Transcript Peled et al. MET amp POSTER AACR2016 Draft

172
Salvage MET amplification detection and therapy through cell-free DNA NGS
in a progressing lung cancer patient
1
Peled ,
1
Belilovski ,
2
Soussan-Gutman ,
3
Lanman ,
3
Talasaz
Nir
Anna
Lior
Richard B.
AmirAli
1
2
3
Affiliation: Tel Aviv University, Tel Aviv, Israel; Oncotest Teva, Teva Pharmaceuticals, Shoham, Israel; Guardant Health, Inc., Redwood City, CA
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.
Results
Figure 1.
B
• 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 pre-disease performance
without restriction (ECOG Performance Status = 0) and is
symptom-free.
Crizotinib
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 70Table 1.
gene ctDNA NGS panel (Guardant360™,
Table 1) that includes all NCCNrecommended 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.
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) NonSmall 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.
Figure 2.
PIK3CA mutation
5.0%
MEK1 (MAP2K1) mutation
5.0%
KRAS mutation
1.0%
EML4-ALK and
other fusions
1.0%
Other
3.3%
EMT to SCLC RB1 loss
or inactivating
mutation6.0%
NF1 loss or
inactivating mutation
1.0%
PTEN loss or
inactivating
mutation 4.0%
EGFR T790M
50.0%
BRAF mutation
1.0%
FGFR3 fusions
0.6%
ERBB3 (HER3) amp
or mutation
2.0%
ERBB2 (HER2) amp
12.0%
MET amp
4.0%
EGFR exon 20
EGFR L747S,
insertion
D761Y, T854A, 0.1%
4.0%