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Phase I study of the anti-MET antibody onartuzumab in patients with solid tumors and MET-positive lung cancer

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Summary

Onartuzumab is a monovalent, humanized, monoclonal antibody that showed significant survival benefits in combination with erlotinib in MET-positive non-small-cell lung cancer (NSCLC) in pre-specified subgroup analyses of a randomized phase II study. We conducted a two-stage, open-label, multicenter, phase I study of onartuzumab in Japanese patients. Stage 1 investigated the safety, tolerability, pharmacokinetics (PK), and recommended dose of onartuzumab in patients with solid tumors, and Stage 2 determined the safety, tolerability, and PK of onartuzumab plus erlotinib in patients with MET-positive NSCLC. Nine patients received onartuzumab monotherapy (4, 15, or 30 mg/kg on Day 1 of each 21-day cycle) in Stage 1, and six patients received onartuzumab (15 mg/kg) plus erlotinib (150 mg/day) in Stage 2. There were no dose-limiting toxicities in either stage. Serious adverse events (AEs) occurred in one patient in Stage 1 (convulsion), and two patients in Stage 2 (once case each of diarrhea, vomiting, and pulmonary embolism), but there were no grade 4 AEs or AEs leading to death. Onartuzumab PKs were linear in the dose range of 4 to 30 mg/kg, and were not affected by co-administration with erlotinib. PK parameters of onartuzumab were similar to those reported in non-Japanese patients. A partial response was observed in a patient with MET immunohistochemistry 3+ NSCLC without MET gene amplification. Based on these results, the recommended dose of onartuzumab in Japanese patients with solid tumors is 15 mg/kg every 21 days. The combination of onartuzumab with erlotinib is feasible in Japanese patients with MET-positive lung cancer.

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Acknowledgments

We thank all of the participating patients and their families, as well as the investigators, study coordinators, operations staff, and the onartuzumab project team (Chugai Pharmaceutical Co., Ltd.). We especially acknowledge the help of Dr. Kawano, Dr. Kaburaki, and Dr. Saito from the Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan. Support for third-party writing assistance for this manuscript was provided by Chugai Pharmaceutical Co., Ltd.

Compliance with ethical standards

The protocol was approved by the institutional review board of the two participating medical centers. The study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines, and all patients provided written informed consent prior to any study-related procedures.

Conflicts of interest

Makoto Nishio has received honoraria from Chugai, Pfizer and Eli Lilly. Hiroshi Nokihara has received honoraria from Sanofi, Eli Lilly and Boehringer Ingelheim. Hidehito Horinouchi has received research support from National Cancer Center Research and Development Fund and honoraria from Johnson & Johnson, Taiho and Eli Lilly. Shunji Takahashi has received research support from Chugai, Taiho, Sanofi, Zenyaku and Novartis and honoraria from Astrazeneka, Novartis, Astellas and Daiichisankyo. Noboru Yamamoto has received support from a project sponsor Quintiles, Chugai, BMS, Astellas, Novartis and Taiho. Yasuhide Yamada has received honoraria from Taiho and Chugai. Masaichi Abe and Takashi Tahata are employees of Chugai, and Takashi Tahata holds stock in Chugai. Tomohide Tamura has received honoraria from Chugai, Eli Lilly, Kyowa Kirin, Pfizer and Exelixis.

Atsushi Horiike, Shinji Nakamichi, Hiroshi Wakui, Fumiyoshi Ohyanagi, Keita Kudo, Noriko Yanagitani, and Yasutoshi Kuboki declare that they have no conflicts of interest.

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Authors and Affiliations

  1. Department of Thoracic Medical Oncology, Cancer Institute Hospital of Japanese Foundation for Cancer Research, 3-10-6 Ariake, Koto-ku, Tokyo, 135-8550, Japan

    Makoto Nishio, Atsushi Horiike, Fumiyoshi Ohyanagi, Keita Kudo, Noriko Yanagitani, Shunji Takahashi & Yasutoshi Kuboki

  2. National Cancer Center Hospital, Tokyo, Japan

    Hiroshi Nokihara, Hidehito Horinouchi, Shinji Nakamichi, Hiroshi Wakui, Noboru Yamamoto, Yasuhide Yamada & Tomohide Tamura

  3. Chugai Pharmaceutical Co., Ltd., Tokyo, Japan

    Masaichi Abe & Takashi Tahata

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  1. Makoto Nishio
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  2. Atsushi Horiike
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  14. Masaichi Abe
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  15. Takashi Tahata
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  16. Tomohide Tamura
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Corresponding author

Correspondence to Makoto Nishio.

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Nishio, M., Horiike, A., Nokihara, H. et al. Phase I study of the anti-MET antibody onartuzumab in patients with solid tumors and MET-positive lung cancer. Invest New Drugs 33, 632–640 (2015). https://doi.org/10.1007/s10637-015-0227-5

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  • DOI: https://doi.org/10.1007/s10637-015-0227-5

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