Case series of MET exon 14 skipping mutation-positive non-small-cell lung cancers with response to crizotinib and cabozantinib

Wang, Samantha X.Y.; Zhang, Bing M.; Wakelee, Heather A.; Koontz, Michael Zach; Pan, Minggui; Diehn, Maximilian; Kunder, Christian A.; Neal, Joel W.

doi:10.1097/cad.0000000000000765

Cited by 35 publications

(20 citation statements)

References 14 publications

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“…The TKI cabozantinib, which inhibits multiple RTKs in addition to MET, has also been reported to have efficacy in MET exon 14 skipping tumors [54,55]. An Italian phase II trial is currently evaluating cabozantinib in patients with MET-amplified NSCLC or MET exon 14 skipping NSCLC (CABinMET study, NCT03911193).…”

Section: Tumors With Met Exon 14 Skipping Are Sensitive To Met Tkismentioning

confidence: 99%

The promise of selective MET inhibitors in non-small cell lung cancer with MET exon 14 skipping

Salgia

Sattler

Scheele

et al. 2020

Cancer Treatment Reviews

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Dysregulated activation of the MET tyrosine kinase receptor is implicated in the development of solid tumors and can arise through several mechanisms, including gene amplification, overexpression of the receptor and/or its ligand hepatocyte growth factor (HGF), and the acquisition of activating mutations. The most common activating mutations cause exon 14 to be skipped during MET mRNA splicing. This in-frame deletion, known as MET exon 14, results in production of a shortened receptor that lacks a juxtamembrane domain but retains affinity for HGF. However, the negative regulatory function located within this protein sequence is lost, leading to receptor accumulation on the cell surface and prolonged activation by HGF. MET mutations causing exon 14 skipping appear to be true oncogenic drivers and occur in patients and tumors with distinct characteristics.Increasing evidence suggests that tumors carrying such mutations are sensitive to MET inhibition, raising the hope that selective MET inhibitors will provide patients with optimal anticancer activity with minimal toxicity.We discuss the prospects for selective MET inhibitors in the treatment of non-small cell lung cancer harboring MET exon 14 skipping.

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Section: Tumors With Met Exon 14 Skipping Are Sensitive To Met Tkismentioning

confidence: 99%

The promise of selective MET inhibitors in non-small cell lung cancer with MET exon 14 skipping

Salgia

Sattler

Scheele

et al. 2020

Cancer Treatment Reviews

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show abstract

“…This alteration has been described as a potential oncogenic driver, showing mostly mutual exclusiveness with other oncogenic driver mutations [5,12,15]. Several studies in small series suggest that patients, harboring a METex14del, respond well to cMET tyrosine kinase inhibitors (TKI), such as crizotinib, tepotinib, capmatinib and cabozantinib [10,[16][17][18][19][20][21].…”

Section: Introductionmentioning

confidence: 99%

Highly accurate DNA-based detection and treatment results of MET exon 14 skipping mutations in lung cancer

et al. 2020

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The oncogenic MET exon 14 skipping mutation (METex14del) is described to drive 1.3 %-5.7 % of non-small-cell lung cancer (NSCLC) and multiple studies with cMET inhibitors show promising clinical responses. RNA-based analysis seems most optimal for METex14del detection, however, acquiring sufficient RNA material is often problematic. An alternative is DNA-based analysis, but commercially available DNA-based panels only detect up to 63 % of known METex14del alterations. The goal of this study is to describe an optimized DNA-based diagnostic test for METex14del in NSCLC, including clinical features and follow-up of patients treated with cMET-targeted therapy and consequent resistance mechanisms. Material and methods: Routinely processed diagnostic pathology non-squamous NSCLC specimens were investigated by a custom-made DNA-based targeted amplicon-based next generation sequencing (NGS) panel, which includes 4 amplicons for METex14del detection. Retrospectively, histopathological characteristics and clinical follow up were investigated for advanced non-squamous NSCLC with METex14del. Results: In silico analysis showed that our NGS panel is able to detect 96 % of reported METex14 alterations. METex14del was found in 2 % of patients with non-squamous NSCLC tested for therapeutic purposes. In total, from May 2015-Sep 2018, METex14del was found in 46 patients. Thirty-six of these patients had advanced nonsquamous NSCLC, they were predominantly elderly (76.5 years [53-90]), male (25/36) and (ex)-smokers (23/ 36). Five patients received treatment with crizotinib (Pfizer Oncology), in a named patient based program, disease control was achieved for 4/5 patients (3 partial responses, 1 stable disease) and one patient had a mixed response. Two patients developed a MET D1228N mutation during crizotinib treatment, inducing a resistance mechanism to crizotinib. Conclusions: This study shows that METex14del can be reliably detected by routine DNA NGS analysis. Although a small cohort, patients responded well to targeted treatment, underlining the need for routine testing of METex14del in advanced non-squamous NSCLC to guarantee optimal personalized treatment.

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“…In recent years, splice site mutations have been discovered in MET, leading to exon 14 skipping. NSCLC patients who were carrying this splice variant typically overexpressed MET and showed a response to MET small molecule inhibitors such as crizotinib and cabozantinib (40). In this study, X1010_splice was found to be the most frequent mutation type in LUAD.…”

Section: Discussionmentioning

confidence: 58%

Spectrum of Mesenchymal–Epithelial Transition Aberrations and Potential Clinical Implications: Insights From Integrative Pancancer Analysis

Zhou

et al. 2020

Front. Oncol.

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Background: The receptor tyrosine kinase mesenchymal-epithelial transition factor (MET) is frequently altered in cancers and is a common therapeutic target for cancers with MET variants. However, abnormal MET alterations and their associations with patient outcome across different cancer types have not been studied simultaneously. In this study, we try to fill the vacancy in a comprehensive manner and capture the full MET alteration spectrum. Methods: A total of 10,967 tumor samples comprising 32 cancer types from The Cancer Genome Atlas (TCGA) datasets were analyzed for MET abnormal expression, mutations, and copy number variants (CNVs). Results: MET abnormal expression, alteration frequency, mutation site distribution, and functional impact varied across different cancer types. Lung adenocarcinoma (LUAD) has most targetable mutations located in the juxtamembrane domain, and both high expression and amplification of MET are significantly associated with poor prognosis. Kidney renal papillary cell carcinoma (KIRP) harbored the third highest alteration frequency of MET, which was dominated by mutations. While most mutations were in the Pkinase_Tyr domain, a few were targetable. Pancreatic adenocarcinoma (PAAD) harbors very few alterations, but increased MET expression is associated with poor outcomes. Esophageal carcinoma (ESCA), stomach adenocarcinoma (STAD), and ovarian serous cystadenocarcinoma (OV) had similar characteristics: a high frequency of MET CNVs but relatively few MET mutations, and high MET expression associated with poor prognosis. Conclusion: This study provided significant and comprehensive information regarding MET abnormal expression, alterations (mutations and CNVs), and their clinical associations among 32 cancer types and offered insights into the full MET alteration spectrum and its implications for prognosis and treatment.

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Case series of MET exon 14 skipping mutation-positive non-small-cell lung cancers with response to crizotinib and cabozantinib

Cited by 35 publications

References 14 publications

The promise of selective MET inhibitors in non-small cell lung cancer with MET exon 14 skipping

The promise of selective MET inhibitors in non-small cell lung cancer with MET exon 14 skipping

Highly accurate DNA-based detection and treatment results of MET exon 14 skipping mutations in lung cancer

Spectrum of Mesenchymal–Epithelial Transition Aberrations and Potential Clinical Implications: Insights From Integrative Pancancer Analysis

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