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Bevacizumab is a humanized recombinant monoclonal antibody that neutralizes vascular endothelial growth factor, an agent with proangiogenic effects in melanoma. Interferon alpha (IFN-α) has antiangiogenic properties through its ability to downregulate basic-fibroblast growth factor levels. We hypothesized that the coadministration of these agents would lead to tumor regression. Patients with metastatic melanoma received bevacizumab 15 mg/kg intravenously on day 1 of the 2-week cycle. IFN-α was administered thrice weekly at 5 MU/m subcutaneously during cycle 1 and was increased to 10 MU/m during cycle 2. Patients were restaged every 6 cycles. Patients with stable disease or a response continued with therapy. Baseline serum vascular endothelial growth factor and fibroblast growth factor 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 5 patients exhibited stable disease that lasted more than 24 weeks (range: 30 to 122 wk). Median progression-free survival and overall survival were 4.8 and 17 months, respectively. Significantly lower fibroblast growth factor 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.

Ocular melanomas represent 5% of all melanomas; of these, 85% are uveal (ie, involving the iris, ciliary body, or choroid), making it the most common primary intraocular tumor.1,2 Uveal melanoma is more common in males and whites. However, unlike cutaneous melanoma, there is no clear evidence implicating sunlight as an etiologic factor.2 The relative 5-year survival rate for uveal melanoma (77%–84%) has not changed significantly in the past 25 years, regardless of whether enucleation or plaque radiotherapy is employed as treatment for the primary tumor.2 Angiogenesis with tumor neovascularization has been proven to be a critical factor in the progression of malignant melanoma.3 Vascular endothelial growth factor (VEGF) is known to be an important modulator of this process.4 Endothelial cells express a family of tyrosine receptor kinases which bind VEGF with high affinity.5 Binding of VEGF to its receptor activates several intracellular signaling pathways that induce endothelial cell mitosis and migration.6 VEGF promotes tumor metastasis via its ability to induce endothelial cell proliferation, migration, and survival.7 Inhibition of VEGF-induced angiogenesis slows tumor growth in murine models.8 Ocular melanoma may be especially sensitive to the inhibition of angiogenesis, since melanoma metastases are known to be highly vascular.9 Previous studies have demonstrated that ocular melanoma cell lines are proangiogenic, and that freshly isolated ocular melanoma cells elaborate proangiogenic factors, particularly VEGF.10–14 Bevacizumab (Avastin) is a recombinant humanized murine antihuman VEGF monoclonal antibody that recognizes all isoforms of VEGF with high affinity (Kd approx. 8 × 10−10 M). Several phase III clinical trials have shown that bevacizumab is effective in metastatic colon,15 lung,16 breast,17,18 and renal cancers.19 A randomized phase III trial demonstrated that the administration of bevacizumab with irinotecan, 5-fluorouracil, and leucovorin led to improved overall survival, progression-free survival, clinical response rate, and duration of response as compared with chemotherapy alone in patients with metastatic colorectal cancer.15 Hypertension, proteinuria, hemorrhage (primarily in patients with lung cancer), poor wound healing,20 and an increase in arterial thromboembolic events were the primary adverse events associated with bevacizumab administration.21 Although bevacizumab has not been used in clinical trials to treat ocular melanoma, intraocular administration of bevacizumab resulted in complete resolution of neovascularization in a patient with a cutaneous melanoma that had metastasized to the vitreous of the eye.22 In melanoma, interferon-alpha2b (IFN-α2b) is administered at high doses of 10 MU/m2 subcutaneously thrice weekly for 1 year as an adjunct to surgical resection of high-risk early stage tumors. Low dose IFN-α2b has antiproliferative activity and inhibits tumor-induced angiogenesis.23,24 In murine models, daily IFN-α2b therapy down-regulates the expression of basic fibroblast growth factor (bFGF), a critical factor for tumor neovascularization. 23 In addition, IFN-α2b has also been used at doses of up to 3 MU/m2 per day to treat life-threatening hemangiomas of infancy with remarkable success.25 Previous work in our laboratory has demonstrated that IFN-α2b inhibits the secretion of VEGF in several melanoma cell lines.26 We hypothesized that the combination of bevacizumab and high dose IFN-α2b would inhibit tumor angiogenesis and mediate regression of metastatic disease in patients with ocular melanoma. The primary objective of this pilot trial was to assess the tolerability and objective response rate in patients with metastatic ocular melanoma who received bevacizumab with IFN-α2b.