1. Clinical Activity Observed in a Phase 1 Dose-Escalation Trial of an Oral MET and ALK Inhibitor, PF
EL Kwak1, DR Camidge2, J Clark1, GI Shapiro3, RG Maki4,
MJ Ratain5, B Solomon6, Y-J Bang7, S-H Ou8, R Salgia5
On behalf of the investigators on this trial, I would like to thank the meeting organizers for allowing me the opportunity to present our study:
1. Massachusetts General Hospital 5. University of Chicago Cancer Center
2. University of Colorado Cancer Center 6. Peter MacCallum Cancer Centre
3. Dana-Farber Cancer Institute 7. Seoul National University
4. Memorial Sloan-Kettering Cancer Center 8. University of California at Irvine

2. Cytoplasmic Fusion Variants of ALKPF
Potent & selective ATP competitive oral inhibitor of MET and ALK kinases and their oncogenic variants
Cytoplasmic Fusion Variants of ALK
MET
ALK
b a Y P TM
Extracellular
Intracellular
Kinase Y P
Kinase Y P
Kinase
PF is a potent and selective ATP competitive oral inhibitor of MET and ALK tyrosine kinases and their oncogenic variants.
The normal functions of MET and ALK receptor tyrosine kinases can be subverted by mutation, amplification, or translocation events, leading to inappropriate activation of their signaling pathways and oncogenic transformation.
One example of such an event is nucleophosmin fusion to the tyrosine kinase domain of ALK, as is seen in a subset of anaplastic large cell lymphomas.
Another example the fusion of EML4 to the tyrosine kinase domain of ALK, recently reported in a subset of NSLCs.
SEMA
Extracellular TM TM TM TM
Intracellular P P P P
Kinase Y Y Y Y P P P P Y Y Y Y
NPM-ALK
EML4-ALK Y Y Y Y P P P P Y Y Y Y P P P P Y Y P P P P Y Y P P P P Y Y Y Y

3. Study Dosing and Objectives
PF dosing schedule:
Continuous oral administration for 28 days per cycle.
A single Day -7 dose was administered to establish PK.
1. Phase I dose escalation
Determine the safety profile of PF
Determine recommended phase 2 dose (RP2D).
Determine the PK profile after oral dosing.
2. Recommended Phase 2 Dose Cohort (RP2D)
Enroll patients with MET or ALK activation into a
Molecular Cohort.
Focused study on patients with ALK fusion after
observing preliminary evidence of dramatic activity.
Our clinical trial was a first in man study of PF
The drug was dosed as a continous oral administration for 28 days per cycle.
There were 2 major components to the trial. The first was a dose escalation to determine saftey, the recommended Phase 2 dose, and pharmacokinetics.
The second portion of the trial took place at the RP2D ,and had a goal of enrolling patients with MET or ALK activation into a molecular cohort.
We focused the study on patients with tumors harboring ALK fusion after observing preliminary evidence of dramatic activity, and I will present this data during the second half of the presentation.

4. PF-02341066: Phase 1 Dose Escalation
Key Eligibility
Advanced malignancy
(excluding leukemias)
Age ≥ 18 years
Refractory to or
no standard care
ECOG PS 0 or 1
Adequate organ function
Stable brain metastases
Patient Characteristics
37 patients entered
Most common tumor types:
CRC (6), Sarcoma (4), NSCLC (3), ASPS (2), IMT (2), Bladder (2), Pancreas (2), Ovarian (2)
Mean age: 49 years
Male% : Female% = 57 : 43
Race: 89% white
ECOG: PS 0 = 43%, PS 1 = 54%
Prior therapies >3: 44%
This was a first-in-man phase 1 dose escaltion clinical trial with the Key eligibility and patient characteristics summarized below.
37 patients were entered representing a variety of tumors listed here. Many were heavily pretreated.

5. PF-02341066: Dose Escalation Cohort 5 300 mg BID Cohort 6 250 mg BID
50 mg QD
Cohort 2
100 mg QD
MDZ Sub-Study
Cohort 3
200 mg QD
200 mg BID
Cohort 5
300 mg BID
Cohort 6
250 mg BID
MTD / RP2D
MTD = Maximum Tolerated Dose
RP2D = Recommended Phase 2 Dose
MDZ = Midazolam (In-vitro data indicated that
PF is a major substrate and
inhibitor of CYP3A activity).

