In a phase I/II study reported in the Journal of Clinical Oncology, Eric Bouffet, MD, and colleagues found that trametinib alone or in combination with dabrafenib was safe and showed activity in pediatric patients with BRAF V600–mutant low-grade glioma.

Eric Bouffet, MD

Study Details

In the international four-part trial, a total of 139 patients with relapsed or refractory malignancies were enrolled between January 2015 and December 2020. Patients underwent dose testing and pharmacokinetic analysis for different dose levels of trametinib monotherapy (n = 91) and dose testing and pharmacokinetic analysis for dose levels of dabrafenib in combination with trametinib (n = 48). Evaluation of selected phase II doses was performed in disease-specific expansion phases with trametinib monotherapy and combination therapy in 49 patients with BRAF V600–mutant low-grade glioma.

Dose Selection and Responses

Dose testing resulted in selection of phase II doses of trametinib for monotherapy or in combination treatment of 0.032 mg/kg once daily for patients aged < 6 years and 0.025 mg/kg once daily for patients aged ≥ 6 years; no dose-limiting toxicities were observed at these dose levels. The selected dabrafenib doses for use in combination therapy were 5.25 mg/kg for patients aged < 12 years and 4.5 mg/kg for those aged ≥ 12 years divided into two equal doses daily; no dose-limiting toxicities were observed with the combination at these dose levels.

Among 49 patients with BRAF V600–mutant low-grade glioma, 13 received trametinib monotherapy, including 3 at different doses during dose finding (1 at phase II dose) and 10 during expansion at the phase II dose; 36 received combination therapy, including 16 during dose finding (13 at phase II doses) and 20 during expansion at phase II doses. Median durations of exposure to study treatment ranged from 19 to 24 months across the dose-finding and expansion phases.

Among 13 patients receiving trametinib monotherapy, objective responses (all partial) were observed in 2 patients (15%, 95% confidence interval [CI] = 1.9%–45.4%), with stable disease seem in an additional 6 (46%). Both responses were ongoing at data cutoff, with an estimated 24-month duration of response rate of 100%.

Among 36 patients receiving combination therapy, objective responses (all partial) were observed in 9 patients (25%, 95% CI = 12.1%–42.2%), with stable disease in an additional 23 (64%). Median duration of response was 33.6 months (95% CI = 11.2 months to not reached), with seven responses ongoing at data cutoff. The estimated 24-month duration of response rate was 80%.

Median progression-free survival was 16.4 months (95% CI = 3.2 months to not reached) in the trametinib monotherapy group and 36.9 months (95% CI = 36.0 months to not reached) in the combination group.

Adverse Events

Among the 49 patients with low-grade glioma, treatment-related grade ≥ 3 adverse events occurred in 38% of 13 patients in the trametinib monotherapy group (paronychia, mucosal inflammation, and rash in 1 patient each) and in 39% of 36 patients in the combination group (most commonly pyrexia [in 11%] and abdominal pain [in 6%]). The most common treatment-related adverse events of any grade were paronychia (54%) and diarrhea and dry skin (46% each) in the trametinib group and pyrexia (50%) and dry skin (42%) in the combination group. Treatment-related serious adverse events occurred in 38% and 22% of patients. Without regard to causality attribution, adverse events led to discontinuation of trametinib monotherapy in 54% of patients and to discontinuation of trametinib and dabrafenib in 22%. No treatment-related deaths were reported.  

The investigators concluded, “The trial design provided efficient evaluation of pediatric dosing, safety, and efficacy of single-agent and combination targeted therapy. Age-based and weight-based dosing of trametinib with or without dabrafenib achieved target concentrations with manageable safety and demonstrated clinical efficacy and tolerability in BRAF V600–mutant low-grade glioma.”

Dr. Bouffet, of The Hospital for Sick Children, Toronto, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by Novartis Pharmaceuticals Corporation. For full disclosures of the study authors, visit ascopubs.org.