COMBINED BRAF, MEK, AND PD-1/PD-L1 AXIS BLOCKADE COMPARED TO DUAL BRAF/MEK INHIBITION FOR PATIENTS WITH METASTATIC MELANOMA HARBORING BRAF MUTATIONS: A SYSTEMATIC REVIEW AND META-ANALYSIS

Introduction: The successful blockade of the PD-1/PD-L1 axis and the incorporation of BRAF/MEK inhibitors (BRAF/MEKi) yielded significant improvements in response rates and survival for patients with metastatic melanoma (MM). As a result, immune-checkpoint inhibitors and targeted-therapies (TT), used separately, have become standard of care for those with advanced disease harboring a BRAF mutation. More recently, supported by preclinical data suggesting enhanced antitumor activity, randomized clinical trials (RCT) have addressed the efficacy of combinatorial approaches including both TT and ICP, with conflicting results. Aim: We sought to evaluate the efficacy and safety of the combined blockade of PD-1/PD-L1 and BRAF/ MEK (triplet) versus BRAF/MEKi (doublet) in BRAF V600-mutant MM patients. Methods: We performed a systematic review and meta-analysis to assess the efficacy/safety of the triplet over BRAF/MEKi in the frontline setting, encompassing studies published in MEDLINE and EMBASE from 2016 to Sep/2020 and presented as abstracts at ASCO Annual Meeting and ESMO Congress. RCT allowing for a direct comparison of triplet versus doublet regimens were selected for data extraction and analyses. We obtained the pooled effect estimates through random-effects model assuming a p-value < 0.05 as statistically significant. Results: we identified 1784 studies, of which 3 RCTs were selected. The use of triplet regimens resulted in a statistically significant improvement in progression-free survival (PFS) (HR: 0.79, 95% CI 0.68-0.91, p=0.001) and overall survival (OS) (HR: 0.81, CI 0.67-0.98, p=0.03). Triplet regimens were also associated with increased incidence of grades 3/4 adverse events (AEs) (HR: 0.57, CI 0.42-0.78, p=0.004), any grade pyrexia (HR: 0.50; 0.39-0.65, p<0.00001), arthralgia (HR: 0.73, CI 0.56-0.95, p=0.02), elevated AST (HR: 0.63, CI 0.48-0.83, p=0.001) and ALT (HR: 0.60, CI 0.42-0.85, p=0.005). Nevertheless, rates of treatment discontinuation due to AEs and the incidence of serious AEs were similar (p=0.11). Conclusion: Treatment regimens combining anti-PD-1/ PD-L1 agents and BRAF/MEKi resulted in a statistically significant improvement in PFS and OS. Despite higher incidence of grades 3/4 AEs, rates of treatment-related discontinuation was not increased. These results merit careful interpretation as all RCTs are still ongoing and mature data are expected.