Download Peled POSTER MET amp case RL

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.