Antitumor activity of crizotinib in lung cancers harboring a MET exon 14 alteration

Drilon, Alexander; Clark, Jeffrey W.; Weiss, Jared; Ou, Sai‐Hong Ignatius; Camidge, D. Ross; Solomon, Benjamin; Otterson, Gregory A.; Villaruz, Liza C.; Riely, Gregory J.; Heist, Rebecca S.; Awad, Mark M.; Shapiro, Geoffrey I.; Satouchi, Miyako; Hida, Toyoaki; Hayashi, Hidetoshi; Murphy, Danielle; Wang, Sherry; Li, Sherry; Usari, Tiziana; Wilner, Keith D.; Paik, Paul K.

doi:10.1038/s41591-019-0716-8

Cited by 296 publications

(277 citation statements)

References 45 publications

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“…In an analysis of 148 patients harboring the METex14 mutation, 63% of the cohort's NSCLCs expressed PD-L1: 1-49% for 22% and >50% for 41%. 100 Their median tumor mutation burden was 3.8 mutations/megabase, lower than that of a control historical cohort, whose tumors did not carry the METex14 mutation (5.7 mutation/megabase: P<0.001).…”

Section: Immunotherapy For Patients With a Met-pathway-signaling Abnomentioning

confidence: 75%

“…73,98,99 Updated results from the PROFILE-1001 study, in which 69 treatment-naïve or chemotherapy-refractory, METex14+ NSCLC patients participated, showed three complete responses and 18 partial responses (ORR, 32% [95% CI: 21-45]) with median PFS at 7.3 [95% CI: 5.4-9.1] months. 100 In the METRO study, which included 26 crizotinibtreated patients (16 with MET amplification, nine harboring the METex14 mutation and one with concurrent abnormalities), the ORR was 20% for patients with METex14 mutations, with median PFS at 2.6 [95% CI: 2.2-3.0] months and median OS at 3.8 months [95% CI: 1.7 -5.8]. No difference between MET-amplified and METex14-mutated patients was found for any clinical endpoint.…”

Section: Evaluation Of Anti-met Agents In Patients With Nsclcs Harbormentioning

confidence: 99%

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<p>Targeting the MET-Signaling Pathway in Non-Small–Cell Lung Cancer: Evidence to Date</p>

Bylicki¹,

Paleiron²,

Assié³

et al. 2020

OTT

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The c-MET proto-oncogene (MET) plays an important role in lung oncogenesis, affecting cancer-cell survival, growth and invasiveness. The MET receptor in non-small-cell lung cancer (NSCLC) is a potential therapeutic target. The development of high-output nextgeneration sequencing techniques has enabled better identification of anomalies in the MET pathway, like the MET exon-14 (METex14) mutation. Moreover, analyses of epidermal growth factor-receptor (EGFR) and mechanisms of resistance to tyrosine-kinase inhibitors (TKIs) demonstrated the importance of MET amplification as an escape mechanism in patients with TKI-treated EGFR-mutated NSCLCs. This review summarizes the laboratory findings on MET and its anomalies, trial results on METex14 alterations and MET amplification in non-EGFR mutated NSCLCs, and acquired resistance to TKI in EGFR-mutated NSCLCs. The outcomes of the first trials with anti-MET agents on non-selected NSCLC patients or those selected for MET overexpression were disappointing. Two situations seem the most promising today for the use of anti-MET agents to treat these patients: tumors harboring METex14 and those EGFR-sensitive mutation mutated under TKI-EGFR with a MET-amplification mechanism of resistance or EGFR-resistance mutation.

