Patients with high-grade and low-grade brain tumors who carry the BRAF V600E mutation were treated with dabrafenib and trametinib saw clinically meaningful results.
The combination of dabrafenib (Tafinlar) and trametinib (Mekinst) showed clinically meaningful activity for patients with high- and low-grade brain tumors and who carry a BRAF V600E mutation, according to data from the phase 2 ROAR study (NCT02034110).1
Findings from the ongoing trial indicated that one third of the 45 patients treated with the combination experienced tumor shrinkage by 50% or more. A total of 13 patients with low-grade gliomas were enrolled in the study, 9 of whom had an objective response to treatment, translating to a response rate of 69%.
“This is the first time that any targeted drug has been shown to work in glioblastoma in a clinical trial,” lead author Patrick Wen, MD, director of the Center for Neuro-Oncology at Dana-Farber Cancer Institute, said in a press release.2
A total of 206 patients with BRAF V600E–mutant disease were enrolled on the trial. At the data cutoff, 45 patients were included in the high-grade glioma cohort plus 13 patients in the low-grade glioma group. At data cutoff, 13% of patients were still receiving treatment, 9% were in follow-up, and 20% had withdrawn from the study. In the low-grade group, the median time since diagnosis was 6.9 years. At the data cutoff, 38% of patients were still receiving treatment, 8% were in follow-up, and 23% had withdrawn consent. The median follow-up was 32.2 months. Additionally, the mean duration of exposure to dabrafenib was 27.3 months, as well as 26.7 months for trametinib.
A total of 33% of patients in the high-grade glioma group had an objective response (95% CI, 20%-49%), with 3 complete responses, and 12 partial responses. The median duration of investigator assessed response was 36.9 months (95% CI, 7.4-44.2), and the independent radiology review showed a median duration of response of 13.6 months (95% CI, 4.6-43.4). The median progression-free survival (PFS) for the high-grade cohort was 3.8 months (95% CI, 1.8-9.2) and the overall survival (OS) was 17.6 months (95% CI, 9.5-45.2). The median PFS by independent radiology review was 4.5 months (95% CI, 1.8-7.4).
The low-grade group had an objective response by independent radiology review and investigator assessment of 69% (95% CI, 39%-91%). Additionally, 1 patient had a complete response, 6 had partial responses, and 2 had minor responses. The median duration of investigator assessed response was not reached (95% CI, 5.5–not reached [NR]), and the median duration of response by independent radiology review was 27.5 months (95% CI, 3.8-39).
The median PFS (95% CI, 7.4-NR) and OS were not reached (95% CI, 11.6-NR), and the median PFS independent radiology review was 14.0 months (95% CI, 4.7-46.9).
Across both groups, 53% of patients experienced grade 3/4 adverse effects (AEs) with the most common being fatigue (9%), decreased neutrophil count (9%), headache (5%), and neutropenia (5%). AEs led to dose reductions in 38% of patients, and interruptions occurred in 41% of patients, with permanent discontinuation occurring in 9% of patients.
Serious AEs were seen in 33% of patients in the high-grade group with the most common being seizure (9%), vomiting (4%), headache (4%), and nausea (4%). Twenty-three percent of patients in the low-grade group experienced serious AEs, the most common of which were pyrexia (8%), urinary tract infection (8%), vomiting (8%), anemia (8%), adrenocortical insufficiency (8%), hydrocephalus (8%), and neck pain (8%).
A total of 58% of patients died in the high-grade group due to disease progression (51%) or other reasons (2%); 2 patients had an unknown cause of death. In the low-grade group, 31% of patients died from disease progression.
1. Wen PY, Stein A, van den Bent M, et al. Dabrafenib plus trametinib in patients with BRAFV600E-mutant low-grade and high-grade glioma (ROAR): a multicentre, open-label, single-arm, phase 2, basket trial. Lancet Oncol. Published Online November 24, 2021. doi:10.1016/S1470-2045(21)00578-7
2. Targeted drug combination shows unprecedented activity in some highly aggressive brain tumors. News Release. Dana-Farber Cancer Institute. November 24, 2021. Accessed November 30, 2021. https://bit.ly/31fAsrS