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EML4-ALK: Oncogene Addiction Meets
Personalized Medicine
Thomas J Lynch, MDJonathan and Richard Sackler Professor of Internal Medicine
Director, Yale Cancer CenterPhysician-in-Chief, Smilow Cancer Hospital
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Disclosure Slide
ConsultantBoehringer Ingelheim Pharmaceuticals Inc, Merck and Company Inc, SuperGen Inc
Stockholder Infinity Pharmaceuticals Inc
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NCI SEER Cancer Statistics, WHO Fact Sheet
Lung Cancer 2011
• USA– 190,000 cases of lung cancer– 165,000 deaths– 165,300 cases of NSCLC– 115,000 cases of adenocarcinoma– 28,500 cases of lung cancer in never smokers
• Global– 1.4 million deaths from lung cancer
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Cancer 2011
• Cancer is a disease caused by abnormal genes that “drive” either excessive cell growth or inadequate cell destruction
• Imbalance of growth and death signals leads to growth of cancer cells into tumors
• Tumors then proceed to grow and metastasize• Understanding which genes drive which cancers will
provide a “roadmap” to curing cancer
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MacConall LE and Garraway LA. J Clin Oncol 2010;28:5219-28.
Major Classes of Genomic Alterations That Give Rise to Cancer• Point mutations• Copy number alterations
– Deletions– Amplifications
• Translocations– Examples: BCR-ABL, EML4-ALK
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2011: Lung Adenocarcinoma —Multiple Molecular Subsets
Courtesy William Pao
Adeno
Squam
Large
Small
KRAS
Unknown
EGFR
HER2
BRAF
ALK fusionPIK3CA
MEK1
ROS fusionPDGFR amp
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Adeno
Squam
Large
Small
KRAS
Unknown
EGFR
HER2
ALK fusion
2011: Never Smoker Lung Adenocarcinoma (US) — Almost All Molecular Subsets Defined!
Pham D et al. J Clin Oncol 2006;24(11):1700.Stephens P et al. Nature 2004;431(7008):525.Shaw AT et al. J Clin Oncol 2009;27(26):4247.Riely GJ et al. Clin Cancer Res 2008;14(18):5731.
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With permission from Kwak EL et al. N Engl J Med 2010;363:1693-703. Copyright © 2010 Massachusetts Medical Society.
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EML4-ALK Fusion Gene in NSCLC (Non-Small Cell Lung Cancer)
Soda M et al. Nature 2007;448;561.
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Soda M et al. Nature 2007;448:561-567.
EML4-ALK Is a Potent “Oncogenic” Driver• Expression plasmids generated for wild-type EML4
and ALK, wild-type and mutant EML4-ALK, and v-Ras were introduced into mouse 3T3 fibroblasts.
• In vitro cell transformation and in vivo tumor formation in mice observed with only EML-4ALK, NPM-ALK or v-Ras expressing cells.
• Inhibition of ALK leads to dramatic in vivo tumor regression.
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PIPPIP22
PLC-PLC-YY
IPIP33
MEKMEK
RASRAS
ErKErKS6KS6K
mTORmTOR
STAT3/5STAT3/5
BADBAD
PI3KPI3K
ALK Pathway
1. Inamura K et al. J Thorac Oncol 2008;3:13–17. 2. Soda M et al. Proc Natl Acad Sci USA 2008;105:19893–19897.
Figure based on: Chiarle R et al. Nat Rev Cancer 2008;8(1):11–23; Mossé YP et al. Clin Cancer Res 2009;15(18):5609–5614.
* Subcellular localization of the ALK fusion gene, while likely to occur inthe cytoplasm, is not confirmed.1,2
Translocation
Or
ALK ALK fusion protein*
Tumor cellproliferation
Inversion
Cell survival
AKTAKT
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1 Shaw AT et al. J Clin Oncol 2009;27(26):4247-4253.With permission from Bang Y et al. Proc ASCO 2010;Abstract 3.
FISH = fluorescence in situ hybridization * Assay is positive if rearrangements can be detected in ≥15% of cells
FISH Assay for ALK Rearrangement*
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Shaw AT et al. J Clin Oncol 2009;27(26):4247-53.
