Acquired Mechanism of Crizotinib Resistance in NSCLC with MET Exon 14 Skipping

Jin, Wei; Shan, Baoen; Hu, Liu; Zhou, Shoubing; Li, Wenjuan; Pan, Jing; Lin, Lin; Hu, Dandan; Pan, Yueyin

doi:10.1016/j.jtho.2019.04.021

Cited by 21 publications

(18 citation statements)

References 5 publications

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“…Klempner et al 9 reported a similar case of intracranial activity of cabozantinib after intracranial progression following crizotinib therapy. Acquired mutations which impair the activity of crizotinib but can be overcome by tepotinib should be investigated in further studies 11 …”

Section: Discussionmentioning

confidence: 99%

Dramatic intracranial response to tepotinib in a patient with lung adenocarcinoma harboring MET exon 14 skipping mutation

et al. 2021

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Mesenchymal‐epithelial transition (MET) pathway activation is associated with the mechanisms that influence properties affecting cancer cell survival and invasiveness. The MET exon 14 skipping mutation (METex14del) is found in 2%–3% of patients with non‐small cell lung cancer (NSCLC). Previous studies reported that NSCLC patients harboring a METex14del responded well to MET‐tyrosine kinase inhibitors (TKIs), including tepotinib. Tepotinib is a highly selective, once‐daily oral MET inhibitor that has shown promising clinical activity in patients with NSCLC with METex14del. The Food and Drug Administration accepted a new drug application for tepotinib as a treatment for patients with metastatic NSCLC harboring METex14del in February 2021 [Correction added on 5 March 2021, after first online publication: the FDA approval date for tepotinib has been corrected from ‘September 2019’ to ‘February 2021’.]. However, in the previous clinical trials involving MET‐TKIs, only patients with stable central nervous system metastases were eligible, and those with untreated symptomatic brain metastases (BMs) were excluded. Therefore, the efficacy and safety of MET‐TKIs in that population remains unknown. We herein report a case of dramatic intracranial response to tepotinib in a patient with symptomatic BMs from lung adenocarcinoma harboring METex14del. In the current report, the symptoms derived from multiple BMs (headache and loss of appetite) rapidly disappeared, and brain magnetic resonance imaging (MRI) examination showed that all the lesions were too small to measure only 23 days after the commencement of tepotinib. For NSCLC patients with multiple BMs, whole‐brain irradiation is a standard‐of‐care therapy, but its adverse effects on neurocognition are concerning. Tepotinib might therefore be a therapeutic option for NSCLC patients with symptomatic multiple BMs harboring METex14del.

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Section: Discussionmentioning

confidence: 99%

Dramatic intracranial response to tepotinib in a patient with lung adenocarcinoma harboring MET exon 14 skipping mutation

et al. 2021

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“…Our interpretation is supported by clinical, radiological and metabolic response to crizotinib, and the emergence of the typical MET D1246 N resistance mutation as escape mechanism. MET D1246 N has previously been described to occur under crizotinib treatment in lung cancer harboring MET exon 14 skipping mutations [5,6]. Given the preclinical [3], epidemiological [4] and now clinical evidence, we propose to regard MET c-Cbl binding site mutations as a distinct subtype of MET exon 14 alterations.…”

Section: Discussionmentioning

confidence: 97%

Clinical response to crizotinib and emergence of resistance in lung adenocarcinoma harboring a MET c-Cbl binding site mutation

et al. 2020

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“…Similar to other oncogene-directed therapies, treatment with MET TKIs can lead to acquisition of resistance by cancer cells through different mechanisms, including ontarget mechanisms, such as secondary mutations within the kinase domain, and off-target mechanisms, such as activation of alternative oncogenic signaling pathways (116). In MET exon 14-altered NSCLC, secondary mutations in the kinase domain of MET have been identified, mainly in single cases, and associated with resistance to different types of MET inhibitors (92,(117)(118)(119)(120)(121)(122)(123)(124)(125). Mutations involving the A-loop residues D1228 and Y1230 confer resistance to type I MET inhibitors by altering their binding to the kinase domain, but do not affect type II inhibitors binding, that have been shown to be effective in the presence of these mutations (92,117).…”

Section: Intrinsic and Acquired Resistance To Met Inhibitorsmentioning

confidence: 99%

A narrative review of MET inhibitors in non-small cell lung cancer with MET exon 14 skipping mutations

Santarpía¹,

Massafra²,

Gebbia³

et al. 2021

Transl Lung Cancer Res

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Treatment of advanced non-small cell lung cancer (NSCLC) has radically improved in the last years due to development and clinical approval of highly effective agents including immune checkpoint inhibitors (ICIs) and oncogene-directed therapies. Molecular profiling of lung cancer samples for activated oncogenes, including epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), c-ros oncogene 1 (ROS1) and BRAF, is routinely performed to select the most appropriate up-front treatment.However, the identification of new therapeutic targets remains a high priority. Recently, MET exon 14 skipping mutations have emerged as novel actionable oncogenic alterations in NSCLC, sensitive to MET inhibition. In this review we discuss: (I) MET gene and MET receptor structure and signaling pathway; (II) MET exon 14 alterations; (III) current data on MET inhibitors, mainly focusing on selective MET tyrosine kinase inhibitors (TKIs), in the treatment of NSCLC with MET exon 14 skipping mutations. We identified the references for this review through a literature search of papers about MET, MET exon 14 skipping mutations, and MET inhibitors, published up to September 2020, by using PubMed, Scopus and Web of Science databases. We also searched on websites of main international cancer congresses (ASCO, ESMO, IASLC) for ongoing studies presented as abstracts. MET exon 14 skipping mutations have been associated with clinical activity of selective MET inhibitors, including capmatinib, that has recently received approval by FDA for clinical use in this subgroup of NSCLC patients. A large number of trials are testing MET inhibitors, also in combinatorial therapeutic strategies, in MET exon 14-altered NSCLC. Results from these trials are eagerly awaited to definitively establish the role and setting for use of these agents in NSCLC patients.

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Acquired Mechanism of Crizotinib Resistance in NSCLC with MET Exon 14 Skipping

Abstract: MET exon 14 splice site (3082-3082þ15del16) MET exon 14 splice site (3081-3082þ14del) MET exon 5 C526F MET exon 19 D1246N MET, MNNG HOS Transforming gene; del, deletion.

Cited by 21 publications

References 5 publications

Dramatic intracranial response to tepotinib in a patient with lung adenocarcinoma harboring MET exon 14 skipping mutation

Dramatic intracranial response to tepotinib in a patient with lung adenocarcinoma harboring MET exon 14 skipping mutation

Clinical response to crizotinib and emergence of resistance in lung adenocarcinoma harboring a MET c-Cbl binding site mutation

A narrative review of MET inhibitors in non-small cell lung cancer with MET exon 14 skipping mutations

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