FDA approves dabrafenib with trametinib for pediatric patients with low-grade glioma with a BRAF V600E mutation

On March 16, 2023, the Food and Drug Administration approved dabrafenib (Tafinlar, Novartis) with trametinib (Mekinist, Novartis) for pediatric patients 1 year of age and older with low-grade glioma (LGG) with a BRAF V600E mutation who require systemic therapy. The FDA also approved new oral formulations of both drugs suitable for patients who cannot swallow pills.

This represents the first FDA approval of a systemic therapy for the first-line treatment of pediatric patients with LGG with a BRAF V600E mutation.

View full prescribing information for Tafinlar and Mekinist.

Efficacy was evaluated in Study CDRB436G2201 (NCT02684058), a multicenter, open-label trial in patients with LGG (WHO grades 1 and 2) requiring first systemic therapy. Patients were randomized 2:1 to dabrafenib plus trametinib (D+T) or carboplatin plus vincristine (C+V). BRAF mutation status was identified prospectively by local or central laboratory tests. Retrospective testing of available tumor samples by the central laboratory was also performed to evaluate mutation status. Patients received age- and weight-based dosing of D+T until they were no longer deriving benefit or experienced unacceptable toxicity. C+V were dosed based on body surface area at 175 mg/m² and 1.5 mg/m² (0.05 mg/kg for patients < 12 kg), respectively, as one 10-week induction course, followed by eight 6-week cycles of maintenance therapy.

The major efficacy outcome measure was overall response rate (ORR) by independent review based on RANO LGG (2017) criteria. Additional efficacy outcome measures were progression- free survival (PFS) and overall survival (OS). The primary analysis was performed when all patients had completed at least 32 weeks of therapy.

In the LGG cohort, 110 patients were randomized to D+T (n=73) or C+V (n=37). ORR was 46.6% (95% CI: 34.8, 58.6) in the D+T arm and 10.8% (95% CI: 3.0, 25.4) for those receiving C+V (p= <0.001). DOR was 23.7 months (95% CI: 14.5, not estimable) in the D+T arm and not estimable (95% CI: 6.6, not estimable) in the C+V arm. PFS was 20.1 months (95% CI: 12.8, not estimable) 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. At the time of the interim analysis of OS conducted when all patients had completed at least 32 weeks of treatment or had discontinued earlier, there was one death on the C+V arm. The OS results at the interim analysis did not reach statistical significance.

In the pooled safety population of pediatric patients receiving D+T (N=166), the most common (>20%) adverse reactions were pyrexia (66%), rash (54%), headache (40%), vomiting (38%), musculoskeletal pain (36%), fatigue (31%), dry skin (31%), diarrhea (30%), nausea (26%), epistaxis and other bleeding events (25%), abdominal pain (24%), and dermatitis acneiform (23%). The most common (>2%) Grade 3 or 4 laboratory abnormalities were decreased neutrophil count (20%), increased alanine aminotransferase (3.1%), and aspartate aminotransferase increased (3.1%).

The recommended doses for dabrafenib and trametinib in pediatric patients are based on body weight; dabrafenib is administered orally twice daily and trametinib is administered orally once daily. Dabrafenib and trametinib are administered until disease progression or unacceptable toxicity.

This review was conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence. Project Orbis provides a framework for concurrent submission and review of oncology drugs among international partners. For this review, FDA collaborated with Israel’s Ministry of Health and Switzerland’s Swissmedic. The application reviews are ongoing at the other regulatory agencies.

This review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment.

This application was granted priority review, breakthrough designation and orphan drug designation. FDA expedited programs are described in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System or by calling 1-800-FDA-1088.

For assistance with single-patient INDs for investigational oncology products, healthcare professionals may contact OCE’s Project Facilitate at 240-402-0004 or email OncProjectFacilitate@fda.hhs.gov.

For information on the COVID-19 pandemic, see the following resources:

Follow the Oncology Center of Excellence on Twitter @FDAOncology.