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A phase II trial of a selective c-Met inhibitor tivantinib (ARQ 197) monotherapy as a second- or third-line therapy in the patients with metastatic gastric cancer

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Summary

Background Tivantinib is a selective, non-ATP competitive, small-molecule inhibitor of c-Met and is under development in several cancers including non-small cell lung and hepatocellular carcinoma. Activation of c-Met has been frequently found in metastatic gastric cancer (MGC) and is associated with poor prognosis. In this single-arm study, we evaluated the efficacy of tivantinib monotherapy in Asian patients with previously treated MGC. This is the first clinical report from the trials evaluating the efficacy of a selective c-Met inhibitor for MGC. Patients and methods Eligibility criteria included: MGC with at least one measurable lesion; 1 or 2 prior chemotherapy regimens; and ECOG PS 0 or 1. Tivantinib was daily administered orally. The primary endpoint was the disease control rate (DCR). Pre-treatment tumor tissue was collected to evaluate the biomarkers related to efficacy. Results Thirty patients, including 12 patients with prior gastrectomy, received tivantinib: median age 62.5 years; ECOG PS 0/1 (8/22); 1/2 prior regimen (16/14). No objective response was observed, and DCR was 36.7 %. Median progression-free survival was 43 days (95 % CI: 29.0-92.0). Grade 3 or 4 adverse events occurred in 13 patients (43.3 %), in whom neutropenia (N = 4) and anemia (N = 4) were recognized as drug-related. c-Met gene amplification was observed in 2 patients (6.9 %). No obvious relationship was identified between efficacy and biomarkers including gene amplification of c-Met, expression of c-Met, p-Met and HGF. Conclusion Tivantinib as a monotherapy showed a modest efficacy in previously treated MGC, and further studies taking account of predictive biomarkers and/or combination with other chemotherapy may be needed in MGC.

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Acknowledgments

We thank the patients, their families, caregivers, and all of the personnel who contribute to patient care and data collection for this study of tivantinib.

We also thank the members of the independent safety monitoring committee: Dr. Kazuo Tamura, Dr. Hiroshi Saito and Dr. Ichinosuke Hyodo, and the members of the central radiology review committee: Dr. Yoshinori Miyata, Dr. Hye-Jin Kang, Dr. Kohki Yoshikawa and Dr. Kunihisa Miyakawa.

Funding

This work was sponsored by Kyowa Hakko Kirin Co., Ltd.

Conflict of interest

Y. K. Kang received honoraria from Kyowa Hakko Kirin Co., Ltd. Y. Kamiya and S. Akinaga are employees of Kyowa Hakko Kirin Co., Ltd. All remaining have declared no conflict of interest.

Ethical standards

This study was conducted in accordance with institutional guidelines, Good Clinical Practice guidelines and the Declaration of Helsinki. Documented approvals from the Institutional Review Boards were obtained. All patients provided written informed consent before study participation.

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Authors and Affiliations

  1. Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 138-736, South Korea

    Yoon-Koo Kang, Min-Hee Ryu & Baek-Yeol Ryoo

  2. Department of Clinical Oncology, Aichi Cancer Center Hospital, 1-1, Kanokoden, Chikusa-ku, Nagoya, 464-8681, Japan

    Kei Muro

  3. Division of Gastrointestinal Oncology, Shizuoka Cancer Center, 1007, Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8777, Japan

    Hirofumi Yasui & Narikazu Boku

  4. Department of Gastrointestinal Medical Oncology, National Hospital Organization Shikoku Cancer Center, 160 Kou Minamiumemoto-cho, Matsuyama, 791-0280, Japan

    Tomohiro Nishina

  5. Development Division, Kyowa Hakko Kirin Co., Ltd., 1-6-1, Ohtemachi, Chiyoda-ku, Tokyo, 100-8186, Japan

    Yukimasa Kamiya & Shiro Akinaga

Authors
  1. Yoon-Koo Kang
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  2. Kei Muro
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  4. Hirofumi Yasui
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  6. Baek-Yeol Ryoo
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  7. Yukimasa Kamiya
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  8. Shiro Akinaga
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Corresponding author

Correspondence to Yoon-Koo Kang.

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Supplemental Figure

Relationship between tumor responses and plasma exposures to tivantinib. Cmax (A), AUC0-12 (B) and Ctrough on day 15 (C) as well as Ctrough on day 29 (D) are dotted for each individual with his/her tumor response. (PDF 19 kb)

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Kang, YK., Muro, K., Ryu, MH. et al. A phase II trial of a selective c-Met inhibitor tivantinib (ARQ 197) monotherapy as a second- or third-line therapy in the patients with metastatic gastric cancer. Invest New Drugs 32, 355–361 (2014). https://doi.org/10.1007/s10637-013-0057-2

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  • DOI: https://doi.org/10.1007/s10637-013-0057-2

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