An open-label pilot study of vemurafenib in previously treated metastatic melanoma patients with brain metastases.

Abstract

8548 Background: Melanoma is a common cause of cerebral metastases, and indicates a poor prognosis. The BRAF inhibitor vemurafenib (V; RG7204, PLX4032) has shown dramatic activity in Phase I and II studies in metastatic melanoma harboring V600-mutated BRAF. These studies excluded patients with active brain metastasis. The activity of V for brain metastases is unknown. Methods: Open label, single arm trial of V to evaluate the safety and efficacy of V in patients with metastatic melanoma with BRAF V600 mutations (by the cobas 4800 BRAF V600 Mutation Test) and non-resectable-brain mets, pretreated by radiotherapy and/or chemotherapy. Patients may have symptoms related to their brain mets and be on a stable dose of steroids. V is administered continuously at the dose of 960 mg BID. Twenty patients are planned to be include in this study. Staging (MRI brain and CT thorax/abdomen) is scheduled every 4 weeks in the first 2 months and then every 8 weeks. In addition, the serum S100 levels are determined. Results: Four patients with V600 BRAF positive melanoma metastatic to the brain and pretreated with temozolamide and/or total brain radiotherapy V are on treatment between 2 and 10 weeks to date. All patients are young (between 24 and 48 years), have 3 to more than 10 brain mets, ECOG PS 0-2 and are on dexamethasone. Two patients were taking morphine to control pain and neurological symptoms. There was no dose reduction for V. AEs included rash, fatigue in two patients and disseminated Herpes zoster and mild transient paresis of nervus facialis in one patient. Two patients’ staging reports are currently available. Patient 1 presented an confirmed partial response in brain and body (RECIST) associated with a reduction of S-100 from 141.6µg/l (pre-treatment) to 4.4µg/l (day 43). Dexamethasone and morphine doses were reduced. Patient 2 showed a minor response in brain and body at week 4 associated with a reduction of S-100 from 35.6µg/l (day 1) to 3.26µg/l (day 15). Conclusions: V has been well tolerated in symptomatic patients with melanoma metastatic to the brain to date. There are early but strong indications for activity in brain mets.