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- Title
Sorafenib in advanced melanoma: a Phase II randomised discontinuation trial analysis.
- Authors
Eisen, T.; Ahmad, T.; Flaherty, K. T.; Gore, M.; Kaye, S.; Marais, R.; Gibbens, I.; Hackett, S.; James, M.; Schuchter, L. M.; Nathanson, K. L.; Xia, C.; Simantov, R.; Schwartz, B.; Poulin-Costello, M.; O'Dwyer, P. J.; Ratain, M. J.
- Abstract
The effects of sorafenib – an oral multikinase inhibitor targeting the tumour and tumour vasculature – were evaluated in patients with advanced melanoma enrolled in a large multidisease Phase II randomised discontinuation trial (RDT). Enrolled patients received a 12-week run-in of sorafenib 400 mg twice daily (b.i.d.). Patients with changes in bi-dimensional tumour measurements <25% from baseline were then randomised to sorafenib or placebo for a further 12 weeks (ie to week 24). Patients with 25% tumour shrinkage after the run-in continued on open-label sorafenib, whereas those with 25% tumour growth discontinued treatment. This analysis focussed on secondary RDT end points: changes in bi-dimensional tumour measurements from baseline after 12 weeks and overall tumour responses (WHO criteria) at week 24, progression-free survival (PFS), safety and biomarkers (BRAF, KRAS and NRAS mutational status). Of 37 melanoma patients treated during the run-in phase, 34 were evaluable for response: one had 25% tumour shrinkage and remained on open-label sorafenib; six (16%) had <25% tumour growth and were randomised (placebo, n=3; sorafenib, n=3); and 27 had 25% tumour growth and discontinued. All three randomised sorafenib patients progressed by week 24; one remained on sorafenib for symptomatic relief. All three placebo patients progressed by week-24 and were re-started on sorafenib; one experienced disease re-stabilisation. Overall, the confirmed best responses for each of the 37 melanoma patients who received sorafenib were 19% stable disease (SD) (ie n=1 open-label; n=6 randomised), 62% (n=23) progressive disease (PD) and 19% (n=7) unevaluable. The overall median PFS was 11 weeks. The six randomised patients with SD had overall PFS values ranging from 16 to 34 weeks. The most common drug-related adverse events were dermatological (eg rash/desquamation, 51%; hand-foot skin reaction, 35%). There was no relationship between V600E BRAF status and disease stability. DNA was extracted from the biopsies of 17/22 patients. Six had V600E-positive tumours (n=4 had PD; n=1 had SD; n=1 unevaluable for response), and 11 had tumours containing wild-type BRAF (n=9 PD; n=1 SD; n=1 unevaluable for response). In conclusion, sorafenib is well tolerated but has little or no antitumour activity in advanced melanoma patients as a single agent at the dose evaluated (400 mg b.i.d.). Ongoing trials in advanced melanoma are evaluating sorafenib combination therapies.British Journal of Cancer (2006) 95, 581–586. doi:10.1038/sj.bjc.6603291 www.bjcancer.com Published online 1 August 2006
- Subjects
MELANOMA; NEUROENDOCRINE tumors; BIOMARKERS; PLACEBOS; CANCER patients; DNA
- Publication
British Journal of Cancer, 2006, Vol 95, Issue 5, p581
- ISSN
0007-0920
- Publication type
Article
- DOI
10.1038/sj.bjc.6603291