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Tepotinib is a highly selective MET tyrosine kinase inhibitor (TKI) that has demonstrated robust and durable clinical activity in patients with MET exon 14 (METex14) skipping non–small‐cell lung cancer (NSCLC). In the Phase II VISION study, patients received oral tepotinib 500 mg once daily. The primary endpoint was an objective response by an independent review committee (IRC) according to RECIST v1.1 criteria. The secondary endpoints included duration of response (DOR), progression‐free survival (PFS), overall survival (OS), and safety. Here we report the analysis of the efficacy and safety of tepotinib in all Japanese patients with advanced METex14 skipping NSCLC from VISION (n = 38) with >18 months' follow‐up. The median age of the Japanese patients was 73 years (range 63–88), 39.5% of patients were ≥75 years old, 68.4% were male, 55.3% had a history of smoking, 76.3% had adenocarcinoma, and 10.5% of patients had known brain metastases at baseline. Overall, the objective response rate (ORR) was 60.5% (95% confidence interval (CI): 43.4, 76.0) with a median DOR of 18.5 months (95% CI: 8.3, not estimable). ORR in treatment‐naïve patients (n = 18) was 77.8% (95% CI: 52.4, 93.6), and in patients aged ≥75 years (n = 15), ORR was 73.3% (95% CI: 44.9, 92.2). The most common treatment‐related adverse event (AE) with any grade was blood creatinine increase (65.8%), which resolved following tepotinib discontinuation. Other common treatment‐related AEs were peripheral edema (60.5%), hypoalbuminemia (34.2%), diarrhea (28.9%), and nausea (15.8%). In summary, tepotinib demonstrated robust and durable clinical activity irrespective of age or therapy line, with a manageable safety profile in Japanese patients with METex14 skipping NSCLC enrolled in VISION. [ABSTRACT FROM AUTHOR]

Mesenchymal epithelial transition (MET) factor alteration in non-small cell lung cancer (NSCLC) includes MET exon 14 skipping alteration (METex14 skipping), MET gene amplification, MET gene mutation (mainly kinase domain mutation), MET gene fusion, and MET protein overexpression. The incidence of METex14 skipping in patients with NSCLC is 0.9–4.0%. At present, drugs targeting METex14 skipping have been approved in China and other countries like Japan and USA. Patients with advanced NSCLC should undergo testing, including METex14 skipping, to screen the population with benefit from targeted therapy with MET inhibitors. The incidence of de novo MET gene amplification in NSCLC patients is 1–5%, the incidence of acquired MET gene amplification in epidermal growth factor receptor tyrosine kinase inhibitor (TKI)-resistant patients is 5–50%, and the incidence in anaplastic lymphoma kinase (ALK) TKI-resistant patients is about 13%; the incidence of MET protein overexpression in NSCLC patients is 13.7–63.7%. Several clinical trials on MET gene amplification and MET protein overexpression are ongoing, which have demonstrated their important guiding significance as biomarkers in the clinical treatment with MET inhibitors. Accurate detection of MET alterations is a prerequisite for MET inhibitor therapy. Since there are many types of MET alterations and related testing methods, as well as many problems and challenges during clinical testing, further sorting and standardization are required. Combined with clinical practice experience, literature review, and expert discussion, the writing group developed this consensus on the three main types of MET alterations (METex14 skipping, MET gene amplification, and MET protein overexpression) in order to guide the practical applications of clinical MET testing. [ABSTRACT FROM AUTHOR]

Abstract Background The c‐MET protein, encoded by the mesenchymal‐epithelial transition factor (MET) gene, can regulate cell proliferation, migration and invasion. Studies have shown that it is one of the essential driver genes for non‐small cell lung cancer (NSCLC). Currently, several clinical studies have carried out objective assessments on the efficacy and safety of different types of MET tyrosine kinase inhibitors (TKIs). However, direct cross‐sectional comparisons between different agents are still not available. Methods Our study was a single‐center retrospective clinical study, which collected the data from MET positive NSCLC patients treated with MET TKIs at the Lung Cancer Center of Peking Union Medical College Hospital. We explored the efficacy and safety of crizotinib versus savolitinib in patients with METex14 skipping and MET amplification, separately. Results Patients with METex14 skipping (median PFS = 10.7 months) had a better clinical response to MET TKIs than MET amplification patients (median PFS = 4.1 months). In the METex14 skipping subgroup, savolitinib did not show better survival benefit with significance than crizotinib (p > 0.05). In the MET amplification subgroup, savolitinib (median PFS = 7.1 months) demonstrated a better progression‐free survival benefit than crizotinib (median PFS = 1.4 months), p = 0.05. The most common adverse effects of both MET TKIs were peripheral edema (41.2%), gastrointestinal reactions (23.5%), and liver injury (14.7%). The incidence rate of peripheral edema was higher in savolitinib than crizotinib. Conclusion In METex14 skipping NSCLC patients, the efficacy of savolitinib and crizotinib did not show significant difference. In MET amplification patients, savolitinib showed better efficacy than crizotinib.

