Early Higher Plasma Regorafenib Concentration Predicts Shorter PFS in Japanese Patients With mCRC

The pharmacokinetics of regorafenib and its active metabolites, M2 and M5, vary widely among individual patients. However, the relationship between these plasma concentrations and therapeutic efficacy remains unclear. Patients with metastatic colorectal cancer (mCRC) receiving regorafenib as third-line or later treatment were enrolled. The initial dose was 120 mg daily for 1 week, then adjusted based on tolerability in a 21-day on, 7-day off cycle. Blood samples were collected on Cycle 1 Day 7, and Ctrough levels of total regorafenib, M2, and M5 were measured using liquid chromatography-tandem mass spectrometry. Thirty-three patients were enrolled, with a median progression-free survival (PFS) of 70 days. The median Ctrough level of regorafenib, M2, and M5 was 2146.9 ng/mL (range: 369.0-5445.9), 1587.2 ng/mL (range: 43.6-6762.7), and 582.9 ng/mL (range: 39.9-352.6), respectively. There was an inverse correlation between PFS and the Ctrough level of regorafenib (r = -0.394, p = 0.023). Patients with regorafenib levels ≥ 2848.4 ng/mL had significantly shorter PFS (median 35 vs. 95 days, HR 3.23, 95% CI 1.45-7.25, p = 0.002). In Cycle 1, more frequent serious adverse events (30.0% vs. 4.3%, p = 0.073) and an increased neutrophil-to-lymphocyte ratio (median: 3.9 (3.0-5.2) vs. 3.1 (1.1-14.5), p = 0.031) were observed in the higher group. Furthermore, the rate of treatment resumption after interruption during Cycle 1 was significantly lower in the higher group (16.7% vs. 88.9%, p = 0.003). A rapid increase in blood concentrations of regorafenib early after administration resulted in severe toxicity and systemic inflammation, which may have subsequently contributed to shorter PFS.