An open-label phase II study of sorafenib and dacarbazine as first-line therapy in patients with advanced melanoma

Sorafenib (SOR) exerts anti-tumor and anti-angiogenic effects via inhibition of VEGFR-1,-2,-3, PDGFR-a, -β and Raf. In a phase I, study SOR + dacarbazine (DTIC) as first-line therapy for advanced melanoma patients (pts) was well-tolerated and had activity. Methods: In this multicenter, phase II, open-label, uncontrolled, 2-stage study, eligibility criteria included: measurable disease by RECIST, ECOG performance status 0 or 1, no prior chemotherapy. Prior immunotherapy was allowed. Planned sample size was 82 pts based on a Simon 2-stage optimal design. Pts were treated with oral SOR 400 mg bid daily combined with repeated 21-day cycles of iv DTIC 1,000 mg/m2 given on day 1 of each cycle until occurrence of progressive disease or intolerable toxicity. The primary endpoint was overall tumor response rate using RECIST. Secondary endpoints included progression-free survival (PFS), overall survival (OS), safety and toxicity. Results: 30 and 53 pts were treated in Stages I and II, respectively. Baseline characteristics were as follows: median age 56 yrs; 60% male, 34% ECOG 1, 80% AJCC Stage IV M1c; 31% elevated LDH. Eight (10%) pts had partial responses, 34 (41%) had stable disease, 32 (39%) had progressive disease and 9 (11%) were not evaluable. The median PFS was 14 wks (95% CI 12, 19; 28% censored). PFS rates at 3 & 6 mos were 56% (45%, 67%; 13% censored) and 33% (22%, 45%; 24% censored), respectively. Median OS was 41 wks (28, 59, 63% censored). Grade 3/4 drug-related adverse events included: neutrophils 33%, platelets 22%, hand-foot skin reaction 8%, fatigue 7% and abdominal pain 6%. 1 patient had febrile neutropenia. To correlate treatment response with mutational status, melanoma samples from 20 pts were analyzed for mutations in B-RAF (exon 15) and PI3Kinase (exons 9 & 20). 3 of 20 samples had V600E mutations in B- RAF; no PI3Kinase alterations were detected. Conclusions: Addition of SOR to DTIC was well-tolerated and resulted in encouraging PFS and OS rates in this poor prognostic cohort of patients. The data are promising as compared with published results of DTIC alone in metastatic melanoma (RR 7.5%, PFS 6 wks; Bedikian et al. 2006). A recently completed randomized Phase II trial will provide additional information on the efficacy of this combination regimen.