ASA404 A NOVEL VASCULAR DISRUPTING AGENT WITH A NEW MECHANSIM OF ACTION

January 14, 2010 (Coronado, California) — The addition of the experimental agent ASA404 to standard chemotherapy appears to improve outcomes in nonsmall-cell lung cancer (NSCLC). The drug, also known as vadimezan and DMXAA, was originally developed by Antisoma, but has since been acquired by Novartis.

According to the pooled results of a randomized phase 2 trial and a subsequent extension study, combining ASA404 with conventional treatment increased survival in patients with advanced squamous and with nonsquamous NSCLC.

The findings were presented here at the American Association for Cancer Research-International Association for the Study of Lung Cancer Joint Conference on Molecular Origins of Lung Cancer: Prospects for Personalized Prevention and Therapy.

Among patients with squamous NSCLC who received the combination therapy, survival was 10.2 months; among those who received only chemotherapy, survival was 5.5 months. In patients with nonsquamous NSCLC, overall survival was 14.9 months for those who received combination therapy and 11 months for those who received chemotherapy alone.

Adding ASA404 to standard therapy did not appear to increase toxicity, and there were no serious adverse events associated with bleeding, pulmonary hemorrhage, or hemoptysis.

"If the results of phase 3 trials confirm these findings, then we may have identified a better treatment option for patients with advanced lung cancer," lead author Mark McKeage, PhD, an associate professor in clinical pharmacology at the University of Auckland in New Zealand, said in an interview.

Different From Other Vascular Disrupters

ASA404 is a small-molecule tumor vascular-disrupting agent that destroys existing tumor vasculature and selectively inhibits tumor blood flow, causing extensive necrosis of the tumor core.

It differs from other vascular-targeting therapies that have been approved or are being investigated, in that it is applicable to both squamous and nonsquamous NSCLC, explained Dr. McKeage. "The efficacy and safety profiles are similar for both groups."

Although treatment options for patients with advanced-stage NSCLC are limited, this is particularly true for patients with squamous histology, because some agents demonstrate limited efficacy or serious toxicity. With agents such as bevacizumab (Avastin) and sorafenib (Nexavar), different safety profiles have been observed in squamous and nonsquamous patients, he pointed out.

As an example, in a phase 2 study that combined bevacizumab with carboplatin and paclitaxel (J Clin Oncol. 2004;22:2184-2191), a higher proportion of patients with squamous NSCLC than with nonsquamous histology experienced life-threatening pulmonary hemorrhage after receiving bevacizumab (31% vs 4%).

Pooled Analysis Shows Improved Survival

In this retrospective analysis, Dr. McKeage and colleagues compared the safety and activity of ASA404 in combination with standard paclitaxel and carboplatin treatment, using pooled results from phase 2 trials of ASA404.

A total of 108 treatment-naive patients with stage IIIb/IV NSCLC were enrolled in a phase 2 multicenter study, and were randomized to receive up to 6 cycles of paclitaxel (175 mg/m²) and carboplatin (AUC 6 mg/mL per min) alone or with ASA404 (1200 mg/m²). Those enrolled in the extension study received the same chemotherapy regimen plus a higher dose of ASA404 (1800 mg/m²).

The data were pooled by histology and by treatment, and the 2 ASA404 doses were aggregated. The safety and activity study end points included response rate, time to tumor progression, and overall survival, and data from the histology subgroups and the treatment group were compared.

For all histologies combined, the median survival was 14.5 months for patients receiving the combination therapy and 8.8 months for chemotherapy alone. Safety data were available for 104 patients, and the most commonly reported grade 3/4 adverse events were blood and lymphatic disorders (n = 19; 18%). The rates of grade 3/4 blood and lymphatic events were not significantly different between the 2 histologic subgroups or between the 2 treatment groups.

"Lung cancer is the only cancer that kills over a million people a year," said Dr. McKeage. "Therapeutic advances have been gradual, incremental, and small in magnitude, but we are taking small steps forward."

These results support the phase 3 trials that are ongoing right now, which have just finished enrollment of 1200 patients, he added. ATTRACT-1 (Antivascular Targeted Therapy: Researching ASA404 in Cancer Treatment), will evaluate the addition of ASA404 to first-line treatment regimens in NSCLC, and ATTRACT-2 will evaluate it as part of second-line therapy. The trials have no restrictions on histology. Dr. McKeage predicted that the first results will be available approximately 1 year from now.

The most promising result from this study was that an improvement in survival was observed, said Paul A. Bunn Jr., MD, professor of medicine and James Dudley chair in cancer research at the University of Colorado, Denver.

"This doesn't mean that the phase 3 trials will be positive, but we have strong data going into it," said Dr. Bunn, who was not involved in the study. "The data are strong enough for the company to embark on an expensive phase 3 trial."

The study was funded by Antisoma. Dr. McKeage reports consulting for and receiving research funding from Antisoma and Novartis.

American Association for Cancer Research-International Association for the Study of Lung Cancer (AACR-IASLC) Joint Conference on Molecular Origins of Lung Cancer: Prospects for Personalized Prevention and Therapy: Abstract A22. Presented January 14, 2010.