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Phase 2 trial of crizotinib in Japanese patients with advanced NSCLC harboring a MET gene alteration: a Co-MET study

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Abstract

Background

MET exon 14 skipping mutations occur in 3–4% and MET high amplifications occur in < 1% of patients with non-small-cell lung cancer (NSCLC). Crizotinib, a selective ATP-competitive small-molecule inhibitor of c-Met, ALK, and ROS1 tyrosine kinases, has shown activity in cancer models with various types of MET activation.

Methods

The Co-MET study is a single-arm phase 2 trial to assess the safety and efficacy of crizotinib in MET inhibitor-naïve patients with advanced NSCLC harboring MET exon 14 skipping mutation (cohort 1) or high MET gene copy number of ≥ 7 (cohort 2). The primary endpoint was the objective response rate (ORR) per RECIST v1.1 by independent radiology review in cohort 1. The key secondary endpoints were the duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety.

Results

A total of 28 patients (23 in cohort 1 and 5 in cohort 2) were enrolled between March 2018 and February 2020. The primary endpoint was met as the ORR (90% confidence interval: CI) in cohort 1 was 38.1% (20.6–58.3). Median DoR, PFS, and OS (95% CI) were 7.6 (1.9-NE), 5.7 (2.1–11.3), 9.1 (4.0–19.9) months, respectively, in cohort 1. ORR in cohort 2 was 40.0% (18.9–92.4). The safety signals were generally consistent with the known safety profile of crizotinib.

Conclusions

Crizotinib showed a clinical activity similar to that of tepotinib and capmatinib in patients with NSCLC harboring MET exon 14 skipping mutations. Clinical trial information: UMIN000031623.

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Acknowledgements

We thank the participating patients and their families as well as all the site investigators and operations staff. We also thank Ms. Yuri Murata and PREMIA Inc. for administrative assistance in managing clinical samples, molecular screening, and clinico-genomic database in LC-SCRUM-Asia. We would like to thank Editage (www.editage.jp) for English language editing.

Funding

This research was supported by AMED under Grant Number JP17ck0106294. Crizotinib was supplied by Pfizer Inc., which was not involved in data collection, data analysis, data interpretation, or writing of the report for publication. All authors had full access to the relevant aggregated study data, and the corresponding author was responsible for the decision to submit the manuscript for publication.

Author information

Authors and Affiliations

  1. Department of Thoracic Oncology, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan

    Kaname Nosaki, Kiyotaka Yoh, Fumihiko Okumura, Shingo Matsumoto & Koichi Goto

  2. Department of Thoracic Oncology, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan

    Ryo Toyozawa & Takashi Seto

  3. Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan

    Hidehito Horinouchi

  4. Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan

    Masahiro Morise

  5. Department of Respiratory Medicine, Okayama University Hospital, Okayama, Japan

    Kadoaki Ohashi

  6. Division of Thoracic Oncology, Shizuoka Cancer Center, Shizuoka, Japan

    Haruyasu Murakami

  7. Department of Thoracic Oncology, Hyogo Cancer Center, Akashi, Japan

    Miyako Satouchi

  8. Department of Respiratory Medicine, Faculty of Medicine, Hokkaido University, Sapporo, Japan

    Jun Sakakibara-Konishi

  9. Department of Respiratory Medicine, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, Japan

    Seiji Yano

  10. Department of Biostatistics, Yamaguchi University Graduate School of Medicine, Ube, Japan

    Mototsugu Shimokawa

Authors
  1. Kaname Nosaki
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  2. Kiyotaka Yoh
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  3. Ryo Toyozawa
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  4. Hidehito Horinouchi
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  5. Masahiro Morise
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  11. Fumihiko Okumura
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  15. Koichi Goto
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Contributions

