MET Amplification (MET/CEP7 Ratio ≥ 1.8) Is an Independent Poor Prognostic Marker in Patients With Treatment-naive Non–Small-cell Lung Cancer

Cheng, Joanne; Tang, Zhenya; Toruner, Gokce; Hu, Shimin; Guo, Ming; Robinson, Marion F.; Medeiros, L. Jeffrey; Tang, Guilin

doi:10.1016/j.cllc.2020.11.002

Cited by 12 publications

(11 citation statements)

References 33 publications

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“…The standard detection method for MET amplification is MET/CEP7 by FISH, whereas MET gene copy number alone may not be sufficiently accurate. 23 In the TATTON study, MET/CEP7 ≥ 2 was equated to MET GCN ≥5. In the PROFILE 1001 study, MET amplification was defined as MET/CEP7 ≥ 1.8.…”

Section: Discussionmentioning

confidence: 99%

Savolitinib versus crizotinib for treating MET positive non‐small cell lung cancer

et al. 2023

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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.

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Section: Discussionmentioning

confidence: 99%

Savolitinib versus crizotinib for treating MET positive non‐small cell lung cancer

et al. 2023

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“…MET amplification can be detected by using fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC). With MET amplification, MET/CEP7 ratio is as follows: low: ≥1.8 to ≤2.2; intermediate: >2.2 to <5; or high: ≥5 will be applied in clinical settings when treating patients with MET inhibitors [ 90 ]. The frequency of MET amplification in NSCLC ranges from 3% to 10% depending on the cut-off of MET copies per cell [ 91 ].…”

Section: Discussionmentioning

confidence: 99%

Landscape of Savolitinib Development for the Treatment of Non-Small Cell Lung Cancer with MET Alteration—A Narrative Review

Zhu

Lu²,

Lü

2022

Cancers

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Non-small cell lung cancer (NSCLC) is increasingly being treated with targeted therapies. Savolitinib (Orpathys®) is highly selective mesenchymal epithelial transition (MET)–tyrosine kinase inhibitor (TKI), which is conditionally approved in China for advanced NSCLC with MET exon 14 skipping mutations (METex14). This article summarizes the clinical development of savolitinib, as a monotherapy in NSCLC with METex14 mutation and in combination with epidermal growth factor receptor (EGFR) inhibitor in post EGFR–TKI resistance NSCLC due to MET-based acquired resistance. Preclinical models demonstrated anti-tumor activities in MET-driven cancer cell line and xenograft tumor models. The Phase Ia/Ib study established an optimized, recommended phase II dose in Chinese NSCLC patients, while TATTON study of savolitinib plus osimertinib in patients with EGFR mutant, MET-amplified and TKI-progressed NSCLC showed beneficial efficacy with acceptable safety profile. In a pivotal phase II study, Chinese patients with pulmonary sarcomatoid carcinoma, brain metastasis and other NSCLC subtype positive for METex14 mutation showed notable responses and acceptable safety profile with savolitinib. Currently, results from ongoing clinical trials are eagerly anticipated to confirm the efficacious and safety benefits of savolitinib as monotherapy and in combination with EGFR–TKI in acquired resistance setting in advanced NSCLC and its subtypes with MET alterations.

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“…In cases of polysomy, the ratio between the MET gene and the centromere of chromosome 7 (MET/CEN7) remains unchanged; however, an elevated ratio indicates true amplification of the MET gene. This distinction is essential for identifying patients who are most likely to respond to MET-targeted therapies [ 78 ]. Recent advancements have enabled next-generation sequencing (NGS) to establish criteria to differentiate between MET gene amplification and chromosome 7 polysomy in cancer, showing a high concordance with FISH analysis [ 79 ].…”

Section: Met Addictionmentioning

confidence: 99%

The MET Oncogene: Thirty Years of Insights into Molecular Mechanisms Driving Malignancy

Crepaldi,

Gallo,

Comoglio

2024

Pharmaceuticals

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The discovery and subsequent research on the MET oncogene’s role in cancer onset and progression have illuminated crucial insights into the molecular mechanisms driving malignancy. The identification of MET as the hepatocyte growth factor (HGF) receptor has paved the path for characterizing the MET tyrosine kinase activation mechanism and its downstream signaling cascade. Over the past thirty years, research has established the importance of HGF/MET signaling in normal cellular processes, such as cell dissociation, migration, proliferation, and cell survival. Notably, genetic alterations that lead to the continuous activation of MET, known as constitutive activation, have been identified as oncogenic drivers in various cancers. The genetic lesions affecting MET, such as exon skipping, gene amplification, and gene rearrangements, provide valuable targets for therapeutic intervention. Moreover, the implications of MET as a resistance mechanism to targeted therapies emphasize the need for combination treatments that include MET inhibitors. The intriguing “flare effect” phenomenon, wherein MET inhibition can lead to post-treatment increases in cancer cell proliferation, underscores the dynamic nature of cancer therapeutics. In human tumors, increased protein expression often occurs without gene amplification. Various mechanisms may cause an overexpression: transcriptional upregulation induced by other oncogenes; environmental factors (such as hypoxia or radiation); or substances produced by the reactive stroma, such as inflammatory cytokines, pro-angiogenic factors, and even HGF itself. In conclusion, the journey to understanding MET’s involvement in cancer onset and progression over the past three decades has not only deepened our knowledge, but has also paved the way for innovative therapeutic strategies. Selective pharmacological inactivation of MET stands as a promising avenue for achieving cancer remission, particularly in cases where MET alterations are the primary drivers of malignancy.

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MET Amplification (MET/CEP7 Ratio ≥ 1.8) Is an Independent Poor Prognostic Marker in Patients With Treatment-naive Non–Small-cell Lung Cancer

Cited by 12 publications

References 33 publications

Savolitinib versus crizotinib for treating MET positive non‐small cell lung cancer

Savolitinib versus crizotinib for treating MET positive non‐small cell lung cancer

Landscape of Savolitinib Development for the Treatment of Non-Small Cell Lung Cancer with MET Alteration—A Narrative Review

The MET Oncogene: Thirty Years of Insights into Molecular Mechanisms Driving Malignancy

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