Abstract
Abstract INTRODUCTION NF2-related schwannomatosis (NF2-SWN) predisposes affected individuals to vestibular schwannomas (VS), non-vestibular schwannomas (NVS), meningiomas, and ependymomas. The rarity of NF2-SWN and the presence of multiple tumor types has impeded clinical trials. We conducted a multi-center, adaptive, platform-basket trial to screen multiple drugs against progressive NF2-SWN tumors. We report the final analysis of the first treatment arm with brigatinib, an oral ALK inhibitor that inhibits multiple tyrosine kinases. METHODS This study enrolled participants ≥ 12 years with NF2-SWN and progressive target tumors (baskets: VS, NVS, meningioma, or ependymoma Radiographic response (RR) was defined as ≥ 20% decrease in target tumor volume from baseline. The primary outcome was RR rate. Secondary outcomes included safety, hearing response, and RR in non-target tumors. Tumor response was evaluated by MRI every 3 months in year 1 and every 6 months thereafter. In stage 1, 20 participants received brigatinib 180 mg daily. Interim analysis suggested activity in NVS and meningioma. Thus, an additional 20 participants with progressive meningioma or NVS were enrolled in stage 2. RESULTS Forty participants (median age 26 years, 12 pediatric, 28 female) were treated. Prior treatment included surgery (90%), radiation therapy (20%) and chemotherapy (55%). Target tumors included 10 VS, 9 NVS, 19 meningiomas, and 2 ependymomas. Overall RR rate was 10% for all target tumors (22% for non-VS, 11% for meningioma, 0% for VS, and 0% for ependymomas). There were no grade 4 or 5 treatment-related adverse events (AEs). The most common AEs were diarrhea (63%), nausea (40%), muscle cramps (33%), increased LDH (35%), increased AST (33%), and increased ALT (23%). CONCLUSION Brigatinib treatment was associated with RR in NVS and meningiomas in a heavily pretreated cohort of participants with progressing NF2-SWN tumors. This novel design provides unique ability to assess treatments for hereditary syndromes with multiple primary tumors.