Background: Approximately 50% of patients with melanoma harbor a BRAF mutation and are eligible for targeted therapy (TT) with BRAFi/MEKi. In spite of a response rate of nearly 70%, roughly half of patients will progress within a year due to development of resistance. Rechallenging patients with BRAFi/MEKi may be an alternative to overcome resistance and improve outcomes. We conducted a systematic review and meta-analysis to evaluate the efficacy and safety of BRAFi/MEKi rechallenge in patients with advanced melanoma. Methods: PubMed, Scopus, the Cochrane Library, ASCO publications, ESMO, and AACR databases were searched for relevant studies. Rechallenge was defined as patients treated with BRAFi/MEKi that developed disease progression or had significant adverse effects and went on an interval treatment or drug holiday, before being reintroduced to BRAFi/MEKi. Efficacy was assessed by objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). Heterogeneity was examined with the I(2) statistics and random-effect model was used to pool studies. Results: Seven studies met inclusion criteria, with a total of 400 patients. The medium follow-up ranged from 6.8 to 15.7 months. Elevated LDH was seen in 48.5% (194/400) of patients, and 53% (164/310) had brain metastases (BM). Prior to rechallenge, 83% (333/400) of patients received immunotherapy as interval treatment, mainly anti-PD-1 and/or anti-CTLA-4, and 10% (40/400) were on a drug holiday. During the rechallenge, 79% (317/400) of patients were treated with the combination of BRAFi/MEKi, whereas 21% (83/400) were treated with BRAFi alone. In a pooled analysis, the median PFS was 5 months (95% CI 4.0 – 5.9), and median OS was 9.8 months (95% CI 9.3 – 20.4). The 1-year OS rate was 42.63% (95% CI 30.25 - 55.02). ORR was 34.25% (95% CI 28.50 - 40), and DCR was 65.01% (95% CI 57.31 - 72.72). Prognostic markers such as BM and elevated LDH were not statistically significant. Treatment was well tolerated without unexpected adverse events. Conclusions: This meta-analysis indicates that advanced melanoma patients with refractory disease benefit from rechallenge with BRAFi/MEKi, particularly from high DCR, with a promising effect on 1-year OS rate. Further randomized controlled trials are warranted to investigate these findings.

^† Median. Os: observational. N: number. y: year. TT: targeted therapy. IT: interval treatment. ICI: immune checkpoint inhibitors.