Anti–PD-1 Antibody Pembrolizumab Is Active in Ipilimumab-Refractory Advanced Melanoma
As reported in The Lancet by Robert et al, the anti–programmed-death receptor-1 (PD-1) antibody pembrolizumab (Keytruda) produced durable responses in a phase I trial in patients with ipilimumab (Yervoy)-refractory melanoma. The study provided the basis for the recent accelerated approval of pembrolizumab for treatment of patients with unresectable or metastatic melanoma with disease progression following treatment with ipilimumab and, in BRAF V600 mutation–positive patients, treatment with a BRAF inhibitor. Pembrolizumab is the first PD-1 inhibitor to be approved for use in the United States.
Study Details
In this open-label, international, multicenter expansion cohort of a phase I trial, 173 patients aged ≥ 18 years with advanced melanoma progressing after at least two ipilimumab doses were randomly assigned to receive pembrolizumab intravenously at 2 mg/kg (n = 89) or 10 mg/kg (n = 84) every 3 weeks until disease progression, intolerable toxicity, or consent withdrawal. The primary endpoint was overall response rate. Overall, 97% of patients were white, 17% had BRAF V600 mutant disease, and 73% had received at least two prior therapies for advanced or metastatic disease.
Responses
Median follow-up was 8 months. The overall response rate was 26% at both doses, including response in 21 of 81 evaluable patients receiving 2 mg/kg group and 20 of 76 evaluable patients receiving 10 mg/kg (difference = 0%, 95% confidence interval = −14 to 13, P = .96).
The recommended starting dose of pembrolizumab in the current setting is 2 mg/kg. Among the 21 patients in the 2-mg/kg group with response, 3 (14%) had disease progression at 2.8, 2.9, and 8.2 months after initial response; 18 (86%) had ongoing responses with durations of 1.4+ to 8.5+ months, including 8 with ongoing responses of ≥ 6 months. Responses were observed in patients with and without BRAF V600–mutant disease.
Adverse Events
Safety profiles were similar in the 2-mg/kg and 10-mg/kg groups. The most common drug-related adverse events of any grade were fatigue (33% and 37%), pruritus (26% and 19%), and rash (18% and 18%). Grade 3 fatigue, which occurred in 3% of patients in the 2-mg/kg group, was the only drug-related grade 3 or 4 adverse event reported in more than one patient. No drug-related deaths were observed.
Two ongoing confirmatory trials with coprimary endpoints of progression-free and overall survival are evaluating pembrolizumab in ipilimumab-refractory and ipilimumab-naive patients with unresectable or metastatic melanoma.
The investigators concluded: “The results suggest that pembrolizumab at a dose of 2 mg/kg or 10 mg/kg every 3 weeks might be an effective treatment in patients for whom there are few effective treatment options.”
Caroline Robert, MD, of Institut Gustave Roussy, is the corresponding author for The Lancet article.
The study was funded by Merck Sharp & Dohme. For full disclosures of the study authors, visit www.thelancet.com.
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