Randomized phase II study of ixabepilone or paclitaxel plus carboplatin in patients with non–small-cell lung cancer prospectively stratified by beta-3 tubulin status

Purpose: Retrospective studies have reported that tumor expression of the beta-3 tubulin (3T) isoform is an unfavorable prognostic factor in non–small-cell lung cancer (NSCLC) treated with tubulin-inhibiting chemotherapy. Ixabepilone is a tubulin-inhibiting agent with low susceptibility to multiple resistance mechanisms including 3T isoform expression in several tumor models. This randomized phase II study evaluated ixabepilone-based chemotherapy in stage IIIb/IV NSCLC, compared with paclitaxel-based chemotherapy. Tumor specimens were prospectively evaluated for 3T expression. Patients and Methods: Patients were stratified by 3T status (positive v negative) and randomly assigned at a ratio of 1:1 to receive ixabepilone (32 mg/m²) and carboplatin (area under concentration-time curve [AUC], 6) or paclitaxel (200 mg/m²) and carboplatin (AUC, 6) for up to six cycles. The primary end point was progression-free survival (PFS) in the 3T-positive subgroup. Results: Ninety-five patients (3T positive, 52; 3T negative, 43) received ixabepilone plus carboplatin; 96 patients (3T positive, 49; 3T negative, 47) received paclitaxel plus carboplatin. No significant differences in median PFS were observed between arms for either subgroup (3T positive, 4.3 months in both arms; 3T negative, 5.8 v 5.3 months). Ixabepilone did not significantly improve overall survival (OS) for the 3T-positive subset or the overall population. Adverse events were similar between the two arms and comparable with those in previous studies. Conclusion: There was no predictive value of 3T in differentiating clinical activity of ixabepilone- or paclitaxel-containing regimens. Ixabepilone did not improve PFS or OS in patients with 3T-positive tumors. 3T-positive patients had worse PFS relative to 3T-negative patients, regardless of treatment; hence, 3T expression seems to be a negative prognostic factor, but not a predictive factor, in advanced NSCLC treated with either ixabepilone or paclitaxel platinum-based doublets.