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

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

doi:10.1016/j.eclinm.2023.101952

Cited by 22 publications

(6 citation statements)

References 21 publications

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“…In these studies, the mPFS for patients with MET exon 14 skipping mutation ranged from 5.4 to 12 months, while for those with MET amp, it was only 1.8–6.7 months. 12 – 23 The findings in our study align with these results. Notably, within all patients with MET amp, those with secondary amp exhibited poorer efficacy compared to the primary amp.…”

Section: Discussionsupporting

confidence: 91%

Assessment of efficacy and safety of MET tyrosine kinase inhibitors in non-small-cell lung cancer patients with MET alterations

Wang,

Xu,

Wang

et al. 2024

Ther Adv Med Oncol

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Background: While targeted therapy has become the standard treatment for certain non-small-cell lung cancer (NSCLC) patients with gene mutation positivity, there remains a lack of enough reports of the efficacy of mesenchymal–epithelial transition (MET) alterations in the real world. Objectives: We aimed to explore the efficacy and toxicity of targeted therapy in NSCLC patients with different types of MET alterations and hope to provide more clinical medication guidance. Design: Designed different subgroups to compare the efficacy and safety of targeted therapy in NSCLC patients with MET alterations. Methods: We conducted analyses on the efficacy and safety of mesenchymal–epithelial transition factor-tyrosine kinase inhibitor (MET-TKI) therapy in NSCLC patients with MET alterations. Tumor response was evaluated based on the Response Evaluation Criteria in Solid Tumors version 1.1 criteria, and both progression-free survival (PFS) and overall survival were determined using the Kaplan–Meier method. Results: Our study encompassed 116 NSCLC patients with MET alterations, including MET ex14 skipping mutation ( n = 50), MET primary amplification (amp) ( n = 25), and secondary amp ( n = 41). Among treated patients, 34 achieved a partial response, while 52 exhibited stable disease. The overall response rate for the entire cohort was 29.31%, with a disease control rate of 74.14%. A significant difference was observed in the median PFS among patients with MET ex14 skipping mutation, MET primary amplification (amp), and secondary amp (10.4 versus 6.6 versus 4.5 months, p = 0.002). In all, 69 patients experienced drug-related adverse effects, with the most common being peripheral edema (35.34%), nausea and vomiting (21.55%), and fatigue (10.34%). In total, 29 patients (25%) encountered drug-related adverse reactions of grade 3 or higher. Conclusion: MET-TKI therapy works better for MET ex14 skipping mutation than other types of MET gene alteration. In the two MET amplified groups, the secondary amp was less effective. This study may provide more research support for the treatment of these patients.

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Section: Discussionsupporting

confidence: 91%

Assessment of efficacy and safety of MET tyrosine kinase inhibitors in non-small-cell lung cancer patients with MET alterations

Wang,

Xu,

Wang

et al. 2024

Ther Adv Med Oncol

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“…The most common treatment-related adverse effect observed was oedema. 105 Further clinical studies on this candidate are in progress (Table 1).…”

Section: Results Of Preclinical and Clinical Studies Of Key Compoundsmentioning

confidence: 99%

“…A phase 1b/2 trial on patients with metastatic Met positive non-small cell lung cancer showed that this drug had manageable toxicity and durable anticancer activity. 61 Other trials are ongoing to evaluate the safety and antitumor activity of glumetinib either as monotherapy or as part of combination therapy (NCT04270591, NCT04797702 and NCT04338243).…”

Section: Pyrazolopyridine-based Protein Kinase Inhibitorsmentioning

confidence: 99%

Pyrazolopyridine-based kinase inhibitors for anti-cancer targeted therapy

Halder,

Rai,

Talukdar

et al. 2024

RSC Med. Chem.

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“… 15 Currently, MET ex14 skipping mutation was recognized as a clinical biomarker for stratifying NSCLC patients based on their predicted response to MET inhibitors. Four selective type Ib small molecule MET inhibitors targeting MET ex14 skipping mutations, including Tepotinib, 16 Capmatinib, 17 Savolitinib 18 and Gumarontinib, 19 were approved or conditionally approved and have become a new standard of care in NSCLC. The combination of MET inhibitor with EGFR inhibitor targeting MET amp also showed promising efficacy for those MET amp-driven EGFR inhibitor resistant NSCLC patients.…”

Section: Introductionmentioning

confidence: 99%

“… 25 Gumarontinib has been conditionally approved by National Medical Products Administration for MET ex14 skipping mutation positive, locally advanced or metastatic NSCLC. 19 Given the crucial significance of MET overexpression in NSCLC population, we pooled data of driver-gene negative NSCLC patients with MET overexpression and with or without MET amp from two single arm studies to (1) explore the efficacy and safety of Gumarontinib; (2) evaluate whether MET overexpression [immunohistochemistry (IHC)3+] could serve as a useful predictor for identifying patients who are likely to benefit from anti-MET therapy.…”

Section: Introductionmentioning

confidence: 99%

A pooled analysis of clinical outcome in driver-gene negative non-small cell lung cancer patients with MET overexpression treated with gumarontinib

Yu,

Dong,

Shi

et al. 2024

Ther Adv Med Oncol

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Background: MET overexpression represents the most MET aberration in advanced non-small-cell lung cancer (NSCLC). However, except MET exon 14 ( METex14) skipping mutation was recognized as a clinical biomarker, the role of MET overexpression as a predictive factor to MET inhibitor is not clear. Objectives: The purpose of the pooled analysis is to explore the safety and efficiency of gumarontinib, a highly selective oral MET inhibitor, in drive-gene negative NSCLC patients with MET overexpression. Design and methods: NSCLC patients with MET overexpression [immunohistochemistry (IHC) ⩾3+ as determined by central laboratory] not carrying epidermal growth factor receptor mutation, METex14 skipping mutation or other known drive gene alternations who received Gumarontinib 300 mg QD from two single arm studies were selected and pooled for the analysis. The efficacy [objective response rate (ORR), disease control rate (DCR), duration of response, progression-free survival (PFS) and overall survival (OS)] and safety [treatment emergent adverse event (TEAE), treatment related AE (TRAE) and serious AE (SAE) were assessed. Results: A total of 32 patients with MET overexpression were included in the analysis, including 12 treatment naïve patients who refused or were unsuitable for chemotherapy, and 20 pre-treated patients who received ⩾1 lines of prior systemic anti-tumour therapies. Overall, the ORR was 37.5% [95% confidence interval (CI): 21.1–56.3%], the DCR was 81.3% (95% CI: 63.6–92.8%), median PFS (mPFS) and median OS (mOS) were 6.9 month (95% CI: 3.6–9.7) and 17.0 month (95% CI: 10.3–not evaluable), respectively. The most common AEs were oedema (59.4%), hypoalbuminaemia (40.6%), alanine aminotransferase increased (31.3%). Conclusion: Gumarontinib showed promising antitumour activity in driver-gene negative locally advanced or metastatic NSCLC patients with MET overexpression, which warranted a further clinical trial. Trial registration: ClinicalTrials.gov identifier: NCT03457532; NCT04270591.

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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

Cited by 22 publications

References 21 publications

Assessment of efficacy and safety of MET tyrosine kinase inhibitors in non-small-cell lung cancer patients with MET alterations

Assessment of efficacy and safety of MET tyrosine kinase inhibitors in non-small-cell lung cancer patients with MET alterations

Pyrazolopyridine-based kinase inhibitors for anti-cancer targeted therapy

A pooled analysis of clinical outcome in driver-gene negative non-small cell lung cancer patients with MET overexpression treated with gumarontinib

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