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