H Yoshioka1, K Azuma2, N Yamamoto3, T Takahashi4, M Nishio5, N Katakami6, M J Ahn7, T Hirashima8, M Maemondo9, S W Kim10, M Kurosaki11, S Akinaga11, K Park7, C M Tsai12, T Tamura13, T Mitsudomi14, K Nakagawa15. 1. Department of Respiratory Medicine, Kurashiki Central Hospital, Kurashiki hirotin@kchnet.or.jp. 2. Division of Respirology, Neurology and Rheumatology, Department of Internal Medicine, Kurume University School of Medicine, Kurume. 3. Third Department of Internal Medicine, Wakayama Medical University, Wakayama. 4. Division of Thoracic Oncology, Shizuoka Cancer Center, Nagaizumi. 5. Department of Thoracic Medical Oncology, The Cancer Institute Hospital of JFCR, Tokyo. 6. Division of Integrated Oncology, Institute of Biomedical Research and Innovation Hospital, Kobe, Japan. 7. Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. 8. Department of Thoracic Malignancy, Osaka Prefectural Hospital Organization Osaka Prefectural Medical Center for Respiratory and Allergic Diseases, Habikino. 9. Department of Respiratory Medicine, Miyagi Cancer Center, Natori, Japan. 10. Department of Oncology, ASAN Medical Center, University of Ulsan College of Medicine, Seoul, Korea. 11. R&D division, Kyowa Hakko Kirin Co., Ltd, Tokyo, Japan. 12. Chest Department, Taipei Veterans General Hospital, Taipei, Taiwan. 13. Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo. 14. Departments of Thoracic Surgery. 15. Medical Oncology, Kinki University Faculty of Medicine, Osakasayama, Japan.
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 receivederlotinib 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. TRIAL REGISTRATION NUMBER: NCT01377376.
RCT Entities:
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 NSCLCpatients with WT-EGFR who received erlotinib plus tivantinib (tivantinib group) or erlotinib plus placebo (placebo group). METHODS: A total of 460 NSCLCpatients 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 NSCLCpatients with WT-EGFR. TRIAL REGISTRATION NUMBER: NCT01377376.
Authors: Christos E Kyriakopoulos; Amy M Braden; Jill M Kolesar; Jens C Eickhoff; Howard H Bailey; Jennifer Heideman; Glenn Liu; Kari B Wisinski Journal: Invest New Drugs Date: 2016-12-21 Impact factor: 3.850
Authors: Apurva K Srivastava; Tony Navas; William G Herrick; Melinda G Hollingshead; Donald P Bottaro; James H Doroshow; Ralph E Parchment Journal: Ann Transl Med Date: 2017-01