Phase II Trial of Dabrafenib Plus Trametinib in Relapsed/Refractory BRAF V600-Mutant Pediatric High-Grade Glioma

Abstract

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.

Trial registration: ClinicalTrials.gov NCT02684058.

FIG 1.

(A) Best change from baseline in tumor measurement (independent review per RANO criteria). (B) Percent changes from baseline in tumor measurements at 1 year/last assessment (independent review per RANO criteria; full analysis set). Patients for whom the percent change of target lesions was not available or for whom the BOR was unknown were excluded from the analysis. If the change in tumor size at 1 year/last visit before day 322 was not confirmed by a repeat scan, the BOR may not be consistent with the percent change from baseline. Only patients with measurable disease at baseline were included. Waterfall plots are based on radiographic response per RANO criteria, without consideration of clinical status or corticosteroid use. One patient with a BOR of PD had a radiographic response of SD. ^aSD for ≥16 weeks is recorded at ≥15 weeks (ie, ≥105 days) from treatment start date. ^bOne patient did not have a valid postbaseline assessment and two had SD and/or unconfirmed CR/PR only occurring before week 16. ^cSD for ≥24 weeks is recorded at ≥23 weeks (ie, ≥161 days) from treatment start date. ^dPercent change in target lesion contradicted by overall lesion response of PD. ^ePatients not in the evaluable set. The evaluable set, used for sensitivity analyses, comprised all patients in the as-treated population with centrally confirmed HGG through histology, centrally confirmed positive BRAF V600 mutation status, adequate tumor assessment at baseline, and a follow-up tumor assessment ≥8 weeks after starting treatment (unless disease progression was observed before that time) or had discontinued for any reason. ^fPercent change is 491.43. ^gPatient did not have an assessment at 1 year (defined as day 322-399), and their last visit before day 322 is presented in the figure. BOR, best overall response; CBR, clinical benefit rate; CR, complete response; dab, dabrafenib; HGG, high-grade glioma; ORR, overall response rate; PD, progressive disease; PR, partial response; RANO, Response Assessment in Neuro-Oncology; SD, stable disease; tram, trametinib.

FIG 2.

(A) Time to onset of response by independent assessment. Only the first occurrence of each response (CR, PR) and/or PD are displayed. (B) Duration of response by independent assessment. Off treatment indicates one patient who discontinued treatment due to an adverse event but remained in follow-up for tumor assessment until data cutoff. All other patients either discontinued treatment due to progressive disease or death, or remained on treatment until data cutoff. ^aPatients not in the evaluable set. The evaluable set, used for sensitivity analyses, comprised all patients in the as-treated population with centrally confirmed HGG through histology, centrally confirmed positive BRAF V600 mutation status, adequate tumor assessment at baseline, and a follow-up tumor assessment ≥8 weeks after starting treatment (unless disease progression was observed before that time) or had discontinued for any reason. CR, complete response; HGG, high-grade glioma; NR, not reached; PD, progressive disease; PR, partial response.

FIG 3.

Progression-free survival by independent assessment. ^aOnly includes patients who died without known disease progression.