title: Randomized phase II study of concurrent versus sequential alternating gefitinib and chemotherapy in previously untreated non-small cell lung cancer with sensitive EGFR mutations: NEJ005/TCOG0902.
abstract: BACKGROUND
  The first-line combination of an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) and platinum-based doublet chemotherapy has not been sufficiently evaluated for patients with EGFR-mutant non-small cell lung cancer (NSCLC). This randomized phase II study was designed to select a combination regimen for phase III evaluation.
  
  
  METHODS
  Chemotherapy-naïve patients with advanced non-squamous, EGFR-mutant NSCLC were randomly assigned to receive either a concurrent or a sequential alternating regimen with gefitinib (250 mg) and carboplatin/pemetrexed [area under the curve (AUC) = 6 and 500 mg/m(2); 3-weekly]. The primary end point was progression-free survival (PFS). Secondary end points were overall survival (OS), response, and safety.
  
  
  RESULTS
  All 80 patients enrolled were eligible and assessable for efficacy (41 and 39 patients in the concurrent and sequential alternating regimen groups, respectively). Median PFS was 18.3 months for the concurrent regimen and 15.3 months for the sequential alternating regimen [hazard ratio (HR) 0.71 (0.42-1.20), P = 0.20]. Although OS data are immature (16 and 24 death events), median survival times were 41.9 and 30.7 months in the concurrent and sequential alternating regimen groups, respectively [HR 0.51 (0.26-0.99); P = 0.042]. Response rates were similar in both groups (87.8% and 84.6%). Hematological and non-hematological adverse events were common and reversible; interstitial lung disease was neither frequent nor fatal (two cases in each group; 5% of all patients).
  
  
  CONCLUSIONS
  This is the first randomized study to investigate the efficacy of combinational EGFR-TKI and chemotherapy in the EGFR-mutated setting. Both regimens had promising efficacy with predictable toxicities, although concurrent regimens might provide better OS. The concurrent regimen was chosen to compare with gefitinib monotherapy in our ongoing phase III study.
  
  
  BACKGROUND
  University Hospital Medical Information Network (UMIN) Clinical Trial Registry (UMIN C000002789).
authors: Department of Pulmonary Medicine, Sendai Kousei Hospital, Sendai.
authors: S
authors: S
authors: Sugawara
authors: First Department of Medicine, Hokkaido University School of Medicine, Sapporo. Electronic address: soizumi@med.hokudai.ac.jp.
authors: S
authors: S
authors: Oizumi
authors: Department of Respiratory Medicine, Gunma Prefectural Cancer Center, Gunma.
authors: K
authors: K
authors: Minato
authors: Center for Respiratory Diseases, JCHO Hokkaido Hospital, Sapporo.
authors: T
authors: T
authors: Harada
authors: Department of Respiratory Medicine, Tohoku University Hospital, Sendai.
authors: A
authors: A
authors: Inoue
authors: Department of Respiratory Medicine, National Hospital Organization Asahikawa Medical Center, Asahikawa.
authors: Y
authors: Y
authors: Fujita
authors: Department of Respiratory Medicine, Miyagi Cancer Center, Natori.
authors: M
authors: M
authors: Maemondo
authors: Bioscience Medical Research Center, Niigata University Medical and Dental Hospital, Niigata.
authors: H
authors: H
authors: Yoshizawa
authors: Department of Respiratory Medicine, Niigata City General Hospital, Niigata.
authors: K
authors: K
authors: Ito
authors: Department of Pulmonary Medicine and Oncology, Nippon Medical School, Graduate School of Medicine, Tokyo.
authors: A
authors: A
authors: Gemma
authors: Department of Respiratory Medicine, Ishikawa Prefectural Central Hospital, Kanazawa.
authors: M
authors: M
authors: Nishitsuji
authors: Department of Respiratory Medicine, National Hospital Organization Hokkaido Cancer Center, Sapporo.
authors: M
authors: M
authors: Harada
authors: Department of Medical Oncology, KKR Sapporo Medical Center, Sapporo.
authors: H
authors: H
authors: Isobe
authors: Department of Medical Oncology, Hokkaido University Graduate School of Medicine, Sapporo.
authors: I
authors: I
authors: Kinoshita
authors: Department of Biomedical Statistics and Bioinformatics, Kyoto University Graduate School of Medicine, Kyoto.
authors: S
authors: S
authors: Morita
authors: Department of Respiratory Medicine, Saitama Medical University International Medical Center, Hidaka.
authors: K
authors: K
authors: Kobayashi
authors: Department of Respiratory Medicine, Saitama Medical University, Saitama.
authors: K
authors: K
authors: Hagiwara
authors: Tokyo Cooperative Oncology Group, Tokyo.
authors: M
authors: M
authors: Kurihara
authors: Japan Anti-Tuberculosis Association, Tokyo, Japan.
authors: T
authors: T
authors: Nukiwa
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D016190:Carboplatin / Q000008:administration & dosage; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000401:mortality / Q000473:pathology; D018450:Disease Progression; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics*; D005260:Female; D000077156:Gefitinib; D020022:Genetic Predisposition to Disease; D006801:Humans; D007564:Japan; 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 / Q000008:administration & dosage; D010641:Phenotype; D016016:Proportional Hazards Models; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D011799:Quinazolines / Q000008:administration & dosage* / Q000009:adverse effects; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000068437:Pemetrexed; D016190:Carboplatin; C512478:EGFR protein, human; D066246:ErbB Receptors; D000077156:Gefitinib
keywords: EGFR mutation; EGFR-TKI; chemotherapy; combination; first-line; non-small cell lung cancer