Association of RAS mutational status with clinical outcomes in metastatic colorectal cancer treated with trifluridine/tipiracil or regorafenib

Previous studies demonstrated codon-specific KRAS mutation as a potential biomarker of resistance in metastatic colorectal cancer (mCRC). Our study aimed to evaluate the association of RAS status on survival in patients with mCRC treated with trifluridine/tipiracil (FTD/TPI) or regorafenib. mCRC Patients treated with FTD/TPI combination (FTD/TPIcombo), FTD/TPI monotherapy (FTD/TPImono) or regorafenib were retrospectively enrolled into our study. All patients were classified according to chemotherapy regimen and RAS status. Progression-free survival (PFS) and overall survival (OS) was estimated for comparison. Kaplan–Meier curves were plotted for survival. A total of 263 patients were enrolled into our study, accounting for 79 FTD/TPIcombo, 86 FTD/TPImono and 98 regorafenib. The median PFS and OS were 4.9 m, 3.0 m versus 2.5 m and 15.1 m, 11.3 m versus 7.3 m in FTD/TPIcombo, FTD/TPImono and regorafenib, respectively. The overall response rate were 23%, 7% versus 5% in FTD/TPIcombo, FTD/TPImono and regorafenib, respectively. Patients were stratified according to RAS status, accounting for 129 RASwild, 85 KRASG12mut and 51 RASOTHERmut. For patients with RASwild, the median OS was 16.2 m, 14.7 m and 6.5 m for FTD/TPIcombo, FTD/TPImono and regorafenib, respectively. For patients with KRASG12mut, the median OS was 9.5 m, 5.6 m and 8.4 months for FTD/TPIcombo, FTD/TPImono and regorafenib group, respectively. For patients with RASOTHERmut, the median OS was 13.4 m, 9.9 m and 5.0 months for FTD/TPIcombo, FTD/TPImono and regorafenib group, respectively. In conclusion, FTD/TPIcombo had superior survival across all RAS mutational status. Notably, regorafenib was associated with longer OS than FTD/TPI monotherapy in the KRASG12mut subgroup, whereas FTD/TPI monotherapy yielded longer OS than regorafenib in patients with RASwild and RASOTHERmut status. These results suggest a potential role for RAS status in treatment selection and strongly support the need for prospective, randomized trials to confirm these observations before they can be translated into clinical practice guidelines.