The combination of dabrafenib (Tafinlar) plus trametinib (Mekinist) proved active for treating patients with low- and high-grade brain tumors carrying BRAF V600E mutations, findings from a phase II basket study showed.
In the study of 58 patients, the investigator-assessed overall response rate (ORR) with dabrafenib-trametinib was 33% for patients with high-grade gliomas, including complete response (CRs) in 7%, and reached 69% for those with low-grade tumors, where the CR rate was 8%, reported Vivek Subbiah, MD, of MD Anderson Cancer Center in Houston.
Median duration of response (DOR) stretched beyond 3 years in the high-grade cohort, with a 2-year DOR rate of 68.8%. The median DOR in the low-grade cohort was not reached, with a 2-year DOR rate of 76.2%, according to results presented at the American Association for Cancer Research virtual meeting.
Median progression-free survival (PFS) in the high-grade group was 3.8 months and overall survival (OS) was 17.6 months, with a 2-year OS rate of 41.8%. In the low-grade cohort, median PFS and OS were not reached, and the 2-year OS rate was 83.9%.
“BRAF V600E is an actionable driver mutation and should be considered for routine testing in glioma patients,” Subbiah concluded. “Dabrafenib and trametinib should be considered a meaningful therapeutic option for these patients.”
The combination demonstrated durable clinical benefit in the trial, said Subbiah, including meaningful efficacy in patients with glioblastoma, and the safety profile was consistent with prior experience with the two agents.
BRAF mutations can occur in up to 15% of low-grade gliomas, including up to 80% in anaplastic pleomorphic xanthoastrocytoma, and in roughly 3% of glioblastomas. The combination of dabrafenib (a BRAF inhibitor) plus trametinib (a MEK inhibitor) is a standard option for patients with BRAF V600E-mutant melanoma, anaplastic thyroid cancer, and lung cancer.
From 2014 to 2018, the glioma cohort of the open-label, multicenter phase II study included 13 patients with low-grade tumors (World Health Organization grade I/II) and 45 patients with high-grade gliomas (grade III/IV).
In the low-grade cohort, patients had a median age of 33, 54% had grade II tumors, one patient had an IDH mutation (54% negative, 38% unknown), and the majority had an Eastern Cooperative Oncology Group (ECOG) performance status of 1. Four patients had ganglioglioma, two had diffuse astrocytomas, two had pleomorphic xanthoastrocytomas, and the remaining patients had other histologic subtypes.
Median age in the high-grade cohort was 42, more than two-thirds had grade IV tumors, 7% were positive for IDH mutations, and nearly 60% had an ECOG performance status of 1. Glioblastomas were the most common histology subtype (69%), followed by anaplastic pleomorphic xanthoastrocytomas and anaplastic astrocytomas, in 11% each, and other subtypes in 9%. All had received prior radiotherapy, surgery, or systemic therapies (two or more in 62%).
ORR among was 38% in patients with grade III glioma and 32% in those with glioblastoma. Median PFS and OS were 3.8 months and 45.2 months, respectively, in the grade III subgroup, and 2.8 months and 13.7 months in the glioblastoma group.
A post-hoc analysis of response for the high-grade cohort showed an ORR of 50% in younger patients (ages 18-39) compared to 17% in patients ages 40 and up. Likewise, survival outcomes were both superior in the younger group:
- PFS: 18.5 vs 1.7 months
- OS: 45.2 vs 8.7 months
Nearly all patients (93%) experienced an adverse event (AE) during the study, the most common of which were fatigue (50%), headache (43%), nausea (34%), pyrexia (33%), rash (29%), vomiting (28%), arthralgia (22%), anemia (22%), constipation (21%), nasopharyngitis (21%), and increased AST (21%).
Grade 3/4 AEs occurred in 53% of patients, with the most common grade 3/4 events consisting of fatigue (9%), decreased neutrophils (9%), headache (5%), neutropenia (5%), and increased AST (3%). AEs led to dose reductions in 38% of patients, dose interruptions in 41%, and treatment discontinuation in 9%.
Ian Ingram joined MedPage Today in 2018 as Deputy Managing Editor, and covers oncology for the site.
The research was supported by Novartis.
Subbiah disclosed relevant relationships with Novartis, Incyte, Bayer, Berg Health, Fujifilm, Pharmamar, D3 Pharma, Pfizer, MultiVir, Altum, Amgen, Dragonfly Therapeutics, AbbVie, Takeda, Alfasigma, Turning Point Therapeutics, Agensys, Boston Pharmaceuticals, Boston Biomedical, Idera Pharma, Inhibrx, Exelixis, Blueprint Medicines, Loxo Oncology/Eli Lilly, Medimmune, Helsinn Therapeutics, R-Pharm US, and QED Therapeutics.