COOL - Community in Oncology On Lung Cancer http://www.esanum.it/cool

1. Clinical Activity of the Oral ALK Inhibitor,Clinical Activity of the Oral ALK Inhibitor,
Crizotinib (PF-02341066), in Patients withCrizotinib (PF-02341066), in Patients with
ALKALK-positive Non-small Cell Lung Cancer-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
1
Seoul National University, Seoul, Korea; 2
Massachusetts General Hospital, Boston, MA, USA;
3
University of Colorado Cancer Center, Aurora, CO, USA; 4
Memorial Sloan-Kettering Cancer
Center, New York, NY, USA; 5
Peter MacCallum Cancer Centre, East Melbourne, Australia;
6
University of California at Irvine, Irvine, CA, USA; 7
University of Chicago Cancer Center,
Chicago, IL, USA
Abstract 3ASCO Annual Meeting 2010

2. Potential Oncogenic “Drivers” inPotential Oncogenic “Drivers” in
Non-small Cell Lung Cancer (NSCLC)Non-small Cell Lung Cancer (NSCLC)
ALK (~5%)
Other
Adenocarcinoma
Massachusetts General Hospital, data on file.
[AT Shaw, personal communication]
ALK = anaplastic lymphoma kinase; EGFR = epidermal growth
factor receptor; Her2 = human epidermal growth factor receptor 2;
PIK3CA = phosphoinositide-3-kinase, catalytic, alpha polypeptide

3. ALKALK PathwayPathway
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.
*Subcellular localization of the ALK
fusion gene, while likely to occur in
the cytoplasm, is not confirmed.1,2
Translocation
Or
ALK ALK fusion protein*
Tumor cell
proliferation
Inversion
Cell survival
PI3KPI3K
BADBAD
AKTAKT
STAT3/5STAT3/5
mTORmTOR
S6KS6K
RASRAS
MEKMEK
ErKErK
PLC-PLC-YY
PIPPIP22
IPIP33

4. Soda M et al. Nature 2007;448:561–567
Reprinted by permission from
Macmillan Publishers Ltd: Nature, © 2007
EML4–ALKEML4–ALK is a Potent “Oncogenic” Driveris a Potent “Oncogenic” Driver
3T3
Nude
mice
Tumor/
injection 0/8 0/8 0/8 8/8 0/8 8/8 2/2
Vector EML4 ALK EML4–ALK K589M NPM–ALK v-Ras
Inhibition of ALK leads to dramatic in vivo tumor regression
EML4 = echinoderm microtubule-associated protein-like 4;
NPM = nucleophosmin

5. ~250 kb ~300 kb
t(2;5) ALK gene
breakpoint region
2p23 regionTelomere Centromere
3’ 5’
FISH Assay forFISH Assay for ALKALK Rearrangement*Rearrangement*
Break-apart FISH assay
for ALK-fusion genes1
ALK 29.3
EML4 42.3
ALK break-apart FISH assay
[Courtesy John Iafrate, Massachusetts General Hospital]
1
Shaw AT et al. J Clin Oncol
2009;27:4247–4253
q36.1
q36.3
q37.2
q34
q32.1
q32.3
q33.2
q31.3
q24.3
q24.1
q23.2
q22.2
q22.1
q21.2
q14.3
q14.1
q12.3
q12.1
p12
p13.2
p14
p16.1
p16.3
p22.1
p23.2
p22.3
p24.1
p24.3
p25.2
q36.1
q36.3
q37.2
q34
q32.1
q32.3
q33.2
q31.3
q24.3
q24.1
q23.2
q22.2
q22.1
q21.2
q14.3
q14.1
q12.3
q12.1
p12
p13.2
p14
p16.1
p16.3
p22.1
p23.2
p22.3
p24.1
p24.3
p25.2
Split signal
Non-split signal
*Assay is positive if rearrangements can be detected in ≥15% of cells
FISH = fluorescence in situ hybridization

