Transcript A phase I dose-escalation and pharmacokinetic study of

Clinical Activity of the Oral ALK Inhibitor,
Crizotinib (PF-02341066), in Patients with
ALK-positive Non-small Cell Lung Cancer
Bang Y,1 Kwak EL,2 Shaw A,2 Camidge DR,3 Iafrate AJ,2 Maki RG,4
Solomon B,5 Ou SI,6 Salgia R,7 Clark J2
1Seoul
National University, Seoul, Korea; 2Massachusetts General Hospital, Boston, MA, USA;
3University of Colorado Cancer Center, Aurora, CO, USA; 4Memorial Sloan-Kettering Cancer
Center, New York, NY, USA; 5Peter MacCallum Cancer Centre, East Melbourne, Australia;
6University of California at Irvine, Irvine, CA, USA; 7University of Chicago Cancer Center,
Chicago, IL, USA
ASCO Annual Meeting 2010
Abstract 3
Potential Oncogenic “Drivers” in
Non-small Cell Lung Cancer (NSCLC)
Adenocarcinoma
K-ras
EGFR
B-raf
Her2
Other
PIK3CA
ALK
MET
Other
ALK (~5%)
ALK = anaplastic lymphoma kinase; EGFR = epidermal growth
factor receptor; Her2 = human epidermal growth factor receptor 2;
PIK3CA = phosphoinositide-3-kinase, catalytic, alpha polypeptide
Massachusetts General Hospital, data on file.
[AT Shaw, personal communication]
ALK Pathway
Or
Inversion
Translocation
ALK fusion protein*
ALK
RAS
PI3K
PLC-Y
STAT3/5
MEK
AKT
mTOR
BAD
Cell survival
*Subcellular localization of the ALK
fusion gene, while likely to occur in
the cytoplasm, is not confirmed.1,2
ErK
S6K
PIP2
IP3
Tumor cell
proliferation
1. Inamura K et al. J Thorac Oncol 2008;3:13–17
2. Soda M et al. Proc Natl Acad Sci U S A 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; and Data on file. Pfizer Inc.
EML4–ALK is a Potent “Oncogenic” Driver
Vector
EML4
ALK
EML4–ALK
K589M
NPM–ALK
v-Ras
3T3
Nude
mice
Tumor/
injection
0/8
0/8
0/8
8/8
0/8
8/8
2/2
Inhibition of ALK leads to dramatic in vivo tumor regression
EML4 = echinoderm microtubule-associated protein-like 4;
NPM = nucleophosmin
Soda M et al. Nature 2007;448:561–567
Reprinted by permission from
Macmillan Publishers Ltd: Nature, © 2007
FISH Assay for ALK Rearrangement*
p25.2
p25.2
p24.3
p24.1
p23.2
p22.3
p22.1
p16.3
ALK 29.3
p24.3
EML4 42.3
p16.3
Telomere
2p23 region
p24.1
p23.2
p22.3
p22.1
p16.1
p16.1
p14
p13.2
p14
p13.2
p12
p12
q12.1
q12.3
q12.1
q12.3
q14.1
q14.1
q14.3
q21.2
q14.3
q21.2
q22.1
q22.2
q23.2
q22.1
q22.2
q23.2
q24.1
q24.1
q24.3
q24.3
q31.3
q31.3
q32.1
q32.1
q32.3
q32.3
q33.2
q33.2
q34
q34
q36.1
q36.3
q37.2
q36.1
q36.3
q37.2
Centromere
t(2;5) ALK gene
breakpoint region
3’
5’
~250 kb
~300 kb
Break-apart FISH assay
for ALK-fusion genes1
Non-split signal
Split signal
ALK break-apart FISH assay
[Courtesy John Iafrate, Massachusetts General Hospital]
*Assay is positive if rearrangements can be detected in ≥15% of cells
FISH = fluorescence in situ hybridization
1Shaw
AT et al. J Clin Oncol
2009;27:4247–4253
Patients with ALK-positive NSCLC
Do not Appear to Respond to EGFR TKIs
Platinum-based chemotherapy
ALK
(N=12)
EGFR
(N=8)
WT/WT*
(N=34)
Response rate, %
25
50
35
TTP, months
9
10
8
EGFR TKI
ALK
(N=10)
EGFR
(N=23)
WT/WT*
(N=23)
Response rate, %
0
70
13
TTP, months
5
16
6
TTP for chemotherapy1
TTP for EGFR TKI1
100
80
80
60
60
%
