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Pembrolizumab versus Ipilimumab in Advanced Melanoma.
Robert, Caroline M.D., Ph.D.; Schachter, Jacob M.D.; Long, Georgina V. M.D., Ph.D.; Arance, Ana M.D., Ph.D.; Grob, Jean Jacques M.D., Ph.D.; Mortier, Laurent M.D., Ph.D.; Daud, Adil M.D.; Carlino, Matteo S. M.B., B.S.; McNeil, Catriona M.D., Ph.D.; Lotem, Michal M.D.; Larkin, James M.D., Ph.D.; Lorigan, Paul M.D.; Neyns, Bart M.D., Ph.D.; Blank, Christian U. M.D., Ph.D.; Hamid, Omid M.D.; Mateus, Christine M.D.; Shapira-Frommer, Ronnie M.D.; Kosh, Michele R.N., B.S.N.; Zhou, Honghong Ph.D.; Ibrahim, Nageatte M.D.; Ebbinghaus, Scot M.D.; Ribas, Antoni M.D., Ph.D.; the KEYNOTE-006 investigators *
[Article] New England Journal of Medicine. 372(26):2521-2532, June 25, 2015.

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Background: The immune checkpoint inhibitor ipilimumab is the standard-of-care treatment for patients with advanced melanoma. Pembrolizumab inhibits the programmed cell death 1 (PD-1) immune checkpoint and has antitumor activity in patients with advanced melanoma.

Methods: In this randomized, controlled, phase 3 study, we assigned 834 patients with advanced melanoma in a 1:1:1 ratio to receive pembrolizumab (at a dose of 10 mg per kilogram of body weight) every 2 weeks or every 3 weeks or four doses of ipilimumab (at 3 mg per kilogram) every 3 weeks. Primary end points were progression-free and overall survival.

Results: The estimated 6-month progression-free-survival rates were 47.3% for pembrolizumab every 2 weeks, 46.4% for pembrolizumab every 3 weeks, and 26.5% for ipilimumab (hazard ratio for disease progression, 0.58; P<0.001 for both pembrolizumab regimens versus ipilimumab; 95% confidence intervals [CIs], 0.46 to 0.72 and 0.47 to 0.72, respectively). Estimated 12-month survival rates were 74.1%, 68.4%, and 58.2%, respectively (hazard ratio for death for pembrolizumab every 2 weeks, 0.63; 95% CI, 0.47 to 0.83; P=0.0005; hazard ratio for pembrolizumab every 3 weeks, 0.69; 95% CI, 0.52 to 0.90; P=0.0036). The response rate was improved with pembrolizumab administered every 2 weeks (33.7%) and every 3 weeks (32.9%), as compared with ipilimumab (11.9%) (P<0.001 for both comparisons). Responses were ongoing in 89.4%, 96.7%, and 87.9% of patients, respectively, after a median follow-up of 7.9 months. Efficacy was similar in the two pembrolizumab groups. Rates of treatment-related adverse events of grade 3 to 5 severity were lower in the pembrolizumab groups (13.3% and 10.1%) than in the ipilimumab group (19.9%).

Conclusions: The anti-PD-1 antibody pembrolizumab prolonged progression-free survival and overall survival and had less high-grade toxicity than did ipilimumab in patients with advanced melanoma. (Funded by Merck Sharp & Dohme; KEYNOTE-006 ClinicalTrials.gov number, NCT01866319.)