Résumé
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.
This retrospective international study included patients with dMMR/MSI mCRC treated with ICI all lines between 2014 and 2023, and available BRAF mutation status.
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.
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.
•This retrospective cohort included 909 MSI-H mCRC patients (pts) treated with ICI.•BRAF mutation is not associated with a shorter PFS/OS under ICI across all lines.•The rate of secondary resistance to ICI in 1st line is higher in BRAFm pts.•This poor prognostic value of BRAFm was not observed with the dual ICI.