Regorafenib combined with trifluridine/tipiracil versus regorafenib monotherapy in refractory metastatic colorectal cancer (FDZL-REGOT): A randomized phase 2 trial.

157 Background: For the third-line treatment of metastatic colorectal cancer (mCRC), the standard regimens of regorafenib or trifluridine/tipiracil (TAS-102) monotherapy had demonstrated limited objective response rates (ORR) and progression-free survival (PFS). A phase Ib study reported the promising efficacy with the combination . However, no randomized trials have directly compared the combination against regorafenib monotherapy. This multicenter, randomized, open-label, phase II trial aims to evaluate the efficacy and safety of regorafenib plus TAS-102 versus regorafenib alone in patients with mCRC who have progressed after at least two prior lines of therapy. Methods: Patients progressing after ≥2 prior lines of treatment (including fluoropyrimidines, oxaliplatin, irinotecan) were randomized 1:1 to the combination group and regorafenib group, stratified by RAS status and primary tumor location. The combination group received regorafenib (80mg, qd, q2w) + TAS-102 (35mg/m² bid, d1-5, q2w). The regoragenib group received regorafenib monotherapy (120mg daily, d1-21, q4w). Treatment in each group was continued until disease progression or intolerable toxicity. The primary endpoint was PFS. Secondary endpoints included ORR, disease control rate (DCR) , overall survival (OS) and safety. Results: From July 1 th 2023 to January 31 th 2025, a total of 102 patients were enrolled and randomly assigned in this trial, of whom 51 were assigned to the combination group and 51 to the regorafenib group. 65 (63.7%) were male and 37(36.3%) were female. In the intention to treatment (ITT) analysis, after a median follow-up of 11.7 months, the median PFS (Kaplan–Meier estimate) was 6.10 months (95% CI 4.30-8.17 months) among the participants in the combination group and 2.77months (95% CI 2.10 - 3.47 months) among those in the regorafenib group (HR 0.34; 95% CI 0.21-0.54; p < 0.001). The ORR was 11.0% (6/51) vs. 0 (0/51), and DCR was 66.7% (34/51) vs. 29.4% (15/51) in the combination group and the regorafenib group, separately, in the ITT analysis. Safety profile indicated that 21.6% (11/51) and 19.6% (10/51) participants experienced adverse events with a maximum grade of 3/4 in the the combination group and the regorafenib, respectively. Conclusions: The combination regimen of regorafenib and TAS-102 demonstrated clinically meaningful PFS improvement with manageable toxicity in patients with refractory mCRC, supporting further investigation in phase 3 trials. Clinical trial information: NCT05970705 .