No drug holidays in BRAFV600E glioma patients: an argument for dose reduction of targeted therapies

Abstract

Abstract Background Combined BRAF and MEK inhibition is effective for some BRAFV600E altered gliomas, a cancer for which there are few effective therapies. While recent clinical trials demonstrate objective response rates of 30-40%, tolerable adverse event rates are 70-90% and 12-15% patients stop therapy for toxicity. There are no clear guidelines regarding timing and re-initiation of BRAF-targeted therapies following drug holidays. Here, we describe four patients with rapid disease progression during periods of treatment interruption. All patients experienced response upon resumption of targeted therapy. Methods This is a multi-institutional, retrospective review of 4 patients. Results Three patients were diagnosed with BRAFV600E mutated anaplastic pleomorphic xanthoastrocytoma (aPXA) and one with epithelioid glioblastoma. The age range was 32 to 46; three patients were female and one patient was male. All patients were initially treated with radiation and were subsequently treated with BRAF/MEK inhibitors after disease progression. All patients with aPXA required the targeted therapy to be held due to toxicity and one patient held the therapy prior to transitioning to a novel BRAF-targeted agent. All patients were restarted on BRAF/MEK inhibitors after a drug holiday. Three patients required a dose reduction and all improved clinically following reinitiation. Conclusion Clinical and radiographic progression may occur rapidly upon holding BRAF-targeted therapy, warranting judicious dose-reductions and minimization of drug holidays