6. TTP for EGFR TKI1
1
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
TTP for chemotherapy1
Platinum-based chemotherapy EGFR TKI
Patients withPatients with ALKALK-positive NSCLC-positive NSCLC
Do not Appear to Respond to EGFR TKIsDo 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
Months
0 12 24 36 48 60
100
80
60
40
20
0
EML4–ALK
EGFR
WT/WT
%
Months
0 12 24 36 48 60
100
80
60
40
20
0
%
EML4–ALK
EGFRWT/WT
*WT/WT = wild type: no ALK fusion or EGFR mutation

7. 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 selectivity on 10 of
13 relevant hits
Upstate 102
kinase
13 kinase
“hits” <100X
selective for
c-MET
Kinase % Inhibition
Met(h) 94
Tie2(h) 103
TrkA(h) 102
ALK(h) 100
TrkB(h) 100
Abl(T315I)(h) 98
Yes(h) 96
Lck(h) 95
Rse(h) [SKY] 94
Axl(h) 93
Fes(h) 93
Lyn(h) 93
Arg(m) 91
Ros(h) 90
CDK2/cyclinE(h) 87
Fms(h) 84
EphB4(h) 80
Bmx(h) 79
EphB2(h) 77
Fgr(h) 73
Fyn(h) 68
IR(h) 64
CDK7/cyclinH/MAT1(h) 58
cSRC(h) 58
IGF-1R(h) 56
Aurora-A(h) 54
Syk(h) 52
FGFR3(h) 50
PKCµ(h) 50
BTK(h) 35
CDK1/cyclinB(h) 25
p70S6K(h) 24
PRK2(h) 22
PAR-1Bα(h) 21
PKBß(h) 21
Ret(h) 21
GSK3ß(h) 18
Flt3(h) 17
MAPK1(h) 17
ZAP-70(h) 17
Abl(h) 16
c-RAF(h) 16
PKD2(h) 15
ROCK-II(h) 14
Rsk3(h) 14
GSK3α(h) 11
CDK5/p35(h) 10
PDGFRα(h) 10
Rsk1(h) 7
SGK(h) 6
CHK1(h) 5
ErbB4(h) 5
Rsk2(h) 5
JNK1α1(h) 4
PKBα(h) 4
Blk(m) 3
CDK3/cyclinE(h) 3
PKCι(h) 3
PKCθ(h) 3
CDK2/cyclinA(h) 2
PAK2(h) 2
PKCßI(h) 2
Pim-1(h) 1
PKCη(h) 1
SAPK4(h) 1
CaMKII(r) 0
MKK7ß(h) 0
CaMKIV(h) -1
CHK2(h) -1
CK2(h) -1
JNK2α2(h) -1
MKK6(h) -1
CK1δ(h) -2
PKCα(h) -2
MAPK2(h) -3
MEK1(h) -3
PKCδ(h) -3
PKCε(h) -3
Plk3(h) -3
PKCßII(h) -5
MSK1(h) -6
PDGFRß(h) -6
PKCζ(h) -6
SAPK3(h) -6
MAPKAP-K2(h) -7
PKA(h) -7
AMPK(r) -9
CDK6/cyclinD3(h) -9
CSK(h) -9
SAPK2a(h) -9
JNK3(h) -10
PKBγ(h) -10
IKKα(h) -11
NEK2(h) -11
*The cellular kinase activities were
measured using ELISA capture method
Kinase
IC50 (nM)
mean*
Selectivity
ratio
c-MET 8 –
ALK 20 2X
RON
298 34X
189 22X
Axl
294 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
PDGFRβ >10,000 >1,000X
Pfizer Inc. Data on file
Crizotinib
(PF-02341066)
Crizotinib Selectivity ProfileCrizotinib Selectivity Profile

8. 0.0001 0.01 0.1 1 10
Crizotinib: cell growth inhibition and apoptosis
induction in H3122 cells
Crizotinib concentration (mM)
125
100
75
50
25
0
–25
–50
%control
IC50 = 96 nM
Crizotinib: Induction of Apoptosis inCrizotinib: Induction of Apoptosis in
ALKALK-positive NSCLC Cells-positive NSCLC Cells
Crizotinib: cell growth inhibition in NSCLC
cell lines
1,000
800
600
400
200
0
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
IC50value(nM)
Crizotinib demonstrated potent growth
inhibitory activity against H3122
(ALK fusion) cells
Activated caspase-3
Untreated 50 nM 500 nM
Cell
death
Pfizer Inc. Data on file
IC50 = 50% inhibitory concentration
*MET amplification
*

