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

Gong, Jun; Chehrazi-Raffle, Alexander; Reddi, Srikanth; Salgia, Ravi

doi:10.1186/s40425-018-0316-z

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 endpoint^a	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	BRAF^V600-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

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