EPT-17PHASE I STUDY OF BRAF INHIBITOR (VEMURAFENIB) IN COMBINATION WITH THE MTOR INHIBITOR (EVEROLIMUS) IN BRAF V600E POSITIVE CHILDHOOD AND AYA BRAIN TUMORS

Abstract

Vemurafenib is US FDA approved for the treatment of relapsed or refractory BRAF V600 mutation positive malignant melanoma. It demonstrated activity in multiple non‐melanoma BRAF V 600 mutation cancers as well. Pre‐clinical studies demonstrate that concurrent mTOR inhibition can overcome the innate or acquired resistance to BRAF inhibition. We conducted phase 1 study of vemurafenib and everolimus for BRAF mutated tumor that includes pediatric and AYA brain tumor. Standard 3 + 3 design with step wise does modification was applied. Five patients with BRAFV600E brain tumor with age range from 10 to 38 were treated, two glioblastoma, one optic pathway glioma, one pleomorphic xanthoastrocytoma, one anaplastic astrocytoma. All of the patients were previously treated including BRAF inhibitor as monotherapy for three patients. 480‐720 mg twice a day of Vemurafenib and 2.5‐5 mg daily of Everolimus were given for 3‐19 months. Toxicities included Grade 3 rash. Two heavily pre‐treated patients showed progression of disease after 3 and 4 cycles of treatment. One discontinued the treatment due to noncompliance although radiographic partial response was seen. One showed stable disease for 9 months. One patient remains active on the study with partial response over 18 months. The combination therapy was well tolerated with one exception of Grade 3 rash and the patient was able to continue the treatment with brief cessation of medications. Treatment effect was observed with the combination therapy even for the patients previously treated with BRAF inhibitor monotherapy. This study emphasizes the importance of genomic profiling of pediatric and AYA brain tumors.