Late in 2015, the U. S. Food and Drug Administration (FDA) expanded the label for pembrolizumab (Keytruda), a humanized antibody, to include the initial treatment of patients with unresectable or metastatic melanoma.
Previously, pembrolizumab had received accelerated approval 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 in the initial setting.
The first trial (KEYNOTE-006) 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.1 Patients were randomly assigned (1:1:1) to pembrolizumab at 10 mg/kg intravenously every 2 weeks, pembrolizumab at 10 mg/kg every 3 weeks, or ipilimumab at 3 mg/kg intravenously every 3 weeks for up to 4 doses.
The trial met its coprimary endpoints of overall survival and progression-free survival. The two pembrolizumab 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.
As compared to the ipilimumab arm, a significant improvement in progression-free survival was observed with pembrolizumab at 10 mg/kg every 2 weeks and every 3 weeks, 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 with pembrolizumab at 10 mg/kg every 2 weeks and every 3 weeks, respectively, and was 2.8 months in the ipilimumab arm.
The second trial (KEYNOTE-002) enrolled 540 patients with unresectable or metastatic melanoma who were refractory to prior ipilimumab (and a BRAF inhibitor, if their tumors were BRAF V600 mutation–positive) who were randomly assigned (1:1:1) to either pembrolizumab at 2 mg/kg or 10 mg/kg (both every 3 weeks) or to the investigator’s choice of chemotherapy.2 Among the 155 patients given investigator-choice chemotherapy who had progression on treatment, 55% received pembrolizumab post progression.
The coprimary endpoints were progression-free survival and overall survival. The trial demonstrated a statistically significant improvement in 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.