The combination of dabrafenib plus trametinib led to encouraging and durable responses in patients with low- and high-grade gliomas harboring BRAF V600E mutations, according to the results of the phase II basket study known as ROAR. Results were presented during the virtual edition of the American Association for Cancer Research (AACR) Annual Meeting 2021.1 This dual inhibition of the MAPK pathway employs the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib.
The investigator-assessed objective response rate with the dual inhibition combination was 33% for high-grade gliomas and 69% for low-grade gliomas. Complete responses were achieved in 7% and 8%, respectively.
“Molecular screening strategies that include BRAF V600E mutations will be critical for identifying patients who may benefit from these therapies. BRAF V600E is an actionable driver mutation in glioma, and we recommend that routine testing is adopted in clinical practice for patients with glioma,” stated lead author Vivek Subbiah, MD, of The University of Texas MD Anderson Cancer Center, Houston. “Dabrafenib plus trametinib should be considered a meaningful therapeutic option for these patients.”
Vivek Subbiah, MD
BRAF mutations occur in up to 15% of low-grade gliomas, up to 80% of anaplastic pleomorphic xanthoastrocytomas, and about 3% of glioblastomas. The combination of dabrafenib and trametinib is standard treatment for BRAF V600E–mutated melanoma, anaplastic thyroid cancer, and lung cancer.
The ROAR study is a nonrandomized, open-label, basket trial evaluating dabrafenib plus trametinib in patients with BRAF V600E–mutant rare cancers. The glioma cohort included 13 patients with low-grade glioma and 24 with high-grade glioma (defined as grade 3 or 4 glioma); an expansion cohort of 21 additional patients with high-grade glioma was included in the analysis of response, for a total number of 58 patients.
Treatment consisted of dabrafenib at 150 mg twice daily and trametinib at 2 mg once daily continued until disease progression, unacceptable toxicity, or death. Median follow-up was 12.7 months for the high-grade glioma cohort and 32.2 months for the low-grade glioma cohort. The primary endpoint was investigator-assessed objective response rate; secondary endpoints included progression-free survival, duration of response, and overall survival.
At baseline, the median age of patients in the low-grade cohort was 33; 54% had grade II tumors; one patient had an IDH mutation; and the majority had an Eastern Cooperative Oncology Group (ECOG) performance status of 1. In the high-grade cohort, the median patient age was 42; more than two-thirds had grade IV tumors.
In the high-grade cohort, the best overall response rate was 33% (complete response rate, 6%; partial response rate, 27%). The median duration of response was 36.9 months; the response rate at 24 months was 68.8%. The 6-, 12-, and 24-month overall survival rates were 78.2%, 60.1%, and 41.8%, respectively.
In the low-grade cohort, the objective response rate was 69% (complete response rate, 8%; partial response rate, 61%). The median duration of response was not yet reached at the time of the analysis. The estimated response rate at 24 months was 76.2%.
Median progression-free survival and overall survival in the high-grade cohort with glioblastoma were 2.8 months and 13.7 months, respectively. Median progression-free and overall survival were not yet reached in the low-grade cohort.
A post hoc analysis of response in the high-grade glioma cohort revealed superior outcomes in younger patients. The objective response rate was 50% in patients between the ages of 18 and 39 compared with 17% in those aged 40 or older. Median progression-free survival was 18.5 months for younger patients vs 1.7 months for the older group; overall survival was 45.2 months vs 8.7 months, respectively.
Prior to therapy, next-generation sequencing with a panel of 570 genes was performed for 23 patients in the high-grade glioma cohort and 4 in the low-grade glioma cohort. Of the mutations and copy number variations identified in this analysis of baseline samples, none correlated with response data or were predictive of response.
The most common grade 3 and 4 adverse events reported among all 58 patients were fatigue (9%), decreased neutrophil count (9%), headache (5%), and neutropenia (5%). The most common adverse events of all grades were fatigue (50%), headache (43%), nausea (34%), and fever (33%).
Dose reductions for adverse events occurred in 22 patients (38%), dose interruptions were reported in 24 patients (41%), and treatment discontinuation was necessary in 5 patients (9%).
Comment on Study
Scott Plotkin, MD, a medical neuro-oncologist at Mass General Cancer Center, Boston, commented on the study.
“The results of the study by Subbiah and colleagues are encouraging. Treatment of BRAF-mutant gliomas with dabrafenib and trametinib was associated with greater radiographic response rates and longer overall survival than historical controls. Although the clinical impact of these findings is limited [given the rarity of these tumors], the data suggest that successfully targeting driver mutations in gliomas may significantly improve clinical results. Ultimately, randomized studies will be required to confirm these results,” Dr. Plotkin said. ν
DISCLOSURE: The study was supported by Novartis. Dr. Subbiah has served as a consultant or advisor to Helsinn Therapeutics, Loxo, MedImmune, QED Pharma, and R-Pharm US; has received institutional research funding from AbbVie, Agensys, Alfasigma, Amgen, Bayer, Berg Pharma, Blueprint Medicines, Boston Biomedical, D3 Oncology Solutions, Exelixis, Fujifilm, Genentech/Roche, GlaxoSmithKline, Idera, Incyte, Inhibrx, Loxo, MultiVir, NanoCarrier, Northwest Biotherapeutics, Novartis, Pfizer, PharmaMar, Takeda, Turning Point Therapeutics, and Vegenics; has been reimbursed for travel, accommodations, or other expenses by Bayer, Helsinn Therapeutics, Novartis, and PharmaMar; and has held other relationships with Medscape. Dr. Plotkin holds stock or other ownership interests in NF2 Therapeutics, NFlection Therapeutics, and SonALAsense; has served as a consultant or advisor to Akouos, AstraZeneca, NFlection Therapeutics, and SonALAsense; has received research funding from AstraZeneca and Pfizer; has received institutional research funding from Takeda; has been reimbursed for travel, accommodations, or other expenses by Nflection Therapeutics; and has held uncompensated relationships with Pfizer.
1. Subbiah V, Stein A, van den Bent M, et al: Dabrafenib plus trametinib in BRAF V600E-mutant high-grade and low-grade glioma. AACR Annual Meeting 2021. Abstract CT025. Presented April 11, 2021.