Phase II Trial of Dabrafenib Plus Trametinib in Relapsed/Refractory BRAF V600–Mutant Pediatric High-Grade Glioma
Mené sur 41 patients pédiatriques atteints d'un gliome de haut grade, récidivant ou réfractaire aux traitements et présentant une mutation V600 au niveau du gène BRAF (durée médiane de suivi : 25 mois), cet essai de phase II évalue l'efficacité, du point de vue du taux de réponse globale, de la durée de la réponse, de la survie sans progression et de la survie globale, et la sécurité du dabrafénib en combinaison avec le tramétinib
PURPOSE : BRAF V600 mutation is detected in 5%-10% of pediatric high-grade gliomas (pHGGs), and effective treatments are limited. In previous trials, dabrafenib as monotherapy or in combination with trametinib demonstrated activity in children and adults with relapsed/refractory BRAF V600–mutant HGG. METHODS : This phase II study evaluated dabrafenib plus trametinib in patients with relapsed/refractory BRAF V600–mutant pHGG. The primary objective was overall response rate (ORR) by independent review by Response Assessment in Neuro-Oncology criteria. Secondary objectives included ORR by investigator determination, duration of response (DOR), progression-free survival, overall survival (OS), and safety. RESULTS : A total of 41 pediatric patients with previously treated BRAF V600–mutant HGG were enrolled. At primary analysis, median follow-up was 25.1 months, and 51% of patients remained on treatment. Sixteen of 20 discontinuations were due to progressive disease in this relapsed/refractory pHGG population. Independently assessed ORR was 56% (95% CI, 40 to 72). Median DOR was 22.2 months (95% CI, 7.6 months to not reached [NR]). Fourteen deaths were reported. Median OS was 32.8 months (95% CI, 19.2 months to NR). The most common all-cause adverse events (AEs) were pyrexia (51%), headache (34%), and dry skin (32%). Two patients (5%) had AEs (both rash) leading to discontinuation. CONCLUSION : In relapsed/refractory BRAF V600–mutant pHGG, dabrafenib plus trametinib improved ORR versus previous trials of chemotherapy in molecularly unselected patients with pHGG and was associated with durable responses and encouraging survival. These findings suggest that dabrafenib plus trametinib is a promising targeted therapy option for children and adolescents with relapsed/refractory BRAF V600–mutant HGG.