Transcript Slide 1

ALK INHIBITORS IN
LUNG CANCER THERAPY
Lucio Crinò, MD
Silvestrini Hospital
Perugia, Italy
Identification of Aberrant Forms of the
Anaplastic Lymphoma Kinase
 Expressed in ALCL with t(2;5)
chromosome rearrangement
resulting in a fusion protein of
two genes: the novel tyrosine
kinase gene (ALK) and NPM1
1
2
3 4 5
6 7
80 kDa
 Other chromosome
translocations involving the
ALK locus have also been
identified in several different
human cancers 2,3,4
Detection of phosphoprotein in an ALCL cell
line in SCID mice compared with controls1
ALCL, anaplastic large-cell lymphoma;
NPM, nucleophosmin; SCID, severe
combined immunodeficiency.
1Shiota
M & Mori S. Leuk Lymphoma. 1996;23:2532. 2Pulford K, et al. J Cell Physiol. 2004;199:33058.
3Palmer, et al. Biochem J. 2009;420:345–61. 4Mano. Cancer Sci. 2008;99:2349–55.
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Identification of the EML4-ALK Fusion in
NSCLC
1
HELP
496
981
EML4
Basic
1
WD
496
1059
EML4–ALK variant 1
1
1058
ALK
ALK
1620
Kinase
EML4
TM
~3.6 kb
Exon 21 297 bp
Exon 13
EML4-ALK variant 1
EML, echinoderm microtubule-associated protein-like 4;
HELP, hydrophobic echinoderm mizroxbule-associated protein-like protein
Soda M, et al. Nature. 2007;448:561–67.
3
See alternative slide in back-up (slide 28)
ALK Pathway
Or
Inversion
Translocation
ALK fusion protein*
ALK
Partner gene product
RAS
PI3K
PLC-Y
STAT3/5
AKT
MEK
mTOR
ErK
BAD
IP3
S6K
Cell
survival
PIP2
Tumour cell
proliferation
*Subcellular localisation of the ALK fusion gene, while likely to occur in the cytoplasm, is not confirmed.1,2
BAD, BCL2-associated agonist of death; STAT3, signal transducer and activator of transcription 3; S6K, ribosome protein S6 kinase;
ERK, extracellular signal-regulated kinase.
1Inamura
K, et al. J Thorac Oncol. 2008;3:13–17. 2Soda M, et al. Proc Natl Acad Sci. U S A. 2008;105:19893–97.
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):5609–14; and Pfizer Inc, data on file. 4
EML4–ALK Is a Potent Oncogenic Driver1
Vector
EML4
ALK
EML4–ALK
K589M
NPM–ALK
v-Ras
3T3
Nude
mice
tumour/
injection
0/8
0/8
0/8
8/8
0/8
8/8
2/2
 Other fusion partners for ALK have also been identified, including
NPM, EML4, TPM3, ATIC, TFG, CARS, and CLTC2
TPM3, tropomyosin 3; ATIC, aminoimidazole-4-carboxamide ribonucleotide
formyltransferase 11MP cyclohydrolase; TFG, TRK-fused gene;
CARS, cysteinyl-tRNA synthetase; CLTC, clathrin, heavy chain.
1Soda
M, et al. Nature. 2007;448:561–67.
et al. Mol Cancer. 2010;9:188.
2Zhang,
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ALK Fusion Prevalence in NSCLC
Prospective Data
Retrospective Data
Lung Cancer Mutation Consortium9
RT-PCR
FISH
IHC
1.6%1 - 4.9%2
2.7%3 - 4.2%4
1.7%5 - 8.6%6
2.4%7 - 4.9%2
5.6%8
2.7%5
Adenocarcinoma
% ALK+ patients
Unselected
% ALK+ patients
Adenocarcinoma
RT-PCR, reverse transcription-polymerase chain
reaction; FISH, fluorescence in situ hybridization;
IHC, immunohistochemistry.
1Takahashi,
et al. 2010. 2Wong, et al. 2009. 3Perner, et al. 2008.
et al. 2011.
et al. 2009. 6Paik, et al 2011. 7Takahashi, et al. 2010.
