The following is a summary of “Efficacy and Safety of Trametinib Monotherapy or in Combination With Dabrafenib in Pediatric BRAF V600–Mutant Low-Grade Glioma,” published in the January 2023 issue of Oncology by Bouffet, et al.
Approximately 20% of low-grade gliomas (LGGs) and other pediatric malignancies have BRAFV600 mutations. For a study, researchers sought to outline a phase I/II trial that established pediatric dosage and pharmacokinetics for trametinib with or without dabrafenib, as well as efficacy and safety in a disease-specific cohort with BRAFV600-mutant LGG; other cohorts will be published later.
Patients under the age of <18 with relapsed/refractory cancers were being studied in this four-part phase I/II trial, which is divided into two parts: trametinib monotherapy dose-finding (part A), and disease-specific expansion (part B), dabrafenib + trametinib dose discovery (part C) and disease-specific expansion (part D). To estimate pediatric dose based on steady-state pharmacokinetics, all patients in sections A and C were evaluated for this main goal. Secondary goals were safety and disease-specific efficacy (across sections A–D).
Trametinib (n = 91) or dabrafenib with trametinib (n = 48) were given to 139 patients. Mucosal inflammation (n = 3) and hyponatremia (n = 2) were Trametinib dose-limiting effects in >1 patient (part A). Combination therapy did not cause any toxicities that were dose-limiting (part C). Trametinib dosage in the phase II study was 0.032 mg/kg once daily for patients <6 years and 0.025 mg/kg once daily for individuals ≥6 years; dabrafenib dosage in the combination was as previously identified for monotherapy. Throughout all four research components, 49 patients with BRAFV600-mutant glioma (LGG, n = 47) experienced independently assessed objective response rates of 15% (95% CI, 1.9 to 45.4) for monotherapy (n = 13) and 25% (95% CI, 12.1 to 42.2) for combination (n = 36). Treatment stopping due to adverse events was more prevalent with monotherapy (54% vs. 22%).
The trial’s layout allowed for an effective assessment of the pediatric dose, safety, and effectiveness of single-agent and combination-targeted therapy. Trametinib was dosed according to weight and age to attain target concentrations with controllable safety in BRAF V600-mutant LGG. The method also showed clinical efficacy and tolerability.