Cost-Efficient and Easy to Perform PCR-Based Assay to Identify Met Exon 14 Skipping in Formalin-Fixed Paraffin-Embedded (FFPE) Non-Small Cell Lung Cancer (NSCLC) Samples

O’Brien, Odharnaith; Wright, M.; Ó’Brien, Cathal; Geoghegan, Orla; Leonard, Niamh; Nicholson, Siobhan; Cuffe, Sinéad; Fabre, Aurélie; Jochum, Wolfram; Joerger, Markus; Gray, Steven G.; Finn, Stephen P.

doi:10.3390/diagnostics9010013

Cited by 11 publications

(9 citation statements)

References 42 publications

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“…All patients provided written informed consent. MET Δex14 status and MET GCN were assessed from formalin‐fixed, paraffin‐embedded human tissue at a central laboratory at enrollment by quantitative real‐time RT‐PCR and fluorescence in situ hybridization, respectively 41 . All patients were administered capmatinib 400 mg tablets twice daily in fasting conditions in 21‐day cycles, except in cohorts 6 and 7 where capmatinib was administered regardless of fasting status.…”

Section: Methodsmentioning

confidence: 99%

Capmatinib in Japanese patients with MET exon 14 skipping–mutated or MET‐amplified advanced NSCLC: GEOMETRY mono‐1 study

et al. 2021

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MET mutations leading to exon 14 skipping (METΔex14) are strong molecular drivers for non–small‐cell lung cancer (NSCLC). Capmatinib is a highly potent, selective oral MET inhibitor that showed clinically meaningful efficacy and a manageable safety profile in a global phase II study (GEOMETRY mono‐1, NCT02414139) in patients with advanced METΔex14‐mutated/MET‐amplified NSCLC. We report results of preplanned analyses of 45 Japanese patients according to MET status (METΔex14‐mutated or MET‐amplified) and line of therapy (first‐ [1L] or second‐/third‐line [2/3L]). The starting dose was 400 mg twice daily. The primary endpoint was the objective response rate (ORR) assessed by a blinded independent review committee. A key secondary endpoint was duration of response (DOR). Among METΔex14‐mutated patients, in the 1L group, one patient achieved partial response (DOR of 4.24 months) and the other had stable disease. In the 2/3L group, the ORR was 36.4% (95% confidence interval [CI] 10.9%‐69.2%), median DOR was not evaluable, and progression‐free survival was 4.70 months. One patient (2/3L group) showed partial resolution of brain lesions per independent neuroradiologist review. In MET‐amplified patients with a MET gene copy number of ≥10, the ORR was 100% (2/2 patients) in the 1L group and 45.5% (5/11 patients) in the 2/3L group, with DOR of 8.2 and 8.3 months, respectively. Common treatment‐related adverse events among the 45 Japanese patients were blood creatinine increased (53.3%), nausea (35.6%), and oedema peripheral (31.1%); most were grade 1/2 severity. In conclusion, capmatinib was effective and well tolerated by Japanese patients with METΔex14/MET‐amplified NSCLC, consistent with the overall population.

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Section: Methodsmentioning

confidence: 99%

Capmatinib in Japanese patients with MET exon 14 skipping–mutated or MET‐amplified advanced NSCLC: GEOMETRY mono‐1 study

et al. 2021

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“…Until recently, screening for MET exon 14 skipping was technically challenging. Despite being appropriate for analyzing MET overexpression [84], immunohistochemistry has proved unsuitable for detecting MET exon 14 skipping, as, so far, anti-MET antibodies are not able to distinguish the exon 14-skipped splice variant from wild-type MET [85]. DNA-or RNA-based approaches are more appropriate.…”

Section: Challenges Ahead For Trials Of Met Inhibitors In Patients With Met Exon 14 Skipping Tumorsmentioning

confidence: 99%

“…RNA-based approaches need only to detect the fusion of exons 13 and 15 in the transcribed product [86]. As such, RNA in situ hybridization is possible [85], although RT-PCR-based sequencing approaches are also commonly used [86,87]. However, high-quality RNA is harder to obtain than DNA, as RNA is more susceptible to degradation [86,88].…”

Section: Challenges Ahead For Trials Of Met Inhibitors In Patients With Met Exon 14 Skipping Tumorsmentioning

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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“…IHC is only able to detect MET overexpression, which may occur due to not only METex14 alterations but also increased gene copy number and gene amplification. 24 Several studies have shown MET IHC overexpression poorly predicts for the presence of METex14 alterations. [25][26][27] Furthermore, there may be a high degree of inter-observer variability in the interpretation of IHC.…”

Section: Molecular Diagnostic Approaches For Metex14 Skipping Alteratmentioning

confidence: 99%

“…RNA-based methods of detecting METex14 skipping mutations such as quantitative PCR assays 24 , 37 are based on the detection of a fusion transcript, which in this case, is between MET exon 13 and 15. As such, the interpretation of this assay is more straightforward than that of DNA-based assays for screening purposes.…”

Section: Molecular Diagnostic Approaches For Metex14 Skipping Alteratmentioning

confidence: 99%

Novel Therapies for Metastatic Non-Small Cell Lung Cancer with MET Exon 14 Alterations: A Spotlight on Capmatinib

Tan

Loh

Kwang

et al. 2021

LCTT

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MET exon 14 (METex14) alterations are now an established therapeutically tractable target in non-small cell lung cancer (NSCLC). Recently reported trials of several MET tyrosine kinase inhibitors (TKI) in this patient population have demonstrated promising efficacy data in both the treatment naïve and pre-treated settings and have led to regulatory approvals. This review will focus on practical diagnostic considerations for METex14 alterations, the trial evidence for capmatinib in this molecular subset including dosing and toxicity management, and the future therapeutic landscape of METex14 altered NSCLC.

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Cost-Efficient and Easy to Perform PCR-Based Assay to Identify Met Exon 14 Skipping in Formalin-Fixed Paraffin-Embedded (FFPE) Non-Small Cell Lung Cancer (NSCLC) Samples

Cited by 11 publications

References 42 publications

Capmatinib in Japanese patients with MET exon 14 skipping–mutated or MET‐amplified advanced NSCLC: GEOMETRY mono‐1 study

Capmatinib in Japanese patients with MET exon 14 skipping–mutated or MET‐amplified advanced NSCLC: GEOMETRY mono‐1 study

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

Novel Therapies for Metastatic Non-Small Cell Lung Cancer with MET Exon 14 Alterations: A Spotlight on Capmatinib

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