IL RUOLO DI BMS NELLO SVILUPPO DELL IMMUNO-ONCOLOGIA

IL RUOLO DI BMS NELLO SVILUPPO DELL IMMUNO-ONCOLOGIA Milano, 1 Febbraio 2017 Elisabetta Calabrese, MD PhD Bristol-Myers Squibb Mercury number Italy: IOIT17NP00622-01

AGENDA The past: Story of Immuno-Oncology (@ BMS) The present: Our Commitment to I-O: Extensive Pipeline The future: Objectives and innovation

EVOLUTION OF CANCER THERAPY: IMMUNO-ONCOLOGY (I-O) IS NOW A PILLAR OF CANCER THERAPY Surgery 1846 Radiation Therapy 1901 Chemotherapy 1946 Immunotherapy interferon-α 1986 interleukin-2 1992 Immuno-Oncology sipuleucel-t 2010 ipilimumab 2011 nivolumab 2014 Targeted Therapy imatinib 2001 gefitinib 2003 DeVita VT Jr, Chu E. Cancer Res. 2008;68(21):8643 8653; The American Cancer Society. The History of Cancer. Available from: cancer.org/cancer/cancerbasics/thehistoryofcancer/. Accessed September 2014; Finn OJ. Ann Oncol. 2012;23(suppl 8):viii6 viii9; Mansh M. Yale J Biol Med. 2011;84:381 389; Kirkwood JM, et al. CA Cancer J Clin. 2012;62:309 335.

IMMUNOEDITING: THE ROLE OF THE IMMUNE SYSTEM IN CANCER DEVELOPMENT AND PROGRESSION Elimination Cancer immunosurveillance Effective antigen processing/presentation Effective activation and function of effector cells eg, T-cell activation without co-inhibitory signals Equilibrium Cancer dormancy Genetic instability Tumor heterogeneity Immune selection Escape Cancer progression Tumors may avoid elimination by the immune system through outgrowth tumor cells that can suppress, disrupt, or escape the immune system Activated T cells NK cell Treg Tumor cell Cytokines Normal cells NK=natural killer. Vesely MD, et al. Ann Rev Immunol. 2011;29:235 271.

TUMORS USE COMPLEX, OVERLAPPING MECHANISMS TO EVADE AND SUPPRESS THE IMMUNE SYSTEM A. Ineffective presentation of tumor antigens (eg, downregulation of MHC I) B. Recruitment of immunosuppressive cells with inactive T cells (eg, Tregs, MDSCs) APC Inactive T cell Active T cell Tumorassociated antigens Treg Tumor cells C. Tumor release of immunosuppressive factors (eg, TGF-β, IDO, IL-10) CTLA-4=cytotoxic T-lymphocyte-associated protein 4; IDO= indoleamine 2,3-dioxygenase; IL=interleukin; MDSC=myeloid-derived suppressor cell; MHC=major histocompatibility complex; TGF-β=transforming growth factor beta. Vesely MD et al. Ann Rev Immunol. 2011;29:235 271. Immunosuppressive factors D. T-cell checkpoint dysregulation (eg, PD-1, CTLA-4)

REGULATING THE T CELL IMMUNE RESPONSE Activating receptors CD28 OX40 CD137 Agonistic antibodies T cell stimulation Inhibitory receptors CTLA-4 PD-1 TIM-3 LAG-3 Antagonistic (blocking) antibodies T cell responses are regulated through a complex balance of inhibitory (checkpoint) and activating signals Tumors can dysregulate checkpoint and activating pathways, and consequently immune response Targeting these pathways is an evolving approach to cancer therapy, designed to promote an immune response The image shows only a selection of the receptors/pathways involved. LAG-3=lymphocyte-activation gene 3; TIM-3=T-cell immunoglobulin domain and mucin domain 3. Adapted from Mellman I, et al. Nature. 2011:480;481 489; Pardoll DM. Nat Rev Cancer. 2012;12:252 264.