6. Most Common Treatment-Related Adverse Events (≥ 10%) Dose Escalation Cohorts (N=37)
50 mg QD (n=3)
100 mg QD (n=4)
200 mg QD (n=8)
200 mg BID (n=7)
300 mg BID (n=6)
250 mg BID (n=9)
Grade
1-2 3
Nausea 2 6 4
Vomiting 5
Diarrhea 1
Fatigue
Headache
Visual Disturbance
ALT Increased
AST Increased
DLTs are highlighted in red.
Data in the database as of March 9, 2009

7. PF-02341066: Overview of Pharmacokinetics
Peak plasma concentration occurred at 4 hr after single doses
Plasma elimination half life ~53 hr (at 250 mg BID)
No evidence of non-linearity in PK at doses between
100 mg QD mg BID
Moderate inter-subject variability
(CV 30-69% for AUC and Cmax)
Moderate CYP3A4 inhibitor
(mean 3.6-fold increase in oral MDZ AUC, 90%CI: )

8. PF-02341066 Concentrations vs. Time at Steady State
Cycle 1 Day 15
Time (hr)
PF Median Concentration (ng/mL) 2 4 6 8 10 12
100
200
300
400
500
50mg QD
100mg QD
200mg QD
200mg BID
250mg BID
300mg BID
Cycle 2 Day 1
Target C trough, c-MET
Target C trough, ALK
These graphs show PF steady state concentration vs. time on 2 separate treatment days.
Of note, when dosed at 200 mg bid or higher, plasma concentrations of drug exceeded the levels needed to inhibit ALK and MET in vitro.

9. Patients of Molecular Interest Enrolled into the Dose-Escalation Cohort
200 mg BID cohort
42 yo male with Sarcoma (2p23 ALK+ Inflammatory
Myofibroblastic Tumor), achieved partial response
by cycle 2
300 mg BID cohort
49 yo male with EML4-ALK fusion NSCLC
Dramatic clinical response within cycle 1,
then limited by LFTs
During the dose-escalation portion of the trial, there were 2 patient of molecular interest enrolled.
One was a 42 yo male with inflammatory myofibro

10. 42 yo Male with Inflammatory Myofibroblastic Tumor
(ALK Fusion)
After 2 Cycles
of PF
Pre-Treatment

11. Patients of Molecular Interest Enrolled into the Dose-Escalation Cohort
200 mg BID cohort
42 yo male with Sarcoma (2p23 Inflammatory
Myofibroblastic Tumor), achieved partial response
by cycle 2
300 mg BID cohort
49 yo male with EML4-ALK fusion NSCLC.
Dramatic clinical response within cycle 1,
then limited by LFTs

12. EML4-ALK Fusion in NSCLC
EML4-ALK Frequency:
Adenocarcinoma = 4% (26/662)
At least 7 fusion variants
Nature 448; 561 (2007)

13. Break-Apart FISH Assay
for ALK Fusion Genes
Chromosome 2p23 region
t(2;5) ALK gene
breakpoint region 3’ 5’
~250 kb
~300 kb
Potential Fusion
Partners:
EML4
KIF5B
TFG

14. RP2D Molecular Cohort: NSCLC with ALK Fusion, Patient Characteristics
Median (Range) Age, Years
Gender (Male:Female)
N=19
50 (28-73)
9:10
ECOG PS
4 (21%) 1
12 (63%) 2
3 (16%)
Smoking History
Current Smoker
Former Smoker
5 (26%)
Never Smoker
14 (74%)
Histology
Adenocarcinoma
17 (90%)
Squamous Cell Carcinoma
1 (5%)
Unknown
Prior Treatment
1 Regimen
7 (37%)
2 Regimens
3 Regimens
> 3 Regimens
Data in the database as of March 9, 2009

15. Study Status – NSCLC ALK Patients
27 Patients Dosed: Data Collection Ongoing
18 Patients Entered into Safety Database
19 Patients Evaluable for Response

16. Tumor Responses to PF-02341066 for NSCLC Evaluable Patients with ALK Fusions40 8+ 16 20 8+ 12 2+
13+ 2+ 8+
15+ 8+
23+
15+ 4+
One patient had clinical progression and discontinued without radiographic confirmation.

