title: 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.affiliation: Hospital General Universitario de Alicante, Alicante, Spain.
authors.forename: Bartomeu
authors.initials: B
authors.lastname: Massuti
authors.forename: Manuel
authors.initials: M
authors.lastname: Cobo
authors.forename: Carlos
authors.initials: C
authors.lastname: Camps
authors.forename: Manuel
authors.initials: M
authors.lastname: Dómine
authors.forename: Mariano
authors.initials: M
authors.lastname: Provencio
authors.forename: Vicente
authors.initials: V
authors.lastname: Alberola
authors.forename: Nuria
authors.initials: N
authors.lastname: Viñolas
authors.forename: Rafael
authors.initials: R
authors.lastname: Rosell
authors.forename: Miguel
authors.initials: M
authors.lastname: Tarón
authors.forename: Vanesa
authors.initials: V
authors.lastname: Gutiérrez-Calderón
authors.forename: Pilar
authors.initials: P
authors.lastname: Lardelli
authors.forename: Vicente
authors.initials: V
authors.lastname: Alfaro
authors.forename: Antonio
authors.initials: A
authors.lastname: Nieto
authors.forename: Dolores
authors.initials: D
authors.lastname: Isla
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D019313:BRCA1 Protein / Q000235:genetics*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D004268:DNA-Binding Proteins / Q000235:genetics*; D004149:Dioxoles / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D004720:Endonucleases / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009687:Nuclear Proteins / Q000235:genetics*; D010984:Platinum / Q000627:therapeutic use; D044005:Tetrahydroisoquinolines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000077606:Trabectedin; D014157:Transcription Factors / Q000235:genetics*; D016896:Treatment Outcome; D000099250:DNA Excision Repair Protein ERCC-5
chemical_list: D018906:Antineoplastic Agents, Alkylating; D019313:BRCA1 Protein; D004268:DNA-Binding Proteins; D004149:Dioxoles; D004720:Endonucleases; D009687:Nuclear Proteins; D010984:Platinum; D044005:Tetrahydroisoquinolines; D000077606:Trabectedin; D014157:Transcription Factors; D000099250:DNA Excision Repair Protein ERCC-5; C071447:ERCC1 protein, human