Dabrafenib-trametinib combination active in BRAF V600E-mutant glioma
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Dabrafenib plus trametinib exhibited encouraging activity among patients with recurrent or refractory BRAF V600E mutation-positive glioma, according to study results.
The findings — presented during the virtual American Association for Cancer Research Annual Meeting — suggest the combination may benefit patients with high-grade or low-grade disease, researchers wrote.
“It was encouraging to see early signals of activity with this combination,” Vivek Subbiah, MD, associate professor in the department of investigational cancer therapeutics at The University of Texas MD Anderson Cancer Center, told Healio. “BRAF V600E is an actionable driver mutation and should be considered for routine testing [among patients with glioma] based on these results.”
Gliomas account for approximately one-third of brain and central nervous system tumors, and about 80% of all malignant brain tumors. Outcomes vary considerably by histology and age.
BRAF mutations have been identified in approximately 3% of patients with glioblastoma — the most aggressive form of glioma — and about 15% of those with low-grade gliomas.
“Glioblastoma is the most common primary brain tumor and is characterized by low survival, with only 10% of patients surviving 5years,” Subbiah said. “Novel treatment options are urgently needed.”
The combination of the BRAF inhibitor dabrafenib (Tafinlar, Novartis) and the MEK1/2 inhibitor trametinib (Mekinist, Novartis) is standard treatment for patients with melanoma, non-small cell lung cancer or anaplastic thyroid cancer who have underlying BRAF driver mutations.
The Rare Oncology Agnostic Research (ROAR) study — a nonrandomized, open-label, phase 2 basket trial — was designed to assess the dabrafenib-trametinib combination for patients with BRAF V600E mutation-positive rare cancers.
At AACR, Subbiah reported results from a cohort of 58 adults with histologically confirmed recurrent or progressive glioma.
All patients received 150 mg dabrafenib twice daily and 2 mg trametinib once daily. Treatment continued until disease progression, unacceptable toxicity or death.
Investigator-assessed objective response rate served as the primary endpoint. Secondary endpoints included PFS, duration of response, OS and safety. Molecular characterization of baseline tumor samples served as an exploratory endpoint.
High-grade glioma cohort
Forty-five patients (men, n = 23) had high-grade glioma, defined as grade 3 or grade 4 by WHO 2007 classification. The most common tumor type was glioblastoma (69%), followed by anaplastic pleomorphic xanthoastrocytoma and anaplastic astrocytoma (11% each).
The majority of these patients had received prior radiotherapy (98%), surgery (93%) and chemotherapy (93%).
Three of 29 patients with known isocitrate dehydrogenase (IDH) status had IDH1 mutations, and eight of 17 patients with known methyl guanine methyl transferase (MGMT) status had MGMT promoter methylation.
Median follow-up in this group was 12.7 months (range, 1.1-56.1).
At data cutoff, 35 patients had discontinued treatment, six remained on treatment and four remained in follow-up.
One-third (33%) of patients responded to therapy; three patients achieved complete response and 12 achieved partial response. Researchers reported median duration of response of 36.9 months (95% CI, 7.4-44.2), median PFS of 3.8 months (95% CI, 1.8-9.2) and median OS of 17.6 months (95% CI, 9.5-45.2).
Low-grade glioma cohort
The analysis also included 13 patients (women, n = 9) with low-grade glioma, defined as grade 1 or grade 2 disease per WHO 2007 classification. The most common histology was ganglioglioma (31%), followed by diffuse astrocytoma and pleomorphic xanthoastrocytoma (15% each).
Previous treatments among patients with low-grade glioma included surgery (92%), radiotherapy (62%) and chemotherapy (38%).
One of eight patients with known IDH status had an IDH1 mutation, and neither of the two patients with known MGMT status had MGMT promoter methylation.
Median follow-up in this group was 32.2 months (range, 0.8-71.8).
At data cutoff, seven patients had discontinued therapy, five remained on treatment and one remained in follow-up.
More than two-thirds (69%) of patients responded to therapy; one patient achieved complete response, six achieved partial response and two achieved minimal response. Median duration of response, PFS and OS had not been reached.
‘Encouraging’ results
The dabrafenib-trametinib combination exhibited a safety profile consistent with the safety profiles observed with the regimen for other indications. Researchers did not observe any unexpected toxicities, Subbiah said.
In the glioma cohort, nearly all patients (93%) experienced adverse events, the most common of which were fatigue (50%), headache (43%), nausea (34%) and pyrexia (33%). Thirty-one patients (53%) experienced grade 3 or higher adverse events, the most common of which were fatigue (9%), decreased neutrophil count (9%), headache (5%) and neutropenia (5%).
The ROAR study’s major strength is that it efficiently identified treatments for rare cancers at several different sites with the same genetic mutation, Subbiah said.
The FDA approved the dabrafenib-trametinib combination for treatment of BRAF V600E-mutant anaplastic thyroid cancer based on results of the basket trial. Previously published results from another cohort support this combination as a treatment option for patients with BRAF V600E-mutated biliary tract cancer, Subbiah said.
“BRAF inhibitor drug development beyond melanoma has been challenging,” Subbiah told Healio. “In this context, actionability of BRAF gene by this combination in [high-grade and low-grade glioma] is in itself a significant finding.”
“The [results of the glioma cohort] are encouraging,” Subbiah added. “Other cohorts will be reported once data [are] mature.”
For more information:
Vivek Subbiah, MD, can be reached at vsubbiah@mdanderson.org.
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Subbiah V, et al. Abstract CT025. Presented at: American Association for Cancer Research Annual Meeting (virtual meeting); April 10-15, 2021.
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