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EL Kwak 1 , DR Camidge 2 , J Clark 1 , GI Shapiro 3 , RG Maki 4 ,

Clinical Activity Observed in a Phase 1 Dose-Escalation Trial of an Oral MET and ALK Inhibitor, PF-02341066. EL Kwak 1 , DR Camidge 2 , J Clark 1 , GI Shapiro 3 , RG Maki 4 , MJ Ratain 5 , B Solomon 6 , Y-J Bang 7 , S-H Ou 8 , R Salgia 5.

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EL Kwak 1 , DR Camidge 2 , J Clark 1 , GI Shapiro 3 , RG Maki 4 ,

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  1. 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 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. PF-02341066 Extracellular TM TM TM TM P P P P P P P P Y Y Y Y Y Y Y Y Kinase Kinase Intracellular P P P P P P P P Y Y Y Y Y Y Y Y P P P P P P P P P P P P Y Y Y Y Y Y Y Y Y Y Y Y Kinase P P P P P P P P P P P P Y Y Y Y Y Y Y Y Y Y Y Y P P P P Y Y Y Y P P P P Y Y Y Y Potent & selective ATP competitive oral inhibitor of MET and ALK kinases and their oncogenic variants Cytoplasmic Fusion Variants of ALK MET ALK ba 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 P P P P Y Y P P P P Y Y Y Y P P P P Y Y Y Y P P P P Y Y Y Y

  3. Study 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.

  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%

  5. PF-02341066: Dose Escalation Cohort 5 300 mg BID MDZ Sub-Study Cohort 6 250 mg BID Cohort 4 Cohort 4 MTD / RP2D 200 mg BID Cohort 3 200 mg QD Cohort 2 100 mg QD MDZ Sub-Study Cohort 1 50 mg QD 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).

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

  8. PF-02341066 Concentrations vs. Time at Steady State Cycle 1 Day 15 Cycle 2 Day 1 500 500 50mg QD 50mg QD 100mg QD 100mg QD 200mg QD 200mg QD 200mg BID 200mg BID 250mg BID 250mg BID 300mg BID 300mg BID 400 400 300 300 PF-02341066 Median Concentration (ng/mL) 200 200 Target C trough, ALK 100 100 Target C trough, c-MET 0 0 0 2 4 6 8 10 12 0 2 4 6 8 10 12 Time (hr) Time (hr)

  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

  10. 42 yo Male with Inflammatory Myofibroblastic Tumor (ALK Fusion) After 2 Cycles of PF-02341066 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 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 Fusions 40 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-02341066

  19. Treatment-Related Adverse Events (≥10%) NSCLC Patients with ALK Fusion (N=18) Treatment- Related Grade 1 Grade 2 Grade 3 Grade 4 Total n Adverse Event n (%) n (%) n (%) 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) 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-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.

  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-02341066 • Conduct a Phase 3 clinical trial in NSCLC patients harboring ALK fusions

  22. Acknowledgments 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 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 EfficacyEvaluable NSCLC Patients * Best response to EGFR inhibitor 19 Evaluable: 10 (7 Confirmed; 3 Unconfirmed), 5 SD; 4 PD

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