October 23, 2014 John C. Lin, M.D. Ph.D. Vice President, Experimental Medicine Rational Combination of Immunotherapies in Preclinical Cancer Models

Combination PD-1 and CTLA-4 Abs Leads to A Superior Anti-tumor Activity 1 mg/kg nivolumab + 3mg/kg ipilimumab 5 × 104 B16-BL6 cells Vaccinated on days 3, 6, and 9 with 1 × 106 Fvax Mouse melanoma Human melanoma Wolchok et al. NEJM (June 2013) ORR=9/17 Curran et al PNAS 2010

Pfizer Confidential │ 3 Combination Therapy of  -PD-1 and  -Lag-3 Shows Synergy in MC38 but not in B16 Tumor Model The combined anti-PD-1 and anti-Lag-3 had no effect against established B16 tumors

Combination of Immune Modulators Melero I et al. Clin Cancer Res 2013;19:

Pfizer Confidential │ 5 Syngeneic tumor models in response to single agent 4-1BB treatment 4-1BB resistant models 4-1BB sensitive models (ORU, La Jolla)

Tumor Response in Merkel Cell Carcinoma Patient Treated with 0.6 mg/kg of PF (4-1BB) Baseline PET ScanWeek 16 PET Scan ASCO (2014) Pfizer Confidential │ 6 34 treated, up to 5 mg/kg (as of ASCO 2014) 24 evaluable for response 1 patient - PR (0.6 mg/kg) 1 patient - Mixed response (0.06 mg/kg) 7 patients –Stable disease across multiple doses

Adverse Events-Related No Grade 2 or higher treatment related adverse events were observed up to the current dose level of 5.0 mg/kg AE possibly related to single agent PF-566 up to 1.2 mg/kg are listed below (all Grade 1) Adverse event N (%) Rash 3 (9) Fever 2 (6) Nausea/vomiting 2 (6) Weight loss 1 (3) Headache 1 (3) Fatigue 1 (3) Thrombocytopenia 1 (3) Adapted from ASCO, 2014

Pfizer Confidential │ 8 Vaccination Is Required for Tumor Suppression by anti-4-1BB / anti-CTLA-4 Combination Curran et al. PLoS ONE 2011

Pfizer Confidential │ 9 Induction of PD BB + CD8 T cells by 4-1BB antibody in B16 melanoma bearing mice FSC-A Live/Dead CD3 NK1.1 CD4 CD8 4-1BB PD-1 4-1BB PD-1 CD4+CD8+CD3+Live cells (A) Isotype-treated FSC-A Live/Dead CD3 NK1.1 CD4 CD8 4-1BB PD-1 4-1BB PD-1 CD4+CD8+CD3+Live cells (B) Anti-4-1BB-treated (Chen et al, in press)

Anti-4-1BB and anti-PD1 Combo Therapy Showed Synergistic Anti-tumor Effect in B16 Tumor

Pfizer Confidential │ 11 Strategies to enhance 4-1BB agonism - Combine with immune checkpoint PD-1 inhibitor B16F10 Melanoma 4-1BB/PD-1 combination is superior to 4-1BB/LAG-3 in suppressing B16F10 tumor growth Chen et al. (in press)

Anti-4-1BB and anti-PD1 Combo Therapy Showed Synergistic Anti-tumor Effect in Large Tumors Tumor size between mm 3 Chen et al. (in press)

Pfizer Confidential │ 13 The anti-tumor activity of 4-1BB/PD-1 combination requires CD8+ T cells and INF-  CD8+ T cell depletion abrogates anti-tumor activity Loss of anti-tumor activity in IFN-  -deficient mice Chen et al. (in press)

Anti-4-1BB and anti-PD1 Combo Therapy Increased the Availability of Target Molecules Chen et al. (in press)

Anti-4-1BB and anti-PD1 Treatment Promoted Anti-Tumor Immune Response Chen et al. (in press)

Anti-4-1BB and Anti-PD1 Combo Therapy Induced T Cell Effector/Memory Differentiation Chen et al. (in press)

Anti-4-1BB and Anti-PD1 Combo Therapy Enhanced Antigen-Specific T Cell Response Chen et al. (in press) KSTPFTTL MC38 CD8 dominant epitope

Pfizer Confidential │ 18 Anti-tumor efficacy demonstrated in two murine models –MC38 colon cancer and B16 melanoma –Anti-4-1BB induces PD-1 expression –Increase in memory-phenotype T cells –Tcm and Tem –Eomes up-regulation –Antigen-specific response Summary of Anti-4-1BB / anti-PD-1 combination

Pfizer Confidential │ 19 Acknowledgements Shihao Chen Li-Fen Lee Guang Huan Tu Kathryn Logronio Tim Fisher Mark Elliott Clinical Team Bart Jessen, other Drug Safety R&D members Oncology Business Unit Patients and their family members Rinat and Oncology Research Unit