P45.03 Tepotinib in Patients with MET exon 14 (METex14) Skipping NSCLC as Identified by Liquid (LBx) or Tissue (TBx) biopsy

Felip, E.; Garassino, M.; Sakai, H.; Le, Xiuning; Veillon, Rémi; Smit, Elisabeth De; Cortot, A.; Raskin, Jo; Thomas, Musholt; Viteri, Santiago; Iams, Wade T.; Kim, H.R.; Yang, Jaeseok; Stroh, Christopher; Otto, Gordon; Bruns, Rolf; Paik, P.

doi:10.1016/j.jtho.2021.08.471

Cited by 6 publications

(5 citation statements)

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“…In this precision medicine trial, MET ex14 skipping was prospectively tested using circulating free DNA (cfDNA) from liquid biopsy (LBx) samples or with an RNA-based approach using fresh or archival tissue biopsy (TBx) samples. Independently assessed ORR was consistent between the LBx (49%; 95% CI, 41–57) and TBx groups (51%; 95% CI, 44–59), underscoring the value of non-invasive LBx testing ( 73 ). LBx also enabled collection of longitudinal on-treatment biomarker data, which showed high concordance between the molecular cfDNA response and clinical response based on RECIST ( 74 ).…”

Section: Clinical Development Path Toward Regulatory Approval In Nsclcmentioning

confidence: 67%

The Preclinical Pharmacology of Tepotinib—A Highly Selective MET Inhibitor with Activity in Tumors Harboring MET Alterations

Albers

Friese-Hamim

Clark

et al. 2023

Molecular Cancer Therapeutics

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The mesenchymal–epithelial transition factor (MET) proto-oncogene encodes the MET receptor tyrosine kinase. MET aberrations drive tumorigenesis in several cancer types through a variety of molecular mechanisms including MET mutations, gene amplification, rearrangement, and overexpression. Therefore, MET is a therapeutic target and the selective type Ib MET inhibitor, tepotinib, was designed to potently inhibit MET kinase activity. In vitro, tepotinib inhibits MET in a concentration-dependent manner irrespective of the mode of MET activation, and in vivo, tepotinib exhibits marked, dose-dependent antitumor activity in MET-dependent tumor models of various cancer indications. Tepotinib penetrates the blood–brain barrier and demonstrates strong anti-tumor activity in subcutaneous and orthotopic brain metastasis models, in-line with clinical activity observed in patients. MET amplification is an established mechanism of resistance to EGFR tyrosine kinase inhibitors (TKIs) and preclinical studies show that tepotinib in combination with EGFR TKIs can overcome this resistance. Tepotinib is currently approved for the treatment of adult patients with advanced or metastatic non-small cell lung cancer harboring METex14 skipping alterations. This review focuses on the pharmacology of tepotinib in preclinical cancer models harboring MET alterations, and demonstrates that strong adherence to the principles of the Pharmacological Audit Trail may result in a successful discovery and development of a precision medicine.

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Section: Clinical Development Path Toward Regulatory Approval In Nsclcmentioning

confidence: 67%

The Preclinical Pharmacology of Tepotinib—A Highly Selective MET Inhibitor with Activity in Tumors Harboring MET Alterations

Albers

Friese-Hamim

Clark

et al. 2023

Molecular Cancer Therapeutics

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“… 3 , 10 Our liquid biopsy ctDNA and tumor load analyses confirmed that VISION Cohort B patients ( MET amplification) had poorer baseline prognostic factors than VISION Cohort A and C patients ( MET ex14 skipping, ctDNA cohort only), with higher median tumor load (95.6 versus 68.0 mm) and greater prevalence of ECOG PS 1 (88% versus 76%). 31 Tumor load and ctDNA burden were also higher relative to other advanced lung cancer studies. 32 , 33 , 34 Lower tumor load and ctDNA burden were associated with better outcomes.…”

Section: Discussionmentioning

confidence: 80%

“…This is supported by the associations of higher ctDNA burden with poorer outcomes and/or tumor load in our trial as well as studies in other oncogene-driven subtypes. 31 , 50 , 51 , 52 Nonetheless, the use of liquid biopsies offers advantages over tissue biopsies in terms of convenience, accessibility, and being less invasive. 53 , 54 VISION Cohort B confirmed that liquid biopsy can identify NSCLC with high-level MET amplification and that those patients could benefit from MET-targeted therapy.…”

