Dabrafenib and trametinib vs anti-PD(L)1 for the adjuvant treatment of locally advanced BRAF-mutant melanoma: A systematic review and meta-analysis.

Abstract

e21566 Background: Both Dabrafenib and Trametinib (D+T) and Anti-PD(L)1s, such as Nivolumab and Pembrolizumab, have been shown to improve recurrence-free survival (RFS) in patients with stage III or resected stage IV BRAF-mutant melanoma. However, no randomized controlled trials (RCTs) have directly compared D+T with anti-PD(L)1 therapies in the adjuvant setting, creating uncertainties about the optimal treatment approach. This systematic review and meta-analysis aim to address this knowledge gap. Methods: A comprehensive search of PubMed, Embase, and Scopus was conducted to identify studies comparing D+T with anti-PD(L)1 therapies in patients with stage III or resected stage IV BRAF-mutant melanoma. RCTs and observational studies were eligible. Studies with overlapping populations were excluded. Data were abstracted directly from manuscripts or extracted from Kaplan-Meier curves using Parmar’s method. Statistical analyses employed a random-effects model, with heterogeneity assessed via I² statistics. All calculations were performed using Review Manager 5.4.1. This study was registered with PROSPERO (CRD42024553421). Results: Eight observational studies comprising 2,394 patients (1,231 receiving D+T and 1,163 receiving anti-PD(L)1 therapies) met inclusion criteria. No eligible RCTs were identified. Anti-PD(L)1 agents included Pembrolizumab, Nivolumab, and Toripalimab. Median follow-up times ranged from 10-53 months. D+T demonstrated superior RFS compared to anti-PD(L)1 therapies (HR 0.53, 95% CI 0.40–0.70, p < 0.01; I² = 55%). However, no significant difference was observed in overall survival (OS) (HR 0.83, 95% CI 0.60–1.15, p = 0.27; I² = 0%). Subgroup analyses: a) excluding studies with HRs extracted from Kaplan-Meier curves; and b) focusing on stage IIIA patients, yielded similar results. D+T was associated with a higher rate of treatment discontinuation due to adverse events (AEs), with a relative risk (RR) of 1.57 (95% CI 1.30–1.91, p < 0.01; I² = 0%), corresponding to a risk difference of 8% (95% CI 5%–12%, p < 0.01; I² = 0%). Conclusions: D+T demonstrated superiority over anti-PD(L)1 therapies in terms of RFS. However, no OS benefit was observed, and D+T was associated with a higher risk of treatment discontinuation. These findings should be considered when counseling patients as the choice of adjuvant therapy may need to be tailored to individual preferences and tolerability.