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Table 2 Registration trials leading to the FDA approval of PD-1/PD-L1 inhibitors in melanoma

From: Development of PD-1 and PD-L1 inhibitors as a form of cancer immunotherapy: a comprehensive review of registration trials and future considerations

Study/Agent Tumor (n) Line of therapy Experimental arm Control arm Primary endpointa Ref
KEYNOTE-001 (phase I)/pembrolizumab Advanced melanoma (n = 173) Previously treated with ipilimumab and/or BRAF inhibitor Pembrolizumab 2 mg/kg or 10 mg/kg every 3 weeks   ORR 26% (both doses; difference 0%, 95% CI 14-13, p = 0.96) 14
KEYNOTE-006 (phase III)/pembrolizumab Advanced melanoma (n = 834) First-line (regardless of BRAF mutations status) Pembrolizumab 10 mg/kg every 2 weeks OR every 3 weeks Ipilimumab 3 mg/kg every 3 weeks X4 cycles PFS (6-month) 47.3% vs. 46.4% vs. 26.5% (HR 0.58 for both pembrolizumab regimens vs. ipilimumab 95% CI 0.46-0.72 and 0.47-0.72, respectively, p < 0.001)
OS (1-year) 74.1% vs. 68.4% vs. 58.2% (HR pembrolizumab every 2 weeks 0.63, 95% CI 0.47-0.83, p = 0.0005; HR pembrolizumab every 3 weeks 0.69, 95% CI 0.52-0.90, p = 0.0036)
16
KEYNOTE-002 (phase II)/pembrolizumab Advanced melanoma (n = 540) Refractory to ipilimumab and/or BRAF inhibitor Pembrolizumab 2 mg/kg every 3 weeks OR 10 mg/kg every 3 weeks ICC (paclitaxel+carboplatin, paclitaxel, carboplatin, dacarbazine, or temozolomide) PFS 2 mg/kg (HR 0.57 95% CI 0.45-0.73, p < 0.001) and 10 mg/kg (HR 0.50, 95% CI 0.39-0.64, p < 0.001) compared to ipilimumab
No superiority in OS at this interim analysis
17
CheckMate 037 (phase III)/nivolumab Stage IIIC or IV melanoma (n = 405) Second-line Nivolumab 3 mg/kg every 2 weeks Dacarbazine 1000 mg/m2 every 3 weeks OR carboplatin AUC 6 + paclitaxel 175 mg/m2 every 3 weeks ORR 31.7% (95% CI 23.5-40.8) vs. 10.6% (95% 3.5-23.1) 18
CheckMate 069 phase III)/nivolumab/ipilimumab BRAFV600-WT unresectable or metastatic melanoma (n = 142) First-line Nivolumab 1 mg/kg + ipilimumab 3 mg/kg every 3 weeks X4 cycles then nivolumab alone every 2 weeks Ipilimumab 3 mg/kg every 3 weeks ORR 61% vs. 11% (p < 0.001) 19
CheckMate 067 phase III)/nivolumab/ipilimumab Unresectable or metastatic melanoma (n = 945) First-line Arm 1: Nivolumab 3 mg/kg every 2 weeks
Arm 2: nivolumab 1 mg/kg and ipilimumab 3 mg/kg every 3 weeks for 4 doses followed by nivolumab 3 mg/kg of every 2 weeks
Ipilimumab 3 mg/kg every 3 weeks PFS 6.9 mos (HR compared to ipilimumab 0.57, 99.5% CI 0.43-0.76, p < 0.001 vs. 11.5 mo (HR 0.42, 99.5% CI 0.31-0.57, p < 0.001 compared to ipilimumab) vs. 2.9 mos 20
  1. a Order of results refers to the experimental arm and control arm, respectively. In trials with more than one experimental arm, the endpoints are in the same order as documented in the experimental arm column
  2. FDA Food and Drug Administration, PD-1 programmed cell death 1, PD-L1 programmed death ligand 1, ORR overall response rate, CI confidence interval, PFS progression-free survival, HR hazard ratio, OS overall survival, ICC investigator-choice chemotherapy, AUC area under curve, WT wild-type