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MECHANISMS OF 1ST
GENERATION RESISTANCE
Byoung Chul Cho, M.D., Ph.D.
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CONFLICT OF INTEREST
Research funding: Novartis, Bayer, AstraZeneca, MOGAM Institute,
Dong-A ST
Consulting role: Novartis, AstraZeneca, Boehringer-Ingelheim, Roche,
BMS, Yuhan, Pfizer, Eli Lilly
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1ST GENERATION EGFR-TKI
� Single agent activity of EGFR TKIs
� Response rate: 60%-80%
� PFS 9 – 12 months
� Superior to Chemotherapy
� Standard of care as first line therapy
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0 4 8 12 16 20 24
Time from randomisation (months)
0.0
0.2
0.4
0.6
0.8
1.0
Probability
of PFS
• Response Rate ~70%
• PFS is ~10 months
� Repeat biopsy to identify acquired resistance mechanism
� Design subsequent therapy based on mechanisms
What to do when Gefitinib fails?
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Mechanism Frequency Examples
Secondary mutation/Target modification
50% EGFR (T790M, T263P), EGFR amp, P53
‘Kinase Switch’ (bypass tract)
5-25% MET amp / HGF overexpression, AXL overexpression, HER2 amp
Phenotypic change 5-15%
?
SCLC transformation (Rb loss), squamous cell
Epithelial-mesenchymal transition
Downstream signal activation
5% PTEN loss / PIK3CA mutation
BRAF V600E mutation
Angiogenesis ? VEGF production
RTK internalization ? Altered EGFR trafficking
Drug efflux ? ABCG2 for gefitinib
Sequist LV. Sci Transl Med 2011, Levin PA. JTO 2015; Lee CG, Cho BC. Oncotarget 2016; Niederst MJ. Nature Comm 2015
Well-documented in human samples
MECHANISMS of 1st GENERATION
EGFR TKI
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T790M GATEKEEPER MUTATION
T790
erlotinib
M790HOH
• The most prevalent mechanism of acquired resistance (50% ) to 1st G EGFR TKI
� Steric hindrance (substitution of Threonine to Methionine at codon 790)
� T790M increases receptor’s affinity for ATP
• T790M-harboring tumors display slower growth rates than tumors harboring
sensitizing mutation ("flare" and "re-response”)
• T790M harboring patients has also been found to be associated with a more
indolent phenotype Oxnard GR. CCR 2011
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Pre-exisiting (~10%)
Evolution (~90%)
Drug tolerant
Early resistance
mediated by T790M
Late development of
various resistance
mechanisms
Hata et al. Nature Med 2016
Gene
expression
and
Response to
T790M-targeted
therapy
Pre-existing versus Evolution
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50 y/o female Exon19del+ lung adenocarcinoma
0 mo 1 mo 3 mo
Afatinib Osimertinib
0 day 7 day
T790M+
IC50 for T790M ~300 nM IC50 for T790M ~10 nM
T790M
IF T790M SUBCLONES PREXIST…
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EGFR MUTATION: A MOVING TARGET
EGFRE19del amplification
(target↑)
EGFRT790M mutation
(steric hindrance,
affinity to ATP↑)
EGFRT263P mutation
(EGFR/HER2
heterodimerization)
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MET amplification activates
HER3/AKT Signaling
• Frequency 5-25%
• May be seen concurrently with
T790M and SCLC transformation*
• Coupling of MET to HER3 leads to
sustained activation of PI3K/AKT
signaling
• Clinically meaningful MET
amplification vs. poysomy?
• Standardization of screening
methods (FISH, aCGH, qRT-
PCTR..)?
Janne PA, et al. Science 2007; *Yu HA, et al. Clin Cancer Res 2013
METHER3
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MET INHIBITORS IN CLINICAL TRIALS
Yilong Zhang. Biomedicines 2015
Compound Modality Target(s) Company Cancer Type DevelopmentPhase
Rilotumumab
(AMG 102)
Antibody HGF Amgen Gastric, lung, colon,
brain, ovary, renal
2/3
Ficlatuzumab
(AV-299)
Antibody HGF AVEO
Pharmaceuticals
Lung 1/2
HuL2G7
(TAK701)
Antibody HGF Galaxy Biotech Solid tumors 1
Onartuzumab
(MetMab)
Antibody MET Genentech/Roch
e
Lung, colon, breast 2/3
AMG 337 Small
molecule
MET Amgen Solid tumors 1/2
INC 280 Small
molecule
MET Novartis/Incyte Renal, brain, liver,
lung, melanoma,
head and neck
2
Tivantinib
(ARQ 197)
Small
molecule
MET ArQule/Daiichi-
Sankyo/Kyowa
Hakko Kirin
Lung, colon, breast,
liver, prostate,
myeloma
2/3
Crizotinib
(PF-2341066)
Small
molecule
MET, ALK Pfizer Lung, lymphoma 2/3
Cabozantinib
(XL 184)
Small
molecule
MET, VEGFR2,
RET, KIT, AXL,
FLT3
Exelixis/Bristol-
Myers Squibb
Lung 2/3
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INC280 PLUS GEFITINIB IN MET-
AMPLIFIED EGFR MUTANT NSCLC
AFTER PROGRESSION ON EGFR TKI
ORR 14%
ORR (95% CI) 24% (6.8-49.9)
ORR (95% CI) 50% (31.9-68.1)
Wu YL, et al ASCO 2016
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• TAM family receptor tyrosine kinase
