Trabectedin in patients with advanced non-small-cell lung cancer (NSCLC) with XPG and/or ERCC1 overexpression and BRCA1 underexpression and pretreated with platinum.

Abstract

BACKGROUND:

Previous studies in sarcoma found that a composite gene signature, including high expression of nucleotide excision repair (NER) genes (XPG and/or ERCC1) and low expression of homologous recombination repair (HR) genes (BRCA1), identifies a highly sensitive population of patients with significantly improved outcome to trabectedin. This exploratory phase II trial evaluated a customized trabectedin treatment according to this gene signature in patients with non-small cell lung cancer (NSCLC) after the failure of standard platinum-based treatment.

METHODS:

Patients were selected according to their mRNA expression (elevated XPG and/or ERCC1, with low BRCA1) using the following values as cutoff: XPG=0.99, ERCC1=3.47 and BRCA1=12.00. Trabectedin was administered as a 1.3mg/m(2) 3-hour intravenous infusion every 3 weeks (q3wk). The primary efficacy endpoint was the progression-free survival rate at 3 months. Objective response according to the Response Evaluation Criteria in Solid Tumors (RECIST) was a secondary efficacy endpoint.

RESULTS:

Two of 18 evaluable patients (11.1%; 95% CI, 1.38-34.7%) achieved progression-free survival rate at 3 months. The primary efficacy objective (at least 3 of 18 patients being progression-free at 3 months) was not met, and therefore the trial was early finalized. No objective responses per RECIST were achieved. Four patients had stable disease. Median PFS was 1.3 months, and median overall survival was 5.9 months. Trabectedin was usually well tolerated, with a safety profile similar to that described in patients with other tumor types.

CONCLUSIONS:

Customized treatment with trabectedin 1.3mg/m(2) 3-h q3wk according to composite gene signature (XPG and/or ERCC1 overexpression, and BRCA1 underexpression) was well tolerated, but had modest activity in NSCLC patients pretreated with platinum. Therefore, further clinical trials with trabectedin as single agent in this indication are not warranted.

• Authors: Bartomeu Massuti, Manuel Cobo, Carlos Camps, Manuel Dómine, Mariano Provencio, Vicente Alberola, Nuria Viñolas, Rafael Rosell, Miguel Tarón, Vanesa Gutiérrez-Calderón, Pilar Lardelli, Vicente Alfaro, Antonio Nieto, Dolores Isla
• Journal: Lung cancer (Amsterdam, Netherlands) (Lung Cancer) Vol. 76 Issue 3 Pg. 354-61 (Jun 2012) ISSN: 1872-8332 [Electronic] Ireland
• PMID: 22197612 (Publication Type: Clinical Trial, Phase II, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents, Alkylating
• BRCA1 Protein
• DNA excision repair protein ERCC-5
• DNA-Binding Proteins
• Dioxoles
• Nuclear Proteins
• Tetrahydroisoquinolines
• Transcription Factors
• Platinum
• ERCC1 protein, human
• Endonucleases
• Trabectedin

Topics

• Aged
• Aged, 80 and over
• Antineoplastic Agents, Alkylating (administration & dosage, adverse effects, therapeutic use)
• BRCA1 Protein (genetics)
• Carcinoma, Non-Small-Cell Lung (drug therapy, genetics, mortality)
• DNA-Binding Proteins (genetics)
• Dioxoles (administration & dosage, adverse effects, therapeutic use)
• Endonucleases (genetics)
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Lung Neoplasms (drug therapy, genetics, mortality)
• Male
• Middle Aged
• Neoplasm Staging
• Nuclear Proteins (genetics)
• Platinum (therapeutic use)
• Tetrahydroisoquinolines (administration & dosage, adverse effects, therapeutic use)
• Trabectedin
• Transcription Factors (genetics)
• Treatment Outcome