As reported in The New England Journal of Medicine by Eric Bouffet, MD, of the Hospital for Sick Children, Toronto, and colleagues, a phase II trial has shown a significant improvement in objective response rate and other efficacy outcomes with first-line dabrafenib plus trametinib vs standard chemotherapy in pediatric patients with BRAF V600–mutant low-grade glioma who were scheduled to receive first-line therapy.¹

Eric Bouffet, MD

Study Details

In the open-label trial, 110 patients from sites in 20 countries were randomly assigned 2:1 between September 2018 and December 2020 to receive the kinase inhibitors dabrafenib plus trametinib (n = 73) or standard chemotherapy with carboplatin plus vincristine (n = 37). Dabrafenib was given twice daily at total daily doses of 5.25 mg/kg for those up to age 12 and 4.5 mg/kg for those aged 12 and older, and trametinib was given once daily at 0.032 mg/kg for those up to age 6 and 0.025 mg/kg for those aged 6 and older. Treatment was continued until loss of clinical benefit or unacceptable toxicity. Patients in the chemotherapy group were permitted to cross over to dabrafenib/trametinib upon disease progression. Median patient age was 10 (range, 1–17 years) in the dabrafenib/trametinib group and 8 in the chemotherapy group. The primary outcome measure was independently assessed objective response rate according to Response Assessment in Neuro-Oncology low-grade glioma criteria.

Responses

Median follow-up was 18.9 months (range = 7.9–35.4 months). Objective responses (complete or partial response) were observed in 34 of 73 patients (47%, 95% confidence interval [CI] = 35%–59%) given dabrafenib plus trametinib vs 4 of 37 patients (11%, 95% CI = 3%–25%) given chemotherapy (risk ratio [RR] = 4.31, 95% CI = 1.7–11.2, P < .001). Complete responses were observed in two patients and one patient, respectively. Stable disease was observed in an additional 30 (41%) and 15 (41%) patients, respectively. Median duration of response was 20.3 months (95% CI =12.0 months to not evaluable) vs not evaluable (95% CI = 6.6 months to not evaluable); among responders, responses persisted at 6 months in 86% (95% CI = 66%–94%) vs 100% (95% CI = 100%–100%) and at 12 months in 70% (95% CI = 46%–85%) vs 50% (95% CI = 6%–85%). Among the most common histologic types at diagnosis, objective response was observed in 45% of 22 patients and 8% of 12 patients with pilocytic astrocytoma and 32% of 21 patients and 0% of 9 patients with ganglioglioma.

Clinical benefit (objective response plus stable disease for at least 24 weeks) was observed in 63 patients (86%, 95% CI = 76%–93%) given dabrafenib plus trametinib vs 17 patients (46%, 95% CI = 30%–63%) given chemotherapy (RR = 1.88, 95% CI = 1.3–2.7, P < .001). Median progression-free survival was 20.1 months (95% CI = 7.4 months to not evaluable) with dabrafenib plus trametinib vs 7.4 months (95% CI = 3.6–11.8 months) with chemotherapy (hazard ratio = 0.31, 95% CI = 0.17–0.55, P < .001). Rates at 6 and 12 months were 87% (95% CI = 77%–93%) vs 58% (95% CI = 39%–73%) and 67% (95% CI = 53%–77%) vs 26% (95% CI = 10%–46%).

No deaths were reported in the dabrafenib/trametinib group. One death occurred (from low-grade glioma) in a patient from the chemotherapy group who had crossed over to dabrafenib/trametinib for 22 weeks; the patient died 23 days after the final crossover dose.

Change from baseline in visual acuity was analyzed in 25 vs 11 patients with tumors located near the optic chiasm. Visual acuity remained stable in most patients in each group; visual acuity per eye was improved in 14 of 41 eyes (34%) examined in the dabrafenib/trametinib group vs 2 of 18 eyes (11%) examined in the chemotherapy group.

Adverse Events

The most common adverse events of any grade in the dabrafenib/trametinib group were pyrexia (68% vs 18% in the chemotherapy group), headache (47% vs 27%), and vomiting (34% vs 48%). Grade ≥ 3 adverse events occurred in 47% of the dabrafenib/trametinib group and 94% of the chemotherapy group. The most common adverse event in the dabrafenib/trametinib group included neutropenia (10%), pyrexia (8%), and increased weight (7%); the most common adverse event in the chemotherapy group included decreased neutrophil count (48%), neutropenia (30%), and anemia (24%). Serious adverse events occurred in 40% vs 39% of patients. Adverse events led to discontinuation of treatment in 4% of patients (one case each of chills, fatigue, pyrexia, increased weight, and headache) vs 18% of patients (two cases of infusion-related reaction and one each of headache, neutropenia, eyelid ptosis, hypersensitivity, dizziness, peripheral motor neuropathy, and urticaria).

The investigators concluded: “Among pediatric patients with low-grade glioma with BRAF V600 mutations, dabrafenib plus trametinib resulted in significantly more responses, longer progression-free survival, and a better safety profile than standard chemotherapy as first-line therapy.” 

DISCLOSURE: The study was funded by Novartis. For full disclosures of the study authors, visit nejm.org.

REFERENCE

1. Bouffet E, Hansford JR, Garrè ML, et al: Dabrafenib plus trametinib in pediatric glioma with BRAF V600 mutations. N Engl J Med 389:1108-1120, 2023.