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BRAF/MEK Dual Inhibitors Therapy in Progressive and Anaplastic Pleomorphic Xanthoastrocytoma: Case Series and
Karolina Kata1,2, Juan C Rodriguez-Quintero3,4, Octavio D Arevalo5
11St. Louis Children's Hospital, Washington University School of Medicine, St. Louis, Missouri.
Abstract:
Recurrent and anaplastic pleomorphic xanthoastrocytoma (r&aPXA) is a rare primary brain tumor that is challenging to treat. Two-thirds of PXA tumors harbor a BRAF gene mutation. BRAF inhibitors have been shown to improve tumor control. However, resistance to BRAF inhibition develops in most cases. Concurrent therapy with MEK inhibitors may improve tumor control and patient survival. In this study, we identified 5 patients diagnosed with BRAF-mutated PXA who received BRAF and MEK inhibitors over a 10-year interval at our institution. Patient records were evaluated, including treatments, adverse effects (AEs), outcomes, pathology, next-generation sequencing, and MRI. The median age was 22 years (range, 14-66 years), 60% male, and 60% anaplastic PXA. Median overall survival was 72 months (range, 19-112 months); 1 patient died of tumor-related hemorrhage while off therapy, and the other 4 experienced long-term disease control (21, 72, 98, and 112 months, respectively). Dual BRAF/MEK inhibitors were well tolerated, with only grade 1-2 AEs, including rash, neutropenia, fatigue, abdominal discomfort, and diarrhea. No grade 3-5 AEs were detected. A literature review was also performed of patients diagnosed with BRAF-mutated PXA and treated with BRAF and/or MEK inhibitors through August 2021, with a total of 32 cases identified. The median age was 29 years (range, 8-57 years) and the median PFS and OS were 8.5 months (range, 2-35 months) and 35 months (range, 10-80 months), respectively. The most common AEs were grade 1-2 fatigue and skin rash. Results of this case series and literature review indicate that dual-drug therapy with BRAF and MEK inhibitors for r&aPXA with BRAF V600E mutation may delay tumor progression without unexpected AEs.
Insights
Dual BRAF and MEK inhibitors show promise for treating BRAF-mutated pleomorphic xanthoastrocytoma (PXA), a rare brain tumor. This combination therapy demonstrated good tolerability and long-term disease control in patients with recurrent and anaplastic PXA.
Area of Science:
- Neuro-oncology
- Molecular targeted therapy
- Genetics of brain tumors
Background:
- Recurrent and anaplastic pleomorphic xanthoastrocytoma (r&aPXA) are rare, challenging primary brain tumors.
- BRAF mutations are common in PXA, and BRAF inhibitors offer therapeutic potential but face resistance.
- Concurrent MEK inhibition may overcome resistance and improve outcomes.
Purpose of the Study:
- To evaluate the efficacy and safety of combined BRAF and MEK inhibitors in patients with BRAF-mutated r&aPXA.
- To assess long-term outcomes and adverse events associated with this dual-drug therapy.
- To compare findings with existing literature on BRAF-mutated PXA treated with BRAF and/or MEK inhibitors.
Main Methods:
- Retrospective analysis of 5 patients with BRAF-mutated PXA treated with dual BRAF/MEK inhibitors.
- Evaluation of patient records including treatments, adverse effects (AEs), outcomes, pathology, and next-generation sequencing.
- Comprehensive literature review of similar cases treated with BRAF and/or MEK inhibitors up to August 2021.
Main Results:
- In the case series, median overall survival was 72 months, with 4 of 5 patients achieving long-term disease control.
- Dual BRAF/MEK inhibitors were well-tolerated, with only grade 1-2 AEs observed (e.g., rash, fatigue).
- Literature review of 32 cases showed median PFS of 8.5 months and median OS of 35 months, with common AEs being fatigue and rash.
Conclusions:
- Dual BRAF and MEK inhibitor therapy appears effective in delaying tumor progression for r&aPXA harboring BRAF V600E mutations.
- This combination therapy is associated with a favorable safety profile and manageable adverse events.
- Combined BRAF/MEK inhibition represents a promising therapeutic strategy for BRAF-mutated r&aPXA, warranting further investigation.
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