THE DISCOVERY OF IPILIMUMAB AND NIVOLUMAB Mouse CTLA4 Cloned 1 CTLA4 Binds to B7 2 CTLA-4 is negative regulator of T cell 3-7 Jim Allison mouse cancer model, Inhibition of CTLA4 as anti-cancer Therapy 8 Agreement to develop anti-ctla4 for clinical use 9 Cloning of ipilimumab 10 Yervoy (ipilimumab) Ipilimumab FIH approved in US 1987 1991 1994-1995 1996 1998 1999 2000 2002 2006 2011 2014 Opidivo (nivolumab) approved in US Nivolumab FIH Nivolumab discovered PD-1 is a negative signaling molecule 11 1. Brunet et al (INSERM, Marseille) Nature. 2. Linsely et al (BMS Seattle) JEM 1991 and 1992; 3.Walunas, Bluestone et al. Immunity, 4. Green et al. Immunity 1994, 5.Waterhouse, Mak et al Science, 6. Tivol, Bluestone, Sharp et al Immunity, 7.Krummel and Allison Jem 1995, 8. Leach, Krummel, Allison. Science 1996, 9. Korman, Lonberg, Allison, 10. Keler, Korman et al JIM 2003 (Medarex), 11. Honjo, KO,

1996: INHIBITION OF CTLA4 AS ANTI-CANCER THERAPY 1987 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 CTLA-4 blockade can induce antitumor immunity Leach, Krummel, Allison. Science 1996

POOLED ANALYSIS OF LONG-TERM OS FROM PHASE 2 AND 3 TRIALS OF IPILIMUMAB: INCLUDING EAP 1.0 Proportion Alive 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 N= 4846 Median OS, months (95% CI): 9.5 (9.0 10.0) 3-year OS rate, % (95% CI): 21 (20 22) 0.1 0.0 Ipilimumab CENSORED 0 12 24 36 48 60 72 84 96 108 120 Months Patients at Risk Ipilimumab 4846 1786 612 392 200 170 120 26 15 5 0 Schadendorf D, et al. J Clin Oncol.2015.

NIVOLUMAB: MECHANISM OF ACTION Recognition of tumor by T cell through MHC/antigen interaction mediates IFNγ release and PD-L1/2 upregulation on tumor Priming and activation of T cells through MHC/antigen & CD28/B7 interactions with antigen-presenting cells IFNγ IFNγR MHC T-cell receptor T-cell receptor MHC Tumor cell PD-L1 PD-L2 PD-1 Shp-2 PI3K NFκB Other T cell Shp-2 CD28 PD-1 B7 PD-L1 Dendritic cell PD-1 PD-1 PD-L2 Nivolumab blocks the PD-1 receptor CD28/B7, cluster of differentiation 28/B7; IFNγ, interferon-gamma; IFNγR, IFNγ receptor; MHC, major histocompatibility complex; NFκB, nuclear factor kappa B; PD-L1, programmed death ligand-1; PD-L2, programmed death ligand-2; PI3K, phosphoinositide-3 kinase; Shp-2, ubiquitously expressed tyrosine-specific protein phosphatase. Pardoll DM. Nat Rev Cancer. 2012;12:252 264. Adapted from Pardoll 2012. [1]

NIVOLUMAB: 5 STUDIES EARLY STOPPED IN 18 MONTHS SUPERIORITY IN OS PRIMARY ENDPOINTS Checkmate 066 Melanoma Checkmate 057 nsq-nsclc Checkmate 141 SCCHN June 2014 Jan 2015 Apr 2015 Jul 2015 Jan 2016 Checkmate 017 Sq-NSCLC Checkmate 025 RCC

CHECKMATE 066: MELANOMA OVERALL SURVIVAL Long et al, SMR 2014

CHECKMATE 017: SQUAMOUS NSCLC OVERALL SURVIVAL OS (%) 100 90 80 70 60 50 40 30 1-yr OS rate = 42% mos mo, (95% CI) Nivolumab Nivolumab n = 135 9.2 (7.3, 13.3) Docetaxel n = 137 6.0 (5.1, 7.3) # events 86 113 HR = 0.59 (95% CI: 0.44, 0.79), P = 0.00025 20 Docetaxel 10 1-yr OS rate = 24% 0 0 3 6 9 12 15 18 21 24 Time (months) Number of Patients at Risk Nivolumab Docetaxel Symbols represent censored observations 135 113 86 69 52 31 15 7 0 137 103 68 45 30 14 7 2 0 Spiegel et al, ASCO 2015

