Gumarontinib in patients with non-small-cell lung cancer harbouring MET exon 14 skipping mutations: a multicentre, single-arm, open-label, phase 1b/2 trial

doi:10.1016/j.eclinm.2023.101952

. 2023 Apr 6:59:101952.

doi: 10.1016/j.eclinm.2023.101952. eCollection 2023 May.

Gumarontinib in patients with non-small-cell lung cancer harbouring MET exon 14 skipping mutations: a multicentre, single-arm, open-label, phase 1b/2 trial

Yongfeng Yu¹, Jianya Zhou², Xingya Li³, Koichi Goto⁴, Xuhong Min⁵, Kazumi Nishino⁶, Jiuwei Cui⁷, Lin Wu⁸, Jun Sakakibara⁹, Yongqian Shu¹⁰, Xiaorong Dong¹¹, Lu Li¹², Yasuto Yoneshima¹³, Chengzhi Zhou¹⁴, Xiaoling Li¹⁵, Yiping Zhang¹⁶, Dingzhi Huang¹⁷, Aimin Zang¹⁸, Wei Zhang¹⁹, Xiuwen Wang²⁰, Li Zhang²¹, Chong Bai²², Jian Fang²³, Lejie Cao²⁴, Yanqiu Zhao²⁵, Yan Yu²⁶, Meiqi Shi²⁷, Diansheng Zhong²⁸, Fugen Li²⁹, Meng Li³⁰, Qiuxia Wu²⁹, Jun Zhou²⁹, Minghui Sun²⁹, Shun Lu¹

Affiliations

¹ Department of Medical Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
² Respiratory Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
³ Oncology Department, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
⁴ Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan.
⁵ Radiology Intervention Department, Anhui Chest Hospital, Hefei, China.
⁶ Thoracic Oncology, Osaka International Cancer Institute, Osaka, Japan.
⁷ Oncology Department, The First Bethune Hospital of Jilin University, Changchun, China.
⁸ Second Department of Thoracic Medicine, Hunan Cancer Hospital, Changsha, China.
⁹ Respiratory Medicine, Hokkaido University Hospital, Sapporo, Japan.
¹⁰ Oncology Department, Jiangsu Province Hospital, Nanjing, China.
¹¹ Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
¹² Lung Cancer Center, West China Hospital of Sichuan University, Chengdu, China.
¹³ Respiratory Medicine, Kyushu University Hospital, Fukuoka, Japan.
¹⁴ Oncology, The First Affiliate Hospital of Guangzhou Medical University, Guangzhou, China.
¹⁵ Thoracic Medicine, Liaoning Cancer Hospital & Institute, Shenyang, China.
¹⁶ Thoracic Oncology, Zhejiang Cancer Hospital, Hangzhou, China.
¹⁷ Oncology, Tianjin Medical University Cancer Institute & Hospital, Tianjin, China.
¹⁸ Medical Oncology, Affiliated Hospital of Hebei University, Baoding, China.
¹⁹ Pneumology Department/Institute Office, The First Affiliated Hospital of Nanchang University, Nanchang, China.
²⁰ Oncology, Qilu Hospital of Shandong University, Jinan, China.
²¹ Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Beijing, China.
²² Pneumology Department, Changhai Hospital of Shanghai, Shanghai, China.
²³ Thoracic Oncology Second Department, Beijing Cancer Hospital, Beijing, China.
²⁴ Pneumology Department, The First Affiliated Hospital of University of Science and Technology of China, Hefei, China.
²⁵ Respiratory Department of Internal Medicine, Henan Cancer Hospital, Zhengzhou, China.
²⁶ The Third Ward of Respiratory Medicine Department, Harbin Medical University Cancer Hospital, Harbin, China.
²⁷ Oncology Department, Jiangsu Cancer Hospital, Nanjing, China.
²⁸ Internal Medicine-Oncology, Tianjin Medical University General Hospital, Tianjin, China.
²⁹ Clinical Science Department, Haihe Biopharma Co., Ltd, Shanghai, China.
³⁰ Biostatistic and Data Science, Haihe Biopharma Co., Ltd, Shanghai, China.

PMID: 37096188
PMCID: PMC10121392
DOI: 10.1016/j.eclinm.2023.101952

Gumarontinib in patients with non-small-cell lung cancer harbouring MET exon 14 skipping mutations: a multicentre, single-arm, open-label, phase 1b/2 trial

Yongfeng Yu et al. EClinicalMedicine. 2023.

