Metastatic melanoma has a dismal prognosis with few therapeutic options. Recent advances in understanding its molecular basis have not yet translated into major treatment improvements. Dacarbazine is still considered the standard treatment for metastatic melanoma although its response rate is inferior to 15% and the median survival time reported in clinical trials is less than 1 year. Malignant melanoma is a high vascular tumor and expression of VEGF has been associated with a worse overall prognosis.
Bevacizumab (B) is a humanized monoclonal antibody that targets vascular endothelial growth factor (VEGF), which has demonstrated high activity in combination with chemotherapy in metastatic colorectal, breast, and lung cancer. Bevacizumab has been tested in combination with weekly paclitaxel (P), carboplatin (C) and weekly paclitaxel, temozolamide (T), low dose interferon Alpha-2b (IFNa-2b) in phase II studies and safety with promising efficacy was showed. Response rates up to 26% have been reported. Hematologic toxicity, fatigue, hypertension were the most common side effects. Recently, the results of a randomized phase II study evaluating the activity of bevacizumab in combination with carboplatin+paclitaxel in patients with previously untreated advanced melanoma was reported. Randomization was 2 : 1 and stratified on ECOG PS (0,1) and disease stage (M1a/b, M1c). Carboplatin (AUC=5, maximum of 10 cycles), paclitaxel (175 mg/m2) and Bevacizumab (15 mg/kg) were administered IV on Day 1 every 3 weeks. Evaluations for RECIST response were performed every 2 cycles. Progression free survival (PFS) was the primary endpoint, secondary endpoints included overall survival (OS), response rates (RR) and safety.
214 subjects were randomized from 2/07–8/08. Baseline characteristics were well balanced between treatment groups, 73% of subjects had M1c disease, 54% of M1c subjects had abnormal LDH levels. Median follow up at the time of analysis was approximately 13 months for each arm. There was a trending benefit in PFS with the addition of Bevacizumab (median 5.6 vs 4.2 months, HR 0.78 with 95% CI 0.56–1.09, P=0.14). A statistically significant improvement in OS was observed with CPB vs CP with median of 12.3 vs 8.6 months, HR 0.67 (95% CI 0.46, 0.98), and P=0.04. RR were also higher in the CBP arm (25.5 vs 16.4%, P=0.16). Grade 3–5 AEs occurring with 2% or more incidence over CP included febrile neutropenia, neutropenia, peripheral neuropathy, pulmonary embolism, hypertension, anorexia and musculoskeletal pain. This was the first randomized placebo controlled trial in metastatic melanoma to demonstrate a statistically significant and clinically meaningful improvement in OS. Similar trending benefits were seen in PFS and RR. The majority of subjects had M1c disease. A randomized phase III trial is currently under way.