Pembrolizumab Shows Promise for NSCLC

Results from the phase I KEYNOTE-001 trial indicate that the checkpoint inhibitor pembrolizumab (Keytruda; Merck) improves clinical outcomes for patients with advanced non–small cell lung cancer (NSCLC), particularly those whose tumors express high levels of PD-L1.

The trial's results were reported by Edward Garon, MD, an associate professor of medicine at the University of California, Los Angeles, at the American Association for Cancer Research Annual Meeting 2015 in Philadelphia, PA, April 18–22. The results were published simultaneously in The New England Journal of Medicine (N Engl J Med 2015 Apr 19 [Epub ahead of print]).

By blocking the PD-1 receptor and keeping its ligands PD-L1 and PD-L2 from binding to it, pembrolizumab prevents tumor cells from using this pathway to escape immune surveillance. Based on preliminary data from this study, pembrolizumab has received the FDA's Breakthrough Therapy designation for patients with EGFR– and ALK–wild-type NSCLC who have progressed on or following platinum chemotherapy. The drug was initially approved for the treatment of melanoma.

“For me, the most exciting moment in the development of anti–PD-1 drugs was the realization that lung cancer could respond to this form of immunotherapy,” said Suzanne Topalian, MD, director of the melanoma program at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins in Baltimore, MD. Topalian moderated the press conference at which the findings were presented.

KEYNOTE-001 enrolled 495 patients with advanced NSCLC. In the initial cohort of 182 patients, PD-L1 expression in at least 50% of tumor cells—determined by immunohistochemistry with the antibody 22C3—distinguished patients most likely to respond to pembrolizumab.

That finding was confirmed in a validation cohort of 313 patients, of which approximately one quarter had PD-L1 expression in at least half their tumor cells; 45.2% of them responded to pembrolizumab, with a median progression-free survival (PFS) of 6.3 months. Because so many patients in this group are still alive, their median overall survival (OS) time has not been reached.

In contrast, the respective response rates for patients with less than half of their tumor cells expressing PD-L1 or virtually none of their cells expressing it were 16.5% and 10.7%; median PFS was 3.3 and 2.3 months respectively. The median OS for both groups was 8.8 months.

“This was the largest study of lung cancer patients treated with a checkpoint inhibitor, and the first confirmation that PD-L1 is clearly a marker of response,” Garon said. “I think we can now confidently say that in patients who have PD-L1 in at least half their tumor cells, pembrolizumab is associated with clinical outcomes superior to what would be anticipated with cytotoxic chemotherapy.”

Garon also noted that pembrolizumab was generally well tolerated; fewer than 10% of study participants experienced serious (grade 3 or higher) side effects. Fatigue was the most common drug-related side effect, while the main immune-related adverse events were pneumonitis, infusion reactions, and hypothyroidism.

“We're talking about a patient population that's very difficult to treat, where second- and third-line agents are generally not expected to prolong survival,” Topalian remarked, “so the results with pembrolizumab are especially impressive in this setting.”

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