Codon-specific KRAS mutations predict survival benefit of trifluridine-tipiracil in metastatic colorectal cancer

Genomics has greatly improved how patients with cancer are being treated; however clinicalgrade genomic biomarkers for chemotherapy are currently lacking. A multinational study identified KRAS codon G12 mutations as potential biomarker of resistance in 37 mCRC patients treated with trifluridine-tipiracil (FTD-TPI). In real-world data of 960 FTD-TPC treated mCRC patients KRAS^G12C mutations were significantly associated with poor survival. In the phase 3 RECOURSE trial (800 patients), overall survival was not prolonged with FTD-TPC versus placebo among the 279 patients with KRAS^G12 mutations (HR 0.97; p=0.85) while OS was prolonged among the 60 patients with KRAS^G13 mutations (HR 0.29; p<0.001). In isogenic cell lines and patient-derived organoids, KRAS^G12 mutations were associated with increased resistance to FTD-related genotoxicity. The authors concluder that these data show that KRAS^G12 mutations are biomarkers for reduced OS benefit of FTD-TPI treatment. The data suggest that genomics-based precision medicine may be possible for a subset of chemotherapies.