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

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. This is a multi-institutional, retrospective review of 4 patients. 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. Clinical and radiographic progression may occur rapidly upon holding BRAF-targeted therapy, warranting judicious dose-reductions and minimization of drug holidays