OBJECTIVES: The phase III IMspire150 randomized controlled trial (RCT) showed improved progression-free survival (PFS) with atezolizumab+cobimetinib+vemurafenib (ACV) versus cobimetinib+vemurafenib in treatment-naive (TN) patients with BRAF^V600 mutation–positive (BRAF+) unresectable stage IIIC or stage IV melanoma. This analysis compared the efficacy and safety of ACV relative to other therapies for TN adults with unresectable or metastatic melanoma.

METHODS: Network meta-analyses (NMAs) using a Bayesian framework included studies identified through a systematic literature review of RCTs evaluating TN adults with unresectable stage IIIC/IV melanoma treated with any of the targeted or immunotherapies recommended by treatment guidelines. Endpoints included PFS, objective response rate (ORR), and proportion of patients discontinuing due to adverse events (%_disc). Fixed-effects and random-effects models were evaluated. For PFS, hazard ratios (HRs) were estimated via linear models with identity link functions. For ORR and %_disc, binomial distributions with complementary log-log functions were used to account for differences in follow-up across studies. HRs, credible intervals (CrIs), and the probability to be ranked the best treatment option were evaluated.

RESULTS: Eleven studies were included in the NMAs. In the overall TN patient population, ACV numerically prolongs PFS relative to all comparators. This result was statistically significant for most comparators, including ipilimumab+nivolumab [HR (95% CrI): 0.75 (0.58-0.97)]. ACV is associated with better ORR relative to most comparators; however, this result was not statistically significant. ACV is also associated with better %_disc relative to most comparators but was not statistically significant except relative to ipilimumab+nivolumab [HR (95% CrI): 0.06 (0.00-0.94)]. ACV was ranked the best treatment option in terms of PFS and ORR, and ranked second best behind dacarbazine+trametinib in terms of %_disc.

CONCLUSIONS: ACV had the highest PFS benefit and a low rate of treatment discontinuation compared with other therapies evaluated in this NMA for TN unresectable or metastatic melanoma.