Targeting ALK Receptor Tyrosine Kinase Targeting ALK Receptor Tyrosine Kinase in Inflammatory Myofibroblastic Tumor in Inflammatory Myofibroblastic Tumor

(IMT)(IMT)James E ButrynskiJames E Butrynski11, David R D’Adamo, David R D’Adamo22, Andrew Wolanski, Andrew Wolanski11, ,

Linda AhnLinda Ahn22, Laurie Chiambalero, Laurie Chiambalero11, Kristie Stolgitis, Kristie Stolgitis11, , Pasi A JannePasi A Janne11, Eunice L Kwak, Eunice L Kwak33, Jeffrey W Clark, Jeffrey W Clark33, ,

Keith WilnerKeith Wilner44, James Christensen, James Christensen44, George D Demetri, George D Demetri11, , Robert G MakiRobert G Maki22, Geoffrey I Shapiro, Geoffrey I Shapiro11

1 Dana-Farber Cancer Institute, Boston, MA 1 Dana-Farber Cancer Institute, Boston, MA 2 Memorial Sloan-Kettering Cancer Center, New York, NY2 Memorial Sloan-Kettering Cancer Center, New York, NY3 Massachusetts General Hospital, Boston, MA 3 Massachusetts General Hospital, Boston, MA 4 Pfizer Oncology, La Jolla, CA4 Pfizer Oncology, La Jolla, CA

IMT- What do we knowIMT- What do we know • Myofibroblastic spindle cells with an Myofibroblastic spindle cells with an

inflammatory infiltrateinflammatory infiltrate

• Predilection for children and adolescentsPredilection for children and adolescents

• Common sites mesentery, omentum and Common sites mesentery, omentum and lunglung

• Standard treatment-SurgeryStandard treatment-Surgery

• No established systemic therapyNo established systemic therapy

• Anaplastic Lymphoma Kinase (ALK) Anaplastic Lymphoma Kinase (ALK) expression and expression and ALKALK gene rearrangement gene rearrangement

Courtesy of Jason L. Hornick, M.D., Ph.D.

IMT- What do we knowIMT- What do we know

• ALKALK fusion partners in IMT fusion partners in IMT

–TPM3,4TPM3,4

–RAN-BP2RAN-BP2

–CARSCARS

–ATICATIC

–SEC31L1SEC31L1

Courtesy of Yael Mosse, CCR 2009

HypothesisHypothesis

• ALK inhibitors have a role in ALK inhibitors have a role in refractory IMTrefractory IMT

PF-02341066PF-02341066

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

ON

N

Cl

F

Cl

NN

N

Kinase IC50 (nM)

Mean Selectivity

Ratioα

c-Met 8 ---

ALK 20 2X

RON 248 31X

Axl 308 39X

Tie-2 448 56X

Trk A 580 73X

Trk B 399 50X

PF2341066 was >100X selective for Met/ALK across a panel of 150 additional kinases.

PF2341066 was >100X selective for Met/ALK across a panel of 150 additional kinases.

MET/HGFRMET/HGFR 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

A8081001: Study ObjectivesA8081001: Study Objectives

PF-02341066 dosing schedule: Day minus 7 lead-in, then continuous oral administration for 28 days per cycle.

1. Dose-Escalation Determine the safety profile of PF-02341066. Determine recommended phase 2 dose (RP2D) of PF-02341066. Determine the PK profile of PF-02341066 after oral dosing.

2. Recommended Phase 2 Dose Cohort (RP2D)

Explore anti-tumor activity in an enriched molecular cohort (ALK fusion or MET mutation/amplification). Promising clinical activity seen in ALK fusion patients.

PF-02341066 dosing schedule: Day minus 7 lead-in, then continuous oral administration for 28 days per cycle.

1. Dose-Escalation Determine the safety profile of PF-02341066. Determine recommended phase 2 dose (RP2D) of PF-02341066. Determine the PK profile of PF-02341066 after oral dosing.

2. Recommended Phase 2 Dose Cohort (RP2D)

Explore anti-tumor activity in an enriched molecular cohort (ALK fusion or MET mutation/amplification). Promising clinical activity seen in ALK fusion patients.

