PD-1 inhibitor pembrolizumab, currently being reviewed by the FDA for approval in melanoma, looks promising against advanced melanoma and non–small cell lung cancer. The PD-1 ligand PD-L1 may be a valid biomarker for response.
Immunotherapy is now a byword in cancer treatment, and current pursuits include designing antibodies against the immune system's “negative” checkpoint proteins. Consider ipilimumab (Yervoy; Bristol-Myers Squibb), which binds to and blocks CTLA-4, unleashing an antitumor response led by cytotoxic T cells that CTLA-4 would otherwise hold at bay.
In 2011, ipilimumab became the first immune checkpoint inhibitor approved by the FDA for melanoma. A series of other investigational drugs such as pembrolizumab (MK-3475; Merck) have since sparked further excitement in the immunotherapy field. Pembrolizumab targets a different “negative” immune checkpoint protein called PD-1.
Researchers reported in June that pembrolizumab produces long-term responses in patients with advanced melanoma. Results from the large phase I study of 411 patients were presented at the American Society of Clinical Oncology's Annual Meeting in Chicago, IL.
“Cancer cells use the PD-1 pathway as a signal saying, ‘Don't kill me, immune system,'” said principal investigator Antoni Ribas, MD, PhD, director of the tumor immunology program at the Jonsson Comprehensive Cancer Center of the University of California, Los Angeles. “By blocking PD-1 and preventing its ligands PD-L1 and PD-L2 from binding, pembrolizumab releases the brakes on T cells so they can attack the tumor.”
Initiated in December 2011, the study encompassed three single-agent dosing strategies and seven cohorts that included patients with and without previous ipilimumab treatment. Overall, 34% of patients met the RECIST objective response criteria. As of October 2013, 88% had sustained their objective responses.
The median overall survival has not been reached, with 1-year survival estimated at 69%. The median progression-free survival was 5.5 months. Fatigue, pruritus, and rash were the most common adverse events.
Steven O'Day, MD, an immunologist at the University of Southern California's Keck School of Medicine in Los Angeles, called pembrolizumab's mild toxicity profile “almost unheard of in metastatic cancer.”
Earlier this year, two phase I studies in pembrolizumab-treated advanced melanoma and non–small cell lung cancer (NSCLC) patients found PD-L1 is potentially a predictive biomarker for drug response.
In melanoma, the overall response rate was 46% when tumors expressed PD-L1 compared to 17% when tumors had no PD-L1. In NSCLC, the response rates to pembrolizumab were 37% in patients whose tumors had high pretreatment levels of PD-L1 versus 11% in those with low pretreatment levels. The findings were presented at the American Association for Cancer Research's 2014 Annual Meeting in April.
The FDA has granted priority review to pembrolizumab for advanced melanoma, with a decision anticipated by October 28.
O'Day hailed pembrolizumab as infinitely preferable to the “high collateral damage” of cytokine therapy for melanoma. “This is truly a brave new world for immunotherapy,” he said. “The revolution is here, and it's bursting out of melanoma into other solid tumors.”
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