Impact of KRASG12 mutations on survival with trifluridine/tipiracil plus bevacizumab in patients with refractory metastatic colorectal cancer: post hoc analysis of the phase III SUNLIGHT trial

•Patients with mCRC benefit from third-line treatment with FTD/TPI irrespective of KRASG12 mutational status.•OS is improved in patients receiving FTD/TPI plus bevacizumab versus FTD/TPI, independently of KRASG12 mutational status.•KRAS mutations are not predictive of clinical outcomes with FTD/TPI as monotherapy or in combination with bevacizumab. BackgroundIn 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 KRASG12 mutational status on OS in SUNLIGHT.Patients and methodsIn 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 KRASG12 mutation in the overall population and in patients with RAS-mutated tumors.ResultsOverall, 450 patients were analyzed, including 302 patients in the RAS mutation subgroup (214 with a KRASG12 mutation and 88 with a non-KRASG12 RAS mutation). In the overall population, similar OS outcomes were observed in patients with and without a KRASG12 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 KRASG12 mutation versus those with a non-KRASG12 RAS mutation (HR 1.03, 95% CI 0.76-1.4). FTD/TPI plus bevacizumab improved OS compared with FTD/TPI alone irrespective of KRASG12 mutational status. Among patients with a KRASG12 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 KRASG12 mutation, the median OS was 11.3 versus 7.1 months, respectively (HR 0.59, 95% CI 0.43-0.81).ConclusionsThe presence of a KRASG12 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 KRASG12 status. 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 KRASG12 mutational status on OS in SUNLIGHT. 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 KRASG12 mutation in the overall population and in patients with RAS-mutated tumors. Overall, 450 patients were analyzed, including 302 patients in the RAS mutation subgroup (214 with a KRASG12 mutation and 88 with a non-KRASG12 RAS mutation). In the overall population, similar OS outcomes were observed in patients with and without a KRASG12 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 KRASG12 mutation versus those with a non-KRASG12 RAS mutation (HR 1.03, 95% CI 0.76-1.4). FTD/TPI plus bevacizumab improved OS compared with FTD/TPI alone irrespective of KRASG12 mutational status. Among patients with a KRASG12 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 KRASG12 mutation, the median OS was 11.3 versus 7.1 months, respectively (HR 0.59, 95% CI 0.43-0.81). The presence of a KRASG12 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 KRASG12 status.