title: Sorafenib in advanced melanoma: a Phase II randomised discontinuation trial analysis.
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 > or =25% tumour shrinkage after the run-in continued on open-label sorafenib, whereas those with > or =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 > or =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 > or =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.
authors.affiliation: Royal Marsden Hospital, Downs Road, Surrey SMT 5PT, UK. tim.eisen@icr.ac.uk
authors.forename: T
authors.initials: T
authors.lastname: Eisen
authors.forename: T
authors.initials: T
authors.lastname: Ahmad
authors.forename: K T
authors.initials: KT
authors.lastname: Flaherty
authors.forename: M
authors.initials: M
authors.lastname: Gore
authors.forename: S
authors.initials: S
authors.lastname: Kaye
authors.forename: R
authors.initials: R
authors.lastname: Marais
authors.forename: I
authors.initials: I
authors.lastname: Gibbens
authors.forename: S
authors.initials: S
authors.lastname: Hackett
authors.forename: M
authors.initials: M
authors.lastname: James
authors.forename: L M
authors.initials: LM
authors.lastname: Schuchter
authors.forename: K L
authors.initials: KL
authors.lastname: Nathanson
authors.forename: C
authors.initials: C
authors.lastname: Xia
authors.forename: R
authors.initials: R
authors.lastname: Simantov
authors.forename: B
authors.initials: B
authors.lastname: Schwartz
authors.forename: M
authors.initials: M
authors.lastname: Poulin-Costello
authors.forename: P J
authors.initials: PJ
authors.lastname: O'Dwyer
authors.forename: M J
authors.initials: MJ
authors.lastname: Ratain
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use* / Q000633:toxicity; D001557:Benzenesulfonates / Q000627:therapeutic use* / Q000633:toxicity; D017931:DNA Primers; D005260:Female; D011905:Genes, ras; D006801:Humans; D008297:Male; D008545:Melanoma / Q000098:blood supply / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008875:Middle Aged; D009367:Neoplasm Staging; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D016133:Polymerase Chain Reaction; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D011725:Pyridines / Q000627:therapeutic use* / Q000633:toxicity; D012449:Safety; D000077157:Sorafenib
chemical_list: D020533:Angiogenesis Inhibitors; D001557:Benzenesulfonates; D017931:DNA Primers; D010671:Phenylurea Compounds; D011725:Pyridines; D009536:Niacinamide; D000077157:Sorafenib; D048493:Proto-Oncogene Proteins B-raf