Dabrafenib/Trametinib Combo Yields Tumor Shrinkage in BRAF V600E+ High- and Low-Grade Brain Tumors

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 At data cutoff, 13% of patients were still receiving treatment, 9% were in follow-up, and 20% had withdrawn from the study.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 At the data cutoff, 38% of patients were still receiving treatment, 8% were in follow-up, and 23% had withdrawn consent.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.

References

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