Kaname Nosaki: Conceptualization, Methodology, Investigation, Resources, Writing – original draft, Writing—review & editing, Project administration. Kiyotaka Yoh: Conceptualization, Methodology, Investigation, Resources, Writing—review & editing, Supervision, Project administration, Funding acquisition. Ryo Toyozawa: Investigation, Resources, Writing—review & editing. Hidehito Horinouchi: Investigation, Resources, Writing—review & editing. Masahiro Morise: Investigation, Resources, Writing—review & editing. Kadoaki Ohashi: Investigation, Resources, Writing—review & editing. Haruyasu Murakami: Investigation, Resources, Writing—review & editing. Miyako Satouchi: Investigation, Resources, Writing—review & editing. Jun Sakakibara-Konishi: Investigation, Resources, Writing—review & editing. Seiji Yano: Investigation, Resources, Writing—review & editing. Fumihiko Okumura: Investigation, Resources, Writing—review & editing. Shingo Matsumoto: Investigation, Resources, Writing—review & editing. Mototsugu Shimokawa: Methodology, Formal analysis, Investigation, Data curation, Writing—review & editing. Takashi Seto: Conceptualization, Methodology, Investigation, Resources, Writing—review & editing, Supervision, Project administration. Koichi Goto: Investigation, Resources, Writing—review & editing, Supervision.

Corresponding author

Correspondence to Kiyotaka Yoh.

