title: Intercalated combination of chemotherapy and erlotinib for patients with advanced stage non-small-cell lung cancer (FASTACT-2): a randomised, double-blind trial.
abstract: BACKGROUND
  The results of FASTACT, a randomised, placebo-controlled, phase 2 study, showed that intercalated chemotherapy and erlotinib significantly prolonged progression-free survival (PFS) in patients with advanced non-small-cell lung cancer. We undertook FASTACT-2, a phase 3 study in a similar patient population.
  
  
  METHODS
  In this phase 3 trial, patients with untreated stage IIIB/IV non-small-cell lung cancer were randomly assigned in a 1:1 ratio by use of an interactive internet response system with minimisation algorithm (stratified by disease stage, tumour histology, smoking status, and chemotherapy regimen) to receive six cycles of gemcitabine (1250 mg/m(2) on days 1 and 8, intravenously) plus platinum (carboplatin 5 × area under the curve or cisplatin 75 mg/m(2) on day 1, intravenously) with intercalated erlotinib (150 mg/day on days 15-28, orally; chemotherapy plus erlotinib) or placebo orally (chemotherapy plus placebo) every 4 weeks. With the exception of an independent group responsible for monitoring data and safety monitoring board, everyone outside the interactive internet response system company was masked to treatment allocation. Patients continued to receive erlotinib or placebo until progression or unacceptable toxicity or death, and all patients in the placebo group were offered second-line erlotinib at the time of progression. The primary endpoint was PFS in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT00883779.
  
  
  RESULTS
  From April 29, 2009, to Sept 9, 2010, 451 patients were randomly assigned to chemotherapy plus erlotinib (n=226) or chemotherapy plus placebo (n=225). PFS was significantly prolonged with chemotherapy plus erlotinib versus chemotherapy plus placebo (median PFS 7·6 months [95% CI 7·2-8·3], vs 6·0 months [5·6-7·1], hazard ratio [HR] 0·57 [0·47-0·69]; p<0·0001). Median overall survival for patients in the chemotherapy plus erlotinib and chemotherapy plus placebo groups was 18·3 months (16·3-20·8) and 15·2 months (12·7-17·5), respectively (HR 0·79 [0·64-0·99]; p=0·0420). Treatment benefit was noted only in patients with an activating EGFR gene mutation (median PFS 16·8 months [12·9-20·4] vs 6·9 months [5·3-7·6], HR 0·25 [0·16-0·39]; p<0·0001; median overall survival 31·4 months [22·2-undefined], vs 20·6 months [14·2-26·9], HR 0·48 [0·27-0·84]; p=0·0092). Serious adverse events were reported by 76 (34%) of 222 patients in the chemotherapy plus placebo group and 69 (31%) of 226 in the chemotherapy plus erlotinib group. The most common grade 3 or greater adverse events were neutropenia (65 [29%] patients and 55 [25%], respectively), thrombocytopenia (32 [14%] and 31 [14%], respectively), and anaemia (26 [12%] and 21 [9%], respectively).
  
  
  CONCLUSIONS
  Intercalated chemotherapy and erlotinib is a viable first-line option for patients with non-small-cell lung cancer with EGFR mutation-positive disease or selected patients with unknown EGFR mutation status.
  
  
  BACKGROUND
  F Hoffmann-La Roche.
authors.affiliation: Guangdong Lung Cancer Institute, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
authors.forename: Yi-Long
authors.initials: YL
authors.lastname: Wu
authors.forename: Jin Soo
authors.initials: JS
authors.lastname: Lee
authors.forename: Sumitra
authors.initials: S
authors.lastname: Thongprasert
authors.forename: Chong-Jen
authors.initials: CJ
authors.lastname: Yu
authors.forename: Li
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authors.lastname: Zhang
authors.forename: Guia
authors.initials: G
authors.lastname: Ladrera
authors.forename: Vichien
authors.initials: V
authors.lastname: Srimuninnimit
authors.forename: Virote
authors.initials: V
authors.lastname: Sriuranpong
authors.forename: Jennifer
authors.initials: J
authors.lastname: Sandoval-Tan
authors.forename: Yunzhong
authors.initials: Y
authors.lastname: Zhu
authors.forename: Meilin
authors.initials: M
authors.lastname: Liao
authors.forename: Caicun
authors.initials: C
authors.lastname: Zhou
authors.forename: Hongming
authors.initials: H
authors.lastname: Pan
authors.forename: Victor
authors.initials: V
authors.lastname: Lee
authors.forename: Yuh-Min
authors.initials: YM
authors.lastname: Chen
authors.forename: Yan
authors.initials: Y
authors.lastname: Sun
authors.forename: Benjamin
authors.initials: B
authors.lastname: Margono
authors.forename: Fatima
authors.initials: F
authors.lastname: Fuerte
authors.forename: Gee-Chen
authors.initials: GC
authors.lastname: Chang
authors.forename: Kasan
authors.initials: K
authors.lastname: Seetalarom
authors.forename: Jie
authors.initials: J
authors.lastname: Wang
authors.forename: Ashley
authors.initials: A
authors.lastname: Cheng
authors.forename: Elisna
authors.initials: E
authors.lastname: Syahruddin
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Qian
authors.forename: James
authors.initials: J
authors.lastname: Ho
authors.forename: Johan
authors.initials: J
authors.lastname: Kurnianda
authors.forename: Hsingjin Eugene
authors.initials: HE
authors.lastname: Liu
authors.forename: Kate
authors.initials: K
authors.lastname: Jin
authors.forename: Matt
authors.initials: M
authors.lastname: Truman
authors.forename: Ilze
authors.initials: I
authors.lastname: Bara
authors.forename: Tony
authors.initials: T
authors.lastname: Mok
mesh_terms: D061605:Administration, Intravenous; D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001208:Asia; D016190:Carboplatin / Q000008:administration & dosage; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000401:mortality / Q000473:pathology; D016009:Chi-Square Distribution; D002945:Cisplatin / Q000008:administration & dosage; D004252:DNA Mutational Analysis; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D018572:Disease-Free Survival; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics; D000069347:Erlotinib Hydrochloride; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D016016:Proportional Hazards Models; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D011799:Quinazolines / Q000008:administration & dosage; D013997:Time Factors; D016896:Treatment Outcome; D000093542:Gemcitabine
chemical_list: D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D003841:Deoxycytidine; D016190:Carboplatin; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors; D002945:Cisplatin; D000093542:Gemcitabine