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Salvage MET amplification detection and therapy through cell-free DNA NGS in a progressing lung cancer patient Nir Peled1, Anna Belilovski1, Lior Soussan-Gutman2, Richard B. Lanman3, AmirAli Talasaz3 Affiliation: 1Thoracic Cancer Unit, Davidoff Cancer Center, Tel-Aviv University [email protected], 2Teva Pharmaceuticals, Israel, 3Guardant Health, Inc., Redwood City, California Background • Genotyping of metastatic non-small cell lung cancer (NSCLC) has become standard of care, targeting the canonical driver mutations in seven genes: EGFR, BRAF, ERBB2 (HER2), MET and fusions in ALK, RET, and ROS1. • NCCN guidelines also recommend repeat tissue biopsy in patients progressing on EGFR inhibitors to identify targetable resistance mutations such as EGFR T790M, MET amplification, etc.1 • Targeted next generation sequencing (NGS) of cell-free circulating tumor DNA (ctDNA) may identify druggable resistance mechanisms without an invasive tissue biopsy, or when tissue is obtained but DNA quantity is not sufficient (QNS) for analysis. Case • A 70-year-old former light smoker (15 packs/year) with pulmonary fibrosis and moderate pulmonary hypertension was diagnosed with a 30 mm right middle lobe stage IIIA lung adenocarcinoma and treated with definitive chemoradiotherapy. After five months, mediastinal, liver, and multiple bone metastases were diagnosed. After two months of treatment with a targeted therapeutic regimen (afatinib) for a rare EGFR mutation (I744F), a significant progression occurred. The patient was not a candidate for chemotherapy and there was no tissue available for molecular testing. Methods • CtDNA testing was performed with a 70-gene ctDNA NGS panel (Guardant360™, Table 1) that includes all NCCN-recommended somatic genomic variants for solid tumors and completely sequences the critical exons in 70 genes to identify all four major types of genomic alterations: single nucleotide variants (SNVs), selected indels and fusions, and copy number amplifications (CNA) in 16 genes with high sensitivity (85% in stage III/IV solid tumors) and ultra-high specificity (>99.9999%).2 • CNA for MET and other genes have been validated against cell lines with known amplifications and are reported as 1+, 2+ or 3+ with the latter representing the absolute copy number of the gene in blood at the 90th percentile and higher. Results • CtDNA NGS testing identified a high-level MET amplification (copy number of 53.6 in circulation) (Figure 1A). • The test was repeated on a second tube of blood submitted at the same time point, with the second test showing a similar MET gene copy number (60.0). • Crizotinib was prescribed to target the MET amplification with immediate clinical improvement and a significant imaging response on CT/PET scans (Figure 1B). • Three months after start of treatment the patient is fully active, able to carry on all predisease performance without restriction (ECOG Performance Status = 0) and is symptom-free. Conclusions 1. Analysis of ctDNA in this metastatic NSCLC cancer patient identified MET gene amplification and the patient had a dramatic response to crizotinib. 2. Liquid biopsy methods such as ddPCR may identify EGFR T790M, but NGS methods may be required to detect the other 50% of the secondary resistance mechanisms (Figure 2), such as MET amplification - which occurs in 5% of patients on EGFR inhibitors.3 3. CtDNA detection of MET amplification as a key resistance mechanism after EGFR TKI therapy is feasible with a targeted NGS method when tissue is not accessible or biopsy performed but was QNS for genotyping. References 1 Ettinger DS. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) Non-Small Cell Lung Cancer Version 4.2016. January 2016. www.nccn.org. 2 Lanman RB, Mortimer SA, Zill OA, et al. Analytical and Clinical Validation of a Digital Sequencing Panel for Quantitative, Highly Accurate Evaluation of Cell-Free Circulating Tumor DNA. PloS One. 2015;10(10):e0140712. 3 Camidge DR, Pao W, Sequist LV. Acquired resistance to TKIs in solid tumours: learning from lung cancer. Nat Rev Clin Oncol. 2014;11(8):473-481.