%
100
40
40
20
20
EGFR
EML4–ALK
0
0
12
WT/WT
24
36
Months
WT/WT
EML4–ALK
0
48
*WT/WT = wild type: no ALK fusion or EGFR mutation
60
EGFR
0
12
1Shaw
24
36
Months
48
60
AT et al. J Clin Oncol 2009;27:4247–4253
Crizotinib Selectivity Profile
Upstate 102
kinase
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 kinase
“hits” <100X
selective for
c-MET
Crizotinib
(PF-02341066)
Kinase
IC50 (nM)
mean*
Selectivity
ratio
c-MET
8
–
ALK
20
2X
298
34X
189
22X
294
34X
322
37X
Tie-2
448
52X
Selectivity findings
Trk A
580
67X
Trk B
399
46X
Abl
1,159
166X
IRK
2,887
334X
• Crizotinib – ALK and
c-MET inhibition at
clinically relevant dose
levels
Lck
2,741
283X
Sky
>10,000
>1,000X
VEGFR2
>10,000
>1,000X
PDGFR
>10,000
>1,000X
RON
Axl
*The cellular kinase activities were
measured using ELISA capture method
• Crizotinib – low probability
of pharmacologically
relevant inhibition of any
other kinase at clinically
relevant dose levels
Pfizer Inc. Data on file
Crizotinib: Induction of Apoptosis in
ALK-positive NSCLC Cells
Crizotinib: cell growth inhibition in NSCLC
cell lines
Crizotinib: cell growth inhibition and apoptosis
induction in H3122 cells
125
100
800
% control
IC50 value (nM)
1,000
600
400
75
IC50 = 96 nM
50
25
0
200
–25 0.0001 0.01
H1993
H3122
H23
H1734
H82
H520
H526
SKMES1
H2347
H1975
H1838
H226
H1703
H647
H1755
CALU6
CALU1
H358
H1581
H2087
H1651
HCC827
HCC2935
H1355
H1573
H1650
H1666
H2405
A549
0
–50
0.1
1
10
Cell
death
Crizotinib concentration (mM)
*
Crizotinib demonstrated potent growth
inhibitory activity against H3122
(ALK fusion) cells
IC50 = 50% inhibitory concentration
*MET amplification
Untreated
50 nM
500 nM
Activated caspase-3
Pfizer Inc. Data on file
Crizotinib: First-in-human/Patient Trial
Cohort 5 (n=6)
2 DLTs: grade 3 fatigue
300 mg BID
Part 1:
Dose escalation
Cohort 6 (n=9)
Cohort 4 (n=7)
250 mg BID
MTD/RP2D
200 mg BID
Cohort 3 (n=8)
1 DLT: grade 3 ALT
elevation
200 mg QD
Cohort 2 (n=4)
100 mg QD
Cohort 1 (n=3)
50 mg QD
ALT = alanine aminotransferase
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, study
ongoing
Crizotinib Overview of Pharmacokinetics:*
All Patients Enrolled in Dose Escalation
Median plasma concentration,
cycle 1 day 15 (ng/mL)
500
50 mg QD
200 mg BID
100 mg QD
250 mg BID
200 mg QD
300 mg BID
400
300
● t1/2 ~53 hours at
250 mg BID
● No evidence of
non-linearity in PK
● No food effect on PK
● Moderate CYP3A4
inhibitor
200
Target Ceff (ALK)
100
0
0
2
4
6
8
Time (hours)
Ceff = efficacious concentration; CYP = cytochrome P450; t1/2 = terminal elimination half-life; PK = pharmacokinetics
*Please refer to (abstract 2596): Pharmacokinetics (PK) of PF-02341066, a dual ALK/c-MET inhibitor after multiple oral
doses to advanced cancer patients. (9:00 AM, Monday, June 7)
Clinical and Demographic Features of
Patients with ALK-positive NSCLC
Mean (range) age, years
Gender, male/female
N=82
51 (25–78)
43/39
Performance
status,* n (%)
0
1
2
3
24 (29)
44 (54)
13 (16)
1 (1)
Race, n (%)
Caucasian
Asian
46 (56)
29 (35)
Smoking
history, n (%)
Never smoker
Former smoker
Current smoker
62 (76)
19 (23)
1 (1)
Histology, n (%)
