ID #854 Updated findings from a phase 1 study of savolitinib in recurrent, progressive, or refractory medulloblastoma (MB), high-grade glioma (HGG), diffuse intrinsic pontine glioma (DIPG), and central nervous system (CNS) tumors harboring MET aberrations: A Pediatric Brain Tumor Consortium Trial: PBTC-049

Abstract Background Aberrant activation of mesenchymal epithelial transition receptor (MET) contributes to tumorigenesis in pediatric CNS tumors making MET inhibition a potential therapeutic target in this patient population. Methods We conducted a first-in-children multicenter phase 1 trial of the MET inhibitor savolitinib in children with recurrent or refractory MB, HGG and DIPG. The main objectives were to determine the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) of once-daily oral savolitinib and to characterize its toxicity and pharmacokinetics. Following MTD/RP2D determination, an efficacy expansion cohort limited to participants with MET-altered CNS tumors (including MET mutations, fusions, MET/HGF amplification) was activated. Results 41 participants were enrolled (median age: 12.5 years, range 5.3-21.5); 1 was deemed ineligible. The MTD/RP2D was 350 mg/m2 (dose level 3). Two dose-limiting toxicities (grade 3 fatigue, grade 3 ALT elevation) occurred. The most common grade 3/4 adverse events at least possibly related to savolitinib were neutropenia and lymphopenia (each 3/39, 7.7%), and leukopenia (2/39, 5.1%). In the phase 1 cohort, 1 objective response was observed in a participant with recurrent HGG on dose level 1 (150 mg/m2); they completed 39 treatment courses. Three participants with progressive DIPG remained on treatment for a median of 9 courses (range 4-24); One other participant with recurrent HGG remained on treatment for 7 courses.The median (range) apparent oral savolitinib clearance was 30.4 L/h/m2 (3.8–220.1) and half-life 3.2 hr (1.63–22.2). Among 7 participants with tumors harboring MET aberrations, 2 demonstrated sustained stable disease for 6 courses, while none achieved an objective response. Correlative analyses are underway. Conclusions Savolitinib was well-tolerated in children with recurrent CNS tumors with an MTD/RP2D of 350 mg/m2. Although preliminary antitumor activity was observed in the phase 1 cohort, no objective responses were seen in biomarker-selected participants.