Dataset Information

Co-occurring Alterations in the RAS-MAPK Pathway Limit Response to MET Inhibitor Treatment in MET Exon 14 Skipping Mutation-Positive Lung Cancer.

ABSTRACT: PURPOSE:Although patients with advanced-stage non-small cell lung cancers (NSCLC) harboring MET exon 14 skipping mutations (METex14) often benefit from MET tyrosine kinase inhibitor (TKI) treatment, clinical benefit is limited by primary and acquired drug resistance. The molecular basis for this resistance remains incompletely understood. EXPERIMENTAL DESIGN:Targeted sequencing analysis was performed on cell-free circulating tumor DNA obtained from 289 patients with advanced-stage METex14-mutated NSCLC. RESULTS:Prominent co-occurring RAS-MAPK pathway gene alterations (e.g., in KRAS, NF1) were detected in NSCLCs with METex14 skipping alterations as compared with EGFR-mutated NSCLCs. There was an association between decreased MET TKI treatment response and RAS-MAPK pathway co-occurring alterations. In a preclinical model expressing a canonical METex14 mutation, KRAS overexpression or NF1 downregulation hyperactivated MAPK signaling to promote MET TKI resistance. This resistance was overcome by cotreatment with crizotinib and the MEK inhibitor trametinib. CONCLUSIONS:Our study provides a genomic landscape of co-occurring alterations in advanced-stage METex14-mutated NSCLC and suggests a potential combination therapy strategy targeting MAPK pathway signaling to enhance clinical outcomes.

SUBMITTER: Rotow JK

PROVIDER: S-EPMC6980768 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Co-occurring Alterations in the RAS-MAPK Pathway Limit Response to MET Inhibitor Treatment in MET Exon 14 Skipping Mutation-Positive Lung Cancer.

Rotow Julia K JK Gui Philippe P Wu Wei W Raymond Victoria M VM Lanman Richard B RB Kaye Frederic J FJ Peled Nir N Fece de la Cruz Ferran F Nadres Brandon B Corcoran Ryan B RB Yeh Iwei I Bastian Boris C BC Starostik Petr P Newsom Kimberly K Olivas Victor R VR Wolff Alexander M AM Fraser James S JS Collisson Eric A EA McCoach Caroline E CE Camidge D Ross DR Pacheco Jose J Bazhenova Lyudmila L Li Tianhong T Bivona Trever G TG Blakely Collin M CM

Clinical cancer research : an official journal of the American Association for Cancer Research 20190923 2

<h4>Purpose</h4>Although patients with advanced-stage non-small cell lung cancers (NSCLC) harboring <i>MET</i> exon 14 skipping mutations (<i>MET</i>ex14) often benefit from MET tyrosine kinase inhibitor (TKI) treatment, clinical benefit is limited by primary and acquired drug resistance. The molecular basis for this resistance remains incompletely understood.<h4>Experimental design</h4>Targeted sequencing analysis was performed on cell-free circulating tumor DNA obtained from 289 patients with ...[more]

PMID: 31548343

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Project description:BackgroundA splice-site mutation that results in a loss of transcription of exon 14 in the oncogenic driver MET occurs in 3 to 4% of patients with non-small-cell lung cancer (NSCLC). We evaluated the efficacy and safety of tepotinib, a highly selective MET inhibitor, in this patient population.MethodsIn this open-label, phase 2 study, we administered tepotinib (at a dose of 500 mg) once daily in patients with advanced or metastatic NSCLC with a confirmed MET exon 14 skipping mutation. The primary end point was the objective response by independent review among patients who had undergone at least 9 months of follow-up. The response was also analyzed according to whether the presence of a MET exon 14 skipping mutation was detected on liquid biopsy or tissue biopsy.ResultsAs of January 1, 2020, a total of 152 patients had received tepotinib, and 99 patients had been followed for at least 9 months. The response rate by independent review was 46% (95% confidence interval [CI], 36 to 57), with a median duration of response of 11.1 months (95% CI, 7.2 to could not be estimated) in the combined-biopsy group. The response rate was 48% (95% CI, 36 to 61) among 66 patients in the liquid-biopsy group and 50% (95% CI, 37 to 63) among 60 patients in the tissue-biopsy group; 27 patients had positive results according to both methods. The investigator-assessed response rate was 56% (95% CI, 45 to 66) and was similar regardless of the previous therapy received for advanced or metastatic disease. Adverse events of grade 3 or higher that were considered by investigators to be related to tepotinib therapy were reported in 28% of the patients, including peripheral edema in 7%. Adverse events led to permanent discontinuation of tepotinib in 11% of the patients. A molecular response, as measured in circulating free DNA, was observed in 67% of the patients with matched liquid-biopsy samples at baseline and during treatment.ConclusionsAmong patients with advanced NSCLC with a confirmed MET exon 14 skipping mutation, the use of tepotinib was associated with a partial response in approximately half the patients. Peripheral edema was the main toxic effect of grade 3 or higher. (Funded by Merck [Darmstadt, Germany]; VISION ClinicalTrials.gov number, NCT02864992.).

Dataset Information

Co-occurring Alterations in the RAS-MAPK Pathway Limit Response to MET Inhibitor Treatment in MET Exon 14 Skipping Mutation-Positive Lung Cancer.

Publications

Co-occurring Alterations in the RAS-MAPK Pathway Limit Response to MET Inhibitor Treatment in MET Exon 14 Skipping Mutation-Positive Lung Cancer.

Similar Datasets

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