Triplet therapy with BRAF inhibitor, anti-EGFR agent, and MEK inhibitor in V600E BRAF–mutant colorectal cancer: A meta-analysis.

e15558 Background: The BRAF inhibitor (BRAFi) encorafenib is currently approved in combination with the anti-EGFR agent cetuximab for patients with previously treated V600E BRAF mutant CRC (mCRC). Since resistance to BRAFi can be mediated by either MAPK pathway–dependent or MAPK pathway–independent mechanisms, a triplet therapy (TT) that also includes MEK inhibitors (MEKi) might offer greater benefits than doublet treatment (DT). Moreover, TT could potentially reduce some of the adverse events associated with BRAFi. Over recent years, several studies have evaluated the efficacy of different regimens for treating BRAF mutant mCRC. However, the added value of MEKi remains uncertain. Therefore, we conducted a systematic review and a meta-analysis of the available evidence. Methods: We performed a systematic review of all phase Ib/II/III clinical trials conducted between 2015 and 2023 that investigated BRAFi, MEKi and/or anti-EGFR therapy for V600E BRAF mutant mCRC. A generalized linear mixed model was used to conduct a random effects meta-analysis of logit-transformed single proportions. This allowed us to calculate pooled overall response rates (ORR) and disease control rates (DCR). Results: Seven studies, involving 655 patients, were included for the ORR analysis, while six studies (643 patients) contributed data for DCR. A comparison of TT (BRAFi + MEKi + anti-EGFR) with both DT regimens (BRAFi + MEKi or BRAFi + anti-EGFR) demonstrated a significantly higher ORR for TT (32.6% vs. 19.3%; p=0.044). A similar trend was observed for DCR, although the difference did not reach statistical significance (81.4% vs. 70.1%; p=0.101). When comparing the two DT regimens, the pooled DCR was significantly higher for BRAFi + anti-EGFR compared to BRAFi + MEKi (76.0% vs. 61.7%; p=0.013). However, ORR was similar between the two DTs (p=0.844). The pooled ORR and DCR estimates are presented in Table 1. Conclusions: Our analysis revealed a significant ORR benefit for TT compared to any DT regimen. Among the DT regimens, BRAFi + anti-EGFR showed a higher DCR than BRAFi + MEKi, with comparable ORR. While our findings are limited by the heterogeneity of the included studies, most of which were single-arm trials, they highlight the potential of TT as promising approach that warrants further investigation in future studies, ideally through randomized controlled trials. Pooled overall response rate and disease control rate by treatment type. Treatement Response BRAFi + Anti-EGFR + MEKi (TT) BRAFi + MEKi or BRAFi + anti-EGFR (both DTs) BRAFi+Anti-EGFR BRAFi+MEKi Pooled Estimate 95%CI Pooled Estimate 95%CI Pooled Estimate 95%CI Pooled Estimate 95%CI Overall Response Rate 32.6% 20.5%-47.7% 19.3% 15.4%-23.9% 19.5% 15.0%-24.9% 18.5% 11.5%-28.5% Disease Control Rate 81.4% 70.1%-89.2% 70.1% 60.9%-78.0% 76.0% 70.3%-80.9% 61.7% 50.8%-71.6% CI: confidence Interval.