title: Phase II study of erlotinib plus tivantinib (ARQ 197) in patients with locally advanced or metastatic EGFR mutation-positive non-small-cell lung cancer just after progression on EGFR-TKI, gefitinib or erlotinib.
abstract: BACKGROUND
  Patients with epidermal growth factor receptor (EGFR) activation mutation-positive non-small-cell lung cancer (NSCLC) respond well to EGFR tyrosine kinase inhibitors (EGFR-TKIs), but eventually become resistant in most cases. The hepatocyte growth factor/c-Met (HGF/c-Met) pathway is reported as a poor prognostic factor in various cancers. As c-Met is involved in EGFR-TKI resistance, a c-Met inhibitor and EGFR-TKI combination may reverse the resistance. This study evaluated the efficacy and safety of a c-Met selective inhibitor, tivantinib (ARQ 197), in combination with erlotinib, in Japanese EGFR mutation-positive patients with NSCLC who progressed while on EGFR-TKIs.
  
  
  METHODS
  This study enrolled 45 patients with NSCLC with acquired resistance to EGFR-TKIs, who were orally administered a daily combination of tivantinib/erlotinib. The primary end point was the overall response rate (ORR) and secondary end points included disease control rate, progression-free survival (PFS) and overall survival (OS). The patients underwent a mandatory second biopsy just after progression on EGFR-TKIs. The predictive biomarkers were extensively analysed using tumour and blood samples.
  
  
  RESULTS
  The ORR was 6.7% (95% CI 1.4% to 18.3%), and the lower limit of 95% CI did not exceed the target of 5%. The median PFS (mPFS) and median OS (mOS) were 2.7 months (95% CI 1.4 to 4.2) and 18.0 months (95% CI 13.4 to 22.2), respectively. Both were longer in c-Met high patients (c-Met high vs low: mPFS 4.1 vs 1.4 months; mOS 20.7 vs 13.9 months). Partial response was observed in three patients, all of whom were c-Met and HGF high. The common adverse events and their frequencies were similar to those known to occur with tivantinib or erlotinib alone.
  
  
  CONCLUSIONS
  Although this study did not prove clinical benefit of tivantinib in patients with acquired resistance to EGFR-TKIs, activated HGF/c-Met signalling, a poor prognostic factor, may define a patient subset associated with longer survival by the tivantinib/erlotinib combination.
  
  
  BACKGROUND
  NCT01580735.
authors.affiliation: Division of Respirology, Neurology and Rheumatology, Department of Internal Medicine , Kurume University School of Medicine , Kurume , Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Azuma
authors.affiliation: Department of Thoracic Malignancy , Osaka Prefectural Hospital Organization Osaka Prefectural Medical Center for Respiratory and Allergic Diseases , Habikino , Japan.
authors.forename: Tomonori
authors.initials: T
authors.lastname: Hirashima
authors.affiliation: Third Department of Internal Medicine , Wakayama Medical University , Wakayama , Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Yamamoto
authors.affiliation: Department of Medical Oncology, Kinki University Faculty of Medicine, Osaka-Sayama, Japan; Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Isamu
authors.initials: I
authors.lastname: Okamoto
authors.affiliation: Division of Thoracic Oncology , Shizuoka Cancer Center , Shizuoka , Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Takahashi
authors.affiliation: Department of Thoracic Medical Oncology , The Cancer Institute Hospital of Japanese Foundation for Cancer Research , Tokyo , Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Nishio
authors.affiliation: Center for Innovative Clinical Medicine, Okayama University Hospital , Okayama , Japan.
authors.forename: Taizo
authors.initials: T
authors.lastname: Hirata
authors.affiliation: Department of Pulmonary Medicine and Oncology , Graduate School of Medicine, Nippon Medical School , Tokyo , Japan.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Kubota
authors.affiliation: Department of Respiratory Medicine , Kanazawa University Hospital , Kanazawa , Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Kasahara
authors.affiliation: Department of Thoracic Oncology , Aichi Cancer Center Hospital , Nagoya , Japan.
authors.forename: Toyoaki
authors.initials: T
authors.lastname: Hida
authors.affiliation: Department of Respiratory Medicine , Kurashiki Central Hospital , Kurashiki , Japan.
authors.forename: Hiroshige
authors.initials: H
authors.lastname: Yoshioka
authors.affiliation: R&D Division , Kyowa Hakko Kirin Co, Ltd , Tokyo , Japan.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Nakanishi
authors.affiliation: R&D Division , Kyowa Hakko Kirin Co, Ltd , Tokyo , Japan.
authors.forename: Shiro
authors.initials: S
authors.lastname: Akinaga
authors.affiliation: Department of Genome Biology , Kinki University School of Medicine , Osaka-Sayama , Japan.
authors.forename: Kazuto
authors.initials: K
authors.lastname: Nishio
authors.affiliation: Department of Thoracic Surgery , Kinki University Faculty of Medicine , Osaka-Sayama , Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Mitsudomi
authors.affiliation: Department of Medical Oncology , Kinki University Faculty of Medicine , Osaka-Sayama , Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Nakagawa
keywords: EGFR mutation positive; EGFR-TKI resistance; Non-small cell lung cancer; Tivantinib; c-Met inhibitor