Abstract B136: Highly accurate DNA-based detection of MET exon 14 skipping mutations in non-small cell lung cancer and clinical response upon targeted treatment
Authors: Pruis Melinda , Geurts WRR , Thüsen JH von der , Meijssen IC , Dinjens WNM , Aerts JGJV , Lolkema MP , Dubbink HJ , Paats MS 
Published: March 2020

Background: Approximately 1.6%-5.7% of non-small cell lung cancers (NSCLC) are described to be driven by oncogenic MET exon 14 skipping mutations (METex14del). Although currently no therapy is registered specifically against METex14del, Phase I/II clinical trials and named patient based programs with cMET inhibitors show promising results. RNA-based analysis seems most optimal for METex14del detection, because theoretically, it would capture all MET exon 13-exon 15 fusions, regardless of the underlying DNA changes. However, acquiring sufficient RNA is often problematic. An alternative is DNA-based analysis, but commercially available DNA-based panels only detect up to 63% of known METex14del alterations. The goal of this study is to describe an optimized DNA-based diagnostic test for METex14del, and to report the histologic and clinical features of a real world METex14del non-squamous NSCLC patient cohort, including follow-up of patients treated with cMET-targeted therapy and consequent resistance mechanisms to cMET inhibition. Methods: Routine diagnostic pathology NSCLC FFPE specimens were investigated by a custom-made DNA-based targeted amplicon-based next generation sequencing (NGS) panel which includes 4 amplicons for METex14del detection. Retrospectively, histopathological characteristics and clinical follow up were investigated for advanced NSCLC with METex14del. We only present data of patients receiving crizotinib in a named patient based program (Pfizer Oncology). Results: In silico analysis showed that our custom-made NGS panel can detect 96% of reported METex14 alterations. From Jan 2016 - May 2018, METex14del was found in 2% of patients with NSCLC tested for therapeutic purposes (31/1496). Outside above mentioned timeframe and tested for other purposes, an additional 15 patients were detected, making a total of 46 NSCLC patients with METex14del, since introduction of our panel in May 2015. Adenocarcinoma was the most common histological type (31/46, 68.9%), followed by sarcomatoid carcinoma (8/46, 17.8%). Thirty-six patients had advanced NSCLC, they were predominantly male (69% vs 31%) and mostly (ex) smokers (64% vs 31%), with a median age of 76.5 years at disease onset [range 53-90]. Eleven patients were treated with targeted therapy, either with crizotinib in named patient based program or in clinical trials. With crizotinib, disease control was achieved for 4 out of 5 patients (3 PR [PFS 4 -12 mo], 1 SD [14 mo]). Biopsy at progression revealed a resistance mechanism (MET c.3682G&gt;A; p.D1228N) to crizotinib in two patients, respectively, 6 and 12 months after start of crizotinib treatment. Conclusions: In this study, we show that we can detect 96% of the known MET exon 14 skipping mutations using our custom-made DNA based NGS approach for DNA isolated from FFPE tissue. In this large consecutive series, METex14del was found in 2% of NSCLC, mostly elderly patients, in a good condition and with a smoking history. Although a small cohort, patients responded well to targeted treatment, underlining the need for routine testing of METex14del in advanced non-squamous NSCLC to guarantee optimal personalized treatment.

Citation Format: Melinda Pruis, WRR Geurts, JH von der Thüsen, IC Meijssen, WNM Dinjens, JGJV Aerts, MP Lolkema, HJ Dubbink, MS Paats. Highly accurate DNA-based detection of MET exon 14 skipping mutations in non-small cell lung cancer and clinical response upon targeted treatment [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B136. doi:10.1158/1535-7163.TARG-19-B136