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FDA Approval Summary: Dabrafenib in Combination with Trametinib for BRAFV600E Mutation-Positive Low-Grade Glioma
Michael I Barbato1, Jeannette Nashed1, Diana Bradford1
1Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland.
Abstract:
On March 16, 2023, the FDA approved dabrafenib in combination with trametinib (Tafinlar, Mekinist; Novartis Pharmaceuticals Corporation) for the treatment of pediatric patients with low-grade glioma (LGG) with a BRAFV600E mutation who require systemic therapy. FDA also approved oral formulations of both drugs suitable for patients who cannot swallow pills. This approval was based on the LGG cohort from study CDRB436G2201 (NCT02684058), a multicenter, open-label trial in which pediatric patients with LGG with a BRAFV600E mutation were randomly assigned 2:1 to dabrafenib plus trametinib (D+T) or carboplatin plus vincristine (C+V). The overall response rate (ORR) by independent review based on Response Assessment in Neuro-oncology LGG (2017) criteria was assessed in 110 patients randomly assigned to D+T (n = 73) or C+V (n = 37). ORR was 47% [95% confidence interval (CI), 35-59] in the D+T arm and 11% (95% CI, 3.0-25) in the C+V arm. Duration of response (DOR) was 23.7 months (95% CI, 14.5-NE) in the D+T arm and not estimable (95% CI, 6.6- NE) in the C+V arm. Progression-free survival (PFS) was 20.1 months (95% CI: 12.8, NE) and 7.4 months (95% CI, 3.6- 11.8) [HR, 0.31 (95% CI, 0.17-0.55); P < 0.001] in the D+T and C+V arms, respectively. The most common (>20%) adverse reactions were pyrexia, rash, headache, vomiting, musculoskeletal pain, fatigue, diarrhea, dry skin, nausea, hemorrhage, abdominal pain, and dermatitis acneiform. This represents the first FDA approval of a systemic therapy for the first-line treatment of pediatric patients with LGG with a BRAFV600E mutation.
Insights
The FDA approved dabrafenib plus trametinib for pediatric low-grade glioma with BRAFV600E mutation. This targeted therapy showed superior response rates and progression-free survival compared to chemotherapy.
Area of Science:
- Oncology
- Pediatric Medicine
- Pharmacology
Background:
- Low-grade glioma (LGG) is the most common primary brain tumor in children.
- BRAFV600E mutations are found in approximately 20% of pediatric LGGs.
- Systemic therapy options for pediatric LGG with BRAFV600E mutations have been limited.
Purpose of the Study:
- To evaluate the efficacy and safety of dabrafenib plus trametinib versus carboplatin plus vincristine in pediatric patients with LGG and a BRAFV600E mutation.
- To report the first FDA approval of a targeted systemic therapy for this patient population.
Main Methods:
- A multicenter, open-label trial (CDRB436G2201) randomly assigned pediatric patients with LGG and BRAFV600E mutation to dabrafenib plus trametinib (D+T) or carboplatin plus vincristine (C+V).
- Overall response rate (ORR) was assessed by independent review using Response Assessment in Neuro-oncology LGG criteria.
- Progression-free survival (PFS) and duration of response (DOR) were key secondary endpoints.
Main Results:
- The ORR was 47% in the D+T arm versus 11% in the C+V arm.
- Median PFS was 20.1 months with D+T compared to 7.4 months with C+V (Hazard Ratio: 0.31; P < 0.001).
- The most common adverse reactions in the D+T arm included pyrexia, rash, and headache.
Conclusions:
- Dabrafenib plus trametinib demonstrated superior efficacy compared to carboplatin plus vincristine in pediatric patients with LGG and BRAFV600E mutation.
- This combination represents a significant advancement and the first FDA-approved targeted systemic therapy for this indication.
- Oral formulations were also approved, improving accessibility for pediatric patients.
