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; Jianya Zhou; Xingya Li; Koichi Goto; Xuhong Min; Kazumi Nishino; Jiuwei Cui; Lin Wu; Jun Sakakibara; Yongqian Shu; Xiaorong Dong; Lu Li; Yasuto Yoneshima; Chengzhi Zhou; Xiaoling Li; Yiping Zhang; Dingzhi Huang; Aimin Zang; Wei Zhang; Xiuwen Wang; Li Zhang; Chong Bai; Jian Fang; Lejie Cao; Yanqiu Zhao; Yan Yu; Meiqi Shi; Diansheng Zhong; Fugen Li; Meng Li; Qiuxia Wu; Jun Zhou; Minghui Sun; Shun Lu

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

EClinicalMedicine. 2023 Apr 6:59:101952. doi: 10.1016/j.eclinm.2023.101952. eCollection 2023 May.

Authors

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.

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.

Associated data

ClinicalTrials.gov/NCT04270591