17. Molecular Cohort: NSCLC ALK Fusion
Overall Response Rate = 53%
(10/19 pts)
Disease Control Rate at 8 weeks = 79% (15/19 pts)
4 patients had progression at first evaluation

18. 48 yo Female Non-Smoker with
NSCLC ALK Fusion
Pre-Treatment
After 2 Cycles PF

19. Treatment-Related Adverse Events (≥10%) NSCLC Patients with ALK Fusion (N=18)
Grade 1
Grade 2
Grade 3
Grade 4
Total n
Adverse Event
n (%)
n (%)
n (%)
n (%)
(%)
Nausea
11 (61)
11 (61)
Vomiting
7 (39)
7 (39)
Diarrhea
6 (33)
6 (33)
Visual Disturbance
4 (22)
4 (22)
ALT Increased
2 (11)
1 (6)
3 (17)
Constipation
2 (11)
1 (6)
3 (17)
Cough
2 (11)
2 (11)
Data in the database as of March 9, 2009

20. Conclusions The MTD and RP2D of oral PF-02341066 is 250 mg BID.
The most frequent AEs were mild and moderate GI-related and fatigue. All AEs were manageable and reversible.
Treatment with PF resulted in dramatic clinical activity against tumors carrying activating ALK gene fusions.
Results of this trial support the importance of incorporating prospective molecular profiling into early-phase clinical trials for targeted therapies.

21. PF-02341066: Future Directions
For the Molecular Cohort
Focus efforts on identifying patients with MET amplification or mutations
Conduct genetic characterization of ALK fusion partners and EML4-ALK variants in responders
and non-responders
Conduct molecular analyses of other
determinants of response
Clinical Development of PF
Conduct a Phase 3 clinical trial in NSCLC patients harboring ALK fusions

22. Acknowledgments All The Research Staff All The Patients
Seoul National University
Massachusetts General Hospital
John Iafrate*, Jeffrey Clark, Eunice Kwak Thomas Lynch, Alice Shaw, Panos Fidias
Jeffrey Engelman, Marguerite Parkman
Yung-Jue Bang, Woo-Ho Kim*, Dong-Wan Kim
Se-Hoon Lee, Do Youn Oh, Sae-Won Han
Peter MacCallum Cancer Centre
Dana-Farber Cancer Institute
Benjamin Solomon, Alex Dobrovic*, Stephen
Fox*, Hongdo Do*, Toni-Maree Rogers*
Geoffrey Shapiro, Pasi Janne*, James Butrynski, Leena Gandhi, Andrew Wolanski Suzanne Hitchcock-Bryan, Charles Lee
University of Colorado
Ross Camidge, Marileila Garcia*, S. Gail
Eckhardt, Wells Messersmith
Beth Israel Deaconess
Medical Center
University of California - Irvine
Bruce Dezube, Daniel Costa, Myles Clancy
Sai Hong Ou
Memorial Sloan Kettering
University of Chicago
Finally, I’d like to acknowledge contributing investigators from Karmanos Cancer Center, The Mayo Clinic, The University of Alabama-Birmingham, and The Ireland Cancer Center, Case Western Reserve.
I’d also like to acknowledge the efforts of colleagues advancing the MEK inhibitor program at Pfizer…
Click….
And most importantly, I’d like to acknowledge the patients without whose support this ambitious study would not have been possible.
Thank you for your attention.
Robert Maki, Suresh C. Jhanwar*
Linda Ahn, Cory Ornelas
Ravi Salgia, Mark Ratain, David Geary
Leonardo Faoro, Rajani Kanteti
All The Research Staff
Pfizer
Isan Chen, James Christensen, Victoria Cohan, Gina Emory, Ray Lu, Sophia Randolph, Weiwei Tan, Greg Wei, Keith Wilner
All The Patients
* Molecular Profiling Contributor
Funding provided by Pfizer

23. ALK-Related Efficacy Evaluable NSCLC Patients
Patient ID
Previous Treatments
Best Response
PF-1066 Best Response
Duration of Response
Status 1 SD PR
12 wk
Discontinued (5 mo)
2 (erlotinib)
PD*,PR*
15 wk +
Ongoing (8 mo +)
SD,SD*
23 wk +
Ongoing (7 mo +) PD 3
PD,PD,PD
8 wk +
Ongoing (4 mo +) 2
PD,SD
13 wk +
7 (gefitinib)
PD,SD,PD*,SD,SD,SD,PD
Ongoing (2 mo +) 
5 (gefitinib)
SD,SD,PD*,PR, PR
uPR
4 wk +
Ongoing (3 mo +)  
SD/PD/PD
2 wk +
3 (erlotinib)
SD/PD/*SD  
 N/A  
N/A
SD*,SD,PD
Discontinued (PD) (10 mo)
1 (erlotinib)
PD*
Discontinued (PD) (4 mo)
SD,PD*
Discontinued (PD) (5 mo)  
Discontinued (<1 mo)   
Discontinued (1 mo)   
SD,SD,PD*
4 (erlotinib)
PD*,PR,PR,SD
Discontinued (1 mo)
* Best response to EGFR inhibitor
19 Evaluable: 10 (7 Confirmed; 3 Unconfirmed), 5 SD; 4 PD