Cobimetinib plus atezolizumab in BRAFV600 wild-type melanoma: primary results from the randomized phase 3 IMspire170 study

ABSTRACT Background Emerging data suggest that the combination of MEK inhibitors with immunotherapeutic agents may result in improved efficacy in melanoma. We evaluated whether combining MEK inhibition and immune checkpoint inhibition was more efficacious than immune checkpoint inhibition alone in patients with previously untreated BRAFV600 wild-type advanced melanoma. Patients and methods IMspire170 was an international, randomized, open-label, phase 3 study.Patients were randomized 1:1 to receive cobimetinib (60 mg, days 1-21) plus anti–programmed death-ligand 1 atezolizumab (840 mg every 2 weeks) in 28-day cycles or anti–programmed death-1 pembrolizumab (200 mg every 3 weeks) alone until loss of clinical benefit, unacceptable toxicity, or consent withdrawal.The primary outcome was progression-free survival (PFS), assessed by an independent review committee in the intention-to-treat population. Results Between December 11, 2017, and January 29, 2019, 446 patients were randomized to receive cobimetinib plus atezolizumab (n = 222) or pembrolizumab (n = 224).Median follow-up was 7.1 months (interquartile range [IQR] 4.8-9.9) for cobimetinib plus atezolizumab and 7.2 months (IQR 4.9-10.1) for pembrolizumab.Median PFS was 5.5 months (95% CI 3.8-7.2) with cobimetinib plus atezolizumab versus 5.7 months (95% CI 3.7-9.6) with pembrolizumab (stratified hazard ratio 1.15 [95% CI 0.88-1.50]; P = 0.30).Hazard ratios for PFS were consistent across prespecified subgroups.In exploratory biomarker analyses, higher tumor mutational burden was associated with improved clinical outcomes in both treatment arms.The most common grade 3-5 adverse events were increased blood creatine phosphokinase (10.0% with cobimetinib plus atezolizumab vs 0.9% with pembrolizumab), diarrhea (7.7% vs 1.9%), rash (6.8% vs 0.9%), hypertension (6.4% vs 3.7%), and dermatitis acneiform (5.0% vs 0).Serious adverse events occurred in 44.1% of patients with cobimetinib plus atezolizumab and 20.8% with pembrolizumab. Conclusion Cobimetinib plus atezolizumab did not improve PFS compared with pembrolizumab monotherapy in patients with BRAFV600 wild-type advanced melanoma.