According to the results of the PHASE II clinical study ROAR, in patients with low-level and high-level glioma with BRAF V600E mutations, the combination of ’dabrafenib’ and'trametinib’ can produce an encouraging and long-lasting response. The results were presented in the virtual edition of the 2021 annual meeting of the American Association for Cancer Research (AACR). The dual inhibition of the MAPK pathway can be achieved by using the BRAF inhibitor Dabrafenib and the MEK inhibitor trametinib.
For high-grade gliomas, the investigator-assessed objective response rate for the dual-inhibition combination was 33%, compared to 69% for low-grade gliomas. Complete responses reached 7% and 8%, respectively.
Lead Author Vivek Subbiah, MD, of the University of Texas MD Anderson Cancer Center at Houston, said: “Molecular screening strategies, including BRAF V600E mutations, are essential to identify patients who may benefit from these therapies. BRAF V600E is an actionable driver mutation in glioma, and we recommend routine testing for glioma patients in clinical practice. For these patients, 'dalafenib’ plus'trametinib’ should be regarded as a meaningful treatment option. ”
BRAF mutations occur in as many as 15% of low-grade gliomas, as many as 80% of anaplastic astrocytomas and approximately 3% of glioblastomas. The combination of ’darafenib’ and'trametinib’ is the standard treatment for melanoma, anaplastic thyroid cancer and lung cancer with BRAF V600E mutations.
Research details
The ROAR study is a non-randomized, open-label randomized trial evaluating 'dalafenib’ and'trametinib’ in patients with rare cancer with BRAF V600E mutations. The glioma cohort included 13 low-grade gliomas and 24 high-grade gliomas (defined as grade 3 or 4 gliomas). Another 21 high-level glioma patients were included in the response analysis as an extended cohort. The total number of patients is 58 patients.
Treatment consists of 150 mg of 'dalafenib’ twice a day and 1 mg of'trametinib’ twice a day until there is disease progress, unacceptable toxicity or death. The median follow-up time for the high-level glioma cohort was 12.7 months, and the median follow-up time for the low-level glioma cohort was 32.2 months. The main endpoint is the objective response rate evaluated by the researcher. Secondary endpoints include progress-free survival, response duration, and overall survival.
At baseline, the median age of patients in the lower cohort was 33 years; 54% had grade II cancer; one patient had an IDH mutation; and the majority of patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 1. In the higher cohort, the median age of patients was 42 years. More than two-thirds of patients had grade IV cancer.
Key Results
In the high-level cohort, the optimal overall remission rate was 33% (the complete remission rate was 6%; the partial remission rate was 27%). The median remission time was 36.9 months; the response rate at 24 months was 68.8%. The total survival rates of 6, 12 and 24 months were 78.2%, 60.1% and 41.8%, respectively.
In the lower grade cohort, the objective response rate was 69% (complete response rate 8%; partial response rate 61%). The median duration of response had not yet been reached at the time of analysis. The estimated response rate at 24 months was 76.2%.
In the high-grade glioblastoma cohort, the median progression-free survival and overall survival were 2.8 months and 13.7 months, respectively. In the low-grade cohort, median progression-free survival and overall survival have not yet been reached.
Post-hoc analysis of responses in a high-grade glioma cohort showed a better prognosis in younger patients. The objective response rate (ORR) was 50% in patients aged 18 to 39 years, compared to 17% in patients over 40 years of age. The median progression-free survival (PFS) was 18.5 months in younger patients and 1.7 months in older patients. Overall survival was 45.2 months and 8.7 months, respectively.
Prior to treatment, next-generation sequencing of 570 genomes was performed on 23 patients in the high-grade glioma cohort and 4 patients in the low-grade glioma cohort. Among the mutations and copy number variations identified in the baseline sample analysis, none were associated with response data or predicted response.
Among all 58 patients, the most common grade 3 and 4 adverse events were fatigue (9%), neutropenia (9%), headache (5%), and neutropenia (5%). The most common adverse events across all grades were fatigue (50%), headache (43%), nausea (34%), and fever (33%).
Adverse events included dose reduction in 22 patients (38%), dose interruption in 24 patients (41%), and treatment discontinuation in 5 patients (9%).
Research Review
Scott Plotkin, MD, a medical neuro-oncologist at Massachusetts General Hospital Cancer Center, Boston, commented on the study.
The results from Subbiah and colleagues are encouraging. Treatment of BRAF-mutant gliomas with dabrafenib and trametinib resulted in higher imaging response rates and longer overall survival compared to historical controls. While the clinical implications of these findings are limited [given the rarity of these tumors], the data suggest that successfully targeting driver mutations in gliomas can significantly improve clinical outcomes. Ultimately, randomized studies will be needed to confirm these results,” said Dr. Plotkin.
