FDA Approves Dabrafenib Plus Trametinib for Pediatric Patients With BRAF V600E–Mutated Low-Grade Glioma

FDA

The FDA has approved dabrafenib (Tafinlar) with trametinib (Mekinist) for the treatment of pediatric patients 1 year of age and older with low-grade glioma 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.

The regulatory decision was supported by data from the phase 2/3 TADPOLE trial (NCT02684058), which demonstrated that patients treated with dabrafenib plus trametinib (n = 73) achieved an overall response rate (ORR) of 46.6% (95% CI, 34.8%-58.6%) compared with 10.8% (95% CI, 3.0%-25.4%) for patients treated with carboplatin plus vincristine (n = 37; P < .001).

Patients in the dabrafenib/trametinib arm experienced a median duration of response of 23.7 months (95% CI, 14.5-not estimable [NE]); this was NE (95% CI, 6.6-NE) in the carboplatin/vincristine arm. The median progression-free survival (PFS) was 20.1 months (95% CI, 12.8-NE) for dabrafenib/trametinib and 7.4 months (95% CI, 3.6-11.8) for carboplatin/vincristine (HR, 0.31; 95% CI, 0.17-0.55; P < .001).

“Pediatric cancer research is vital to uncover new treatment methods for a population,” Eric Bouffet, MD, FRCPC, principal investigator of the TADPOLE trial and associate scientist emeritus at The Hospital for Sick Children (SickKids), stated in a news release.² “Developing targeted therapies based on the unique genetic features of a patient’s tumor is the future of pediatric cancer care.”

The multicenter, open-label TADPOLE trial enrolled patients with World Health Organization grade 1 and 2 low-grade glioma who required first systemic therapy. BRAF mutation status was identified prospectively by local or central laboratory tests, and retrospective testing of available tumor samples was also performed by central laboratory tests to evaluate mutation status.

Patients needed to be between 12 months and 17 years of age with BRAF V600–mutant low-grade glioma with progressive disease following surgical excision, or be non-surgical candidates with necessity to begin first systemic treatment because of a risk of neurological impairment with progression.³ Measurable disease was also required.

Key exclusion criteria included prior treatment with dabrafenib, trametinib, or another RAF, MEK, or ERK inhibitor; a history of allergic reaction or contraindications to the use of carboplatin or vincristine; a stem cell transplant within the past 3 months; or a history of heart disease.

Patients were randomly assigned in a 2:1 fashion to receive dabrafenib plus trametinib or carboplatin plus vincristine.¹ Patients in the experiemental arm were given age- and weight-based dosing of dabrafenib plus trametinib until benefit was no longer derived or they experienced unacceptable toxicity. Those in the control arm received 175 mg/m² of carboplatin and 1.5 mg/m² (0.05 mg/kg for patients less than 12 kg) of vincristine, based on body weight, as one 10-week induction course, followed by eight 6-week cycles of maintenance therapy.

ORR by independent review based on Response Assessment in Neuro-Oncology (RANO) low-grade glioma (2017) criteria served as the trial's primary end point. Secondary end points included PFS and overall survival (OS).

At the time of the interim analysis, when all patients had completed at least 32 weeks of treatment or discontinued earlier, 1 death was reported in the control arm. The OS data at the interim analysis did not reach statistical significance.

Regarding safety, in pooled data from a population of pediatric patients receiving dabrafenib/trametinib (n = 166), the most common any-grade adverse effects (AEs) reported in more than 20% of patients included 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 grade 3/4 laboratory abnormalities occuring in more than 2% of patients included decreased neutrophil count (20%), increased alanine aminotransferase (3.1%), and increased aspartate aminotransferase (3.1%).

“It is more important than ever to test for genetic mutations in patients living with low-grade glioma. This FDA approval may offer new hope to pediatric patients living with BRAF V600E low-grade glioma,” Roger Packer, MD, senior vice president of the Center for Neurosciences and Behavioral Medicine at Children’s National Hospital, stated in a press release.² “This has the potential to change the way healthcare providers treat these pediatric patients, offering a significant advancement compared to chemotherapy.”

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 16, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/
2. Novartis Tafinlar + Mekinist approved by FDA for pediatric patients with BRAF V600E low-grade glioma, the most common pediatric brain cancer. News release. Novartis. March 16, 2023. Accessed March 16, 2023. https://www.novartis.com/news/media-releases/
3. Phase II pediatric study with dabrafenib in combination with trametinib in patients with HGG and LGG. ClinicalTrials.gov. Updated January 30, 2023. Accessed March 16, 2023. https://clinicaltrials.gov/ct2/show/NCT02684058