Adenocarcinoma
Squamous
Other
79 (96)
1 (1)
2 (2)
Prior treatment
regimens, n (%)
0
1
2
≥3
Not reported
5 (6)
27 (33)
15 (18)
34 (41)
1 (1)
*Performance status = Eastern Cooperative Oncology Group
Tumor Responses to Crizotinib for Patients
with ALK-positive NSCLC
Maximum change in tumor size (%)
60
Progressive disease
Stable disease
40
Confirmed partial response
Confirmed complete response
20
0
–20
–30%
–40
–60
–80
–100
*
*Partial response patients with 100% change have non-target disease present
77% of Patients with ALK-positive NSCLC
Remain on Crizotinib Treatment
Individual patients
• Duration of treatment
(median: 5.7 months)
0–3 mo
13 pts
>3–6 mo
29 pts
>6–9 mo
24 pts
>9–12 mo
9 pts
>12–18 mo
4 pts
>18 mo
3 pts
0
3
6
9
12
15
Treatment duration (months)
N=82; red bars represent discontinued patients
18
• Reasons for discontinuation
– Related AEs
1
– Non-related AEs
1
– Unrelated death
2
– Other
2
– Progression
13
21
Clinical Activity of Crizotinib in
Patients with ALK-positive NSCLC
● Objective response rate (ORR): 57% (95% CI: 46, 68%)
– 63% including 5 as yet unconfirmed PRs
– 57% (8/14) for patients with performance status 2 or 3
No. prior
regimens*
ORR
% (n/N)
0
80 (4/5)
1
52 (14/27)
2
67 (10/15)
≥3
56 (19/34)
* Unknown for 1 patient
● Response duration: 1 to 15 months
● DCR† (CR/PR/SD at 8 weeks): 87% (95% CI: 77, 93%)
†Disease
control rate
Progression-free survival probability
Median PFS has Not been Reached
70% of Patients in Follow-up for PFS
1.00
PFS probability at 6 months: 72%
(95% CI: 61, 83%)
0.75
0.50
0.25
Median follow-up for PFS: 6.4 months
(25–75% percentile: 3.5–10 months)
95% Hall–Wellner confidence bands
0.00
0
2.5
5.0
7.5
10.0
12.5
Progression-free survival (months)
15.0
17.5
Treatment-related Adverse Events in
ALK-positive NSCLC (≥10%)
Adverse event
Grade 1
n (%)
Grade 2
n (%)
Grade 3
n (%)
Grade 4
n (%)
Total
n (%)
Nausea
43 (52)
1 (1)
0
0
44 (54)
Diarrhea
38 (46)
1 (1)
0
0
39 (48)
Vomiting
35 (43)
1 (1)
0
0
36 (44)
Visual disturbance*
34 (42)
0
0
0
34 (42)
Constipation
18 (22)
2 (2)
0
0
20 (24)
Peripheral edema
13 (16)
0
0
0
13 (16)
Dizziness
12 (15)
0
0
0
12 (15)
Decreased appetite
11 (13)
0
0
0
11 (13)
Fatigue
8 (10)
0
0
0
8 (10)
*Changes in light/dark accommodation (no abnormalities on ophthalmologic exam)
N=82
Treatment-related Grade 3/4 Adverse Events
in ALK-positive NSCLC
Adverse event
Grade 3
n (%)
Grade 4
n (%)
Any adverse event
10 (12)
1 (1)
ALT elevation*
4 (5)
1 (1)
AST elevation
5 (6)
0
Lymphopenia
2 (2)
0
Hypophosphatemia
1 (1)
0
Neutropenia
1 (1)
0
Hypoxia
1 (1)
0
Dyspnea
1 (1)
0
Pulmonary embolism
1 (1)
0
*Based on laboratory data (n=71), ALT increase to grade 1, 52%; to grade 2, 4%
(In preclinical toxicology studies, no histologic changes in the liver were observed)
1 patient discontinued for ALT elevation
Summary
● Treatment with crizotinib resulted in impressive clinical activity in
patients with ALK-positive advanced NSCLC
– ORR: 57%
– DCR at 8 weeks: 87%
– PFS probability at 6 months: 72%
● Crizotinib was well tolerated
– The most frequent adverse events were mild and moderate