. 2023 Apr 6:59:101952.

doi: 10.1016/j.eclinm.2023.101952. eCollection 2023 May.

Authors

Affiliations

¹ Department of Medical Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
² Respiratory Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
³ Oncology Department, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
⁴ Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan.
⁵ Radiology Intervention Department, Anhui Chest Hospital, Hefei, China.
⁶ Thoracic Oncology, Osaka International Cancer Institute, Osaka, Japan.
⁷ Oncology Department, The First Bethune Hospital of Jilin University, Changchun, China.
⁸ Second Department of Thoracic Medicine, Hunan Cancer Hospital, Changsha, China.
⁹ Respiratory Medicine, Hokkaido University Hospital, Sapporo, Japan.
¹⁰ Oncology Department, Jiangsu Province Hospital, Nanjing, China.
¹¹ Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
¹² Lung Cancer Center, West China Hospital of Sichuan University, Chengdu, China.
¹³ Respiratory Medicine, Kyushu University Hospital, Fukuoka, Japan.
¹⁴ Oncology, The First Affiliate Hospital of Guangzhou Medical University, Guangzhou, China.
¹⁵ Thoracic Medicine, Liaoning Cancer Hospital & Institute, Shenyang, China.
¹⁶ Thoracic Oncology, Zhejiang Cancer Hospital, Hangzhou, China.
¹⁷ Oncology, Tianjin Medical University Cancer Institute & Hospital, Tianjin, China.
¹⁸ Medical Oncology, Affiliated Hospital of Hebei University, Baoding, China.
¹⁹ Pneumology Department/Institute Office, The First Affiliated Hospital of Nanchang University, Nanchang, China.
²⁰ Oncology, Qilu Hospital of Shandong University, Jinan, China.
²¹ Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Beijing, China.
²² Pneumology Department, Changhai Hospital of Shanghai, Shanghai, China.
²³ Thoracic Oncology Second Department, Beijing Cancer Hospital, Beijing, China.
²⁴ Pneumology Department, The First Affiliated Hospital of University of Science and Technology of China, Hefei, China.
²⁵ Respiratory Department of Internal Medicine, Henan Cancer Hospital, Zhengzhou, China.
²⁶ The Third Ward of Respiratory Medicine Department, Harbin Medical University Cancer Hospital, Harbin, China.
²⁷ Oncology Department, Jiangsu Cancer Hospital, Nanjing, China.
²⁸ Internal Medicine-Oncology, Tianjin Medical University General Hospital, Tianjin, China.
²⁹ Clinical Science Department, Haihe Biopharma Co., Ltd, Shanghai, China.
³⁰ Biostatistic and Data Science, Haihe Biopharma Co., Ltd, Shanghai, China.

PMID: 37096188
PMCID: PMC10121392
DOI: 10.1016/j.eclinm.2023.101952

Abstract

Background: Approximately 3-4% of patients with non-small-cell lung cancer (NSCLC) have MET exon 14 (METex14) skipping mutations. We report primary results from the phase 2 stage of a phase 1b/2 study of gumarontinib, a selective, potent, oral MET inhibitor, in patients with METex14 skipping mutation-positive (METex14-positive) NSCLC.

Methods: The single-arm, multicentre, open-label, phase 2 stage of the GLORY study was conducted at 42 centres across China and Japan. Adults with locally advanced or metastatic METex14-positive NSCLC received oral gumarontinib 300 mg once daily in continuous 21-day cycles until disease progression, intolerable toxicity, or withdrawal of consent. Eligible patients had failed one or two prior lines of therapy (not including a MET inhibitor), were ineligible for/refused chemotherapy, and had no genetic alterations targetable with standard therapies. The primary endpoint was objective response rate in patients with a valid baseline tumour assessment, by blinded independent review. The study was registered at ClinicalTrials.gov (NCT04270591).

