title: Gefitinib plus chemotherapy versus placebo plus chemotherapy in EGFR-mutation-positive non-small-cell lung cancer after progression on first-line gefitinib (IMPRESS): a phase 3 randomised trial.
abstract: BACKGROUND
  Optimum management strategies for patients with advanced non-small-cell lung cancer (NSCLC) with acquired resistance to EGFR tyrosine-kinase inhibitors are undefined. We aimed to assess the efficacy and safety of continuing gefitinib combined with chemotherapy versus chemotherapy alone in patients with EGFR-mutation-positive advanced NSCLC with acquired resistance to first-line gefitinib.
  
  
  METHODS
  The randomised, phase 3, multicentre IMPRESS study was done in 71 centres in 11 countries in Europe and the Asia-Pacific region. Eligible patients were aged at least 18 years with histologically confirmed, chemotherapy-naive, stage IIIB-IV EGFR-mutation-positive advanced NSCLC with previous disease control with first-line gefitinib and recent disease progression (Response Evaluation Criteria in Solid Tumors version 1.1). Participants were randomly assigned (1:1) by central block randomisation to oral gefitinib 250 mg or placebo once daily in tablet form; randomisation did not include stratification factors. All patients also received the platinum-based doublet chemotherapy cisplatin 75 mg/m(2) plus pemetrexed 500 mg/m(2) on the first day of each cycle. After completion of a maximum of six chemotherapy cycles, patients continued their randomly assigned treatment until disease progression or another discontinuation criterion was met. All study investigators and participants were masked to treatment allocation. The primary endpoint was progression-free survival in the intention-to-treat population. Safety was assessed in patients who received at least one dose of study treatment. The study has completed enrolment, but patients are still in follow-up for overall survival. This trial is registered with ClinicalTrials.gov, number NCT01544179.
  
  
  RESULTS
  Between March 29, 2012, and Dec 20, 2013, 265 patients were randomly assigned: 133 to the gefitinib group and 132 to the placebo group. At the time of data cutoff (May 5, 2014), 98 (74%) patients had disease progression in the gefitinib group compared with 107 (81%) in the placebo group (hazard ratio 0·86, 95% CI 0·65-1·13; p=0·27; median progression-free survival 5·4 months in both groups [95% CI 4·5-5·7 in the gefitinib group and 4·6-5·5 in the placebo group]). The most common adverse events of any grade were nausea (85 [64%] of 132 patients in the gefitinib group and 81 [61%] of 132 patients in the placebo group) and decreased appetite (65 [49%] and 45 [34%]). The most common adverse events of grade 3 or worse were anaemia (11 [8%] of 132 patients in the gefitinib group and five [4%] of 132 patients in the placebo group) and neutropenia (nine [7%] and seven [5%]). 37 (28%) of 132 patients in the gefitinib group and 28 (21%) of 132 patients in the placebo group reported serious adverse events.
  
  
  CONCLUSIONS
  Continuation of gefitinib after radiological disease progression on first-line gefitinib did not prolong progression-free survival in patients who received platinum-based doublet chemotherapy as subsequent line of treatment. Platinum-based doublet chemotherapy remains the standard of care in this setting.
  
  
  BACKGROUND
  AstraZeneca.
authors.affiliation: Department of Medicine, Gustave Roussy Cancer Campus and University Paris-Sud, Villejuif, France.
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Soria
authors.affiliation: Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China.
authors.forename: Yi-Long
authors.initials: YL
authors.lastname: Wu
authors.affiliation: Department of Medical Oncology, The Faculty of Medicine, Kinki University, Osakasayama City, Osaka, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Nakagawa
authors.affiliation: Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
authors.forename: Sang-We
authors.initials: SW
authors.lastname: Kim
authors.affiliation: Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China.
authors.forename: Jin-Ji
authors.initials: JJ
authors.lastname: Yang
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, The Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
authors.forename: Myung-Ju
authors.initials: MJ
authors.lastname: Ahn
authors.affiliation: Department of Thoracic Medical Oncology, Peking University School of Oncology, Beijing Cancer Hospital and Institute, Beijing, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Oncology, The National Taiwan University Hospital and College of Medicine, Taipei, Taiwan.
authors.forename: James Chih-Hsin
authors.initials: JC
authors.lastname: Yang
authors.affiliation: Department of Thoracic Cancer, Cancer Centre, West China Hospital, West China Medical School, Sichuan University, Sichuan, China.
authors.forename: You
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Thoracic Oncology, Kinki-chuo Chest Medical Center, Osaka, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Atagi
authors.affiliation: Medical Oncology Service, Hospital Universitario 12 de Octubre, Madrid, Spain.
authors.forename: Santiago
authors.initials: S
authors.lastname: Ponce
authors.affiliation: Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
authors.forename: Dae Ho
authors.initials: DH
authors.lastname: Lee
authors.affiliation: Department of Medical Oncology, The First Hospital of China Medical University, Shengyang City, China.
authors.forename: Yunpeng
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Division of Thoracic Oncology, National Cancer Centre Hospital East, Chiba, Japan.
authors.forename: Kiyotaka
authors.initials: K
authors.lastname: Yoh
authors.affiliation: Department of Respiratory Diseases, The First Affiliated Hospital of College of Medicine, Zhejiang University, Zhejiang, China.
authors.forename: Jian-Ying
authors.initials: JY
authors.lastname: Zhou
authors.affiliation: AstraZeneca, Shanghai, China.
authors.forename: Xiaojin
authors.initials: X
authors.lastname: Shi
authors.affiliation: AstraZeneca, Macclesfield, UK.
authors.forename: Alan
authors.initials: A
authors.lastname: Webster
authors.affiliation: AstraZeneca, Shanghai, China.
authors.forename: Haiyi
authors.initials: H
authors.lastname: Jiang
authors.affiliation: State Key Laboratory of South China, Hong Kong Cancer Institute, Department of Clinical Oncology, The Chinese University of Hong Kong, Prince of Wales Hospital, Sha Tin, Hong Kong, China. Electronic address: tony@clo.cuhk.edu.hk.
authors.forename: Tony S K
authors.initials: TS
authors.lastname: Mok
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001208:Asia; D014408:Biomarkers, Tumor / Q000235:genetics*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000401:mortality / Q000473:pathology; D002945:Cisplatin / Q000008:administration & dosage; D018450:Disease Progression; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D005060:Europe; D005260:Female; D000077156:Gefitinib; D020022:Genetic Predisposition to Disease; D005971:Glutamates / Q000008:administration & dosage; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives; D006801:Humans; D007262:Infusions, Intravenous; 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; D000068437:Pemetrexed; D010641:Phenotype; D016016:Proportional Hazards Models; D011446:Prospective Studies; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D011799:Quinazolines / Q000008:administration & dosage; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; D005971:Glutamates; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000068437:Pemetrexed; D006147:Guanine; C512478:EGFR protein, human; D066246:ErbB Receptors; D002945:Cisplatin; D000077156:Gefitinib