8Rodig, et al. 2009. 9Kris, et al. Presented at ASCO 2011. Abstract CRA7506.
4Paik,
5Boland,
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UNIVERSTY OF TORINO – DEPT. OF CLINICAL & BIOLOGICAL SCIENCES
Status of Actionable Driver Mutations in
Lung Adenocarcinoma Tumor Specimens
No mutation detected
KRAS (22%)
NRAS<1%
MEK1<1%
EGFR (18%)
MET AMP<1%
EML4-ALK (7%)
HER2 1%
Double mutants (2%)
PIK3CA 1%
Alk Fusion Prevalence in
NSCLC: Retrospective Data
BRAF (2%)
AKT1
RT-PCR
FISH
IHC
1.6%1 - 4.9%2
2.7%3 - 4.2%4
1.7%5 - 8.6%6
2.4%7 - 4.9%2
5.6%8
2.7%5
% ALK+ patients
Unselected
% ALK+ patients
Adenocarcinoma
4Paik,
Johnson D, et al. ECCO ESMO 2011. Abstract 9018.
1Takahashi, et al. 2010. 2Wong, et al. 2009. 3Perner, et al. 2008.
et al. 2011. 5Boland, et al. 2009. 6Paik, et al 2011. 7Takahashi, et al. 2010.
8Rodig, et al. 2009.
Patients With ALK Fusion Represent a Specific
Molecular Subset of Adenocarcinoma
 Patients with the ALK fusion gene
may not benefit from agents such as
EGFR TKIs
Percent progression free
 ALK-positive patients display
similar sensitivity to platinum-based
chemotherapy compared with ALKnegative patients1
Percent progression free
TTP on platinum-based chemotherapy
100
80
100
EGFR
WT/WT
EML4-ALK
80
60
P =.004
(ALK vs EGFR)
40
20
0
EGFR
WT/WT
EML4-ALK
60
TTP on EGFR-TKI monotherapy
ALK may predict sensitivity to EML4–ALK
inhibition but resistance to EGFR TKIs
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24
36
Time (months)
48
60
Patients with ALK-positive disease (n=15): 5 months
Patients with EGFR-positive disease (n=25): 16 months
Patients with EGFR WT/WT disease (n=49): 6 months
40
20
0
12
24
36
Time (months)
48
60
1Shaw
AT, et al. J Clin Oncol. 2009;27:4247‒53.
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Clinical Impact of ALK Rearrangement:
A Single Center, Retrospective, Case-match Study
 1100 patient cases with lung cancer of non-squamous histology were
collected in the NSCLC database of Seoul National University
Hospital
 257 samples which were EGFR wild type or unresponsive to prior
EGFR TKI therapy underwent FISH for ALK testing
 Each patient with an ALK-positive tumour was matched to:
 Two patients with EGFR-mutation positive tumours and
 Two patients with ALK WT/EGFR WT tumours (WT/WT)
 Matching variables included: age at diagnosis, sex, and stage of
disease (IIIB or IV)
Kim DW, et al. Presented at ASCO 2011; Abstract 7515.
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Overall Survival and Progression-Free Survival
by Genetic Characteristics
OS
100
PFS of EGFR-TKI treated patients
100
ALK+ (N=22)
ALK+ (N=10)
EGFR mut+ (N=40)
EGFR mut+ (N=44)
80
WT/WT (N=44)
PFS (%)*
OS (%)
80
60
40
40
20
0
0
20
40
60
Months
80
100
*Excludes ALK-positive patients
enrolled due to previous nonresponse to EGFR TKIs
60
20
0
WT/WT (N=24)
0
10
20
30
40
Months
 Early investigations do not support ALK rearrangement as a favourable prognostic
factor
 ALK-positive patients might be more resistant to EGFR TKI treatment compared with
WT/WT patients
 Patients who had received an ALK inhibitor were not included in this study
Kim DW, et al. Presented at ASCO 2011; Abstract 7515.
