FDA Approves Dabrafenib Plus Trametinib in Low-Grade Glioma With BRAF V600E Mutation

The FDA has approved dabrafenib (Tafinlar) plus trametinib (Mekinist) for pediatric patients who are 1 year or older and require systemic therapy for low-grade glioma harboring a BRAF V600E mutation, according to a press release from the agency.¹

The approval is based on data from the phase 2 CDRB436G2201 (NCT02684058) trial for patients with low-grade glioma who require systemic therapy. In patients receiving dabrafenib plus trametinib, the overall response rate (ORR) was 46.6% (95% CI, 34.8%-58.6%) vs 10.8% (95% CI, 3.0%-25.4%) for those receiving carboplatin plus vincristine.

In the low-grade glioma cohort, 110 patients were enrolled with 73 in the combination arm and 37 in the chemotherapy arm. Patients were randomly assigned 2:1 and BRAF V600E mutations were determined through laboratory tests.

In the combination arm, age- and weight-based dosing were given until patients no longer derived benefit or had unacceptable toxicity. In the chemotherapy arm, dosing was based on body surface area at 175 mg/m² and 1.5 mg/m², respectively, as a single 10-week induction followed by 8, 6-week cycles of maintenance.

The primary end point was ORR, with secondary end points being duration of response (DOR), time to response, overall survival (OS), and progression-free survival (PFS).

In the dabrafenib plus trametinib arm, the DOR was 23.7 months (95% CI, 14.5-not estimable [NE]) vs NE (95% CI, 6.6-NE) in the chemotherapy arm. Patients had a median PFS of 20.1 months (95% CI, 12.8-NE) in the dabrafenib plus trametinib arm and 7.4 months (95% Ci, 3.6-11.8) in the chemotherapy arm (HR, 0.31; 95% CI, 0.17-0.55; P = .001).

Of note, at the time of the interim analysis for OS which had been conducted in all patients who had completed at least 32 weeks of treatments or had discontinued earlier, there was 1 death in the chemotherapy arm. Additionally, the OS did not reach statistical significance.

In the dabrafenib plus trametinib arm, the safety population included 166 patients. The most common adverse effects were pyrexia (66%), rash (54%), headache (40%), vomiting (38%), and musculoskeletal pain (36%). Grade 3 or 4 laboratory abnormalities included decreased neutrophil count (20%), increased alanine aminotransferase (3.1%), and increased aspartate aminotransferase (3.1%).

The primary results of this trial were presented at the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting.² Additionally, in June 2022, the FDA granted accelerated approval to the indication for adult and pediatric patients 6 years and older with unresectable or metastatic solid tumors harboring mutations in BRAF V600E following progression on previous treatment who have no satisfactory alternative treatment options.³

References

1. FDA approves dabrafenib with trametinib for pediatric patients with low-grade glioma with a BRAF V600E mutation. News release. FDA. March 16, 2023. Accessed March 17, 2023. https://bit.ly/3JMBdN7
2. Bouffet E, Hansford J, Garré ML. Primary analysis of a phase II trial of dabrafenib plus trametinib (dab + tram) in BRAFV600–mutant pediatric low-grade glioma (pLGG). J Clin Oncol. 2022;40(suppl 17):LBA2002. doi:10.1200/JCO.2022.40.17_suppl.LBA2002
3. Novartis Tafinlar + Mekinist receives FDA approval for first tumor-agnostic indication for BRAF V600E solid tumors. News release. Novartis. June 22, 2022. Accessed March 17, 2023. https://bit.ly/3QUkPf9