� Promotes cancer cell proliferation,
migration and survival
� Inhibits proinflammatory cytokine
response and immune activation
• AXL overexpression is highly
correlates with mesenchymal
phenotype
AXL PATHWAY IN LUNG CANCER
Levin PA et al. JTO 2016
GAS6
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ResistantBaseline Acquired resistance
AX
LV
imen
tin
Marker Number positive (%)
Concurrent EGFR T790M mutation
AXL 7/35 (20) 2
GAS6 7/28 (25) 1
Activation of the AXL kinase causes resistance
to Erlotinib in lung cancer
Zhang Z, et al Nature Gen 2012
Axl
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AXL INHIBITORS IN CLINICAL TRIALS
Agent Target Protein Axl IC50 Clinical Trial Phase
Cabozantinib Axl, MET,
VEGFR2, RET, Kit,
Flt-1,3,4, Tie2
7 nM NCT01639508
NCT00596648
NCT01708954
NCT01866410
2
1 and 2
2
2
Crizotinib Axl, ALK, MET,
RON, ROS1
294 nM NCT02034981 2
ASLAN002 Axl, RON, MET,
Tyro3, Mer, Flt-3
1.1 nM NCT01721148 1
MGCD265 Axl, MET,
VEGFR2
NCT00697632 1
MGCD516 Axl, RET, TRK,
DDR2, MET, Kit,
VEGFR, PDGFR
14 nM NCT02219711 1
BGB324 Axl 14 nM NCT02424617 2
BPI-9016 Axl, MET NCT02478866 1
Levin PA et al. JTO 2016
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SCLC TRANSFORMATION
EGFR TKI
• Frequency 5-15%• Clonal evolution (“harboring original activating EGFR mutation”)• Loss of EGFR expression ���� resistant to EGFR TKI• Clinical behavior of SCLC
� Rapid acceleration of growth rate� Initial response to chemotherapy followed by rapid clinical
deterioration• Sensitive to BCL2 family inhibitor (ABT-263)
EGFR mutant lung adenocarcinoma EGFR mutant SCLC
Niederst MJ, et al. Nature Comm 2015; Fukui, T. et al. Cancer Sci 2007; Tatematsu, A. et al. Clin Cancer Res 2008
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RESISTANT EGFR MUTANT SCLC
HAVE GENETIC LOSS OF RB1
Niederst MJ, et al. Nature Comm 2015
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HETEROGENEITY
SCLC
NSCLC
Modified from Niederst MJ, et al. Nature Comm 2015
After progression on erlotinib
“Genomic divergence”
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CLONAL EVOLUTION
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SELECTION PRESSURE
It’s like playing an endless game of whack-a-mole
SCLC
MET
T790M
BRAF
Axl
Is combination therapy a solution?
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OTHER RESISTANCE MECHANISMS
HER2 Amplification (8-12%)
BRAF V600E mutation (~1%)
More than one mechanism
of acquired resistance can exist (~4%)*
*Yu HA, et al. Clin Cancer Res 2013; Takezawa K, et al. Cancer Discov 2012; Pao W. AACR 2012 #1897
Epithelial-mesenchymal transition (?)
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A NEW STANDARD OF CARE MAY
CHANGE LANDSCAPE OF ACQUIRED
RESISTANCE TO 1ST GENERATION EGFR TKI
Stahel, et al. ECC 2015Seto, et al. Lancet Oncol 2014
JO25567 BELIEF
Combining EGFR-TKI with antiangiogenic agent in EGFR mutant NSCLC
T790M suppressive activity?
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By-pass track
Target Mutation /
modification
Activation of downstream
effectors
EGFR E19del / T790M
G719S / T263P
MET amplification
Axl upregulation
PIK3CA mutation
1st G EGFR TKI + MET inhibitor
1st G EGFR TKI + PI3K
inhibitor
SCLC
transformationPhenotypic changes
BCL2 family
inhibitior (ABT-263)
Modified Garraway Cancer Discovery 2012
How can we use mechanisms
of resistance for therapy?
3rd G EGFR-TKI
2nd G EGFR TKI
1st G EGFR TKI + Axl inhibitor
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How can we identify additional
mechanims of resistance?
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Response
ResistanceIon PGMTM Sequencer
Progress
Sanger Sequencing (PCR-based assays) vs. NGS
Gene rearrangement
Copy number variation
“Hotspot mutations”
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GENOMIC PROFILES OF TUMORS
WITH ACQUIRED RESISTANCE
Median depth 607x
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GENOMIC LANDSCAPE IN
POST-TKI TUMORS
T790M = 12/17 (70%)(None pre-existing)
T790M-
T790M+
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WHAT COULD BE UNKNOWNS?
~30%
Predominantly
genomic
mechanisms
Epigenome?
miRNA?Mir-34 and mir-199a/b
downregulate Axl mRNA.
Mudduluru et al. Oncogene 2011
Unknown
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� Understanding mechanisms of acquired resistance improve clinical outcomes
� EGFR T790M gatekeeper mutation
� Bypass tract (MET, AXL, HER2)
� SCLC transformation
• Ultra-deep sequencing/RNA-seq may reveal more comprehensive pictures of acquired resistance mechanisms to 1st
G EGFR TKIs
Summary
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HAVE A PLEASANT STAY IN SEOUL!