Impact of codon-level KRAS mutations on response to TAS-102, TAS-102+bevacizumab, or regorafenib in metastatic colorectal cancer.

Abstract

66 Background: Regorafenib and trifluridine/tipiracil (TAS-102) with or without bevacizumab are frequently used in the management of refractory metastatic colorectal cancer (mCRC). Recent studies suggest KRAS mutations might modulate responses to TAS-102. This study evaluates the effect of codon-level KRAS mutations on survival in mCRC patients receiving regorafenib or TAS-102 +/- bevacizumab. Methods: Using data from the Flatiron Health Research Database, mCRC patients treated with TAS-102, TAS-102 + bevacizumab, or regorafenib were analyzed. Patients were stratified by codon-level KRAS mutation status (wild-type [wt], codon 13, codon 12, or other mutations). To address confounding, inverse propensity score weighting was applied. To ensure adequate power for overall and subgroup analyses, we used fully parametric survival models. Based on the Bayesian Information Criterion, the Weibull regression was selected, and the ratio of median survival (RM) was reported as the measure of treatment effect. Progression-free survival (PFS) and overall survival (OS) were evaluated using weighted Kaplan-Meier estimation and weighted Weibull regression. Results: A total of 2,972 adults were included; 1200 treated with regorafenib, 1301 treated with TAS-102, and 471 with TAS-102 + bevacizumab. KRAS mutations were observed in 58% of patients. For patients with wt KRAS , TAS-102 + bevacizumab improved PFS compared with TAS-102 monotherapy (RM 1.48, 95% CI 1.38–1.58) but not OS (RM 1.05, 95% CI 1.00-1.11). In wt KRAS patients, there was no statistically significant difference between TAS-102 monotherapy and regorafenib with regard to PFS or OS. In patients with any KRAS mutation, TAS-102 + bevacizumab improved both PFS (RM 1.19, 95% CI 1.12–1.27) and OS (RM 1.12, 95% CI 1.07–1.17) compared to TAS-102 alone. In patients with any KRAS mutation, regorafenib had inferior PFS (RM 0.92, 95% CI 0.86–0.98) compared to TAS-102 alone, but there was no difference in OS (RM 1.05, 95% CI 1.00-1.10). In patients with codon 12 mutations, regorafenib was associated with improved OS (RM 1.10, 95% CI 1.03–1.17) compared to TAS-102 monotherapy while TAS-102 + bevacizumab was not (RM 1.05, 95% CI 0.99-1.11). In patients with codon 13 mutations, TAS-102 plus bevacizumab was associated with improved OS (RM 1.25, 95% CI 1.12–1.40), while there was no difference between regorafenib and TAS-102 monotherapy (RM 0.92, 95% CI 0.82–1.05). Conclusions: These results suggest that codon-level KRAS mutations may influence treatment outcomes with TAS-102 and regorafenib in refractory mCRC. Additional preclinical and prospective clinical studies further assessing the impact of codon-level KRAS mutations on response to therapy in this patient population are warranted.