Clinical trials of vascular disrupting agents in advanced non--small-cell lung cancer

Tumor vascular disrupting agents (VDAs), such as the flavonoid compound ASA404 and the tubulin-binding compound combretastatin, selectively disrupt established tumor blood vessels, inhibit tumor blood flow, and induce extensive necrosis at the core of solid tumors. A rationale for combining tumor VDAs with standard chemotherapy for treating advanced non-small-cell lung cancer (NSCLC) includes their complementary actions on different spatial regions of solid tumors and their additive or synergistic preclinical activity in animal models of lung cancer. A randomized, phase II, multicenter, open-label trial with a single-arm extension phase evaluated outcomes in a total of 104 patients (> 18 years of age) with histologically confirmed stage IIIb or stage IV, previously untreated NSCLC that in this trial was treated with ASA404 plus standard chemotherapy vs. standard chemotherapy alone. Adding ASA404 to standard chemotherapy numerically improved tumor response, time to disease progression, and overall survival in this phase II trial, without significantly increasing the incidence or severity of side effects. Other randomized phase II and phase III clinical trials of ASA404 and combretastatin combined with standard chemotherapy in advanced NSCLC are currently ongoing or will be reported shortly.