Meta-analysis of randomized phase II-III trials evaluating triplet combinations of immunotherapy and targeted therapy for BRAF V600-mutant unresectable or metastatic melanoma.

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9541 Background: Immune-checkpoint inhibitors (ICI) and targeted-therapies (TT) have become standard options for BRAF -V600 metastatic melanoma (B-mut MM) patients. However, still more than 50% of those patients do not respond or relapse to these current strategies. Preclinical and translational data suggest that ICI plus TT may improve treatment outcomes in patients with B-mut MM, but with conflicting results in the clinical setting. Methods: We performed a systematic review and meta-analysis of randomized phase II-III studies published until January 2022 comparing first-line ICI+TT vs TT alone in B-mut MM. We obtained summary estimates through random-effects models. Overall survival (OS) and progression-free survival (PFS) were the main outcomes retrieved but we look also at difference in responses and adverse events. Results: We summarized data from 3 independent trials and we showed a significant advantage in terms of PFS and OS for the experimental arms in B-mut MM patients treated with ICI+TT rather than TT alone. The summary estimate indicates a significant 23% decrease in risk of progression (SHR = 0.77, 95%CI: 0.66-0.89, with no between-study heterogeneity I2= 0%) and a significant 21% reduction in risk of death (SHR = 0.79, 95%CI: 0.66-0.96, with no heterogeneity I2= 0%). However, no difference was shown (p-value = 0.56) between arms in terms of summary Objective Response Rate (ORR) estimates (Summary ORR doublet = 65.4% [61.5%; 69.2%] and Summary ORR triplet = 67% [63%; 70.9%], respectively). From the subgroup analysis on PFS risk estimates, no significant differences were observed in summary HRs by age ( < 65 vs ≥65 years, p-value = 0.11), sex (female vs male, p-value = 0.58), ECOG PS (0 vs 1, p-value = 0.36), LDH levels (lower vs upper, p-value = 0.59) and PDL1 status (positive vs negative, p-value = 0.89). Significant differences were found in frequencies of grade 3 or more adverse events with higher number of events occurring in B-mut MM vs TT alone (Summary Odd Ratio = 2.01, 95%CI: 1.16-3.47, I2= 74%), whereas no significant differences were found in terms of any adverse event between arms (SOR = 1.83, 95%CI: 0.70-4.78, I2= 0%). Conclusions: This study supports and extend the discussion on first-line available combinations to be offered to B-mut MM patients. Combining ICI with TT demonstrated an effective advantage on both PFS and OS, although augmenting toxicities. Further biomarker-driven investigation may identify patient subpopulations who could benefit from ICI+TT combinations in order to expand their window of therapeutic opportunities.