Is there a role for targeting vascular endothelial growth factor/receptor axis in the treatment of patients with metastatic melanoma?

Until recently, immunotherapy and cytotoxic chemotherapy were the mainstays of systemic therapy for patients with metastatic melanoma. Although interleukin (IL)-2 received approval for the treatment of metastatic melanoma from the US Food and Drug Administration in 1998 for its ability to induce a long-term durable response, it has not been widely used because it causes severe toxicity but elicits a meaningful clinical benefit in only a small subset of patients. Among cytotoxic drugs, dacarbazine and temozolomide have been the most commonly used agents; however, the objective response rates for these drugs are low (< 10%), and the median duration of progression-free survival (PFS) is< 2 months. The use of the combination regimen of carboplatin and paclitaxel for the treatment of patients with advanced melanoma has gained traction due to its seemingly longer duration of PFS and its tolerability, which have been demonstrated in several multicenter trials, but to the best of my knowledge this regimen has never been compared with dacarbazine or temozolomide in a randomized study. The response rate for this combination regimen is approximately 16% in the first-line treatment setting, and the median PFS duration is 4 months. nab-Paclitaxel is an albumin-bound nanoparticle form of paclitaxel that allows a higher concentration of paclitaxel for binding and avoids the need for the additive polyethoxylated castor oil. On the basis of its improved clinical benefit and more favorable safety profile over paclitaxel in patients with advanced breast cancer, nab-paclitaxel has been evaluated in patients with metastatic melanoma. In a multicenter phase 2 study, the response rate of weekly nab-paclitaxel was 22% among 37 chemotherapy-naive patients, and the median PFS duration was 4.5 months. In a phase 2 study of the combination of nab-paclitaxel and carboplatin reported by Kottschade et al, the median duration of PFS was 4 months and the median duration of overall survival (OS) was 11 months among chemotherapy-naive patients. A large, randomized phase 3 study (ClinicalTrials.gov identifier NCT00864253) to compare the clinical efficacy of nab-paclitaxel and dacarbazine has been completed, and the results will be available shortly. Melanomas are known to be highly vascular tumors, and their progression is associated with the induction of angiogenesis. Vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and IL-8 are angiogenic factors that appear to play important roles in the angiogenic stimulation of melanoma progression. In addition, VEGF has been implicated in tumor resistance to cytotoxic drugs. In previously reported in vitro experiments, the repeated treatment of melanoma cells with dacarbazine induced drug resistance and the selection of more aggressive clones through upregulation of VEGF expression. Bevacizumab, a humanized monoclonal antibody against VEGF, was evaluated in patients with metastatic melanoma, but its single-agent clinical activity was found to be only modest in a phase 2 study. This disappointing singleagent activity in melanoma is not surprising, because it is the case for most solid tumors except those whose growth is driven by VEGF signaling, such as renal cell carcinoma. However, bevacizumab has been shown to improve clinical outcomes in various tumors, including non-small cell lung cancer, breast cancer, and colorectal cancer, when it is combined with chemotherapeutic agents. In patients with melanoma, there appears to be some additive clinical benefit to combining bevacizumab with cytotoxic agents. In a multicenter phase 2 trial, von Moos et al demonstrated that the disease control rate (objective response and disease stabilization rate at week 12) for the combination of temozolomide and