Clinical Activity Observed in

a Phase 1 Dose-Escalation Trial of an Oral

MET and ALK Inhibitor, PF-02341066

Clinical Activity Observed in

a Phase 1 Dose-Escalation Trial of an Oral

MET and ALK Inhibitor, PF-02341066

EL Kwak1, DR Camidge2, J Clark1, GI Shapiro3, RG Maki4,

MJ Ratain5, B Solomon6, Y-J Bang7, S-H Ou8, R Salgia5

EL Kwak1, DR Camidge2, J Clark1, GI Shapiro3, RG Maki4,

MJ Ratain5, B Solomon6, Y-J Bang7, S-H Ou8, R Salgia5

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 University4. Memorial Sloan-Kettering Cancer Center 8. University of California at

Irvine

PF-02341066PF-02341066

Potent & selective ATP competitive oral inhibitor of MET and ALK kinases and their oncogenic variants

Potent & selective ATP competitive oral inhibitor of MET and ALK kinases and their oncogenic variants

ON

N

Cl

F

Cl

NN

NMETMET ALKALK

YYPP

YYPP

TMTM

YYPP

YYPP

YYPP

YYPP

SEMA

TMTMExtracellular

Intracellular

YYPP

YYPP

Kinase

YYPP

YYPPYYPPYYPP

YYPP

YYPP

TMTM

YYPP

YYPP

YYPP

YYPP

TMTMExtracellular

Intracellular

YYPP

YYPP

Kinase

YYPP

YYPP

YYPP

YYPP

YYPP

YYPP

YYPP

YYPP

KinaseYY

PP

YYPP

YYPP

YYPP

YYPP

YYPP

YYPP

YYPP

Kinase

Cytoplasmic Fusion Variants of

ALK

Cytoplasmic Fusion Variants of

ALK

NPM-ALKNPM-ALK EML4-ALKEML4-ALK

Study Dosing and ObjectivesStudy Dosing and Objectives

PF-02341066 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-02341066. 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.

PF-02341066 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-02341066. 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.

PF-02341066: Phase 1 Dose EscalationPF-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

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%

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%

PF-02341066: Dose EscalationPF-02341066: Dose Escalation

MTD = Maximum Tolerated Dose

RP2D = Recommended Phase 2 Dose

MDZ = Midazolam (In-vitro data indicated that

PF-02341066 is a major substrate and

inhibitor of CYP3A activity).

MTD = Maximum Tolerated Dose

RP2D = Recommended Phase 2 Dose

MDZ = Midazolam (In-vitro data indicated that

PF-02341066 is a major substrate and

inhibitor of CYP3A activity).

Cohort 4Cohort 4

Cohort 1Cohort 1

50 mg QD50 mg QD

Cohort 2Cohort 2

100 mg QD100 mg QDMDZ Sub-StudyMDZ Sub-Study

Cohort 3Cohort 3

200 mg QD200 mg QD

Cohort 4Cohort 4

200 mg BID200 mg BID

Cohort 5Cohort 5

300 mg BID300 mg BID

Cohort 6Cohort 6

250 mg BID250 mg BID

MDZ Sub-StudyMDZ Sub-Study

MTD / RP2DMTD / RP2D

Most Common Treatment-Related Adverse Events (≥ 10%)

Dose Escalation Cohorts (N=37)

Data in the database as of March 9, 2009Data in the database as of March 9, 2009

DLTs are highlighted in red.DLTs are highlighted in red.

Adverse Event

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 1-2 1-2 3 1-2 1-2 3 1-2 3

Nausea 2 3 6 0 3 4 0 4 0

Vomiting 2 2 5 0 2 2 0 3 0

Diarrhea 3 0 1 0 2 0 0 2 0

Fatigue 2 2 0 0 0 0 2 1 1

Headache 0 2 1 0 1 0 0 0 0

                   

Visual Disturbance

0 0 0 0 1 1 0 0 0

ALT Increased 0 0 0 1 1 0 0 0 0

AST Increased 0 0 0 0 1 0 0 0 0

PF-02341066: Overview of Pharmacokinetics

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 - 300 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:

2.7-4.9)

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 - 300 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:

2.7-4.9)

PF-02341066 Concentrations vs.

Time at Steady State

PF-02341066 Concentrations vs.

Time at Steady State

Cycle 1 Day 15

Time (hr)

PF-0

23

41

06

6 M

edia

n C

once

ntr

ati

on (

ng/m

L)

0 2 4 6 8 10 1201

00

20

03

00

40

05

00

50mg QD100mg QD200mg QD200mg BID250mg BID300mg BID

Cycle 2 Day 1

Time (hr)

0 2 4 6 8 10 1201

00

20

03

00

40

05

00

50mg QD100mg QD200mg QD200mg BID250mg BID300mg BID

Target C trough, c-MET

Target C trough, ALK

Patients of Molecular Interest Enrolled

into the Dose-Escalation Cohort

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

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

300 mg BID cohort

49 yo male with EML4-ALK fusion NSCLC

Dramatic clinical response within cycle 1,

then limited by LFTs

42 yo Male with Inflammatory Myofibroblastic Tumor

(ALK Fusion)

Pre-Treatment After 2 Cycles of PF-02341066

Patients of Molecular Interest Enrolled

into the Dose-Escalation Cohort

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

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

300 mg BID cohort

49 yo male with EML4-ALK fusion NSCLC.