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Section: Immunotherapy For Patients With a Met-pathway-signaling Abnomentioning

confidence: 75%

Section: Evaluation Of Anti-met Agents In Patients With Nsclcs Harbormentioning

confidence: 99%

<p>Targeting the MET-Signaling Pathway in Non-Small–Cell Lung Cancer: Evidence to Date</p>

Bylicki¹,

Paleiron²,

Assié³

et al. 2020

OTT

View full text Add to dashboard Cite

show abstract

“…37 Numerous MET-targeting agents currently are in early-phase trials, including TKIs, antibodies, bispecific antibodies, and drug-antibody conjugates (Table 1). 32,34,36,[38][39][40][41][42][43] Attempts have been made to combine TKIs with ICIs for the treatment of NSCLC. Toxicity was shown to be the most important limitation; to the best of our knowledge, no signal for synergy has clearly emerged to date.…”

Section: Targeting Metmentioning

confidence: 99%

The METeoric rise of MET in lung cancer

Friedlaender

Drilon

Banna

et al. 2020

Cancer

Self Cite

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Over the years, there has been a continuous increase in clinically relevant driver mutations in patients with non-small cell lung cancer (NSCLC). Among these, dysregulated activation of the MET tyrosine kinase receptor has gained importance due to the recent development of quite effective treatments. MET dysregulation encompasses a heterogeneous array of alterations leading to the prolonged activation of the cellular MET (c-MET or MET) receptor and downstream proliferation pathways. It can arise through several mechanisms, including gene amplification, overexpression of the receptor and/or its ligand hepatocyte growth factor, and the acquisition of activating mutations. MET mutations are found in approximately 3% to 5% of patients with NSCLC, mainly adenocarcinoma, and are overrepresented in the sarcomatoid subtype. De novo MET amplifications are found in 1% to 5% of NSCLC cases, also predominantly in adenocarcinoma. In the current review, the authors discussed the biology of MET, how to diagnose clinically relevant alterations, and the rising clinical importance of these alterations in light of the emergence of multiple targeted therapies, both within the context of MET as a driver of resistance and in its own right. Cancer 2020;126:4826-4837.

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“…Recently, case studies and early‐phase trials in MET ex14‐mutated NSCLC have demonstrated durable responses to multitarget TKIs, such as crizotinib and cabozantinib [11–13], as well as MET‐selective TKIs, such as tepotinib and capmatinib [14–16]. MET TKIs may also improve overall survival in patients with MET ex14 mutations [17].…”

Section: Molecular Tumor Boardmentioning

confidence: 99%

Tepotinib Efficacy in a Patient with Non-Small Cell Lung Cancer with Brain Metastasis Harboring an HLA-DRB1-MET Gene Fusion

et al. 2020

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Alterations in c‐MET, a tyrosine kinase receptor encoded by the MET gene, have been reported in approximately 3% of non‐small cell lung cancer (NSCLC) cases and carry important treatment implications. The best studied genetic alterations are exon 14 skipping and gene amplification; however, gene rearrangement has also been described, and multiple fusion partners have been reported. Recently, in METex14‐mutated NSCLC, multitarget tyrosine kinase inhibitors (TKIs), such as crizotinib and cabozantinib, as well as MET‐selective TKIs, such as tepotinib and capmatinib, have demonstrated durable responses. In this study, we present the case of a 41‐year‐old woman with advanced NSCLC harboring an HLA‐DRB1‐MET gene fusion. The patient was offered successively two different MET multikinase inhibitors, crizotinib and cabozantinib, and the selective inhibitor tepotinib. Each time, including under tepotinib, the patient experienced rapid and complete responses associated with a tremendous improvement in her physical function. Key Points To our knowledge, this is the first report of a patient with non‐small cell lung cancer harboring an HLA‐DRB1‐MET gene fusion demonstrating a clinical response to multiple MET inhibitors, including tepotinib. This finding illustrates the efficacy and rationale to targeting MET regardless of fusion partner and gives insight to pooling of patients with different MET fusion products in trials assessing safety and efficacy of novel molecules.

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Antitumor activity of crizotinib in lung cancers harboring a MET exon 14 alteration

Cited by 296 publications

References 45 publications

<p>Targeting the MET-Signaling Pathway in Non-Small–Cell Lung Cancer: Evidence to Date</p>

<p>Targeting the MET-Signaling Pathway in Non-Small–Cell Lung Cancer: Evidence to Date</p>

The METeoric rise of MET in lung cancer

Tepotinib Efficacy in a Patient with Non-Small Cell Lung Cancer with Brain Metastasis Harboring an HLA-DRB1-MET Gene Fusion

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