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 aberra
Ralph Salloum, Clinton Stewart, Kathleen Schieffer, Steaphanie Balow, Daniel Leino, Alicia Lenzen, Angela Waanders, Patricia Baxter, Holly Lindsay, Tina Poussaint, Nathan Robeson, Natasha Pillay Smiley, Sonia Partap, Jason Fangusaro, Arzu Onar-Thomas, Katrina O’Halloran, Maryam Fouladi, Ira DunkelAbstract
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.