Regorafenib dose escalation versus fixed dosing in refractory metastatic colorectal cancer: Survival outcomes from a sub-analysis of the ReTrITA study.

136 Background: The ReTrITA study is a large, multicenter retrospective analysis evaluating real-world outcomes of regorafenib (R) and trifluridine/tipiracil (T) in refractory metastatic colorectal cancer (mCRC) across 17 Italian centers (2012–2023). This prespecified subgroup analysis focused on the impact of different initial regorafenib dosing strategies on survival outcomes. Methods: Patients treated with regorafenib (n = 713) were stratified into three groups according to starting dose: ReDOS stepwise escalation (n = 313), fixed reduced dose <160 mg (n = 142), and standard 160 mg dose (n = 258). Primary endpoints were progression-free survival (PFS) and overall survival (OS). Survival was estimated with the Kaplan–Meier method and compared by log-rank tests. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated using Cox proportional hazards models. Results: Median OS was 7.4 months (95% CI, 6.4–8.9) for ReDOS, 8.3 months (95% CI, 6.3–10.0) for <160 mg, and 6.1 months (95% CI, 6.0–10.1) for 160 mg, with no significant differences (log-rank χ² = 1.95, p = 0.3781). HRs confirmed the lack of OS benefit: 0.90 (95% CI, 0.72–1.11) for ReDOS vs <160 mg and 1.05 (95% CI, 0.87–1.25) for ReDOS vs 160 mg. In contrast, PFS differed significantly across groups (log-rank χ² = 11.77, p = 0.0028). Median PFS was 3.1 months (95% CI, 3.0–35.6) for ReDOS, 3.8 months (95% CI, 3.4–28.1) for <160 mg, and 3.9 months (95% CI, 3.5–66.2) for 160 mg. HRs indicated a reduced risk of progression or death with ReDOS compared with <160 mg (HR 0.83, 95% CI, 0.67–1.02) and 160 mg (HR 0.75, 95% CI, 0.63–0.89). Conclusions: In this large real-world cohort, initial regorafenib dosing strategy did not influence OS, but PFS outcomes significantly favored the ReDOS escalation approach, which was associated with a reduced risk of progression compared with the standard dose. These results support the potential clinical value of gradual dose escalation in optimizing regorafenib therapy in refractory mCRC.