title: Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study.
abstract: BACKGROUND
  Activating mutations in EGFR are important markers of response to tyrosine kinase inhibitor (TKI) therapy in non-small-cell lung cancer (NSCLC). The OPTIMAL study compared efficacy and tolerability of the TKI erlotinib versus standard chemotherapy in the first-line treatment of patients with advanced EGFR mutation-positive NSCLC.
  
  
  METHODS
  We undertook an open-label, randomised, phase 3 trial at 22 centres in China. Patients older than 18 years with histologically confirmed stage IIIB or IV NSCLC and a confirmed activating mutation of EGFR (exon 19 deletion or exon 21 L858R point mutation) received either oral erlotinib (150 mg/day) until disease progression or unacceptable toxic effects, or up to four cycles of gemcitabine plus carboplatin. Patients were randomly assigned (1:1) with a minimisation procedure and were stratified according to EGFR mutation type, histological subtype (adenocarcinoma vs non-adenocarcinoma), and smoking status. The primary outcome was progression-free survival, analysed in patients with confirmed disease who received at least one dose of study treatment. The trial is registered at ClinicalTrials.gov, number NCT00874419, and has completed enrolment; patients are still in follow-up.
  
  
  RESULTS
  83 patients were randomly assigned to receive erlotinib and 82 to receive gemcitabine plus carboplatin; 82 in the erlotinib group and 72 in the chemotherapy group were included in analysis of the primary endpoint. Median progression-free survival was significantly longer in erlotinib-treated patients than in those on chemotherapy (13.1 [95% CI 10.58-16.53] vs 4.6 [4.21-5.42] months; hazard ratio 0.16, 95% CI 0.10-0.26; p<0.0001). Chemotherapy was associated with more grade 3 or 4 toxic effects than was erlotinib (including neutropenia in 30 [42%] of 72 patients and thrombocytopenia in 29 [40%] patients on chemotherapy vs no patients with either event on erlotinib); the most common grade 3 or 4 toxic effects with erlotinib were increased alanine aminotransferase concentrations (three [4%] of 83 patients) and skin rash (two [2%] patients). Chemotherapy was also associated with increased treatment-related serious adverse events (ten [14%] of 72 patients [decreased platelet count, n=8; decreased neutrophil count, n=1; hepatic dysfunction, n=1] vs two [2%] of 83 patients [both hepatic dysfunction]).
  
  
  CONCLUSIONS
  Compared with standard chemotherapy, erlotinib conferred a significant progression-free survival benefit in patients with advanced EGFR mutation-positive NSCLC and was associated with more favourable tolerability. These findings suggest that erlotinib is important for first-line treatment of patients with advanced EGFR mutation-positive NSCLC.
  
  
  BACKGROUND
  F Hoffmann-La Roche Ltd (China); Science and Technology Commission of Shanghai Municipality.
authors.affiliation: Department of Oncology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China. caicunzhou@yahoo.com.cn
authors.forename: Caicun
authors.initials: C
authors.lastname: Zhou
authors.forename: Yi-Long
authors.initials: YL
authors.lastname: Wu
authors.forename: Gongyan
authors.initials: G
authors.lastname: Chen
authors.forename: Jifeng
authors.initials: J
authors.lastname: Feng
authors.forename: Xiao-Qing
authors.initials: XQ
authors.lastname: Liu
authors.forename: Changli
authors.initials: C
authors.lastname: Wang
authors.forename: Shucai
authors.initials: S
authors.lastname: Zhang
authors.forename: Jie
authors.initials: J
authors.lastname: Wang
authors.forename: Songwen
authors.initials: S
authors.lastname: Zhou
authors.forename: Shengxiang
authors.initials: S
authors.lastname: Ren
authors.forename: Shun
authors.initials: S
authors.lastname: Lu
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.forename: Chengping
authors.initials: C
authors.lastname: Hu
authors.forename: Chunhong
authors.initials: C
authors.lastname: Hu
authors.forename: Yi
authors.initials: Y
authors.lastname: Luo
authors.forename: Lei
authors.initials: L
authors.lastname: Chen
authors.forename: Ming
authors.initials: M
authors.lastname: Ye
authors.forename: Jianan
authors.initials: J
authors.lastname: Huang
authors.forename: Xiuyi
authors.initials: X
authors.lastname: Zhi
authors.forename: Yiping
authors.initials: Y
authors.lastname: Zhang
authors.forename: Qingyu
authors.initials: Q
authors.lastname: Xiu
authors.forename: Jun
authors.initials: J
authors.lastname: Ma
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.forename: Changxuan
authors.initials: C
authors.lastname: You
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D016190:Carboplatin / Q000008:administration & dosage; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000628:therapy*; D002681:China; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000235:genetics*; D000069347:Erlotinib Hydrochloride; D005260:Female; D017353:Gene Deletion; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D011799:Quinazolines / Q000008:administration & dosage / Q000627:therapeutic use*; D000093542:Gemcitabine
chemical_list: D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D003841:Deoxycytidine; D016190:Carboplatin; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D000093542:Gemcitabine