Background
Phase III RCT of 631 patients with unresectable or metastatic melanoma that progressed after ipilimumab (and a BRAF inhibitor if BRAF-mutant), randomized 2:1 to nivolumab vs investigator-choice chemotherapy.
Interventions and follow up
Arm A: Nivolumab 3mg/kg IV q2wk
Arm B: Investigator choice: dacarbazine 1000mg/m2 q3wk or paclitaxel 175mg/m2 + carboplatin AUC 6 q3wk
Primary endpoints: objective response rate and overall survival
Median follow-up: ~2yr
Arm B: Investigator choice: dacarbazine 1000mg/m2 q3wk or paclitaxel 175mg/m2 + carboplatin AUC 6 q3wk
Primary endpoints: objective response rate and overall survival
Median follow-up: ~2yr
Results
ORR: 31.7% vs 10.6% (nivolumab vs chemotherapy)
mOS: 16mo vs 14mo; HR 0.95, 95%CI 0.73-1.24
Durability: nivolumab responses were more durable than chemotherapy responses
mOS: 16mo vs 14mo; HR 0.95, 95%CI 0.73-1.24
Durability: nivolumab responses were more durable than chemotherapy responses
Adverse events
Grade 3-4 treatment-related AEs: 9% with nivolumab vs 31% with chemotherapy
Discontinuation due to AEs: 2% (nivolumab) vs 8% (chemotherapy); grade 3-4 nivolumab events included increased lipase, ALT, fatigue, and anemia (each ~1%); no treatment-related deaths reported with nivolumab
Discontinuation due to AEs: 2% (nivolumab) vs 8% (chemotherapy); grade 3-4 nivolumab events included increased lipase, ALT, fatigue, and anemia (each ~1%); no treatment-related deaths reported with nivolumab
Conclusions
Nivolumab produced markedly higher and more durable response rates than chemotherapy in ipilimumab-refractory melanoma with a substantially better safety profile, though the OS difference was not statistically significant.
Key Limitations
OS not significant, likely confounded by crossover and subsequent therapies; open-label design; heterogeneous chemotherapy comparator; conducted entirely in the post-ipilimumab refractory setting.
Clinical Context
Supported FDA accelerated approval of nivolumab for ipilimumab-refractory melanoma (2014) and EMA approval. Helped establish anti-PD-1 therapy in advanced melanoma. Updated analysis (Larkin J et al, JCO, 2018, PMID:28671856). ESMO endorses anti-PD-1 for advanced melanoma.