In the first randomized trial to compare two approved immune checkpoint inhibitors as first-line therapy for patients with advanced melanoma, pembrolizumab yielded significantly better treatment outcomes than ipilimumab for all endpoints studied, according to KEYNOTE-006 phase III trial data presented at the AACR Annual Meeting 2015 and simultaneously published in the New England Journal of Medicine.

"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, M.D., Ph.D., 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-PD1 antibody pembrolizumab at two different dosing regimens versus the anti-CTLA4 antibody ipilimumab."

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.

"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," Ribas said.

Of the 834 patients with metastatic melanoma enrolled in this phase III trial, 66 percent were treatment-naïve and 79 percent had tumors that had the PD-L1 protein. Patients were randomly assigned (1:1:1) to 10 mg/kg pembrolizumab every two weeks, 10 mg/kg pembrolizumab every three weeks, or four doses of 3 mg/kg ipilimumab every three weeks. 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 six weeks thereafter. The primary endpoints were progression-free survival (PFS) and overall survival (OS); secondary endpoints were overall response rate (ORR) and safety.

According to data from the second interim analysis, at six months after treatment, PFS was 45 percent for pembrolizumab arms and 26 percent for ipilimumab; OS for patients in the pembrolizumab arms was about 87 percent compared with 75 percent for those in the ipilimumab arm. ORR was 33 percent for pembrolizumab arms and 12 percent for ipilimumab.

At 12 months after treatment, OS rates were 74 percent and 68 percent for the two pembrolizumab arms, respectively, while it was 58 percent for ipilimumab. Further, the outcome with pembrolizumab was superior to ipilimumab in all subset analyses of prespecified groups, including PD-L1-postive versus PD-L1-negative tumors.

Drug-related adverse events were lower in the pembrolizumab arms (12 percent) compared with the ipilimumab arm (20 percent).

"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," 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 two decades ago. And now we have clear evidence that this approach helps patients."

This study was funded by Merck. Ribas is a consultant to Merck with the honoraria paid to his institution. Robert is an occasional consultant for MSD, Bristol-Myers Squibb, Roche, Novartis, GlaxoSmithKline, and Amgen, with honoraria.