Tumor vascular supply is a major target in anti-cancer treatment and intense research efforts has resulted in a range of agents approved for clinical use. Vascular targeting strategies can be classified into several approaches including an antiangiogenic approach by targeting vascular endothelial growth factor (VEGF) and its receptors through monoclonal antibodies (bevacizumab) and tyrosine kinase inhibitors (vandetanib, sorafenib). This approach inhibits endothelial proliferation and migration, targeting new blood vessel formation of smaller, solid tumors with a major effect on the periphery of the tumor. A second method is the vascular disrupting approach. Vascular disrupting agents (VDAs) act primarily on endothelial cells and pericytes of established tumor vasculature, resulting in blood vessel occlusion, tumor ischemia and necrosis with a major effect on the central part of the tumor (7, 8). The VDAs currently in clinical development include vadimezan (ASA404), plinabulin (NPI-2358) and combretastatin A4 phosphate (CA4P). ASA404 (5,6-dimethylxanthenone-4-acetic acid or DMXAA) is a small-molecule, flavonoid tumor-vascular disrupting agent. The major mode of action of ASA404 antitumor activity is to induce the synthesis of tumor necrosis factor (TNF)-alpha. In addition, ASA404 can induce vascular endothelial cell apoptosis in tumors independently of TNF-alpha induction (9).

In this issue of the Journal of Thoracic Disease, McKeage and Jameson report on a retrospective analysis of pooled data from phase II studies of ASA404 to compare safety and efficacy between squamous and non-squamous NSCLC patients (10). Data from untreated patients with advanced stage NSCLC who were randomized to receive up to carboplatin (C) and paclitaxel (P) alone or with ASA404 (1200 mg/m²) (11), or enrolled in an extension study to receive CP and ASA404 (1800 mg/m²) (12), were pooled by histology and by treatment, with aggregation of the two ASA404 doses.

Although the study was not powered for a statistical comparison of outcomes, a numerically higher response rate, time to progression (TTP) and median survival was seen in patients with both squamous and nonsquamous NSCLC treated with chemotherapy and ASA404 compared with those receiving chemotherapy alone. In the squamous patients, the response rate was 14.3% for the chemotherapy alone and 40% for chemotherapy plus ASA404, whilst in non-squamous patients the rates were 25% and 31.7%, respectively. The TTP was 1.6 months for CP alone and 5.6 months for CP plus ASA404 for squamous patients and 4.8 months and 5.5 months, respectively, for nonsquamous patients. In patients with squamous histology, the median survival was 10.2 months and 5.5 months for CP with and without ASA404, respectively, and 14.9 months and 11months, respectively in nonsquamous patients. Overall, the addition of ASA404 to CP was well tolerated in both squamous and nonsquamous patients, with no evidence of hemoptysis in either group. No biomarker analyses were reported.