Section: Discussionmentioning

confidence: 99%

Tepotinib in patients with non-small cell lung cancer with high-level MET amplification detected by liquid biopsy: VISION Cohort B

Le,

Paz-Ares,

Van Meerbeeck

et al. 2023

Cell Reports Medicine

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“…Given the prevalence of MET amplification as a driver of resistance to EGFR TKIs, accurate and reliable biomarker testing for this oncogenic alteration is important to identify patients who could benefit from targeted therapy. Despite the advantages of liquid biopsy over tissue biopsy in terms of invasiveness and speed, tissue biopsy analysis using FISH is associated with higher sensitivity and reliability in detecting MET amplification in NSCLC ( 31, 32 ). Although MET amplification can be detected using next-generation sequencing (NGS) methods, FISH has been shown to be the most sensitive diagnostic tool, with MET amplification detected in 63% versus 25% of patients by FISH and NGS, respectively ( 33 ).…”

Section: Discussionmentioning

confidence: 99%

Randomized Trial of Tepotinib Plus Gefitinib versus Chemotherapy in EGFR-Mutant NSCLC with EGFR Inhibitor Resistance Due to MET Amplification: INSIGHT Final Analysis

Liam

Ahmad²,

Hsia

et al. 2023

Clinical Cancer Research

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Purpose: The final analyses of the INSIGHT phase II study evaluating tepotinib (a selective MET inhibitor) plus gefitinib versus chemotherapy in patients with MET-altered EGFR-mutant NSCLC (data cut-off: September 3, 2021). Patients and methods: Adults with advanced/metastatic EGFR-mutant NSCLC, acquired resistance to first-/second-generation EGFR inhibitors, and MET gene copy number (GCN) ≥5, MET:CEP7 ≥2, or MET IHC 2+/3+ were randomized to tepotinib 500 mg (450 mg active moiety) plus gefitinib 250 mg once daily, or chemotherapy. Primary endpoint was investigator-assessed progression-free survival (PFS). MET-amplified subgroup analysis was preplanned. Results: Overall (N=55), median PFS was 4.9 versus 4.4 months (stratified HR 0.67 [90% CI: 0.35, 1.28]) with tepotinib plus gefitinib versus chemotherapy. In 19 patients with MET amplification (median age 60.4 years; 68.4% never-smokers; median GCN 8.8; median MET/CEP7 2.8; 89.5% with MET IHC 3+), tepotinib plus gefitinib improved PFS (HR 0.13; 90% CI: 0.04, 0.43) and overall survival (OS; HR 0.10; 90% CI: 0.02, 0.36) versus chemotherapy. Objective response rate was 66.7% with tepotinib plus gefitinib versus 42.9% with chemotherapy; median duration of response was 19.9 versus 2.8 months. Median duration of tepotinib plus gefitinib was 11.3 months (range: 1.1–56.5), with treatment >1 year in six (50.0%) and >4 years in three patients (25.0%). Seven patients (58.3%) had treatment-related grade ≥3 adverse events with tepotinib plus gefitinib, and five (71.4%) with chemotherapy. Conclusions: Final analysis of INSIGHT suggests improved PFS and OS with tepotinib plus gefitinib versus chemotherapy in a subgroup of patients with MET-amplified EGFR-mutant NSCLC, after progression on EGFR inhibitors.

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P45.03 Tepotinib in Patients with MET exon 14 (METex14) Skipping NSCLC as Identified by Liquid (LBx) or Tissue (TBx) biopsy

Cited by 6 publications

References 0 publications

The Preclinical Pharmacology of Tepotinib—A Highly Selective MET Inhibitor with Activity in Tumors Harboring MET Alterations

The Preclinical Pharmacology of Tepotinib—A Highly Selective MET Inhibitor with Activity in Tumors Harboring MET Alterations

Tepotinib in patients with non-small cell lung cancer with high-level MET amplification detected by liquid biopsy: VISION Cohort B

Randomized Trial of Tepotinib Plus Gefitinib versus Chemotherapy in EGFR-Mutant NSCLC with EGFR Inhibitor Resistance Due to MET Amplification: INSIGHT Final Analysis

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