gastrointestinal events and mild visual disturbances
Conclusions
● These results are an example of rapid clinical development from
target identification, to clinical validation, and supports a
personalized approach to NSCLC treatment
● For patients with ALK-positive NSCLC, crizotinib may offer a
potential new standard of care
Current Crizotinib Clinical Trials
PROFILE 1007
Key entry criteria
● Positive for ALK by central
laboratory
● 1 prior chemotherapy
(platinum-based)
R
A
N
D
O
M
I
Z
E
Crizotinib 250 mg BID (n=159)
administered on a continuous
dosing schedule
Pemetrexed 500 mg/m2 or
docetaxel 75 mg/m2 (n=159)
infused on day 1 of a 21-day cycle
N=318
PROFILE 1005
Key entry criteria
● Positive for ALK by central
laboratory
● Progressive disease in Arm B of
study A8081007
Crizotinib 250 mg BID (N=250)
N=250
● >1 prior chemotherapy
PROFILE 1007: NCT00932893; PROFILE 1005: NCT00932451
administered on a continuous
dosing schedule
Acknowledgments
● We would like to thank all of the participating patients and their families, as well as the global
network of investigators, research nurses, study coordinators, and operations staff
Massachusetts General Hospital
● John Iafrate,* Jeffrey Clark, Eunice Kwak,
Alice Shaw, Eunice Kwak, Thomas Lynch,
Panos Fidias, Jeffrey Engelman, Marguerite
Parkman
Dana-Farber Cancer Institute
● Geoffrey Shapiro, Pasi Janne,* James
Butrynski, Leena Gandhi, Andrew Wolanski
Suzanne Hitchcock-Bryan, Charles Lee
Beth Israel Deaconess Medical Center
● Bruce Dezube, Daniel Costa, Myles Clancy
Memorial Sloan Kettering Cancer Center
● Robert Maki, Suresh C. Jhanwar,* Linda Ahn,
Lindsey Burge
Seoul National University
● Woo-Ho Kim,* Dong-Wan Kim, Se-Hoon Lee,
Do Youn Oh, Sae-Won Han, Tae-Min Kim
●
Peter MacCallum Cancer Centre
● Benjamin Solomon, Alex Dobrovic,* Stephen
Fox,* Hongdo Do*, Toni-Maree Rogers,*
Allison Lamb
University of Colorado
● Ross Camidge, Marileila Garcia,* S. Gail
Eckhardt, Wells Messersmith
University of California – Irvine
●
Sai-Hong Ou, Antonio Sanchez, Katie
Gottbreht
University of Chicago
● Ravi Salgia, Mark Ratain, David Geary,
Leonardo Faoro, Rajani Kanteti
Pfizer
● James Christensen, Victoria Cohan, Gina
Emory, Paulina Selaru, Martin Shreeve, Jamey
Skillings, Sreesha Srinivasa, Patricia
Stephenson, Weiwei Tan, Greg Wei, Keith
Wilner
*Molecular profiling contributor
This study was supported by funding from Pfizer Inc. Editorial Support was provided by Jessica Stevens
at ACUMED® (Tytherington, UK) with funding from Pfizer Inc.
Permissions for Use of Figures
● Break-apart FISH assay for ALK-fusion genes, slide 5; TTP graphs, slide 6
– AT Shaw et al. Clinical features and outcome of patients with non–small-cell
lung cancer who harbor EML4-ALK. J Clin Oncol 2009;27:4247–4253.
Reprinted with permission. © 2008 American Society of Clinical Oncology. All
rights reserved
● Figure on slide 4
– Soda M et al. Identification of the transforming EML4–ALK fusion gene in
non-small-cell lung cancer. Nature 2007;448:561–567. Reprinted by
permission from Macmillan Publishers Ltd: Nature, © 2007