Abstract B008: Pharmacokinetics of daraxonrasib (RMC-6236): transporter and enzyme impact on a first-in-class pan-RAS molecular glue

Daraxonrasib (RMC-6236) is an innovative, first-in-class oral pan-RAS inhibitor leveraging a unique molecular glue mechanism to target all forms of RAS proteins. It is currently in phase III clinical trials and aims to treat solid tumors harboring RAS mutations, including NSCLC, PDAC and CRC. KRAS-mutant NSCLC develops brain metastases in 30% of patients. Effective therapies are urgently needed and the blood-brain barrier (BBB) poses an additional therapeutic hurdle. Pharmacokinetic studies of anticancer drugs serve as a foundation for designing effective dosing regimens, optimizing the formulation of a drug, assessing the bioavailability, identifying potential safety concerns and anticipating clinical drug–drug interactions of new therapies. Here, We assessed how drug efflux transporters expressed at the BBB (ABCB1, ABCG2), drug-metabolizing enzymes (CYP3A, CES1, CES2), and drug uptake transporters (OATP1A/1B) affect the plasma exposure and organ disposition of oral daraxonrasib in mice. In vitro, human ABCB1 transported daraxonrasib. The pharmacokinetics of orally administered daraxonrasib were studied in transporter- and enzyme-deficient mice, and in CYP3A4-humanized mice. Compared to wild-type controls, Abcb1a/b- and Oatp1a/1b-deficient mice had significantly increased plasma exposure of daraxonrasib, suggesting that these proteins transport daraxonrasib in vivo. Observed Abcb1a/b-mediated transport of daraxonrasib across the BBB was validated by oral co-administration of the ABCB1/ABCG2 inhibitor elacridar, resulting in 20-fold increased brain penetration in wild-type mice. In CYP3A4-humanized Cyp3a -/- mice, the plasma exposure of daraxonrasib was significantly (>3-fold) reduced. Hepatic metabolism was mildly reduced in Ces1-deficient mice, whereas Ces2 knockout mice showed unchanged daraxonrasib pharmacokinetics. Thus, daraxonrasib is a well-transported substrate of human ABCB1 in vitro and mouse Abcb1a in vivo, with pronounced effects on reducing plasma exposure and brain penetration of daraxonrasib. These phenomena might limit the efficacy of daraxonrasib against brain metastases. Elacridar co-administration represents a potential pharmacokinetic boosting strategy to target brain metastases during daraxonrasib treatment. Furthermore, Oatp1a/1b proteins appear to mediate hepatic uptake and clearance of daraxonrasib, and possibly the intestinal uptake is also facilitated. Finally, daraxonrasib clearance appears to be substantially mediated by human CYP3A4. Both the latter findings suggest that plasma levels of this oral drug could be sensitive to genetic polymorphisms and/or drug-drug or drug-food interactions affecting OATP and CYP3A activity. These findings may provide a mechanistic basis for optimizing daraxonrasib combination and boosting strategies in clinical settings. Citation Format: Davinia Arguedas, Viët Bui, Tjon Law, Jamie Rijmers, Renaud Tissier, M. Cristina Lebre, Jos H. Beijnen, Alfred H. Schinkel. Pharmacokinetics of daraxonrasib (RMC-6236): transporter and enzyme impact on a first-in-class pan-RAS molecular glue [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RAS Oncogenesis and Therapeutics; 2026 Mar 5-8; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(5_Suppl_1):Abstract nr B008.