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MET exon 14 mutations as targets in routine molecular analysis of primary sarcomatoid carcinoma of the lung.

ABSTRACT: MET exon 14 splicing mutations are new targetable oncogenic drivers reported in 3% of non-small cell lung cancer (NSCLC) cases and have been shown to be more common in pulmonary sarcomatoid carcinomas (PSCs). This study sought to screen mutations affecting MET exon 14 splice sites in a large SC cohort of Caucasian patients, with a large adenocarcinoma cohort as internal control.We tested 81 patients with SC and 150 with adenocarcinoma for splice site DNA mutations leading to RNA splicing-based skipping of MET exon 14. To this end, we employed a mass spectrometry-based custom-designed PCR assay for routine analysis of whole MET exon 14 and flanking intronic regions using formalin-fixed paraffin-embedded (FFPE) tumor samples.Our results revealed a 4.9% mutation rate for MET exon 14 mutations in Caucasian SC patients, which is, though highly variable, within the usual range reported in NSCLC. Discrepancies with previous results reported in SC could be accounted for the small number of cases, ethnicity, epithelial component, and percentage of other driver mutations, such as KRAS, in the patient populations studied. Based on our study findings, SC patients should be screened for MET exon 14 mutations in the same manner as adenocarcinoma patients.

SUBMITTER: Saffroy R

PROVIDER: S-EPMC5522077 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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MET exon 14 mutations as targets in routine molecular analysis of primary sarcomatoid carcinoma of the lung.

Saffroy Raphaël R Fallet Vincent V Girard Nicolas N Mazieres Julien J Sibilot Denis Moro DM Lantuejoul Sylvie S Rouquette Isabelle I Thivolet-Bejui Françoise F Vieira Thibaut T Antoine Martine M Cadranel Jacques J Lemoine Antoinette A Wislez Marie M

Oncotarget 20170601 26

MET exon 14 splicing mutations are new targetable oncogenic drivers reported in 3% of non-small cell lung cancer (NSCLC) cases and have been shown to be more common in pulmonary sarcomatoid carcinomas (PSCs). This study sought to screen mutations affecting MET exon 14 splice sites in a large SC cohort of Caucasian patients, with a large adenocarcinoma cohort as internal control.We tested 81 patients with SC and 150 with adenocarcinoma for splice site DNA mutations leading to RNA splicing-based s ...[more]

PMID: 28418914

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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

MET exon 14 mutations as targets in routine molecular analysis of primary sarcomatoid carcinoma of the lung.

Publications

MET exon 14 mutations as targets in routine molecular analysis of primary sarcomatoid carcinoma of the lung.

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