Bevacizumab is a humanized recombinant monoclonal antibody that neutralizes vascular endothelial growth factor, an agent with pro-angiogenic effects in melanoma. Interferon-alpha (IFN-α) has anti-angiogenic properties via its ability to down-regulate basic-fibroblast growth factor levels. We hypothesized that the co-administration of these agents would lead to tumor regression. Patients with metastatic melanoma received bevacizumab 15 mg/kg iv on day 1 of the 2 week cycle. IFN-α was administered thrice weekly at 5 MU/m2 sc during cycle 1 and was increased to 10 MU/m2 during cycle 2. Patients were restaged every 6 cycles. Patients with stable disease or a response continued with therapy. Baseline serum VEGF and FGF were measured. Twenty-five patients were accrued. Mean age was 58.4 years. Eleven patients required IFN-α dose reductions due to toxicity. Common grade 3 toxicities associated with IFN-α included fatigue and myalgia. Bevacizumab administration was associated with grade 2–3 proteinuria in 6 patients. Grade 4 adverse events were pulmonary embolus (1), myocardial infarction (1), and stroke (1). Six patients had a partial response, and five patients exhibited stable disease that lasted greater than 24 weeks (range 30–122 weeks). Median PFS and OS were 4.8 months and 17 months, respectively. Significantly lower FGF levels were observed in patients with a partial response compared to those with stable or progressive disease (p=0.040). Administration of bevacizumab with IFN led to a clinical response in 24% of patients with stage IV melanoma and stabilization of disease in another 20% of patients. This regimen has activity in advanced melanoma.

Objectives We hypothesized that administration of bevacizumab, a monoclonal antibody that neutralizes vascular endothelial growth factor, in combination with high-dose interferon-alpha2b (IFN-α2b), an inhibitor of basic fibroblast growth factor, would have clinical activity in patients with metastatic ocular melanoma. Methods Patients with metastatic ocular melanoma received bevacizumab (15 mg/kg intravenously every 2 weeks) plus IFN-α2b (5 MU/m2 subcutaneously 3 times weekly for 2 weeks followed by a dose of 10 MU/m2 subcutaneously thereafter). Patients exhibiting a clinical response or stabilization of disease were treated until disease progression. Results In this pilot study, 5 patients were treated (3 men, 2 women) with a mean age of 63.8 years (range, 53–71 years). Overall, the regimen was well-tolerated. The following adverse events were noted: grade 3 dyspnea (2 patients), grade 3 and 4 fatigue (2), grade 3 muscle weakness (1), grade 3 anorexia (1), grade 1 and 2 proteinuria (2), and grade 3 diarrhea (1). All adverse events resolved with a treatment holiday or dose reduction. One patient had reduction in tumor burden of 23% by Response Evaluation Criteria in Solid Tumors criteria and 2 patients had stabilization of disease lasting 28 and 36 weeks, respectively. Two patients failed to respond and progressed after 6 and 7 weeks of therapy. Conclusion Bevacizumab and IFN-α2b were well tolerated in this patient population, and clinical activity was observed. Further study of high-dose IFN-α2b in combination with bevacizumab in this setting is warranted.

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