Ripretinib (DCC-2618) pharmacokinetics (PK) in a Phase I study in patients with gastrointestinal stromal tumors (GIST) and other advanced malignancies: A retrospective evaluation of the PK effects of proton pump inhibitors (PPIs)

Objectives: Ripretinib is a novel, oral kinase switch control inhibitor of KIT and PDGFRα. Encouraging clinical benefit from the phase 1 dose escalation and expansion study as measured by ORR, DCR and PFS in 2nd, 3rd, and >4th line GIST patients with a favorable tolerability profile at doses >100 mg/day has been previously reported (ESMO 2018, abstract #1603O). It has been reported that more than 40% of GIST patients use acid-reducing agents. PPIs are the most potent acid-reducing agents that may impair the absorption of kinase inhibitors 1,2. This retrospective analysis aims to explore whether ripretinib can be used regardless of concomitant PPI use. Methods: The analysis assessed the impact of PPIs on the plasma concentration of ripretinib using PK data from the expansion cohort at the recommended Phase 2 dose of 150 mg QD. Plasma concentrations of ripretinib and its active metabolite DP-5439 obtained from patients who used or did not use PPIs were compared on Cycle 1 Day 1 (C1D1, n=106) and Day 15 (C1D15, n=102). Patients using PPIs were defined as those who continuously took PPIs for at least 4 days prior to C1D1 or C1D15. Patients who did not use PPIs were defined as those who did not take PPIs or any other acid-reducing agents during the study. Results: PK profiles were consistent between patients using and not using PPIs (Table 1), indicating a low likelihood of a clinically significant drug interaction between PPIs and ripretinib. Conclusions: This retrospective PK analysis provides supporting evidence that restriction of co-administration of PPIs with ripretinib may not be necessary. A dedicated drug interaction study is planned to provide a definitive assessment. References: 1. Smelick et al, Mol. Pharmaceutics 2013, 10, 4055−4062 2. Budha et al, Clin Pharmacol Ther. 2012, 92(2):203-13 Citation Format: Filip Janku, Michael Heinrich, Ping Chi, Albiruni Abdul Razak, Margaret von Mehren, Michael Gordon, Kristen Ganjoo, Jonathan Trent, Robin L. Jones, Hans Gelderblom, Kelli Running, Jing Wang, Rodrigo Ruiz-Soto, Suzanne George. Ripretinib (DCC-2618) pharmacokinetics (PK) in a Phase I study in patients with gastrointestinal stromal tumors (GIST) and other advanced malignancies: A retrospective evaluation of the PK effects of proton pump inhibitors (PPIs) [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 CT058.