The advent of biomarker-guided treatments has transformed therapeutic approaches in metastatic colorectal cancer (mCRC). Lately, KRAS G12 alterations, the predominant RAS variants in mCRC, have emerged as potential indicators of reduced response to trifluridine/tipiracil (FTD/TPI) alone. It remains unclear if this potential resistance persists when FTD/TPI is administered alongside bevacizumab. This investigation sought to evaluate the effectiveness of FTD/TPI combined with bevacizumab across different RAS mutation profiles in a clinical practice setting. Individuals with mCRC treated with FTD/TPI plus bevacizumab across any therapy stage at five Austrian oncology facilities, with documented genomic profiling, were included. Information was gathered retrospectively via medical record review. Differences in survival outcomes were assessed with log-rank testing. Adjusted Cox proportional hazards models incorporated multiple known prognostic factors. The analysis encompassed 123 cases of mCRC. Overall survival (OS) medians were nearly identical between RAS wild-type (WT) cases [9.63 months (95% CI 8.055–13.775)] and RAS-mutated cases [8.78 months (95% CI 8.055–11.014)], a finding upheld in multivariable analysis accounting for confounders; hazard ratio (HR) 1.05 (95% CI 0.618–1.785; P = 0.857). Furthermore, KRAS G12 mutation status showed no impact on outcomes. Specifically, OS reached 8.88 months (95% CI 7.332–12.921) among those with KRAS G12 alterations versus 9.47 months (95% CI 8.088–11.375) in RAS WT or non-KRAS G12 cases [HR 0.822 (95% CI 0.527–1.282; P = 0.387)]. Evidence from this clinical practice cohort suggests that FTD/TPI combined with bevacizumab delivers comparable benefits regardless of RAS mutation profile, implying that bevacizumab could counteract the possible diminished activity of FTD/TPI alone in KRAS G12-altered tumors.