Clinical Features and Outcome of Patients withNon-Small Cell Lung Cancer Who Harbor EML4-ALK
• 141 pts screened for ALK fusions, 13% positive• M>F, young, non-smokers• No overlap between EGFR and Kras mutants• Refractory to EGFR TKIs• Typical chemo responses (not increased as with EGFR
mutations)• Signet ring cells are commonly found in
EML4-ALK-positive tumors
Alice T. Shaw, Beow Y. Yeap, Mari Mino-Kenudson, Subba R. Digumarthy, Daniel B. Costa, Rebecca S. Heist, Benjamin Solomon, Hannah Stubbs, Sonal Admane, Ultan McDermott, Jeffrey Settleman, Susumu Kobayashi, Eugene J. Mark, Scott J. Rodig, Lucian R. Chirieac, Eunice L. Kwak, Thomas J. Lynch, and A. John Iafrate
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Shaw AT et al. J Clin Oncol 2009;27:4247–4253.
ALK(N = 12)
EGFR(N = 8)
WT/WT* (N = 34)
Response rate, % 25 50 35
TTP, months 9 10 8
Platinum-based chemotherapy
EGFR TKI
Patients with ALK-Positive NSCLC Do Not Appear to Respond to EGFR TKIs
ALK(N = 10)
EGFR
(N = 23)WT/WT* (N = 23)
Response rate, % 0 70 13
TTP, months 5 16 6
* WT/WT = wild type: no ALK fusion or EGFR mutation
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Selectivity findings
• Crizotinib – ALK and c-MET inhibition at clinically relevant dose levels
• Crizotinib – low probability of pharmacologically relevant inhibition of any other kinase at clinically relevant dose levels
Cellular kinase selectivity of crizotinib
KinaseIC50 (nM)
mean Selectivity
ratio
c-MET 8 —
ALK 20 2X
RON298 34X
189 22X
Axl294 34X
322 37X
Tie-2 448 52X
Trk A 580 67X
Trk B 399 46X
Abl 1,159 166X
IRK 2,887 334X
Lck 2,741 283X
Sky >10,000 >1,000X
VEGFR2 >10,000 >1,000X
PDGFRß >10,000 >1,000X
Crizotinib (PF-02341066)
Crizotinib Selectivity Profile
13 kinase “hits” <100x selective for c-MET
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Cohort 2 (n=4)
100 mg QD
Cohort 3 (n=8)
200 mg QD
Cohort 4 (n=7)
200 mg BID
Cohort 5 (n=6)
300 mg BID
Cohort 6 (n=9)
250 mg BIDMTD/RP2D
Part 2:Molecularly enriched cohorts
(ALK and c-MET)
Enrolling patients with ALK-positive NSCLC after preliminary observation of impressive activity in a few patients
• Data from database April 7, 2010• Data presented for 82 patients• Phase II target accrual (open): 400
Part 1:Dose escalation
Crizotinib: First-in-Human/Patient Trial
1 DLT: grade 3 ALTelevation
2 DLTs: grade 3 fatigue
Cohort 1 (n=3)
50 mg QD
ALT = alanine aminotransferase
With permission from Kwak EL et al. ASCO 2009;Abstract 3509.
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Pre-treatment
After 2 cyclescrizotinib
Kwak EL et al. N Engl J Med 2010;363:1693-703. Copyright © 2010 Massachusetts Medical Society.
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60
40
20
0
–20
–40
–60
–80
–100
Progressive disease
Stable disease
Confirmed partial response
Confirmed complete response
Max
imum
cha
nge
in tu
mor
siz
e (%
)
–30%
Tumor Responses to Crizotinib for Patients with ALK-positive NSCLC
*Partial response patients with 100% change have non-target disease present *
Kwak EL et al. N Engl J Med 2010;363:1693-703. Copyright © 2010 Massachusetts Medical Society.
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Median PFS Has Not Been Reached 70% of Patients in Follow-up for PFS
1.00
0.75
0.50
0.25
0.00
Pro
gres
sion
-fre
e su
rviv
al p
roba
bilit
y
0 2.5 5.0 7.5 10.0 12.5 15.0 17.5Progression-free survival (months)
PFS probability at 6 months: 72% (95% CI: 61, 83%)
Median follow-up for PFS: 6.4 months (25–75% percentile: 3.5–10 months) 95% Hall-Wellner confidence bands
Kwak EL et al. N Engl J Med 2010;363:1693-703. Copyright © 2010 Massachusetts Medical Society.
