Results of REARRANGE trial: A randomized phase 2 study comparing different dosing approaches for regorafenib (REG) during the first cycle of treatment in patients (pts) with metastatic colorectal cancer (mCRC)

Introduction: REG is a multi-kinase inhibitor that improves overall survival vs placebo in refractory mCRC. However, REG adverse tolerability profile often limits its use on normal clinical practice. Different dose-repurposing strategies have been explored to improve REG tolerability. Here we report the results of the largest trial exploring the impact of initial flexible dosing on REG tolerability. Methods: Refractory mCRC pts were randomized 1:1:1 to standard dose 160 mg/day 3 weeks (w) on 1 w off (SD), reduced dose 120 mg/day 3 w on 1 w off (RD) or intermittent dose 160 mg 1 w on 1 w off (ID). Pts in RD or ID escalated to SD after cycle 1 if no limiting toxicity ocurred. Primary endpoint was % of pts with G3/4 treatment related adverse events (AE) on each arm. Secondary endpoints were: OS, PFS, TTF, DCR, % of pts starting C3, dose intensity and tolerability. Trial positivity threshold was stablished on 20% decrease in the % of pts with G3/4 AEs in RD or ID compared to SD. Results: From Jul 2016 to Sept 2017, 299 pts were randomized. Safety population set was: 100 SD, 98 RD, 99 ID. Median num. of prior lines and age were 4 and 64 years. % of pts with G3/G4 AE were: 60 SD, 56 RD, 55 ID (c2 0.7262). Forty-five % of pts on RD and 64% on ID were escalated to SD after C1 and % of pts starting C3 were: SD 39%, RD 44%, ID 35% (c2 0.6309). OS/arm was: 7.4 months (m) SD, 8.6 m RD and 7.1 m ID (long rank 0.7222). PFS: SD 1.94 m, RD 2.0 m, ID 2.0 m (long rank 0.3795). DCR: SD 33%, RD 36%, ID 35%. Median treatment duration was: SD 3.2 m, RD 3.7 m, ID 3.8. Safety profile is in the table. Conclusion: Though REARRANGE did not meet its primary endpoint of improving REG global tolerability in either RD or ID arms, flexible dosing showed numerical improvement on relevant AEs like fatigue, HFSR and hypertension, without jeopardizing efficacy. These findings support the use of REG flexible dosing as an alternative option.