Yoon Highlights Potential Benefit With Second-Line Pembrolizumab, Followed by Subsequent Therapy, in Advanced Gastric/GEJ Cancer

Harry H. Yoon, MD

Second-line pembrolizumab (Keytruda), followed by any subsequent therapy, was associated with longer overall survival (OS) in patients with advanced gastric/gastroesophageal junction (GEJ) cancer, according to results from the phase 3 KEYNOTE-061 trial (NCT02370498).

In the randomized, open label analysis, investigators sought to explore the differences in OS in response to immediate subsequent therapy, following disease progression, in patients who had been given pembrolizumab or paclitaxel in the second-line setting. The goal was to understand whether pembrolizumab potentiates the effects of subsequent therapy, specifically immediate subsequent ramucirumab (Cyramza) plus paclitaxel over other regimens.

In the trial, 3 different analyses were performed. A total of 395 patients were randomized 1:1 to pembrolizumab (n = 196) or paclitaxel (n = 199). On the pembrolizumab arm, following disease progression, 103 patients did not receive a third-line therapy, 26 received ramucirumab plus paclitaxel, and 67 patients received a different third-line regimen. Conversely, on the paclitaxel arm, 82 patients did not receive third-line therapy and 117 patients received any third-line therapy following disease progression.

Results showed that, at 18 months, patients who received pembrolizumab with any subsequent therapy had a 36.6% OS rate versus 20.5% in patients who were given paclitaxel with any subsequent therapy. Patients who received ramucirumab/paclitaxel following pembrolizumab had a median OS of 13.1 months versus 10.1 months in those who had received paclitaxel. Additionally, 19% of patients whose disease progressed on second-line pembrolizumab experienced long-term OS after receiving subsequent therapy.

“We wanted to understand the role of post-study therapy, specifically post-immunotherapy and what its role was in explaining the apparent discrepancy between progression-free survival (PFS) and OS in immunotherapy trials in gastric cancer,” said lead study author Harry H. Yoon, MD. “We thought the best way to approach this would be a study where patients were randomized to receive either anti–PD-L1 therapy or chemotherapy.”

In an interview with OncLive, Yoon, an associate professor of oncology, a consultant in the Department of Oncology of the Division of Medical Oncology, and the co-chair of the Esophageal/Gastric Cancer Disease Group at Mayo Clinic, discussed OS data from the phase 3 KEYNOTE-061 trial, limitations to the research, and next steps.

OncLive: Could you provide some background on the KEYNOTE-061 trial? What was the design and goal of the research?

Yoon: Before the KEYNOTE-061 trial, randomized data suggested that nivolumab was superior to placebo in late-line treatment of patients with advanced gastric/GEJ cancer. Data also showed that PD-L1 blockade did not outperform chemotherapy in the third-line setting.

KEYNOTE-061 was the first time that anti–PD-L1 was compared head-to-head in a randomized trial with chemotherapy in the second-line setting. We found that pembrolizumab had a shorter PFS compared with chemotherapy. However, somehow the OS was comparable to that of chemotherapy. Pembrolizumab did not show superiority over chemotherapy and the trial did not meet its primary end point. It was very odd that PFS was shorter in the pembrolizumab arm compared with the chemotherapy arm and yet the OS was similar between the arms. The question was, “Why would the PFS be shorter and yet catch up by the time OS happened?” Since then, more trials in this space have demonstrated a similar pattern with regard to survival curves. We have seen this pattern in other cancer types, but not to this degree or with this level of consistency between studies as in gastric cancer.

What were the results from the trial?

We did 2 main types of analyses. One was looking at patients who never went on to subsequent therapy; they never went on to third-line therapy. We looked at their OS and, beyond 6-12 months of follow-up, the pembrolizumab arm seemed to be doing better than the paclitaxel arm. Again, these patients never received third line therapy. About 17% were alive on the pembrolizumab arm compared with 7% on the paclitaxel arm.

In the beginning, the pembrolizumab arm was doing a little bit worse than the paclitaxel arm before crossing over and then doing better. A minority of patients who seemed to have long-term benefit on pembrolizumab alone, whereas that didn't seem to be the case with paclitaxel.

We also looked at patients who did go on to receive subsequent post-study therapy in both arms. We discovered that patients who received pembrolizumab followed by any third-line therapy, had better OS compared with patients who were randomized to the paclitaxel arm and went on to receive third-line therapy.

We thought there could be confounding because of other factors, for example, maybe the pembrolizumab group seemed to be doing better because they were healthier or had better prognostic factors. We made adjustments for patient characteristics and that strengthened the association, indicating that the patients in the pembrolizumab arm who received third-line therapy had better survival than the patients on the paclitaxel arm who received subsequent therapy.

What are the next steps for this research?

We have an investigator-initiated, randomized, phase 2 trial that will soon be open. We will be specifically looking at a predefined sequential administration of immunotherapy followed by chemotherapy. This randomized trial will set out to determine the best combination post-immunotherapy regimen. We’re hoping that the results will help us learn about what’s happening inside the tumor tissue as these therapies are being administered. We also hope to find the best combination regimen that can be administered in a future phase 3 trial.

Where should the future efforts focus?

Future research should focus on understanding the impact of PD-L1 blockade on the tumor and immune microenvironment. Understanding what's happening in the tissue is an area where there's a major gap in knowledge. Some of these agents may be having both adverse and immune promoting impact.

What is the take-home message of this research?

The big message is that we still have a lot to learn in this space. We're just scratching the surface. Enrollment to clinical trials is critical, and so is encouraging patients to enroll, even in the trials that have serial biopsies. We need to understand the impact of these agents, especially the impact of immunotherapy on the tumor immune microenvironment. With that knowledge, we'll be able to create better strategies that more effectively find a way for immunotherapy and other therapies to cooperate in the fight against cancer.

Reference

Yoon HH, Fuchs CS, Özgüroğlu M, et al. KEYNOTE-061: response to subsequent therapy following second-line pembrolizumab or paclitaxel in patients with advanced gastric or gastroesophageal junction adenocarcinoma. Ann Oncol. 2020;31(suppl 3):236. doi:10.1016/j.annonc.2020.04.065