4108 Background: The BRAF V600E mutation defines an actionable subset of rare cancers. Metastatic BTC carries a poor prognosis, with median survival under one year on standard chemotherapy. Given the rarity of BRAF V600E-mutated BTC and the absence of RCTs, rigorous evidence synthesis is needed; existing data for dabrafenib plus trametinib come only from single arm basket trials such as ROAR and NCI-MATCH. The low prevalence of this mutation limits the feasibility of large randomized studies. This SRMA aimed to quantify the efficacy of dual BRAF/MEK inhibition in BTC and explore potential histology dependent differences in response. Methods: We performed a systematic review and meta-analysis (SRMA) pooling single arm Phase II basket trial cohorts (N = 53 BTC; N = 17 CNS). Seven case reports were summarized qualitatively and excluded from pooled analyses. The primary endpoint was pooled overall response rate (ORR). A random effects model was used. Subgroup and heterogeneity analyses were performed given the tissue-specific behavior of V600E-driven tumors. Histology was evaluated as an exploratory moderator and heterogeneity was quantified. Results: In the pooled cohort of 70 patients (53 BTC and 17 CNS), the overall ORR was 45.3% (95% CI: 24.5-66.9%). Heterogeneity for the BTC subgroup was moderate (I 2 = 62.6%), while overall pooled heterogeneity across all studies was low (I 2 = 14%). ORR in BTC was numerically higher than in Central nervous system (CNS) cohorts (34.9%) but subgroup differences did not reach statistical significance (P = 0.3386). The observed median OS of 13.5 months in the ROAR BTC cohort compares favourably with historical outcomes commonly reported in the 6-12 month range for advanced BTC. The consistency of pooled estimates, despite non-randomized designs, suggests a stable treatment signal while acknowledging that causality cannot be inferred from uncontrolled data. Median progression-free survival was 9.0 months in BTC and 5.5-8.0 months in CNS cohorts. Median OS in the ROAR BTC cohort was 13.5 months (95% CI: 10.4-17.6), exceeding historical expectations. The pooled rate of Grade ≥3 AEs was 59.2%, consistent with the known safety profile of dabrafenib plus trametinib; no treatment-related deaths were reported. Qualitative data from case reports confirmed regression of CNS metastases and feasibility in patients with severe hepatic dysfunction. Conclusions: Dual BRAF/MEK inhibition shows clinically meaningful activity in BRAF V600E-mutated BTC, with survival exceeding historical expectations. Exploratory analyses indicate histology-dependent differences, supporting tumor-specific therapeutic stratification. These findings align with growing tissue-agnostic evidence for MAPK inhibition and reinforce the value of routine molecular profiling, though conclusions are limited by small cohorts and single arm studies.
Parikh et al. (2026) studied this question.