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.

Abstract

PURPOSE:

Retrospective studies have reported that tumor expression of the beta-3 tubulin (β3T) 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 β3T 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 β3T expression.

PATIENTS AND METHODS:

Patients were stratified by β3T status (positive v negative) and randomly assigned at a ratio of 1:1 to receive ixabepilone (32 mg/m(2)) and carboplatin (area under concentration-time curve [AUC], 6) or paclitaxel (200 mg/m(2)) and carboplatin (AUC, 6) for up to six cycles. The primary end point was progression-free survival (PFS) in the β3T-positive subgroup.

RESULTS:

Ninety-five patients (β3T positive, 52; β3T negative, 43) received ixabepilone plus carboplatin; 96 patients (β3T positive, 49; β3T negative, 47) received paclitaxel plus carboplatin. No significant differences in median PFS were observed between arms for either subgroup (β3T positive, 4.3 months in both arms; β3T negative, 5.8 v 5.3 months). Ixabepilone did not significantly improve overall survival (OS) for the β3T-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 β3T in differentiating clinical activity of ixabepilone- or paclitaxel-containing regimens. Ixabepilone did not improve PFS or OS in patients with β3T-positive tumors. β3T-positive patients had worse PFS relative to β3T-negative patients, regardless of treatment; hence, β3T 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.

• Authors: Martin J Edelman, Claus-Peter Schneider, Chun-Ming Tsai, Heung-Tae Kim, Elisabeth Quoix, Alexander V Luft, Remigiusz Kaleta, Pralay Mukhopadhyay, Ovidiu C Trifan, Laura Whitaker, Martin Reck
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 31 Issue 16 Pg. 1990-6 (Jun 01 2013) ISSN: 1527-7755 [Electronic] United States
• PMID: 23589560 (Publication Type: Clinical Trial, Phase II, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers, Tumor
• Epothilones
• Tubulin
• Tubulin Modulators
• Carboplatin
• ixabepilone
• Paclitaxel

Topics

• Adult
• Aged
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Area Under Curve
• Biomarkers, Tumor (analysis)
• Carboplatin (administration & dosage)
• Carcinoma, Non-Small-Cell Lung (chemistry, drug therapy, secondary)
• Disease-Free Survival
• Drug Administration Schedule
• Epothilones (administration & dosage)
• Female
• Humans
• Lung Neoplasms (chemistry, drug therapy, pathology)
• Male
• Middle Aged
• Neoplasm Staging
• Paclitaxel (administration & dosage)
• Predictive Value of Tests
• Prospective Studies
• Treatment Outcome
• Tubulin (analysis)
• Tubulin Modulators (administration & dosage)