In an interim analysis of a phase II basket trial (ROAR) reported in The Lancet Oncology, Patrick Y. Wen, MD, and colleagues found that the combination of dabrafenib and trametinib produced responses in adult patients with recurrent or progressive BRAF V600E–mutant high-grade and low-grade glioma.
Patrick Y. Wen, MD
Study Details
In the trial, which enrolled patients from sites in 13 countries between April 2014 and July 2018, 45 patients (31 with glioblastoma) were enrolled into a high-grade glioma cohort, and 13 patients were enrolled into a low-grade glioma cohort. Patients received dabrafenib at 150 mg twice daily plus trametinib at 2 mg once daily until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed objective response rate (complete response and partial response in both cohorts, plus minor response in the low-grade glioma cohort).
Responses
Data cutoff for the interim analysis was in September 2020. In the high-grade glioma cohort, median follow-up was 12.7 months (interquartile range [IQR] = 5.4–32.3 months). Objective response was observed in 15 (33%, 95% confidence interval [CI] = 20%–49%) of 45 patients, with complete response seen in 3. An additional 10 patients (22%) had stable disease. Among the 31 patients with glioblastoma, objective response was observed in 10 (32%), with complete response seen in 2. Median duration of response was 36.9 months (95% CI = 7.4–44.2 months). Median progression-free survival was 3.8 months (95% CI = 1.8–9.2 months), and median overall survival was 17.6 months (95% CI = 9.5–45.2 months).
In the low-grade glioma cohort, median follow-up was 32.2 months (IQR = 25.1–47.8 months). Objective response was observed in 9 (69%, 95% CI = 39%–91%) of 13 patients, with complete response in 1 and minor response in 2. An additional three patients (23%) had stable disease. Median duration of response was not reached (95% CI = 5.5 months–not reached), median progression-free survival was not reached (95% CI = 7.4 months–not reached), and median overall survival was not reached (95% CI = 11.6 months–not reached).
Adverse Events
Among all patients, grade ≥ 3 adverse events were reported in 31 (53%), most commonly fatigue (9%), decreased neutrophil count (9%), headache (5%), and neutropenia (5%). Adverse events led to treatment discontinuation in five patients (9%).
Serious adverse events occurred in 15 patients (33%) in the high-grade glioma cohort, with the most common being seizure (9%), followed by vomiting, headache, and nausea (4% each). Serious adverse events occurred in three patients (23%) in the low-grade glioma cohort, with no single event occurring in more than one patient. One patient with high-grade glioma died due to an adverse event (general physical health deterioration) considered unrelated to study treatment.
KEY POINTS
- Objective response was observed in 33% of patients with high-grade glioma and 69% of those with low-grade glioma.
- Median response durations were 36.9 months and not reached, respectively.
The investigators concluded, “Dabrafenib plus trametinib showed clinically meaningful activity in patients with BRAF V600E mutation–positive recurrent or refractory high-grade glioma and low-grade glioma, with a safety profile consistent with that in other indications. BRAF V600E testing could potentially be adopted in clinical practice for patients with glioma.”
Dr. Wen, of the Center for Neuro-Oncology, Dana-Farber Cancer Institute, is the corresponding author for The Lancet Oncology article.
Disclosure: The study was funded by Novartis. For full disclosures of the study authors, visit thelancet.com.
