title: Randomized international phase III trial of ERCC1 and RRM1 expression-based chemotherapy versus gemcitabine/carboplatin in advanced non-small-cell lung cancer.
abstract: OBJECTIVE
  We assessed whether chemotherapy selection based on in situ ERCC1 and RRM1 protein levels would improve survival in patients with advanced non-small-cell lung cancer (NSCLC).
  
  
  METHODS
  Eligible patients were randomly assigned 2:1 to the trial's experimental arm, which consisted of gemcitabine/carboplatin if RRM1 and ERCC1 were low, docetaxel/carboplatin if RRM1 was high and ERCC1 was low, gemcitabine/docetaxel if RRM1 was low and ERCC1 was high, and docetaxel/vinorelbine if both were high. In the control arm, patients received gemcitabine/carboplatin. The trial was powered for a 32% improvement in 6-month progression-free survival (PFS).
  
  
  RESULTS
  Of 331 patients registered, 275 were eligible. The median number of cycles given was four in both arms. A tumor rebiopsy specifically for expression analysis was required in 17% of patients. The median time from informed consent to expression analysis was 11 days. We found no statistically significant differences between the experimental arm and the control arm in PFS (6.1 months v 6.9 months) or overall survival (11.0 months v 11.3 months). A subset analysis revealed that patients with low levels for both proteins who received the same treatment in both treatment arms had a statistically better PFS (P = .02) in the control arm (8.1 months) compared with the experimental arm (5.0 months).
  
  
  CONCLUSIONS
  This demonstrates that protein expression analysis for therapeutic decision making is feasible in newly diagnosed patients with advanced-stage NSCLC. A tumor rebiopsy is safe, required in 17%, and acceptable to 89% (47 of 53) of patients.
authors.affiliation: Karmanos Cancer Institute, Detroit, MI 48201, USA. beplerg@karmanos.org
authors.forename: Gerold
authors.initials: G
authors.lastname: Bepler
authors.forename: Charles
authors.initials: C
authors.lastname: Williams
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Schell
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.forename: Zhong
authors.initials: Z
authors.lastname: Zheng
authors.forename: George
authors.initials: G
authors.lastname: Simon
authors.forename: Shirish
authors.initials: S
authors.lastname: Gadgeel
authors.forename: Xiuhua
authors.initials: X
authors.lastname: Zhao
authors.forename: Fred
authors.initials: F
authors.lastname: Schreiber
authors.forename: Julie
authors.initials: J
authors.lastname: Brahmer
authors.forename: Alberto
authors.initials: A
authors.lastname: Chiappori
authors.forename: Tawee
authors.initials: T
authors.lastname: Tanvetyanon
authors.forename: Mary
authors.initials: M
authors.lastname: Pinder-Schenck
authors.forename: Jhanelle
authors.initials: J
authors.lastname: Gray
authors.forename: Eric
authors.initials: E
authors.lastname: Haura
authors.forename: Scott
authors.initials: S
authors.lastname: Antonia
authors.forename: Juergen R
authors.initials: JR
authors.lastname: Fischer
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000032:analysis* / Q000235:genetics; D016190:Carboplatin / Q000008:administration & dosage; D002289:Carcinoma, Non-Small-Cell Lung / Q000737:chemistry / Q000188:drug therapy* / Q000473:pathology; D004268:DNA-Binding Proteins / Q000032:analysis* / Q000235:genetics; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D018450:Disease Progression; D000077143:Docetaxel; D004720:Endonucleases / Q000032:analysis* / Q000235:genetics; D005240:Feasibility Studies; D005260:Female; D005500:Follow-Up Studies; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007391:International Cooperation; D008175:Lung Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy / Q000379:methods*; D009367:Neoplasm Staging; D012333:RNA, Messenger / Q000032:analysis; D012262:Ribonucleoside Diphosphate Reductase; D043823:Taxoids / Q000008:administration & dosage; D016896:Treatment Outcome; D025521:Tumor Suppressor Proteins / Q000032:analysis* / Q000235:genetics; D000093542:Gemcitabine
chemical_list: D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D012333:RNA, Messenger; D043823:Taxoids; D025521:Tumor Suppressor Proteins; D003841:Deoxycytidine; D000077143:Docetaxel; D016190:Carboplatin; C475286:RRM1 protein, human; D012262:Ribonucleoside Diphosphate Reductase; C071447:ERCC1 protein, human; D004720:Endonucleases; D000093542:Gemcitabine