Abstract
BACKGROUND: In metastatic colorectal cancer (mCRC), KRAS mutations are often associated with poorer survival; however, the prognostic impact of specific point mutations is unclear. In the phase III SUNLIGHT trial, trifluridine/tipiracil (FTD/TPI) plus bevacizumab significantly improved overall survival (OS) versus FTD/TPI alone. We assessed the impact of KRAS(G12) mutational status on OS in SUNLIGHT. PATIENTS AND METHODS: In the global, open-label, randomized, phase III SUNLIGHT trial, adults with mCRC who had received no more than two prior chemotherapy regimens were randomized 1 : 1 to receive FTD/TPI alone or FTD/TPI plus bevacizumab. In this post hoc analysis, OS was assessed according to the presence or absence of a KRAS(G12) mutation in the overall population and in patients with RAS-mutated tumors. RESULTS: Overall, 450 patients were analyzed, including 302 patients in the RAS mutation subgroup (214 with a KRAS(G12) mutation and 88 with a non-KRAS(G12)RAS mutation). In the overall population, similar OS outcomes were observed in patients with and without a KRAS(G12) mutation [median 8.3 and 9.2 months, respectively; hazard ratio (HR) 1.09, 95% confidence interval (CI) 0.87-1.4]. Similar OS outcomes were also observed in the subgroup analysis of patients with a KRAS(G12) mutation versus those with a non-KRAS(G12)RAS mutation (HR 1.03, 95% CI 0.76-1.4). FTD/TPI plus bevacizumab improved OS compared with FTD/TPI alone irrespective of KRAS(G12) mutational status. Among patients with a KRAS(G12) mutation, the median OS was 9.4 months with FTD/TPI plus bevacizumab versus 7.2 months with FTD/TPI alone (HR 0.67, 95% CI 0.48-0.93), and in patients without a KRAS(G12) mutation, the median OS was 11.3 versus 7.1 months, respectively (HR 0.59, 95% CI 0.43-0.81). CONCLUSIONS: The presence of a KRAS(G12) mutation had no detrimental effect on OS among patients treated in SUNLIGHT. The benefit of FTD/TPI plus bevacizumab over FTD/TPI alone was confirmed independently of KRAS(G12) status.