Findings: Between Aug 2, 2019 and Apr 28, 2021, 84 patients were enrolled and received gumarontinib (median follow-up 13.5 months [IQR 8.7-17.1]), at data cut-off (Apr 28, 2022) five patients whose METex14 status could not be confirmed by a central laboratory were excluded from the efficacy analysis. The objective response rate was 66% (95% CI 54-76) overall (n = 79), 71% (95% CI 55-83) in treatment-naïve patients (n = 44), and 60% (95% CI 42-76) in previously-treated patients (n = 35). The most common treatment-related adverse events (any grade) were oedema (67/84 patients, 80%) and hypoalbuminuria (32/84, 38%). Grade ≥3 treatment-emergent adverse events occurred in 45 (54%) patients. Treatment-related adverse events leading to permanent discontinuation occurred in 8% (7/84) of patients.

Interpretation: Gumarontinib monotherapy had durable antitumour activity with manageable toxicity in patients with locally advanced or metastatic METex14-positive NSCLC when used in first line or later.

Funding: Haihe Biopharma Co., Ltd. Supported in part by grants from the National Science and Technology Major Project of China for "Clinical Research of Gumarontinib, a highly selective MET inhibitor" (2018ZX09711002-011-003); the National Natural Science Foundation of China (82030045 to S.L. and 82172633 to YF.Y); Shanghai Municipal Science & Technology Commission Research Project (19411950500 to S.L.); Shanghai Shenkang Action Plan (16CR3005A to S.L.) and Shanghai Chest Hospital Project of Collaborative Innovation (YJXT20190105 to S.L.).

Keywords: Lung cancer; MET inhibitor; MET mutation.

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Conflict of interest statement

G-K reports grants from Haihe Biopharma Co., Ltd., during the conduct of the study; grants and personal fees from Amgen Inc., grants and personal fees from Amgen K.K., personal fees from Amoy Diagnosties Co., Ltd., grants from Amgen Astellas BioPharma K.K., grants and personal fees from AstraZeneca K.K., personal fees from Bayer U.S., grants from Bayer Yakuhin, Ltd., grants from Boehringer Ingelheim Japan, Inc., grants and personal fees from Bristol-Myers Squibb K.K., grants from Blueprint Medicines Corporation, grants and personal fees from Chugai Pharmaceutical Co., Ltd., grants and personal fees from Daiichi Sankyo Co., Ltd., grants and personal fees from Eisai Co., Ltd., grants and personal fees from Eli Lilly Japan K.K., personal fees from Guardant Health Inc., grants from Ignyta, Inc., grants and personal fees from Janssen Pharmaceutical K.K., grants from Kissei Pharmaceutical Co., Ltd., grants from Kyowa Kirin Co., Ltd., personal fees from Life Technologies Japan Ltd., grants from Loxo Oncology, Inc., grants from Medical & Biological Laboratories Co., Ltd., personal fees from Medpace Japan K.K., grants and personal fees from Merck Biopharma Co., Ltd., grants from Merus N.V., grants and personal fees from MSD K.K., grants from NEC Corporation, grants and personal fees from Novartis Pharma K.K., grants and personal fees from Ono Pharmaceutical Co., Ltd., grants from Pfizer Japan Inc., grants from Sumitomo Dainippon Pharma Co., Ltd., grants from Spectrum Pharmaceuticals, Inc., grants from Sysmex Corporation, grants and personal fees from Taiho Pharmaceutical Co., Ltd., grants and personal fees from Takeda Pharmaceutical Co., Ltd., grants from Turning Point Therapeutics, Inc., outside the submitted work. N-K reports grants from Haihe Biopharma Co., Ltd., during the conduct of the study; grants from ONO Pharmaceutical Co., Ltd., grants and personal fees from MSD, grants from Taiho Pharmaceutical Co., Ltd., grants from AbbVie, grants from Daiichi Sankyo Company, Limited, grants from Amgen, grants from Eisai Co., Ltd., grants from Sanofi K.K., grants from Janssen Pharmaceutical K.K., grants from Novartis Pharmaceuticals, grants from Pfizer, grants from Eli Lilly Japan, grants and personal fees from Merck Biopharma Co., Ltd., grants and personal fees from Takeda Pharmaceutical Co., Ltd., grants and personal fees from Chugai pharmaceutical, grants from Merus, grants and personal fees from AstraZeneca, personal fees from Nippon Boehringer Ingelheim, personal fees from Roche Diagnostics, personal fees from Bristol Myers Squibb, personal fees from Nippon Kayaku, outside the submitted work. S-J reports grants from Eli Lilly Japan K.K., grants from Nippon Boehringer Ingelheim Co., Ltd., outside the submitted work. Y-Y reports ‘other’ interests in Taiho Pharmaceutical Co., Ltd., ‘other’ from Takeda Pharmaceutical Company Limited., ‘other’ from Eisai Co., Ltd., outside the submitted work. L-FG, Z-J, L-M, W-QX, and S-MH report personal fees from Haihe Biopharma Co., Ltd, during the conduct of the study; personal fees from Haihe Biopharma Co., Ltd, outside the submitted work. L-S reports grants from Haihe Biopharma Co., Ltd., outside the submitted work. All other authors declare no competing interests.