Dramatic clinical response within cycle 1,

then limited by LFTs

EML4-ALK Fusion in NSCLCEML4-ALK Fusion in NSCLC

Nature 448; 561 (2007)Nature 448; 561 (2007)Nature 448; 561 (2007)Nature 448; 561 (2007)

EML4-ALK Frequency:

Adenocarcinoma = 4% (26/662)

EML4-ALK Frequency:

Adenocarcinoma = 4% (26/662)

At least 7 fusion variantsAt least 7 fusion variants

~250 kb ~300 kb

t(2;5) ALK genebreakpoint region

Chromosome 2p23 region

3’ 5’

Break-Apart FISH Assay for ALK Fusion Genes

Potential Fusion Partners:

• EML4

• KIF5B• TFG

RP2D Molecular Cohort: NSCLC with ALK Fusion, Patient Characteristics

CharacteristicsMedian (Range) Age,

YearsGender (Male:Female)

N=19 50 (28-73)

9:10

ECOG PS 0 4 (21%)

1 12 (63%)

  2 3 (16%)Smoking

HistoryCurrent Smoker

0

Former Smoker 5 (26%)

  Never Smoker 14 (74%)Histology Adenocarcinoma 17 (90%)

Squamous Cell Carcinoma 1 (5%)

  Unknown 1 (5%)Prior

Treatment 1 Regimen 7 (37%)

2 Regimens 4 (21%)

3 Regimens 4 (21%)

  > 3 Regimens 4 (21%)

Data in the database as of March 9, 2009Data in the database as of March 9, 2009

Study Status – NSCLC ALK PatientsStudy Status – NSCLC ALK Patients

27 Patients Dosed: Data Collection Ongoing

18 Patients Entered into Safety Database

19 Patients Evaluable for Response

27 Patients Dosed: Data Collection Ongoing

18 Patients Entered into Safety Database

19 Patients Evaluable for Response

Tumor Size Change

Duration of Response (Weeks)

-100

-80

-60

-40

-20

0

20

40

Green - PR Blue - SD Black - PD

% o

f b

est

chan

ge

fro

m

bas

elin

e

Tumor Responses to PF-02341066 for NSCLC Evaluable Patients with ALK

Fusions

Tumor Responses to PF-02341066 for NSCLC Evaluable Patients with ALK

Fusions

8+8+2020

4040

8+8+ 12122+2+ 13

+13

+ 15+

15+

8+8+

23+

23+

15+

15+

2+2+

1616

8+8+

4+4+

One patient had clinical progression and discontinued without radiographic confirmation.

Molecular Cohort: NSCLC ALK FusionMolecular 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

Overall Response Rate = 53% (10/19 pts)

Disease Control Rate at 8 weeks = 79% (15/19 pts)

4 patients had progression at first evaluation

48 yo Female Non-Smoker with NSCLC ALK Fusion

Pre-Treatment Pre-Treatment After 2 Cycles PF-02341066After 2 Cycles PF-02341066

Treatment-Related Adverse Events (≥10%) NSCLC Patients with ALK Fusion (N=18)

Data in the database as of March 9, 2009Data in the database as of March 9, 2009

Treatment-

Related

Adverse Event

Grade 1

n (%)

Grade 2

n (%)

Grade 3

n (%)

Grade 4

n (%)

Total n

(%)

Nausea 11 (61) 0 0 0 11 (61)

Vomiting 7 (39) 0 0 0 7 (39)

Diarrhea 6 (33) 0 0 0 6 (33)

Visual Disturbance

4 (22) 0 0 0 4 (22)

ALT Increased 0 2 (11) 1 (6) 0 3 (17)

Constipation 0 2 (11) 1 (6) 0 3 (17)

Cough 2 (11) 0 0 0 2 (11)

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-02341066 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.

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-02341066 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.

