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 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

Cytoplasmic Fusion Variants of ALK PF-02341066 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-02341066 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

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. Our clinical trial was a first in man study of PF02341066. 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.

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.

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-02341066 is a major substrate and inhibitor of CYP3A activity).

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

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)

PF-02341066 Concentrations vs. Time at Steady State Cycle 1 Day 15 Time (hr) PF-02341066 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.

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

42 yo Male with Inflammatory Myofibroblastic Tumor (ALK Fusion) After 2 Cycles of PF-02341066 Pre-Treatment

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

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

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

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

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

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.

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

48 yo Female Non-Smoker with NSCLC ALK Fusion Pre-Treatment After 2 Cycles PF-02341066

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

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.

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

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

ALK-Related Efficacy Evaluable NSCLC Patients 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* 15 wk + Ongoing (8 mo +) 10021038 SD,SD* 23 wk + Ongoing (7 mo +) 10021039 PD 10071016 3 PD,PD,PD 8 wk + Ongoing (4 mo +) 10021043 2 PD,SD 13 wk + 10071019 7 (gefitinib) PD,SD,PD*,SD,SD,SD,PD Ongoing (2 mo +)  10071020 5 (gefitinib) SD,SD,PD*,PR, PR uPR 4 wk + Ongoing (3 mo +) 10021023  SD/PD/PD 2 wk + 10081002 3 (erlotinib) SD/PD/*SD 10021045   N/A 10021056  N/A 10021026 SD*,SD,PD Discontinued (PD) (10 mo) 10021040 1 (erlotinib) PD* Discontinued (PD) (4 mo) 10021014 SD,PD* Discontinued (PD) (5 mo) 10021051  Discontinued (<1 mo)  10021058  Discontinued (1 mo)  10071021  SD,SD,PD* 10051003 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