Updated Study Results Shows Activity for Keytruda in Gastric Cancer

Among patients with metastatic gastric cancer treated with the PD-1 inhibitor Keytruda (pembrolizumab), the agent showed promising antitumor activity and manageable side effects, according to updated findings from the KEYNOTE-012 study presented at the 2015 Gastrointestinal Cancers Symposium.

The gastric cancer cohort of the KEYNOTE-012 trial involved 39 patients whose tumors expressed PD-L1. Cancer cells that express PD-L1 bind to a protein called PD-1 found on the surface of T cells, immune cells that would ideally attack cancer cells. By binding to PD-1, the malignant cell switches off the T cell and renders cancer cells invisible to the immune cell.

Patients received Keytruda every two weeks for up to 24 months or until complete response, disease progression or if the side effects became too severe.

In an update of the initial analysis presented in September at the European Society for Medical Oncology, Kei Muro, of the Aichi Cancer Center Hospital in Nagoya, Japan, reported that at 8.8 months’ follow-up, there was strong evidence of anticancer activity. Eight patients experienced partial responses; stable disease was observed in another five. Responses were similar for Asian and non-Asian populations.

For four patients, response was not assessed or able to be determined. Approximately 53 percent of patients had some degree of tumor shrinkage.

“Six of the eight responders were still responding at the time of this analysis,” Muro noted. The median time to response was eight weeks, he said, and median response duration was 24 weeks. Median progression-free survival was 1.9 months. At 6 months, the overall survival (OS) rate was 69 percent. Median OS had not been reached, he reported. “We found a trend toward improved outcomes with higher levels of PD-L1 expression,” Muro added.

Four patients had a treatment-related adverse event of grade 3-5. One death was reported from hypoxia.

The phase 2 KEYNOTE-059 study of Keytruda monotherapy or in combination with cisplatin plus 5-fluorouracil for advanced gastric cancer will be initiated early in 2015.

Ronald Levy, professor and chief of the Division of Oncology at Stanford University School of Medicine, presented a keynote lecture on anti-PD-1 monoclonal antibodies at the meeting, showing enthusiasm for immune therapies in cancer in general. “We have found out that we can use the immune system to kill cancer, and this includes gastrointestinal cancers,” he said.

Commenting on the KEYNOTE-012 findings, in particular, he noted, “Not many of the tumor cells need to express this ligand for this drug to work,” however, he acknowledged that only 40 percent of patients had that 1 percent necessary for eligibility, and the majority did not respond.

“Why do some patients respond and not others?” Levy asked. “Is it PD-L1 expression by the tumor cells or stromal cells in the environment? They can talk to the incoming T cells and shut them off, but they are not perfect as predictors.”

Efforts are underway to try to boost these response rates through combinatorial therapy, he said, and potentially by increasing the expression of the target, the PD-1 ligand.