeted therapy approach?

At this time, it is just the beginning of a new era. Therefore, it can be hard to find the right patients to study in clinical trials when we are looking at a specific gene signature. However, in the future, I think we will find a better way to find the best patients for this class of agents.

Do you see a role for combination therapies with pembrolizumab for this gastric cancer patient population?

Combination treatment should absolutely be considered. Pembrolizumab or another similar agent could be combined with a variety of agents, including other immune checkpoint agents, chemotherapy, or targeted therapy. That is the future of this therapy.

Are there any concerns with toxicities when other agents are combined with pembrolizumab?

In my experience, combining a PD-1 agent and chemotherapy resulted in no additional side effects. However, when an agent like pembrolizumab is combined with another immune checkpoint inhibitor such as ipilimumab (Yervoy), the side effects are increased. There is a concern about the potential toxicities with the combination of two immune checkpoint inhibitors at this time.

Do you see a role for immunotherapy in earlier settings in gastric cancer in the future?

There is some testing that has just started with immunotherapies in the first-line setting. I think this will continue. Immunotherapy agents have the potential to benefit many, many patients in multiple settings in the future.