Prognostic impact of the BRAF V600E mutation in patients with MSI-high metastatic colorectal cancer treated with immune checkpoint inhibitors

Introduction: The prognostic impact of the BRAF V600E mutation in patients with deficient mismatch repair (dMMR)/microsatellite instability (MSI) metastatic colorectal cancer (mCRC) treated with immune checkpoint inhibitors (ICI) is poorly understood. Material and methods: This retrospective international study included patients with dMMR/MSI mCRC treated with ICI all lines between 2014 and 2023, and available BRAF mutation status. Results: Of 909 patients included, 345 (38 %) had BRAF V600E dMMR/MSI mCRC. In multivariable analysis, BRAFm was not associated with a shorter progression-free survival (PFS) and overall survival (OS) from ICI start compared to BRAFwt patients (median PFS: 25.0 vs 41.5 months, adjusted hazard ratio (adjHR)= 0.97, p = 0.8 and OS: 55.1 months vs not reached adjHR= 0.98, p = 0.9). However, in patients treated with ICI in first line, the rate of secondary resistance, defined as the progression after the first 6 months of treatment, was higher in BRAFm patients (20 % vs 11 %, p = 0.02). In patients with disease control for 6 months in 1st line, the PFS and OS from this point onwards were significantly shorter in BRAFm patients (adjHR for PFS 2.09, p = 0.03 and adjHR for OS 2.80, p = 0.019). The poor prognostic value of the BRAF mutation was no longer observed in patients treated with anti-PD1 and anti-CTLA4 combination. Conclusions: In patients with dMMR/MSI mCRC, the BRAF V600E mutation is not associated with a shorter PFS/OS on ICI treatment in the overall population across all lines. However, specifically in patients treated in the first-line setting, our results suggest that the BRAF mutation is associated with a higher rate of secondary resistance, suggesting that a combination of PD1 and CTLA4 inhibitors upfront may be of particular interest in these patients.