Regorafenib is the first small-molecule multikinase inhibitor with survival benefit as a salvage line therapy for metastatic colorectal cancer (mCRC). However, severe toxicities often occur early and require dose reduction and/or interruption. To improve dose intensity and treatment outcome, we investigated regorafenib dose escalation strategy with low starting dose. The association between systemic exposure and tolerability was also analyzed.
In this phase II, single arm, multicenter study, we enrolled patients with refractory mCRC. Regorafenib was initiated at 120 mg/day. In patients who experienced neither hand-foot skin reaction nor grade ≥2 adverse reactions without dose reduction or interruption until day 15 in the first cycle, the dose of regorafenib was escalated to standard dose of 160 mg/day at day 15. The primary endpoint was disease control rate (DCR). With power of 80% and two-sided alpha of 5%, 67 patients were required to reject 30% of DCR expecting 45% of DCR. Serum concentrations of regorafenib and its active metabolites (M-2, N-oxide metabolite; M-5, N-oxide/N-desmethyl metabolite) at days 8, 15 and 22 in the first cycle were assessed.
From September 2016 to December 2017, 68 patients were enrolled. The DCR was 32.4% (95% CI, 21.5-44.8) with no patients achieving complete or partial response. The dose of regorafenib was escalated to 160 mg at day 15 in only six patients of 39 patients without dose reduction or interruption until day 15. In 55 patients without dose reduction or interruption due to adverse reactions until day8, the serum concentrations of regorafenib at day 8 in the six patients whose dose was escalated to 160 mg were significantly lower than those in the other 49 patients (median, 3978 nM; range, 2487-13614 nM vs. 6951 nM; 2822-17621 nM; P = 0.028). The serum concentrations of sum of regorafenib and active metabolites (M-2 and M-5) at day 8 showed similar tendency (6582 nM; 2913-21388 nM vs. 11730 nM; 4596-33211 nM; P = 0.064).
This dose escalation strategy with low starting dose for regorafenib did not improve DCR. Lower systemic exposure was associated with better tolerability.
Clinical trial identification
Legal entity responsible for the study
T. Masuishi: Honoraria: Bayer. H. Satake: Honoraria: Bayer, Chugai Pharma, Eli Lilly Japan, Merck Serono, Takeda, Taiho Pharmaceutical, Yakult Honsha. N. Boku: Investigator initiated trial funded by Bayer. All other authors have declared no conflicts of interest.