AACR 2015: Pembrolizumab Is Better Than Ipilimumab for Advanced Melanoma in Phase III Trial
In the first randomized trial to compare two U.S. Food and Drug Administration–approved immune checkpoint inhibitors as first-line therapy for patients with advanced melanoma, pembrolizumab (Keytruda) yielded significantly better treatment outcomes than ipilimumab (Yervoy) for all endpoints studied. These findings, the results of the phase III KEYNOTE-006 trial, were presented at the AACR Annual Meeting 2015, held April 18 to 22 in Philadelphia (Abstract CT101). This study is being simultaneously published in The New England Journal of Medicine.
Study Details
Currently, ipilimumab is the standard of care for the first-line therapy for patients with metastatic melanoma, and pembrolizumab is approved as second-line therapy for patients with metastatic melanoma whose tumors no longer respond to ipilimumab or BRAF inhibitors.
“This study is the first clinical trial to compare head-to-head two immune checkpoint inhibitors as front-line therapy for melanoma,” said Antoni Ribas, MD, PhD, Professor of Hematology and Oncology and Director of the Tumor Immunology Program Area at UCLA Jonsson Comprehensive Cancer Center. “We opened this global clinical trial in 16 countries and enrolled more than 800 patients to test the anti–PD-1 antibody pembrolizumab at two different dosing regimens vs the anti-CTLA4 antibody ipilimumab. We are delighted to declare that the clinical trial met all of its statistical endpoints, and we found that pembrolizumab is superior to ipilimumab as first-line therapy,” Dr. Ribas said.
Of the 834 patients with metastatic melanoma enrolled in this phase III trial, 66% were treatment-naive, and 79% had tumors that had the PD-L1 protein. Patients were randomly assigned (1:1:1) to 10 mg/kg pembrolizumab every 2 weeks, 10 mg/kg pembrolizumab every 3 weeks, or four doses of 3 mg/kg ipilimumab every 3 weeks.
Survival Outcomes and Response Rates
The investigators assessed treatment responses by two criteria—RECIST v1.1 and immune-related response criteria—12 weeks after the initiation of treatment and every 6 weeks thereafter. The primary endpoints were progression-free survival and overall survival; secondary endpoints were overall response rate and safety. According to data from the second interim analysis, at 6 months after treatment, progression-free survival was 45% for the pembrolizumab arms and 26% for ipilimumab; overall survival for patients in the pembrolizumab arms was about 87% compared with 75% for those in the ipilimumab arm. Overall response rate was 33% for the pembrolizumab arms and 12% for ipilimumab.
At 12 months after treatment, overall survival rates were 74% and 68% for the every-2-week and every-3-week pembrolizumab arms, respectively, while it was 58% for ipilimumab. Further, the outcome with pembrolizumab was superior to ipilimumab in all subset analyses of prespecified groups, including PD-L1–positive vs PD-L1–negative tumors.
Drug-related adverse events were lower in the pembrolizumab arms (12%) compared with the ipilimumab arm (20%).
Results Exceed Expectations
“These results meet and exceed the baseline assumptions of the benefit of pembrolizumab over ipilimumab. I hope the drug regulatory agencies around the world act fast on approving pembrolizumab for front-line therapy for metastatic melanoma,” Dr. Ribas said. “I think we made a remarkable advance in the treatment of patients with melanoma,” he added. “We had the biggest change in our thinking about how to use the immune system to treat cancer 2 decades ago. Now we have clear evidence that this approach helps patients.”
The lead investigator of the trial, Caroline Robert, MD, PhD, Head of the Dermatology Unit at the Institut Gustave-Roussy in Paris, said, “As of today, pembrolizumab is still not on the market in Europe, except in the context of an expanded access program after failure of ipilimumab. We also look forward to having pembrolizumab in Europe as a front-line therapy for metastatic melanoma, and we hope that these results accelerate the process.”
This study was funded by Merck. Dr. Ribas is a consultant to Merck with honoraria paid to his institution. Dr. Robert is an occasional consultant for MSD, Bristol-Myers Squibb, Roche, Novartis, GlaxoSmithKline, and Amgen, with honoraria.
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