FDA Expands Pembrolizumab Label to Include Approval in Initial Treatment of Unresectable or Metastatic Melanoma
On December 18, 2015, the U.S. Food and Drug Administration (FDA) expanded the pembrolizumab (Keytruda) label to include approval of the drug for the treatment of patients with unresectable or metastatic melanoma. This expansion now includes the initial treatment of patients with unresectable or metastatic melanoma with pembrolizumab.
In 2014, pembrolizumab received accelerated approval based on a clinically meaningful, durable objective response rate in patients with unresectable or metastatic melanoma and disease progression following treatment with ipilimumab (Yervoy) and, if BRAF V600 mutation–positive, a BRAF inhibitor. Two new clinical trials described below verify the clinical benefit of pembrolizumab.
The first trial enrolled 834 patients with unresectable or metastatic melanoma who had not received ipilimumab and who had received no more than one line of prior systemic therapy. Patients were randomized (1:1:1) to pembrolizumab at 10 mg/kg intravenously every 2 weeks, or pembrolizumab at 10 mg/kg every 3 weeks, or to ipilimumab at 3 mg/kg intravenously every 3 weeks for up to four doses. Patients treated with pembrolizumab were treated until disease progression.
The trial met its coprimary endpoints of overall survival and progression-free survival as assessed by a blinded independent central review (BICR) per RECIST v1.1. The pembrolizumab at 10 mg/kg every-2-week and every-3-week arms demonstrated statistically significant improvements in overall survival compared to the ipilimumab arm with hazard ratios (HRs) of 0.63 (95% confidence interval [CI] = 0.47–0.83, P < .001) and 0.69 (95% CI = 0.52–0.90, P = .004), respectively.
Median overall survival was not reached in either pembrolizumab arm. Compared to the ipilimumab arm, a significant improvement in progression-free survival was observed in the pembrolizumab at 10 mg/kg every-2-week and every-3-week arms with hazard ratios of 0.58 (95% CI = 0.46–0.72, P < .001) and 0.58 (95% CI = 0.47–0.72, P < .001), respectively. Median progression-free survival was 5.5 and 4.1 months in the pembrolizumab at 10 mg/kg every-2-week and every-3-week arms, respectively, and was 2.8 months in the ipilimumab arm.
The overall response rates were 34%, 33%, and 12% for patients in the pembrolizumab at 10 mg/kg every-2-week, 10 mg/kg every-3-week, and ipilimumab arms, respectively. Median response durations were not reached for any treatment arm.
The second trial enrolled 540 patients with unresectable or metastatic melanoma who were refractory to prior ipilimumab and a BRAF inhibitor if BRAF V600–mutation positive who were randomized (1:1:1) to either pembrolizumab at 2 mg/kg, or 10 mg/kg (both every 3 weeks), or to investigator’s choice of chemotherapy. Among the 155 patients assigned to investigator’s choice of chemotherapy who experienced progression of disease on chemotherapy (confirmed by BICR), 55% received pembrolizumab post progression.
The coprimary endpoints were progression-free survival as assessed by BICR per RECIST 1.1 and overall survival. The trial demonstrated a statistically significant improvement in BICR-assessed progression-free survival in the pembrolizumab at 2 mg/kg arm (HR = 0.57, 95% CI = 0.45–0.73, P < .001) and in the pembrolizumab at 10 mg/kg arm (HR = 0.50, 95% CI = 0.39–0.64, P < .001) compared to chemotherapy. There was no statistically significant difference between either pembrolizumab arm compared to the chemotherapy arm in the interim overall survival analysis.
Safety data were evaluated in 1,567 patients with unresectable or metastatic melanoma who received pembrolizumab at 2 mg/kg every 3 weeks, or 10 mg/kg delivered either every 2 weeks or every 3 weeks. The most serious risks of pembrolizumab are immune-mediated adverse reactions including pneumonitis, colitis, hepatitis, endocrinopathies, and nephritis.
Other clinically significant immune-mediated adverse reactions included arthritis, exfoliative dermatitis, bullous pemphigoid, uveitis, myositis, Guillain-Barré syndrome, myasthenia gravis, vasculitis, pancreatitis, hemolytic anemia, and inflammatory foci in brain parenchyma resulting in partial seizures. The most common adverse events reported included fatigue, pruritus, rash, constipation, nausea, diarrhea, and decreased appetite.
In exposure-response analyses across the dose range of pembrolizumab at 2 mg/kg every 3 weeks and 10 mg/kg every 3 weeks in the second trial, no relationship was observed between efficacy or safety and pembrolizumab exposure.
The recommended dose and schedule for pembrolizumab is 2 mg/kg administered as an intravenous infusion every 3 weeks until disease progression or unacceptable toxicity.