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Safety and Tolerability of c-MET Inhibitors in Cancer

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Abstract

The role of aberrant hepatocyte growth factor receptor (c-MET, also known as tyrosine-protein kinase MET)/hepatocyte growth factor (HGF) signaling in cancer progression and invasion has been extensively studied. c-MET inhibitors have shown promising pre-clinical and early phase clinical trial anti-tumor activity in several tumor types, although results of most phase III trials with these agents have been negative. To date, two small molecule c-MET inhibitors, cabozantinib and crizotinib, have been approved by regulatory authorities for the treatment of selected cancer types, but several novel c-MET inhibitors (either monoclonal antibodies or small molecule c-MET tyrosine kinase inhibitors) and treatment combinations are currently under study in different settings. Here we provide an overview of the mechanism of action and rationale of c-MET inhibition in cancer, the efficacy of approved agents, and novel promising c-MET-inhibitors and novel targeted combination strategies under development in different cancer types, with a focus on the safety profile and tolerability of these compounds.

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Author notes

  1. Alberto Puccini and Nagore I. Marín-Ramos contributed equally to this work.

Authors and Affiliations

  1. Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Suite 5410, Los Angeles, CA, 90033, USA

    Alberto Puccini, Heinz-Josef Lenz & Francesca Battaglin

  2. Medical Oncology Unit 1, IRCCS Ospedale Policlinico San Martino, Genoa, Italy

    Alberto Puccini

  3. Department of Neurosurgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    Nagore I. Marín-Ramos

  4. Medical Oncology Unit 1, Clinical and Experimental Oncology Department, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy

    Francesca Bergamo, Marta Schirripa, Sara Lonardi, Fotios Loupakis & Francesca Battaglin

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  1. Alberto Puccini
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Contributions

FB, AP and NIM-R drafted the manuscript. FB supervised the manuscript. All authors directly provided their contribution, read and approved the final manuscript.

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Correspondence to Francesca Battaglin.

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Conflict of interest

Francesca Battaglin has received honoraria for lectures from Eli Lilly and Company, and travel/accommodation support from Bayer and Amgen Inc. Heinz-Josef Lenz has received clinical trial financial support from Merck Serono and Roche, honoraria for advisory board membership and lectures from Bayer, Boehringer Ingelheim, Genentech, Pfizer, Merck Serono and Roche, and travel/accommodation support from Bayer, Merck Serono and Roche. Fotios Loupakis has received travel/accommodation support from Amgen Inc., Merck Serono and Roche. Sara Lonardi has received research funding from Merck Serono and Amgen Inc., honoraria for consulting/advisory roles from Amgen Inc., Bayer Healthcare, Merck Serono and Eli Lilly and Company, and honoraria for speakers’ bureau from Eli Lilly and Company, Bristol-Myers Squibb and Roche. Alberto Puccini, Nagore I. Marín-Ramos, Francesca Bergamo and Marta Schirripa have no conflicts of interest that are directly relevant to the content of this manuscript.

Funding

This manuscript was partly supported by the National Cancer Institute (grant number P30CA014089), the Gloria Borges WunderGlo Foundation–The Wunder Project, the Dhont Family Foundation, the San Pedro Peninsula Cancer Guild, the Daniel Butler Research Fund, and the Call to Cure Research Fund. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health.

Additional information

Part of a theme issue on “Safety of Novel Anticancer Therapies: Future Perspectives”. Guest Editors: Rashmi R. Shah, Giuseppe Curigliano.

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Puccini, A., Marín-Ramos, N.I., Bergamo, F. et al. Safety and Tolerability of c-MET Inhibitors in Cancer. Drug Saf 42, 211–233 (2019). https://doi.org/10.1007/s40264-018-0780-x

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