BAY 43-9006 in patients with advanced melanoma: The Royal Marsden experience

Abstract

7506 Background: Approximately 70% of melanomas have an activating mutation in BRAF, leading to elevated RAF kinase activity and cellular proliferation. BAY 43-9006 is a potent RAF kinase inhibitor that retards the growth of human melanoma xenografts. This phase II study aims to determine the clinical benefit and toxicity of BAY 43-9006 in advanced melanoma and to correlate these findings with BRAF status of the patients and their tumours. Methods: Patients with stage IV refractory melanoma were recruited from The Royal Marsden Melanoma Unit and treated with BAY 43-9006 400mg BD orally for 12 weeks after baseline imaging and tumour biopsy. At the 12 week reassessment, patients with objective tumour responses continued BAY 43-9006 until disease progression or unacceptable toxicity. Patients with stable disease were randomised in a double-blind manner between BAY 43-9006 or placebo and followed for on-going response.In the event of disease progression in this cohort, the code was broken and those receiving placebo were re-challenged with BAY 43-9006.Tumour responses were evaluated by CT/MRI at 12 weeks and every 6 weeks thereafter. Tumour biopsies were performed at weeks 0,4 and 12 for sequencing BRAF and identification of downstream activity of RAF kinase. Results: Twenty patients were enrolled between October 2002 and April 2003,the median age was 52 (range 18–69) years. At week 12,1 partial response and 3 stable disease were seen. Fifteen patients had progressive disease before or at 12 weeks. Grade 3 skin toxicity was observed in 5 patients and 2 patients developed hypertension requiring intervention. There was no haematological toxicity and all toxicity was reversible. Laboratory analysis of tumour samples to determine BRAF status will be presented. Conclusions: BAY 43-9006 has very modest activity as a single agent. Preliminary data from combination studies are promising and trials are ongoing. The drug is generally well-tolerated and the determination of BRAF status in patients may allow correlation with clinical behaviour of tumours and efficacy of BAY 43-9006 Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bayer Pharmaceutical Corp. Bayer Bayer Bayer Bayer