title: A randomized, double-blind, placebo-controlled, phase III trial of erlotinib with or without a c-Met inhibitor tivantinib (ARQ 197) in Asian patients with previously treated stage IIIB/IV nonsquamous nonsmall-cell lung cancer harboring wild-type epidermal growth factor receptor (ATTENTION study).
abstract: BACKGROUND
  A previous randomized phase II study demonstrated that the addition of a c-Met inhibitor tivantinib to an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib might prolong progression-free survival (PFS) in patients with previously treated, nonsquamous nonsmall-cell lung cancer (NSCLC). On a subset analysis, the survival benefit was greater in patients with wild-type EGFR (WT-EGFR) than in those with activating EGFR mutations. Herein, this phase III study compared overall survival (OS) between Asian nonsquamous NSCLC patients with WT-EGFR who received erlotinib plus tivantinib (tivantinib group) or erlotinib plus placebo (placebo group).
  
  
  METHODS
  A total of 460 NSCLC patients were planned to be randomized to the tivantinib or placebo group. Primary end point was OS. Secondary end points were PFS, tumor response, and safety. Tissue was collected for biomarker analysis, including c-Met and HGF expression.
  
  
  RESULTS
  Enrollment was stopped when 307 patients were randomized, following the Safety Review Committee's recommendation based on an imbalance in the interstitial lung disease (ILD) incidence between the groups. ILD developed in 14 patients (3 deaths) and 6 patients (0 deaths) in the tivantinib and the placebo groups, respectively. In the enrolled patients, median OS was 12.7 and 11.1 months in the tivantinib and the placebo groups, respectively [hazard ratio (HR) = 0.891, P = 0.427]. Median PFS was 2.9 and 2.0 months in the tivantinib and the placebo groups, respectively (HR = 0.719, P = 0.019). The commonly observed grade ≥ 3 adverse events in the tivantinib group were neutropenia (24.3%), leukopenia (18.4%), febrile neutropenia (13.8%), and anemia (13.2%).
  
  
  CONCLUSIONS
  This study was prematurely terminated due to the increased ILD incidence in the tivantinib group. Although this study lacked statistical power because of the premature termination and did not demonstrate an improvement in OS, our results suggest that tivantinib plus erlotinib might improve PFS than erlotinib alone in nonsquamous NSCLC patients with WT-EGFR.
  
  
  BACKGROUND
  NCT01377376.
authors.affiliation: Department of Respiratory Medicine, Kurashiki Central Hospital, Kurashiki hirotin@kchnet.or.jp.
authors.forename: H
authors.initials: H
authors.lastname: Yoshioka
authors.affiliation: Division of Respirology, Neurology and Rheumatology, Department of Internal Medicine, Kurume University School of Medicine, Kurume.
authors.forename: K
authors.initials: K
authors.lastname: Azuma
authors.affiliation: Third Department of Internal Medicine, Wakayama Medical University, Wakayama.
authors.forename: N
authors.initials: N
authors.lastname: Yamamoto
authors.affiliation: Division of Thoracic Oncology, Shizuoka Cancer Center, Nagaizumi.
authors.forename: T
authors.initials: T
authors.lastname: Takahashi
authors.affiliation: Department of Thoracic Medical Oncology, The Cancer Institute Hospital of JFCR, Tokyo.
authors.forename: M
authors.initials: M
authors.lastname: Nishio
authors.affiliation: Division of Integrated Oncology, Institute of Biomedical Research and Innovation Hospital, Kobe, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Katakami
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: M J
authors.initials: MJ
authors.lastname: Ahn
authors.affiliation: Department of Thoracic Malignancy, Osaka Prefectural Hospital Organization Osaka Prefectural Medical Center for Respiratory and Allergic Diseases, Habikino.
authors.forename: T
authors.initials: T
authors.lastname: Hirashima
authors.affiliation: Department of Respiratory Medicine, Miyagi Cancer Center, Natori, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Maemondo
authors.affiliation: Department of Oncology, ASAN Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
authors.forename: S W
authors.initials: SW
authors.lastname: Kim
authors.affiliation: R&D division, Kyowa Hakko Kirin Co., Ltd, Tokyo, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Kurosaki
authors.affiliation: R&D division, Kyowa Hakko Kirin Co., Ltd, Tokyo, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Akinaga
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: K
authors.initials: K
authors.lastname: Park
authors.affiliation: Chest Department, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: C M
authors.initials: CM
authors.lastname: Tsai
authors.affiliation: Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo.
authors.forename: T
authors.initials: T
authors.lastname: Tamura
authors.affiliation: Departments of Thoracic Surgery.
authors.forename: T
authors.initials: T
authors.lastname: Mitsudomi
authors.affiliation: Medical Oncology, Kinki University Faculty of Medicine, Osakasayama, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Nakagawa
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D066246:ErbB Receptors / Q000378:metabolism*; D000069347:Erlotinib Hydrochloride / Q000627:therapeutic use*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011379:Prognosis; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors; D011760:Pyrrolidinones / Q000627:therapeutic use*; D011804:Quinolines / Q000627:therapeutic use*; D015996:Survival Rate
chemical_list: C551661:ARQ 197; D000970:Antineoplastic Agents; D011760:Pyrrolidinones; D011804:Quinolines; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors; D019859:Proto-Oncogene Proteins c-met
keywords: c-Met inhibitor; erlotinib; nonsmall-cell lung cancer; phase III study; tivantinib