Figures

**Fig. 1**
**Trial profile.** NSCLC = non-small cell lung cancer.

**Fig. 2**
**Best change in target lesion size∗ from baseline assessed by a blinded independent review committee (efficacy analysis set; n = 79).** ∗Predefined as the largest percentage reduction (or smallest percentage increase in the absence of a reduction) in the volume of the target lesion from baseline prior to disease progression.

**Fig. 3**
The association between progression-free survival and variant allele frequency of *MET* mutations in DNA (20 patients) and *MET*ex14 mRNA level in RT-PCR (37 patients) in patients with a response to gumarontinib∗. ∗All responses were partial responses.

See this image and copyright information in PMC

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[1] Gentile A., Trusolino L., Comoglio P.M. The Met tyrosine kinase receptor in development and cancer. Cancer Metastasis Rev. 2008;27(1):85–94. - PubMed

[2] Gentile A., Trusolino L., Comoglio P.M. The Met tyrosine kinase receptor in development and cancer. Cancer Metastasis Rev. 2008;27(1):85–94. - PubMed

[3] Reungwetwattana T., Liang Y., Zhu V., Ou S.I. The race to target MET exon 14 skipping alterations in non-small cell lung cancer: the Why, the How, the Who, the Unknown, and the Inevitable. Lung Cancer. 2017;103:27–37. - PubMed

[4] Reungwetwattana T., Liang Y., Zhu V., Ou S.I. The race to target MET exon 14 skipping alterations in non-small cell lung cancer: the Why, the How, the Who, the Unknown, and the Inevitable. Lung Cancer. 2017;103:27–37. - PubMed

[5] Frampton G.M., Ali S.M., Rosenzweig M., et al. Activation of MET via diverse exon 14 splicing alterations occurs in multiple tumor types and confers clinical sensitivity to MET inhibitors. Cancer Discov. 2015;5(8):850–859. - PubMed

[6] Frampton G.M., Ali S.M., Rosenzweig M., et al. Activation of MET via diverse exon 14 splicing alterations occurs in multiple tumor types and confers clinical sensitivity to MET inhibitors. Cancer Discov. 2015;5(8):850–859. - PubMed

[7] Paik P.K., Drilon A., Fan P.D., et al. Response to MET inhibitors in patients with stage IV lung adenocarcinomas harboring MET mutations causing exon 14 skipping. Cancer Discov. 2015;5(8):842–849. - PMC - PubMed

[8] Paik P.K., Drilon A., Fan P.D., et al. Response to MET inhibitors in patients with stage IV lung adenocarcinomas harboring MET mutations causing exon 14 skipping. Cancer Discov. 2015;5(8):842–849. - PMC - PubMed

[9] Vuong H.G., Ho A.T.N., Altibi A.M.A., Nakazawa T., Katoh R., Kondo T. Clinicopathological implications of MET exon 14 mutations in non-small cell lung cancer - a systematic review and meta-analysis. Lung Cancer. 2018;123:76–82. - PubMed

[10] Vuong H.G., Ho A.T.N., Altibi A.M.A., Nakazawa T., Katoh R., Kondo T. Clinicopathological implications of MET exon 14 mutations in non-small cell lung cancer - a systematic review and meta-analysis. Lung Cancer. 2018;123:76–82. - PubMed

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Gumarontinib in patients with non-small-cell lung cancer harbouring MET exon 14 skipping mutations: a multicentre, single-arm, open-label, phase 1b/2 trial

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Gumarontinib in patients with non-small-cell lung cancer harbouring MET exon 14 skipping mutations: a multicentre, single-arm, open-label, phase 1b/2 trial

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