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Conflict of interest

Kaname Nosaki has received research grants from Takeda, AstraZeneca, MSD K.K, Abbvie, Chugai Pharma, DaiichiSankyo/UCB Japan, and AnHeart Therapeutics and honoraria from AstraZeneca, Chugai Pharma, Lilly, MSD, Pfizer, Taiho Pharmaceutical, Janssen, Ono Pharmaceutical, Takeda, Novartis, and Merck and Advisory Board for Daiichi Sankyo/UCB Japan and Abbvie. Kiyotaka Yoh has received research grants from Abbvie, Amgen, AstraZeneca, Boehringer Ingelheim, Chugai, Daiichi sankyo, Lilly, MSD, Pfizer, Taiho, Takeda and consultation for Boehringer Ingelheim and honoraria from Abbvie, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai, Daiichi sankyo, Janssen, Kyowa kirin, Lilly, Merck Serono, Novartis, Ono, Otsuka, Taiho, Takeda. Ryo Toyozawa has received research grants from Abbvie, Amgen, AnHeart Therapeutics, Daiichi Sankyo, Eli Lilly Japan, Novartis Pharma, Pfizer Japan, Takeda Pharmaceutical and honoraria from AstraZeneca, Chugai Pharmaceutical, Eli Lilly Japan, MSD, Nippon, Boehringer Ingelheim, Novartis Pharma, Ono Pharmaceutical, Pfizer Japan, Taiho Pharmaceutical, Takeda Pharmaceutical. Hidehito Horinouchi has received research grants from MSD, Abbvie, AstraZeneca, BMS, Ono, Daiichi-Sankyo, Janssen, Chugai, Roche and honoraria from AstraZeneca, MSD, Eli Lilly, Ono, BMS, Chugai, Roche, Amgen, Abbvie and Advisory Board for AstraZeneca, Chugai, Roche, ONO, BMS, Abbvie. Masahiro Morise has received research grants from Boehringer-ingelheim, Eli Lilly and honoraria from Boehringer Ingelheim, Daiichi Sankyo, AstraZeneca, Pfizer, Eli Lilly, Chugai Pharmaceutical, Merk Sharp & Dohme (MSD), Ono Pharmaceutical, and Taiho Pharmaceutical. and Principal investigator of pharmaceutical companies initiated trial for Chugai, Astra Zeneca, Ono, Pfizer, Merk serono, Kissei, Taiho and Novartis. Kadoaki Ohashi has received research grants from Nippon Boehringer Ingelheim Co., Ltd., CHUGAI PHARMACEUTICAL CO., LTD., Eli Lilly Japan K.K., DAIICHI SANKYO COMPANY, LIMITED and honoraria from Eli Lilly Japan K.K., Novartis Pharma K.K., CHUGAI PHARMACEUTICAL CO., LTD., Kyowa Kirin Co., Ltd. Haruyasu Murakami has received research grants from Chugai pharma, AstraZeneca, AbbVie, Daiichi Sankyo, IQvia, Taiho Pharmaceutical, Bayer and honoraria from Chugai pharma, Daiichi Sankyo, AstraZeneca, Takeda, Amgen, Ono Pharmaceutical, Bristol-Myers Squibb Japan, MSD, Pfizer, Novartis, Lilly Japan, Taiho Pharmaceutical, Eisai, Nihonkayaku and Advisory Board for Chugai pharma, GAIA BioMedicine, Daiichi Sankyo, Amgen. Miyako Satouchi has received research grants from AstraZeneca, Ono, Bristol Myers Squibb, MSD, Janssen, Amgen, Taiho, Pfizer, Daiichi-Sankyo, Takeda, Eisai, Novartis, GlaxoSmithKline and honoraria from AstraZeneca, Chugai, Eli Lilly, Ono, Bristol Myers Squibb, MSD, Taiho, Pfizer, Novartis, Takeda, Merck, Novartis, Daiichi-Sankyo, Bayer, Amgen, Eisai. Jun Sakakibara-Konishi has received research grants from Lilly. Seiji Yano has received research grants from Takeda, Jansen and honoraria from Pfizer, Chugan, AstraZeneca, Eli Lilly, MSD, Ono, BMS, Amgen, Novartis. Shingo Matsumoto has received research grants from Chugai Pharma, Janssen Pharmaceutical, MSD and honoraria from Eli Lilly, Merck Biopharma, Chugai Pharma, Novartis Pharma, Guardant Health, AstraZeneca. Takashi Seto has received honoraria from Amgen, AstraZeneca, Bristol-Myers Squibb, Chugai Pharmaceutical, Eli Lilly Japan, MSD, Novartis Pharma, Ono Pharmaceutical, Pfizer Japan, Takeda Pharmaceutical, Towa Pharmaceutical and employee of Precision Medicine Asia. Koichi Goto has received research grants from Amgen Inc., Amgen K.K., Amgen Astellas, BioPharma K.K., AstraZeneca K.K., Bayer Yakuhin, Ltd., Boehringer Ingelheim Japan, Inc., Bristol-Myers Squibb K.K., Chugai Pharmaceutical Co., Ltd., Craif Inc., DAIICHI SANKYO Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan K.K., Haihe Biopharma Co., Ltd. Ignyta,Inc., Janssen Pharmaceutical K.K., KISSEI PHARMACEUTICAL CO., LTD., Kyowa Kirin Co., Ltd., Life Technologies Japan Ltd., Loxo Oncology, Inc., LSI Medience Corporation., MEDICAL& BIOLOGICAL LABORATORIES CO., LTD., Merck Biopharma Co., Ltd., Merus N.V., MSD K.K., Novartis Pharma K.K., Ono Pharmaceutical Co., Ltd., Pfizer Japan Inc., Pfizer R&D Japan G.K., Precision Medicine Asia Co., Ltd., RIKEN GENESIS CO., LTD., Sumitomo Pharma Co., Ltd., Spectrum Pharmaceuticals, Inc., Sysmex Corporation., Taiho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Turning Point Therapeutics,Inc., Xcoo, Inc. and honoraria from Amgen K.K., Amoy Diagnosties Co.,Ltd., AstraZeneca K.K., Bayer U.S., Boehringer Ingelheim Japan, Inc., Bristol-Myers Squibb K.K., Chugai Pharmaceutical Co., Ltd., DAIICHI SANKYO Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan K.K., Guardant Health Inc., Janssen Pharmaceutical K.K., Merck Biopharma Co., Ltd., Nippon Kayaku Co.,Ltd., Novartis Pharma K.K., Ono Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., RIKEN GENESIS CO., LTD., Taiho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Thermo Fisher Scientific K.K. and Advisory Board for Amgen Inc., Amgen K.K., DAIICHI SANKYO Co., Ltd., Eli Lilly Japan K.K., Haihe Biopharma Co., Ltd., Janssen Pharmaceutical K.K., SYNEOS HEALTH CLINICAL K.K.. The other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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Nosaki, K., Yoh, K., Toyozawa, R. et al. Phase 2 trial of crizotinib in Japanese patients with advanced NSCLC harboring a MET gene alteration: a Co-MET study. Int J Clin Oncol (2024). https://doi.org/10.1007/s10147-024-02543-x

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