ATTRACT-1: ASA404 failed to improve outcomes in advanced NSCLC

Lara PN. J Clin Oncol. 2011;doi:10.1200/JCO.2011.35.0660.

The addition of the novel vascular-disrupting agent ASA404 to front-line chemotherapy did not affect OS or PFS in patients with stage IIIB or stage IV non–small cell lung cancer.

The phase 3 Antivascular Targeted Therapy: Researching ASA404 in Cancer Treatment (ATTRACT-1) trial was stopped early for futility at interim analysis.

From April 2008 to October 2009, patients with newly diagnosed disease were randomly assigned to 1,800 mg/m² IV ASA404 (vadimezan) plus carboplatin and paclitaxel (n=649) or placebo plus carboplatin and paclitaxel (n=650). The median age was 61 years; 72% of patients were white and 75% had nonsquamous tumor histology. Adenocarcinoma (67%) was the most common subtype, and 91% of patients had stage IV disease.

Median OS was 13.4 months for ASA404 and 12.7 months for placebo. There was no statistically significant difference in OS between the two treatment arms (HR=1.01; 95% CI, 0.85-1.19). Researchers said there was no difference for OS by histology or sex.

PFS at 12 months was 6.7% in the ASA404 arm vs. 6.9% in the placebo arm. Median PFS was 5.5 months in both groups, and there was not a statistically significant difference (HR=1.04; 95% CI, 0.91-1.19).

Two patients in the experimental group had complete response and 158 had partial response compared with three complete responses and 157 partial responses in the placebo group. Rates for disease stabilization (39.6% vs. 39.5%) and progressive disease (15.7% vs. 15.8%) were also similar between the two groups.

In an accompanying editorial, LoRusso, Boerner and Hunsberger said the failure of ASA404 in this phase 3 trial should not have been a surprise. Sample size and variability of the estimates in the phase 2 results should have tempered expectations, they wrote.

<>“On a large scale, the failure of AS404 illustrates the painful reality of oncology drug development as it relates to the advancement from phase 2 to phase 3: The transition is marked by inefficiency,” they wrote. “These failures translate into thousands of patients and millions of dollars expended toward an outcome with little to no tangible benefit. Carefully scrutinizing phase 2 data and defining efficacy differentials may be pivotal to decrease the failure rate of future phase 3 trials. Excitement over differences in median survival must be tempered when P values indicate the differences have a high probability of being a result of chance.”

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