PFS
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Current Crizotinib Clinical Trials
PROFILE 1007: NCT00932893; PROFILE 1005: NCT00932451
Key entry criteria
• Positive for ALK by central laboratory
• 1 prior chemotherapy (platinum-based)
N=318
PROFILE 1007
Crizotinib 250 mg BID (N=250)administered on a continuous
dosing schedule
Key entry criteria
• Positive for ALK by central laboratory
• Progressive disease in Arm B of study A8081007
• >1 prior chemotherapy
PROFILE 1005
RANDOMIZE
N=250
Crizotinib 250 mg BID (n=159)administered on a continuous
dosing schedule
Pemetrexed 500 mg/m2 ordocetaxel 75 mg/m2 (n=159)infused on day 1 of a 21-day cycle
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Molecular Profiling
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Kris MG et al.
Proc ASCO 2011;Abstract CRA7506.
Identification of Driver Mutations in Tumor Specimens from 1,000 Patients with Lung Adenocarcinoma: The Lung Cancer Mutation Consortium (LCMC)
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Kris MG et al. Proc ASCO 2011;Abstract CRA7506.
Lung Cancer Mutation Consortium: Patients and Study Plan
Use data to selecttherapy
(erlotinib with EGFRmutation)
Recommended clinicaltrial of agent
specific for target
Report toLCMCvirtual
database
Mutational analysisCLIA-certified lab at LCMC site:
KRAS, EGFR, EML4-ALK, BRAF,HER2, PIK3CA, NRAS, MEK1,
AKT1, MET amplification Report tophysician
1,000 patientsStage IV
ECOG PS 0-2Lung adenocarcinoma
Sufficient tissue (paraffin)Informed consent
Centralconfirmation of
adenocarcinomadiagnosis(1 slide)
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Lung Cancer Mutation Consortium:LCMC Protocols Linked to Specific Molecular Lesions Detected (I)
Target Agent(s) LCMC Lead
EGFRErlotinib + OSI 906Erlotinib + MM 121
C RudinL Sequist
KRASTivantinib + Erlotinib
GSK1120212J SchillerP Jänne
MET Amplification
EML4-ALK Crizotinib R Camidge
NRAS GSK1120212 P Jänne
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Lung Cancer Mutation Consortium:LCMC Protocols Linked to Specific Molecular Lesions Detected (II)
Target Agent LCMC Lead
MEK1 GSK1120212 P Jänne
BRAF (V600E) GSK2118434 B Johnson
BRAF (not V600E) GSK1120212 P Jänne
HER2 Afatinib M Kris
PIK3CA BKM120 J Engelman
AKT1
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Kris MG et al. Proc ASCO 2011;Abstract CRA7506.
Lung Cancer Mutation Consortium: Using LCMC Data to Guide Care – MSKCC Patients
121Enrolled
102Multiplex mutation testingand/or FISH completed
60 (59%)Driver mutations found
31 (30%)Received therapy
targeted tospecific mutation
19 – Erlotinib as initial therapy16 – Clinical trial of agent for identified mutation
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Conclusions
• In 516 tumor samples analyzed by IHC and FISH, 54% were positive for a driver mutation.
• Mutational status information is being used in real time to select erlotinib as initial therapy and direct patients to linked trials.
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Schema of personalized medicine.
Originally published by the American Society of Clinical Oncology. MacConaill LE, Garraway LA. J Clin Oncol 2010;28:5219-5228.
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Genome Statistics
• 29,000 human genes
• Average gene 3,000 bases but wide variation exists
• 99.9% of our bases are exactly the same from person to person
• Functions are unknown for 50% of the discovered genes
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Advances in massively parallel technologies have dramatically reduced the cost of sequencing
Originally published by the American Society of Clinical Oncology. MacConaill LE, Garraway LA. J Clin Oncol 2010;28:5219-5228.
Co
st P
er B
ase
of
DN
A (
US
$) 100
101
0.10.01
0.0010.00011E-051E-061E-071E-081E-091E-10
1975 1980 1985 1990 1995 2000 2005 2010 2015 2020 2025Years
US $/base pair
US $/IPS (Moore’s Law)
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Progress in Sequencing the Human Genome
• 2000– 12 years– 1,800,000,000 USD
• 2010– 12 days– 20,000 USD
• 2011– 5 days– 5,000 USD
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Yale Genome Statistics
• Human genome 3.2 billion bases or 3.2 Gbases
• September 2010 Yale sequences 1.8 trillion bases or 1,800 Gbases
• September 2010 Yale sequenced the equivalent of 562 human genomes!
• January 2011 Yale sequenced 1,300 human genomes!
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• 2008: EGFR and Ras mutation testing routine
• 2009: Molecular genotyping — snapshot
• 2010: Whole genome sequencing begins experimentally
• 2012: Routine WGS available to patients
Will we be ready?
Post-Genome World