Abstract 4353: A phase I open-label positron-emission tomography study to determine brain exposure of [11C]savolitinib in healthy volunteers

Abstract Introduction: Savolitinib is a potent, oral highly selective small molecule MET kinase inhibitor and is capable of inhibiting tumor growth in vivo when used as a monotherapy or in combination therapy for multiple indications harboring MET aberrations (MET amplification or MET overexpression). The use of savolitinib in combination with osimertinib is currently being evaluated in NSCLC patients with EGFR mutations and MET amplification. Patients with EGFR mutations appear to have a higher incidence (50-60%) of brain metastasis1. Preclinical data suggest that savolitinib penetrates the blood-brain barrier (BBB) which is important to prevent or treat brain metastasis. This study was conducted to determine brain distribution and exposure of a microdose of carbon-11 labelled savolitinib using positron emission tomography (PET), in healthy adult volunteers under physiological conditions (i.e. when the BBB is intact). Methods: This was an open-label, non-randomised, single-center study. The study was comprised of two site visits and follow-up call. The first visit included screening, the second visit involved two PET examinations. For the first PET examination (PET1), a single microdose (≤10 μg) of [11C]savolitinib was administered. The second PET examination (PET2) using [11C]savolitinib took place the same day, approximately 2 hours after the administration of a single oral 300 mg dose of savolitinib. Radioactivity in brain and arterial blood were measured. Kinetic PET parameters describing brain distribution and exposure were quantified: percent injected dose entering the brain, %IDmax_brain; time to maximum concentration in brain, Tmax; free brain to free plasma partition coefficient Kp, uu. Results: Seven participants, 2 males, 5 females, 51-64 years of age were examined. [11C]savolitinib entered the brain at a mean 0.80 %IDmax_brain (range: 0.65% to 0.93%, n = 7) and uniformly distributed in all brain regions. When the participants were pre-treated with a 300 mg oral dose of savolitinib the %IDmax_brain values were found to be similar (mean: 0.81 %IDmax_brain, range: 0.69% to 0.99%, n = 6). The median Tmax_brain values at PET1 and PET2 examination were 1.45 minutes (range: 0.22 to 10.95 minutes) and 1.72 minutes (range: 0.17 to 11.03 minutes) and the mean±SD for Kp, uu was 0.29±0.08 (range: 0.21 to 0.46) and 0.35 ± 0.04 (range: 0.30 to 0.41), respectively. Conclusion: PET brain imaging in healthy volunteers showed that savolitinib penetrates the BBB and distributes to the brain following IV injection of a microdose of [11C]savolitinib. Reference: Makoto Nishino et al. 2019. Brain metastases in oncogene-driven non-small cell lung cancer. Transl Lung Cancer Res. S298-S307. Citation Format: Kowser Miah, Zsolt Cselényi, Jonas Svensson, Aurelija Jucaite, Ike Igwegbe, Caitlin Muldoon, Miriam Zanuy Porquet, Kenneth Dahl, Peter Johnström, Miguel A. Cortés González, Antonia Högnäsbacka, Andrea Varrone, Karthick Vishwanathan, Magnus Schou. A phase I open-label positron-emission tomography study to determine brain exposure of [11C]savolitinib in healthy volunteers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4353.