9. 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
Part 1:
Dose escalation
Crizotinib: First-in-human/Patient TrialCrizotinib: First-in-human/Patient Trial
1 DLT: grade 3 ALT
elevation
2 DLTs: grade 3 fatigue
Cohort 1 (n=3)
50 mg QD
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 BID
MTD/RP2D
ALT = alanine aminotransferase

10. Crizotinib Overview of Pharmacokinetics:*Crizotinib Overview of Pharmacokinetics:*
All Patients Enrolled in Dose EscalationAll Patients Enrolled in Dose Escalation
● t1/2 ~53 hours at
250 mg BID
● No evidence of
non-linearity in PK
● No food effect on PK
● Moderate CYP3A4
inhibitor
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)
500
400
300
200
100
0
Medianplasmaconcentration,
cycle1day15(ng/mL)
0 2 4 6 8
Time (hours)
50 mg QD 200 mg BID
100 mg QD 250 mg BID
200 mg QD 300 mg BID
Target Ceff (ALK)

11. Clinical and Demographic Features ofClinical and Demographic Features of
Patients withPatients with ALKALK-positive NSCLC-positive NSCLC
N=82
Mean (range) age, years 51 (25–78)
Gender, male/female 43/39
Performance
status,* n (%)
0 24 (29)
1 44 (54)
2 13 (16)
3 1 (1)
Race, n (%) Caucasian 46 (56)
Asian 29 (35)
Smoking
history, n (%)
Never smoker 62 (76)
Former smoker 19 (23)
Current smoker 1 (1)
Histology, n (%) Adenocarcinoma 79 (96)
Squamous 1 (1)
Other 2 (2)
Prior treatment
regimens, n (%)
0 5 (6)
1 27 (33)
2 15 (18)
≥3 34 (41)
Not reported 1 (1)
*Performance status = Eastern Cooperative Oncology Group

12. 60
40
20
0
–20
–40
–60
–80
–100
Progressive disease
Stable disease
Confirmed partial response
Confirmed complete response
Maximumchangeintumorsize(%)
–30%
Tumor Responses to Crizotinib for PatientsTumor Responses to Crizotinib for Patients
withwith ALKALK-positive NSCLC-positive NSCLC
*Partial response patients with 100% change have non-target disease present
*

13. 77% of Patients with77% of Patients with ALKALK-positive NSCLC-positive NSCLC
Remain on Crizotinib TreatmentRemain on Crizotinib Treatment
0 3 6 9 12 15 18 21
Treatment duration (months)
N=82; red bars represent discontinued patients
Individualpatients
• 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
• Reasons for discontinuation
– Related AEs 1
– Non-related AEs 1
– Unrelated death 2
– Other 2
– Progression 13

14. Clinical Activity of Crizotinib inClinical Activity of Crizotinib in
Patients withPatients with ALK-ALK-positive NSCLCpositive 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

15. Median PFS has Not been ReachedMedian PFS has Not been Reached
70% of Patients in Follow-up for PFS70% of Patients in Follow-up for PFS
1.00
0.75
0.50
0.25
0.00
Progression-freesurvivalprobability
0 2.5 5.0 7.5 10.0 12.5 15.0 17.5
Progression-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

16. Treatment-related Adverse Events inTreatment-related Adverse Events in
ALKALK-positive NSCLC (≥10%)-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)*Changes in light/dark accommodation (no abnormalities on ophthalmologic exam)
N=82

17. Treatment-related Grade 3/4 Adverse EventsTreatment-related Grade 3/4 Adverse Events
inin ALKALK-positive NSCLC-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

18. SummarySummary
● 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

19. ConclusionsConclusions
● 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

20. Current Crizotinib Clinical TrialsCurrent 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
R
A
N
D
O
M
I
Z
E
N=250
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

21. AcknowledgmentsAcknowledgments
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
● 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
● 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.

22. Permissions for Use of FiguresPermissions 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