Dabrafenib combined with tramatinib in the treatment of BRAF V600 mutated pediatric gliomas

Detected in pediatric low-grade glioma BRAF V600E mutation is associated with lower response to standard chemotherapy. The finding that dabrafenib, alone and in combination with tramatinib, was effective in BRAF V600-mutated recurrent childhood low-grade glioma in previous trials warrants further evaluation of this combination as first-line treatment.

In this phase 2 trial, pediatric patients with BRAF V600-mutant low-grade glioma scheduled for first-line therapy were randomly assigned in a 2:1 ratio to receive dabrafenib plus tramatinib or standard chemotherapy (carboplatin plus vincristine). The primary outcome was overall response (complete or partial response) assessed independently according to response assessment in neuro-oncology criteria. Clinical benefit (complete or partial response or stable disease≥24 weeks) and progression-free survival (PFS) were also assessed.

A total of110 patients underwent randomization (73 to receive dabrafenib plus tramadol and 37 to standard chemotherapy). At a median follow-up of 18.9 months, 47% of patients who received dabrafenib plus tramatinib and 11% of patients who received chemotherapy had an overall response (hazard ratio, 4.31; 95% confidence interval [CI], 1.7-11.2; P<0.001). Clinical benefit was observed in 86% of patients who received dabrafenib plus tramatinib and in 46% of patients who received chemotherapy (hazard ratio, 1.88; 95% CI, 1.3-2.7). The median progression-free survival time of the dabrafenib combined with tramatinib group was significantly longer than that of the chemotherapy group (20.1 months vs. 7.4 months; hazard ratio 0.31; 95% CI 0.17-0.55; P<0.001). Grade 3 or higher adverse events occurred in 47% of patients who received dabrafenib plus tramatinib, and in 94% of patients who received chemotherapy.

This clinical study shows that dabrafenib plus tramatinib resulted in significantly more responses, longer progression-free survival and a better safety profile compared with standard chemotherapy as first-line treatment in pediatric patients with BRAF V600-mutated low-grade gliomas.

The original drug of dabrafenib is relatively expensive and has been covered by medical insurance since it was launched in China. Currently only eligible patients are reimbursed. The price of each box of 50mg*120 capsules may be around around 10,000. The Turkish version of the original drug Dabrafenib sold overseas, Specifications 75mg*120 capsules, may cost around 10,000 per box (the price may fluctuate due to exchange rates). There are also relatively cheap generics of dabrafenib sold overseas, and their pharmaceutical ingredients are basically the same as those of the original drugs sold domestically and abroad. For example, Specifications produced by Laos Pharmaceutical Factory The price of 75mg*120 tablets per box may be more than 4,000 yuan (the price may fluctuate due to exchange rates).