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-02341066 Conduct a Phase 3 clinical trial in NSCLC

patients harboring ALK fusions

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-02341066 Conduct a Phase 3 clinical trial in NSCLC

patients harboring ALK fusions

AcknowledgmentsAcknowledgments

PfizerIsan Chen, James Christensen, Victoria Cohan, Gina Emory, Ray Lu, Sophia Randolph, Weiwei Tan, Greg Wei, Keith Wilner

All The Patients

Funding provided by PfizerFunding provided by Pfizer

Peter MacCallum Cancer Centre

Peter MacCallum Cancer Centre

Massachusetts General HospitalMassachusetts General Hospital

Dana-Farber Cancer InstituteDana-Farber Cancer Institute

Beth Israel Deaconess Medical CenterBeth Israel Deaconess Medical Center

Memorial Sloan KetteringMemorial Sloan Kettering

Seoul National UniversitySeoul National University

University of California - Irvine

University of California - Irvine

University of ChicagoUniversity of Chicago

University of ColoradoUniversity of Colorado

Geoffrey Shapiro, Pasi Janne*, James Butrynski, Leena Gandhi, Andrew Wolanski Suzanne Hitchcock-Bryan, Charles Lee

Geoffrey Shapiro, Pasi Janne*, James Butrynski, Leena Gandhi, Andrew Wolanski Suzanne Hitchcock-Bryan, Charles Lee

Bruce Dezube, Daniel Costa, Myles ClancyBruce Dezube, Daniel Costa, Myles Clancy

Robert Maki, Suresh C. Jhanwar*Linda Ahn, Cory OrnelasRobert Maki, Suresh C. Jhanwar*Linda Ahn, Cory Ornelas

Yung-Jue Bang, Woo-Ho Kim*, Dong-Wan KimSe-Hoon Lee, Do Youn Oh, Sae-Won HanYung-Jue Bang, Woo-Ho Kim*, Dong-Wan KimSe-Hoon Lee, Do Youn Oh, Sae-Won Han

Benjamin Solomon, Alex Dobrovic*, StephenFox*, Hongdo Do*, Toni-Maree Rogers*Benjamin Solomon, Alex Dobrovic*, StephenFox*, Hongdo Do*, Toni-Maree Rogers*

Ross Camidge, Marileila Garcia*, S. GailEckhardt, Wells MessersmithRoss Camidge, Marileila Garcia*, S. GailEckhardt, Wells Messersmith

Sai Hong OuSai Hong Ou

Ravi Salgia, Mark Ratain, David GearyLeonardo Faoro, Rajani KantetiRavi Salgia, Mark Ratain, David GearyLeonardo Faoro, Rajani Kanteti

John Iafrate*, Jeffrey Clark, Eunice Kwak Thomas Lynch, Alice Shaw, Panos Fidias Jeffrey Engelman, Marguerite Parkman

John Iafrate*, Jeffrey Clark, Eunice Kwak Thomas Lynch, Alice Shaw, Panos Fidias Jeffrey Engelman, Marguerite Parkman

* Molecular Profiling Contributor* Molecular Profiling Contributor

All The Research StaffAll The Research Staff

ALK-Related EfficacyEvaluable NSCLC Patients

ALK-Related EfficacyEvaluable NSCLC Patients

* Best response to EGFR inhibitor* Best response to EGFR inhibitor

19 Evaluable: 10 19 Evaluable: 10 (7 Confirmed; 3 Unconfirmed),(7 Confirmed; 3 Unconfirmed), 5 SD; 4 PD 5 SD; 4 PD19 Evaluable: 10 19 Evaluable: 10 (7 Confirmed; 3 Unconfirmed),(7 Confirmed; 3 Unconfirmed), 5 SD; 4 PD 5 SD; 4 PD

Patient ID Previous Treatments

Best Response

PF-1066 Best Response

Duration of Response Status

10021042 1 SD PR 12 wk Discontinued (5 mo)

10081001 2 (erlotinib) PD*,PR* PR 15 wk + Ongoing (8 mo +)

10021038 2 (erlotinib) SD,SD* PR 23 wk + Ongoing (7 mo +)

10021039 1 PD PR 15 wk + Ongoing (7 mo +)

10071016 3 PD,PD,PD PR 8 wk + Ongoing (4 mo +)

10021043 2 PD,SD PR 13 wk + Ongoing (4 mo +)

10071019 7 (gefitinib) PD,SD,PD*,SD,SD,SD,PD PR 8 wk + Ongoing (2 mo +) 

10071020 5 (gefitinib) SD,SD,PD*,PR, PR uPR 4 wk + Ongoing (3 mo +)

10021023  3 SD/PD/PD uPR 2 wk + Ongoing (2 mo +) 

10081002 3 (erlotinib) SD/PD/*SD uPR 2 wk + Ongoing (2 mo +) 

10021045  1 SD SD  N/A Ongoing (2 mo +) 

10021056  1 SD SD N/A Ongoing (2 mo +) 

10021026 3 (erlotinib) SD*,SD,PD SD N/A Discontinued (PD) (10 mo)

10021040 1 (erlotinib) PD* SD N/A Discontinued (PD) (4 mo)

10021014 2 (erlotinib) SD,PD* SD N/A Discontinued (PD) (5 mo)

10021051  1 PD PD N/A Discontinued (<1 mo) 

10021058  1 PD PD N/A Discontinued (1 mo) 

10071021  3 (erlotinib) SD,SD,PD* PD N/A Discontinued (<1 mo) 

10051003 4 (erlotinib) PD*,PR,PR,SD PD N/A Discontinued (1 mo)