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Has ASA404 been investigated in patients with lung cancer?
ASA404 has been studied in combination with standard chemotherapy as first-line cancer treatment for stage IIIb/IV Non-Small Cell Lung Cancer (NSCLC). The results of a phase Ib/II trial, conducted by von Pawel and colleagues, showed that the addition of ASA404 to standard therapy (paclitaxel 175 mg/m2 plus carboplatin AUC 6 x 30 min) increased median survival by 5.2 months. In this trial patients with previously untreated stage IIIb or IV NSCLC were randomized to receive ASA404 1200 mg/m2 plus standard therapy (n=31), ASA404 1800 mg/m2 plus standard therapy (n=6) or standard therapy alone (n=36). Treatment was administered every 21 days for up to six cycles.
An additional 25 lung cancer patients were given ASA404 1800 mg/m2 plus standard therapy as part of a phase II extension study. Patients were assessed for tumor response, time to progression and overall survival.
Overall response rate was 31.2% in NSCLC patients receiving 1200 mg/m2 ASA404 versus 22.2% in the standard therapy group. At a follow-up period of 12 months, median time to lung cancer tumor progression was 5.4 months in the ASA404 group and 4.4 months for NSCLC patients treated with standard therapy of paclitaxel and carboplatin. As shown in Figure 1, median survival time was 14.0 months in the ASA404 arm and 8.8 months in the standard therapy arm, representing a 5.2-month survival advantage for patients receiving 1200 mg/m2 ASA404.1 In the phase II extension study, patients receiving
1800 mg/m2 ASA404 had a 37.9% response rate, 5.5-month median time to progression and median overall survival of 14.9 months.2
Figure 1. Survival in patients treated with ASA404.
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| Adapted from von Pawel J, Reck M, McKeage M; AS1404-201 Study Group Investigators.1
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ASA404 was well tolerated and did not result in any significant toxicity when added to paclitaxel and carboplatin.
According to the investigators, "[ASA404] is the first vascular disrupting agent to demonstrate proof of concept in a randomized controlled study."1
ASA404 has also been investigated in phase II trials as first-line treatment for hormone-refractory metastatic prostate cancer and in recurrent platinum-sensitive ovarian cancer.3,4
How does ASA404 work?
In order for tumors to grow and metastasize, they must develop and maintain a vascular network that can supply the oxygen and nutrients essential for cell survival and remove toxic by-products of cellular metabolism. ASA404 is a member of a novel class of agents, known as Tumor-Vascular Disrupting Agents (Tumor-VDAs) that target already established tumor blood vessels.
ASA404 disrupts tumor blood vessels through both direct and indirect mechanisms (Figure 2). ASA404 directly induces apoptosis of the endothelial cells that line the tumor vessels, increasing the permeability of these vessels. The indirect effects of ASA404 are
Figure 2. ASA404 disrupts tumor vasculature through direct and indirect mechanisms.
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orchestrated by induction of Tumor Necrosis Factor (TNF) and other cytokines that cause further vascular injury.6-8 Together, the direct and indirect effects of ASA404 result in disruption of tumor blood vessels, inhibition of blood flow and ultimately, necrosis of the tumor.7,8
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