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Status of ALK Inhibitors in Clinical
Development
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Crizotinib: A Selective Inhibitor of ALK and c-MET
Upstate 102
kinase panel
Kinase
Met(h)
Tie2(h)
TrkA(h)
ALK(h)
TrkB(h)
Abl(T315I)(h)
Yes(h)
Lck(h)
Rse(h) [SKY]
Axl(h)
Fes(h)
Lyn(h)
Arg(m)
Ros(h)
CDK2/cyclinE(h)
Fms(h)
EphB4(h)
Bmx(h)
EphB2(h)
Fgr(h)
Fyn(h)
IR(h)
CDK7/cyclinH/MAT1(h)
cSRC(h)
IGF-1R(h)
Aurora-A(h)
Syk(h)
FGFR3(h)
PKCµ(h)
BTK(h)
CDK1/cyclinB(h)
p70S6K(h)
PRK2(h)
PAR-1Bα(h)
PKBß(h)
Ret(h)
GSK3ß(h)
Flt3(h)
MAPK1(h)
ZAP-70(h)
Abl(h)
c-RAF(h)
PKD2(h)
ROCK-II(h)
Rsk3(h)
GSK3α(h)
CDK5/p35(h)
PDGFRα(h)
Rsk1(h)
SGK(h)
CHK1(h)
ErbB4(h)
Rsk2(h)
JNK1α1(h)
PKBα(h)
Blk(m)
CDK3/cyclinE(h)
PKCι(h)
PKCθ(h)
CDK2/cyclinA(h)
PAK2(h)
PKCßI(h)
Pim-1(h)
PKCη(h)
SAPK4(h)
CaMKII(r)
MKK7ß(h)
CaMKIV(h)
CHK2(h)
CK2(h)
JNK2α2(h)
MKK6(h)
CK1δ(h)
PKCα(h)
MAPK2(h)
MEK1(h)
PKCδ(h)
PKCε(h)
Plk3(h)
PKCßII(h)
MSK1(h)
PDGFRß(h)
PKCζ(h)
SAPK3(h)
MAPKAP-K2(h)
PKA(h)
AMPK(r)
CDK6/cyclinD3(h)
CSK(h)
SAPK2a(h)
JNK3(h)
PKBγ(h)
IKKα(h)
NEK2(h)
% Inhibition
94
103
102
100
100
98
96
95
94
93
93
93
91
90
87
84
80
79
77
73
68
64
58
58
56
54
52
50
50
35
25
24
22
21
21
21
18
17
17
17
16
16
15
14
14
11
10
10
7
6
5
5
5
4
4
3
3
3
3
2
2
2
1
1
1
0
0
-1
-1
-1
-1
-1
-2
-2
-3
-3
-3
-3
-3
-5
-6
-6
-6
-6
-7
-7
-9
-9
-9
-9
-10
-10
-11
-11
Cellular selectivity on 10
of 13 relevant hits
13 ‘hits’
<100X
selective
for c-Met
Kinase
IC50 (nM) Selectivity
mean*
ratio
c-Met
8
–
ALK
20
2X
298
34X
189
22X
294
34X
322
37X
Tie2
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
>1000X
VEGFR2
>10,000
>1000X
PDGFRβ
>10,000
>1000X
RON
Axl
Crizotinib
(PF-02341066)
Findings for crizotinib
• High probability of ALK and
c-Met inhibition at clinically
relevant doses
• Low probability of relevant
inhibition of RON, Axl, Tie2, or
Trk at clinical dose levels
*Measured using ELISA capture
method
Pfizer Inc, data on file.
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Crizotinib: First-in-human/Patient Trial
(A8081001)
Part 1:
Dose escalation
(n=37)
Cohort 5 (n=6)
300 mg BID
Cohort 4 (n=7)
200 mg BID
Cohort 3 (n=8)
200 mg QD
Cohort 6 (n=9)
250 mg BID
MTD/RP2D
Part 2:
Molecularly defined cohorts
Cohort 2 (n=4)
100 mg QD
Cohort 1 (n=3)
50 mg QD
BID, twice daily; QD, once daily; MTD, maximum tolerated dose;
RP2D, randomised phase 2 dose.
Modified from: Tan, et al. J Clin Oncol. 2010;28:15S. Abstract 2596.