Background: The c‐MET protein, encoded by the mesenchymal‐epithelial transition factor (MET) gene, can regulate cell proliferation, migration and invasion. Studies have shown that it is one of the essential driver genes for non‐small cell lung cancer (NSCLC). Currently, several clinical studies have carried out objective assessments on the efficacy and safety of different types of MET tyrosine kinase inhibitors (TKIs). However, direct cross‐sectional comparisons between different agents are still not available. Methods: Our study was a single‐center retrospective clinical study, which collected the data from MET positive NSCLC patients treated with MET TKIs at the Lung Cancer Center of Peking Union Medical College Hospital. We explored the efficacy and safety of crizotinib versus savolitinib in patients with METex14 skipping and MET amplification, separately. Results: Patients with METex14 skipping (median PFS = 10.7 months) had a better clinical response to MET TKIs than MET amplification patients (median PFS = 4.1 months). In the METex14 skipping subgroup, savolitinib did not show better survival benefit with significance than crizotinib (p > 0.05). In the MET amplification subgroup, savolitinib (median PFS = 7.1 months) demonstrated a better progression‐free survival benefit than crizotinib (median PFS = 1.4 months), p = 0.05. The most common adverse effects of both MET TKIs were peripheral edema (41.2%), gastrointestinal reactions (23.5%), and liver injury (14.7%). The incidence rate of peripheral edema was higher in savolitinib than crizotinib. Conclusion: In METex14 skipping NSCLC patients, the efficacy of savolitinib and crizotinib did not show significant difference. In MET amplification patients, savolitinib showed better efficacy than crizotinib. [ABSTRACT FROM AUTHOR]

Background: Pulmonary sarcomatoid carcinoma (PSC) is a rare histologic subtype of nonsmall cell lung cancer with limited targeted treatment options. In this study, we aimed to investigate the prevalence of MET ex14 skipping mutation in PSC patients without common targetable mutations in EGFR, KRAS, ALK, ROS1, and RET.Materials and Methods: In total, 46 resected specimens of PSC without these mutations were assessed for MET ex14 skipping mutation by next-generation sequencing (NGS) based on the Oncomine Focus Assay libraries.Results: Among 52 cancer-relevant genes included in the targeted NGS panel, the MET ex14 skipping mutation was the only mutation identified in our cohort, which was present in 4 (9%) of 46 patients. For patients with METex14 skipping mutation, the median overall survival (OS) was 35 months (1050 days) compared with a median OS of 27 months (807 days) for those without METex14 skipping mutation (hazard ratio [HR] = 0.59, P = 0.488). The median disease-free survival (DFS) in METex14 skipping mutation-positive patients was 18 months (540 days) compared with a median DFS of 13.6 months (408 days) for negative patients (HR = 0.76, P = 0.680).Conclusions: These findings reflect the prevalence of MET ex14 skipping mutation as up to 9% in Chinese patients with PSC negative for other common targetable mutations, allowing provision of appropriate genetic counseling and treatment in these patients. A larger population-based study is warranted to determine the clinicopathological and prognostic implications of MET ex14 skipping mutation in PSC. [ABSTRACT FROM AUTHOR]

Introduction: The hepatocyte growth factor (HGF) receptor MET is an oncogenic driver in a subpopulation of Non-small Lung Cancer Cells (NSCLC) at the primary tumor stage or in acquired resistance to treatment with tumor-targeting tyrosine kinase inhibitors (TKIs)., Areas Covered: This article summarizes the mechanisms leading to overexpression and activation of MET by amplification and mutations including exon 14 aberrations. Furthermore, the methods to detect and categorize MET as a tumor driver and the selective TKIs for patient treatment are discussed., Expert Opinion: Activating mutations and rearrangements of kinases in NSCLC are the target of successful therapeutic intervention. However, MET activation involves a number of complex alterations including gene amplification, prevention of degradation by METex14 exon skipping and a host of gene mutations. A high-level MET expression is the precondition for tumor responses to TKIs and the confirmation of MET-dependent tumor progression is difficult in primary lesions and in tumors exhibiting resistance to mutated EGFR-directed therapy in absence of standardized and concordant assays of MET amplification.