Abstract 3883: High unbound plasma concentration of M-2, an active metabolite, is associated with shorter survival in patients with metastatic colorectal cancer who received regorafenib
Authors: Kubota Yutaro , Fujita Ken-ichi , Takahashi Takehiro , Sunakawa Yu , Ishida Hiroo , Hamada Kazuyuki , Ichikawa Wataru , Tsunoda Takuya , Masuo Yusuke , Kato Yukio , Sasaki Yasutsuna 
Published: August 2019

Abstract
Background and Aims: Regorafenib is an oral multikinase inhibitor which showed survival advantage in the later-line chemotherapy in patients with metastatic colorectal cancer (mCRC). This anticancer drug is sequentially metabolized to pharmacologically active metabolites M-2 and M-5 by the hepatic CYP3A. A randomized phase II trial has recently revealed that initial dose of 80 mg/day followed by dose escalations (40 mg/week) was superior to the standard dosing strategy (160 mg/day) with respect to overall survival (OS), resulting in the NCCN guideline recommendation for this dose escalation strategy, although scientific index for rational dose estimation is still limited. The aim of this prospective study was to clarify the association of pharmacokinetics (PK) with clinical outcome of regorafenib in patients with mCRC.
Methods: Consecutive patients with mCRC administered regorafenib at Showa University Hospital were prospectively enrolled in this study. Patients received regorafenib 160 mg once daily for the first 3 weeks of each 4 weeks cycle. Blood samples for PK analysis were obtained on day1 (0-48 h) skipping the second dose on day2, and if possible day15 of treatment (0-24 h). Plasma concentrations of the regorafenib, M-2, and M-5 were analyzed by HPLC or LC-MS/MS. Unbound fraction of these compounds were measured by equilibrium dialysis method.
Results: A total of 36 patients were enrolled between October 2013 and June 2017. The median progression free survival (PFS) was 1.9 months, and the median OS was 6.4 months. Area under the total (protein bound plus unbound) plasma concentration-time curve (AUC) on day1 was the highest in regorafenib (88.5 ± 53.8 µM·h), followed by M-2 and M-5 (37.0 ± 32.9 and 5.9 ± 6.5 µM·h, respectively), whereas AUC calculated based on unbound plasma concentration (uAUC) of M-2 was the highest (9.8 ± 12.0 nM·h), followed by M-5 and regorafenib (2.5 ± 4.3 and 1.8 ± 1.7 nM·h, respectively), reflecting ~10-fold higher unbound fraction in M-2 and M-5 than regorafenib. uAUC of M-2 measured on day15 was also higher than those of M-5 and regorafenib. Patients with the M-2 uAUC of 9.8 nM·h or higher had significantly shorter PFS than those with the uAUC of lower than 9.8 nM·h (30 vs. 74 days, p=0.0092). The highest uAUC value of M-2 may be compatible with its association with PFS, implying that unbound form of M-2 could be primarily important for clinical response.
Conclusion: We thus found that uAUC of active M-2 was the highest as compared to those of regorafenib and M-5, which was associated with shorter PFS.
Citation Format: Yutaro Kubota, Ken-ichi Fujita, Takehiro Takahashi, Yu Sunakawa, Hiroo Ishida, Kazuyuki Hamada, Wataru Ichikawa, Takuya Tsunoda, Yusuke Masuo, Yukio Kato, Yasutsuna Sasaki. High unbound plasma concentration of M-2, an active metabolite, is associated with shorter survival in patients with metastatic colorectal cancer who received regorafenib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3883.