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14
15
16
17
18
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A8081001: Rapid Responses Reported
Day 7
Symptoms at study entry
Cough
Daily low-grade fevers
Anorexia
Right neck pain due to tumour invasion
Day 14
Improvement in symptoms
Significant improvement at day 3, completely resolved by week 2
Resolved by day 3
Gained 1.5 kg of weight by week 2
Resolved by day 3
Ou, et al. J Thorac Oncol. 2010;5(12):2044–46.
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A8081001: Progression-Free Survival (N=119)
Median PFS=10.0 months (95% CI: 8.2, 14.7)
50 events (42%; 40 PD events)
69 patients (58%) censored, 59/69 (86%) in follow-up for PFS
Survival distribution function
1.0
Censored
0.8
95% Hall-Wellner
Band
0.6
0.4
0.2
0
0
n at risk 119
5
10
15
20
73
29
8
1
Months
Camidge DR, et al. Presented at ASCO 2011; Abstract 2501.
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A8081001: Overall Survival
 Median OS had not been reached as of the data cut-off
> 23 deaths (19%)
> 2 patients (2%) censored (lost to follow-up)
> 94 patients (79%) remain in follow-up for OS
 No deaths were related to study treatment
 Survival probabilities from first dose of crizotinib:
 6 months: 90% (95% CI: 82.7, 94.4)
 12 months: 81% (95% CI: 70.9, 87.2)
Camidge DR, et al. Presented at ASCO 2011; Abstract 2501.
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Impact of ALK Inhibition on Overall Survival of
Patients With Advanced, ALK–Positive NSCLC
 Study background and rationale
 The true impact of crizotinib on OS may be difficult to establish in ongoing
randomised phase 3 studies due to crossover
 In the absence of randomised data, determination of survival benefit
requires a comparator population of ALK-positive, crizotinib-naïve patients
 Study objectives
 Examine OS of crizotinib-treated ALK-positive NSCLC patients
 Compare the survival outcomes of crizotinib-treated vs crizotinib-naïve,
ALK-positive NSCLC patients
 Explore the prognostic significance of ALK rearrangement by comparing
the survival outcomes of crizotinib-naïve ALK-positive and ALK-negative
NSCLC patients
Shaw AT, et al. Presented at ASCO 2011; Abstract 7507.
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Study Populations
ALK CRIZOTINIB
ALK CONTROLS
WT/WT CONTROLS
ALK-positive
Crizotinib-treated
N=82
ALK-positive
Crizotinib-naïve
ALK-negative
EGFR-wild type
US/Australia
N=56
US/Australia
N=36
US (MGH)
N=253
2nd/3rd line
N=30
2nd line
N=23
2nd line
N=125
Never/light
smoker
AdenoCA
N=28
Never/light
smoker
AdenoCA
N=21
Never/light
smoker
AdenoCA
N=48
Shaw AT, et al. Presented at ASCO 2011; Abstract 7507.
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Overall Survival: 2nd Line Subset
ALK
Crizotinib
(n=30)
ALK
Control
(n=23)
WT/WT
Control
(n=125)
Median Survival, mo
NR
6
11
1-yr Survival, %
70
44
47
2-yr Survival, %
55
12
32
100%
80%
60%
From 2nd/3rd line crizotinib
HR=0.49, P=.02
40%
20%
0%
0
1
2
Years
3
4
Shaw AT, et al. Presented at ASCO 2011; Abstract 7507.
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Conclusions
 Targeting the ALK fusion gene in NSCLC , a direct driver of oncogenesis, has resulted
in promising clinical response rates and PFS in patients with advanced NSCLC treated
with crizotinib


ORR: 61%
Median PFS: 10 months
 The most frequent adverse events observed with crizotinib were mild and moderate
gastrointestinal events and mild visual disturbances
 Overall survival of patients with advanced, ALK-positive NSCLC treated with 2nd-/3rdline crizotinib is significantly longer than that of clinically comparable, crizotinib-naïve
controls
 Safety and efficacy of a molecularly targeted agent may be assessed in molecularly
defined cohorts directly following traditional phase 1 dose escalation


US FDA has approved crizotinib for ALK-positive NSCLC based on data from this study
Crizotinib has also been successfully filed with the EMA
 These results are an example of rapid clinical development, from target identification to
clinical validation, and support a personalised approach to NSCLC treatment
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