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

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 [Table: see text].