Dabrafenib + trametinib (dab + tram) in relapsed/refractory (r/r) BRAF V600–mutant pediatric high-grade glioma (pHGG): Primary analysis of a phase II trial.
Authors: Hargrave Darren R. , Terashima Keita , Hara Junichi , Kordes Uwe R. , Upadhyaya Santhosh A. , Sahm Felix , Bouffet Eric , Packer Roger J. , Witt Olaf , Sandalic Lali , Kieloch Agnieszka , Russo Mark W. , Cohen Kenneth J. 
Published: June 2022

2009 Background: HGGs comprise ≈10% of pediatric central nervous system tumors and are a leading cause of childhood cancer-related death. Overall response rates (ORRs) with current standards of care are low, particularly in the second line, and 2-y overall survival (OS) rates are ≤35%. BRAF V600 mutation is infrequent (≈5% of pHGGs) but associated with improved survival from time of initial diagnosis. In previous trials, dab monotherapy and dab + tram yielded encouraging outcomes in BRAF V600–mutant HGG in pediatric and adult patients (pts), respectively. We describe the results of a Phase II study (NCT02684058) of dab + tram in r/r BRAF V600–mutant pHGG. Methods: Pts aged 1 to <18 y with BRAF V600–mutant HGGs and Karnofsky/Lansky performance status ≥50% who had failed first-line therapy were enrolled in a single-arm cohort. Pts received dab twice daily (<12 y, 5.25 mg/kg/d; ≥12 y, 4.5 mg/kg/d) + tram once daily (<6 y, 0.032 mg/kg/d; ≥6 y, 0.025 mg/kg/d). The primary endpoint was ORR (independent review; HGG-RANO criteria); secondary endpoints included ORR (investigator review), duration of response (DOR), progression-free survival (PFS), OS, and safety. Results: A total of 41 pts with diverse WHO Grade III/IV gliomas were enrolled; median time since diagnosis was 17.4 mo (range, 2.7-174.3 mo), and most had prior surgery (97.6%), radiotherapy (90.2%), and/or systemic antineoplastic therapy (80.5%). At data cutoff (August 23, 2021; median follow-up, 25.1 mo), 21 pts (51.2%) remained on treatment; most discontinuations (16 of 20) were due to progressive disease. Median exposure was 72.7 wk (range, 1.3-172.1 wk). The primary endpoint was met, with an independently assessed ORR of 56.1% (95% CI, 39.7%-71.5%). Median DOR was 22.2 mo (95% CI, 7.6 mo-not estimable [NE]; 12-mo Kaplan-Meier [KM] DOR rate, 62.2%), and median PFS was 9.0 mo (95% CI, 5.3-24.0 mo; 12-mo KM PFS rate, 44.1%). There were 14 deaths (34.1%), with 12 due to HGG and 2 due to serious adverse events (AEs; encephalomyelitis and intracranial pressure increased [n = 1 each], not treatment related per investigators); median OS was 32.8 mo (95% CI, 19.2 mo-NE; 12-mo KM OS rate, 76.3%). The most common all-cause AEs were pyrexia (51.2%), headache (34.1%), dry skin (31.7%), vomiting (29.3%), and diarrhea (24.4%). Two pts (4.9%) had AEs leading to discontinuation (both rash), and 26 (63.4%) had AEs leading to dose modification. Conclusions: Treatment with dab + tram demonstrated an improvement in ORR, response durability, and survival compared with estimates based on historical observations with current treatment approaches in r/r BRAF V600–mutant pHGG. Safety was consistent with the established profile of dab + tram in other indications. Thus, dab + tram may represent a critical treatment advance for this pt population with high unmet need. Clinical trial information: NCT02684058.