Pharmacokinetics of the oral multikinase inhibitor regorafenib and its association with real‐world treatment outcomes

Purpose Despite the established activity of regorafenib in metastatic colorectal cancer (CRC), gastrointestinal stromal tumor (GIST), and hepatocellular carcinoma (HCC), its toxicity profile has limited clinical use. We aimed to evaluate the pharmacokinetics of regorafenib and its active metabolites M-2/M-5, and to clarify the relationships between total drug-related exposure and clinical outcomes in real-world practice. Methods Blood samples at steady state were obtained during Cycle 1 from patients treated with regorafenib. Plasma concentrations of regorafenib and its metabolites were measured by liquid chromatography–tandem mass spectrometry. The efficacy and safety endpoints were progression-free survival (PFS) and dose-limiting toxicities (DLTs), respectively. The exposure–response relationships were assessed. Results Thirty-four Japanese patients with advanced cancers were enrolled (CRC, n = 26; GIST and HCC, each n = 4). Nine patients started regorafenib treatment at the recommended dose of 160 mg once daily (3 weeks on / 1 week off), while the other patients received a reduced starting dose to minimize toxicities. The median PFS was significantly longer in patients achieving total trough concentrations (C_trough) of regorafenib and M-2/M-5 ≥2.9 µg/mL than those who did not (112 vs. 57 days; p = 0.044). Furthermore, the cumulative incidence of DLTs during the first 2 cycles was significantly higher in patients with summed C_trough levels ≥4.3 µg/mL than in others (p = 0.0003). Conclusions Dose titration of regorafenib to achieve drug-related C_trough levels between 2.9 and 4.3 µg/mL in Cycle 1 may improve efficacy and safety, warranting further investigation in a larger patient population.

Clinical trial registry: Not applicable.