Dose EscalationDose 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

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

Pfizer Confidential

Most Common Treatment-Related Adverse Events Most Common Treatment-Related Adverse Events (≥ 10%) Dose Escalation Cohorts (N=37)(≥ 10%) Dose Escalation Cohorts (N=37)

Adverse EventAdverse 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

DLTs

43 year old male 43 year old male ALK-ALK-rearranged IMTrearranged IMT• June 2007 Ex Lap-omentectomy, right hemicolectomy, June 2007 Ex Lap-omentectomy, right hemicolectomy,

tumor debulking, IOHC with CDDP, Doxorubicin, MMCtumor debulking, IOHC with CDDP, Doxorubicin, MMC• August 2007 to November 2007 AIM X 6August 2007 to November 2007 AIM X 6• November 2007 to February 2008 ImatinibNovember 2007 to February 2008 Imatinib• March 2008 PF-02341066 200mg BIDMarch 2008 PF-02341066 200mg BID• May 2008 unconfirmed PRMay 2008 unconfirmed PR• June 2008 confirmed PRJune 2008 confirmed PR• October 2008 continued PR but some growingOctober 2008 continued PR but some growing• November 2008 PF-02341066 250 mg BIDNovember 2008 PF-02341066 250 mg BID• Dec 2008 Ex lap debulkDec 2008 Ex lap debulk• Jan 2009 PF-02341066 250mg BID. Continues NEDJan 2009 PF-02341066 250mg BID. Continues NED

Courtesy of Jason L. Hornick, M.D., Ph.D.

ALK

Courtesy of Jason L. Hornick, M.D., Ph.D.

FISH

Courtesy of Jason L. Hornick, M.D., Ph.D.

40%

53%

58%57%

Radiographic Response

Response at 3 months in ALK-rearranged IMTPRE POST

21 year old male 21 year old male nonnon ALKALK-rearranged -rearranged IMTIMT

• December 2007 Ex Lap- debulking, partial December 2007 Ex Lap- debulking, partial gastrectomy, partial right colectomy and gastrectomy, partial right colectomy and splenectomysplenectomy

• February 2008 prednisone and ibuprofenFebruary 2008 prednisone and ibuprofen• July 2008 PF-02341066 250mg BIDJuly 2008 PF-02341066 250mg BID• August 2008 increasing Total BiliAugust 2008 increasing Total Bili• August 2008 Hold PF-02341066August 2008 Hold PF-02341066• August 2008 Repeat imaging increasing August 2008 Repeat imaging increasing

abdominal diseaseabdominal disease

ConclusionsConclusions

• Dramatic response to PF-02341066 Dramatic response to PF-02341066 in in ALKALK-rearranged IMT.-rearranged IMT.

• No benefit to PF-02341066 in No benefit to PF-02341066 in nonnon ALK-rearranged IMT ALK-rearranged IMT

Future DirectionFuture Direction

• Phase II in Phase II in ALKALK-rearranged IMT-rearranged IMT

• Clinical trials in other ALK driven Clinical trials in other ALK driven tumorstumors

• Mechanisms of resistance to ALK Mechanisms of resistance to ALK inhibitioninhibition

AcknowledgmentsAcknowledgments

James Christensen, Keith James Christensen, Keith WilnerWilner

The Patients The Patients

Research StaffResearch Staff

Massachusetts General HospitalMassachusetts General Hospital

Dana-Farber Cancer InstituteDana-Farber Cancer Institute Memorial Sloan-KetteringMemorial Sloan-Kettering

Geoffrey Shapiro, George Demetri, Pasi Janne, Jason Hornick, Paola Dal Cin, Monica Bertagnolli, Andrew Wolanski, Laurie Chimbalero, Kristie Stolgitis

Geoffrey Shapiro, George Demetri, Pasi Janne, Jason Hornick, Paola Dal Cin, Monica Bertagnolli, Andrew Wolanski, Laurie Chimbalero, Kristie Stolgitis

Robert Maki, David D’Adamo, Paul Myers, Linda Ahn

Robert Maki, David D’Adamo, Paul Myers, Linda Ahn

John Iafrate, Jeffrey Clark, Eunice KwakJohn Iafrate, Jeffrey Clark, Eunice Kwak

PfizerPfizer