Clinical outcomes of trifluridine/tipiracil plus bevacizumab versus trifluridine/tipiracil or regorafenib in metastatic colorectal cancer: a multicenter cohort study

Background: In patients with pretreated metastatic colorectal cancer (mCRC), trifluridine/tipiracil (FTD–TPI) + bevacizumab has superior efficacy compared with FTD–TPI alone. However, real-world data on outcomes and comparisons with other established therapies including regorafenib are scarce. Additionally, evidence suggests that molecular alterations, such as KRAS^G12 mutations, may affect FTD–TPI efficacy. We aimed to compare clinical outcomes of patients with mCRC treated with FTD–TPI + bevacizumab, FTD–TPI, or regorafenib across molecular subgroups. Patients and methods: This retrospective cohort study included 509 patients treated at six Austrian cancer centers between January 2015 and December 2022. The primary outcome was progression-free survival (PFS), with overall survival (OS) and disease control rate (DCR) as secondary outcomes. Between-group differences were analyzed using Cox and logistic regression. A propensity score analysis using inverse probability of treatment weighting (IPTW) was conducted. Flexible parametric models and restricted mean survival time (RMST) analyses were used to account for time-dependent differences in PFS/OS. Results: In propensity score analysis, patients treated with FTD–TPI + bevacizumab (n = 130) versus FTD–TPI (n = 227) alone or regorafenib (n = 152) had longer PFS [IPTW-adjusted hazard ratio (HR) 0.68, 95% confidence interval (CI) 0.51-0.92, P = 0.012] and higher DCR (IPTW-adjusted odds ratio 3.35, 95% CI 1.81-6.20, P < 0.001). The IPTW-adjusted HR for OS was 0.80 (95% CI 0.58-1.12, P = 0.203). A modest OS benefit of FTD–TPI + bevacizumab was observed within the first 12 months. In RMST-analysis, OS was 12.1 months (95% CI 11.4-12.8 months) for FTD–TPI + bevacizumab compared with 10.6 months (95% CI 9.9-11.2 months) for the controls (P = 0.003). Outcomes were consistent across key molecular subsets, including KRAS and KRAS^G12 mutations. Conclusions: In this large real-world cohort of patients with mCRC, FTD–TPI + bevacizumab was associated with improved PFS and DCR compared with FTD–TPI or regorafenib, with consistent benefit across most molecular subgroups, including KRAS^G12 mutations.