Impact of KRAS codon-specific mutations on survival in metastatic CRC on trifluridine-tipiracil with/without bevacizumab

BACKGROUND: Clinical benefit from later lines of therapy in metastatic colorectal cancer (mCRC) is limited. Patient selection for treatment is crucial for optimal risk-benefit evaluation. Codon-specific KRAS mutations have been implicated as predictive biomarkers for efficacy of trifluridine/tipiracil (TAS-102). However, their predictive impact for TAS-102 plus Bevacizumab (TAS-Bev), the new standard of care in mCRC, is unknown. METHODS: This large patient-based, real-world, retrospective cohort study of mCRC patients who received TAS-102 alone or in combination with bevacizumab between January 1, 2020, and March 1, 2023. A sensitivity analysis was performed in 2 independent cohorts from MD Anderson Cancer Center, Houston, TX, and Tempus AI, Inc., Chicago, IL, prior to polling the data together. RESULTS: A total of 946 mCRC patients were evaluated; KRAS was mutated in 57.8% cases, 39.4% involving G12 codon, and 9.8% G13. We found no association of KRAS-G12 mutations with overall survival (hazard ratio [HR] = 1.1, 95% confidence interval [CI] = 0.90 to 1.25; P = .441) on TAS-102 contradicting the reported predictive impact of these biomarkers. Moreover, we reported inferior overall survival for KRAS-G13 mutant patients (HR = 1.3, 95% CI = 1.02 to 1.69; P = .045). On TAS-Bev, no association was found between KRAS-G12 (HR = 0.8, 95% CI = 0.59 to 1.11; P = .188) or KRAS-G13 (HR = 1.66, 95% CI = 0.99 to 2.79; P = .072) mutations and overall survival. CONCLUSIONS: No significant associations between KRAS-G12 and overall survival were found for TAS-102 or TAS-Bev. Further research is needed to assess the impact of these mutations on combined TAS-Bev therapy prior to any clinical application.