CHECKMATE 057: NON-SQUAMOUS NSCLC OVERALL SURVIVAL 100 90 80 70 Nivolumab (n = 292) Docetaxel (n = 290) mos, mo 12.2 9.4 HR = 0.73 (96% CI: 0.59, 0.89); P = 0.0015 60 OS (%) 50 40 30 1-yr OS rate = 39% 1-yr OS rate = 51% Nivolumab 20 Docetaxel Number of Patients at Risk Nivolumab 292 232 194 169 146 123 62 32 9 0 Docetaxel 10 0 0 3 6 9 12 15 18 21 24 Time (months) 290 244 194 150 111 88 34 10 5 0 27 Paz Ares et al, ASCO 2015

RECOGNITION OF I-O Eight New England Journal of Medicine Publications in 10 months A. Snyder, M.D., et al. November 19, 2014 S.M. Ansell, M.D., et al. December 6, 2014 J. Larkin, et al. May 31, 2015 C. Robert, M.D., Ph.D., et al. November 16, 2014 M.A. Postow, M.D., et al. April 20, 2015 Sagar Lonial, M.D., et al. June 2, 2015 J. Brahmer, M.D., et al. May 31, 2015 H. Borghaei M.D., et al. Sept 27 2015

CHECKMATE 025: NON-SQUAMOUS NSCLC OVERALL SURVIVAL Sharma et al, ESMO 2015 Overall Survival (Probability) 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 3 6 9 12 15 Everolimus Median OS, months (95% CI) Nivolumab 25.0 (21.8 NE) Everolimus 19.6 (17.6 23.1) HR (98.5% CI): 0.73 (0.57 0.93) P = 0.0018 Nivolumab 18 21 24 27 30 33 No. of patients at risk Months Nivolumab 410 389 359 337 305 275 213 139 73 29 3 0 Everolimus 411 366 324 287 265 241 187 115 61 20 2 0 Minimum follow-up was 14 months. 17

CHECKMATE 141: HEAD & NECK CARCINOMA OVERALL SURVIVAL Overall Survival (% of patients) 100 Median OS, mo (95% CI) Nivolumab (n = 240) 7.5 (5.5 9.1) Investigator s Choice (n = 121) 5.1 (4.0 6.0) HR (97.73% CI) 0.70 (0.51 0.96) 0 3 6 9 12 15 18 Months No. at Risk Nivolumab 240 167 109 52 24 7 0 Investigator s Choice 90 80 70 60 50 40 30 20 10 Gillison et al, AACR 2016 0 1-year OS rate (95% CI) 36.0% (28.5 43.4) 16.6% (8.6 26.8) 121 87 42 17 5 1 p-value 0.0101 0

SURVIVAL AS MAJOR BENEFIT Checkmate 066 Melanoma Checkmate 017 Sq-NSCLC Checkmate 057 nsq-nsclc Checkmate 025 RCC Checkmate 141 SCCHN PRIMARY ENDPOINT: OVERALL SURVIVAL Secondary Endpoint: PFS

CHECKMATE 026: NIVO VS CHEMO IN 1L NSCLC OVERALL SURVIVAL ( 5% PD-L1+) OS (%) Months Median OS, months (95% CI) Nivolumab n = 211 14.4 (11.7, 17.4) No. of patients at risk: Nivolumab 211 186 156 133 118 98 49 14 4 0 0 Chemotherapy 212 186 153 137 112 91 50 15 3 1 0 Socinsky et al, ESMO 2016 100 80 60 40 20 0 60.4% in the chemotherapy arm had subsequent nivolumab therapy 43.6% in the nivolumab arm had subsequent systemic therapy Chemotherapy n = 212 13.2 (10.7, 17.1) 1-year OS rate, % 56.3 53.6 HR = 1.02 (95% CI: 0.80, 1.30) Chemotherapy Nivolumab 0 3 6 9 12 15 18 21 24 27 30 All randomized patients ( 1% PD-L1+): HR = 1.07 (95% CI: 0.86, 1.33) 20

NEOADJUVANT NIVOLUMAB IN NSCLC EXPLORATORY ANALYSES OF RESPONSE TO TREATMENT Radiographic response (N=18) RECIST 1.1 N (%) Partial Response 4 (22) Stable Disease 13 (72) Progressive Disease 1 (6) Pathologic downstaging from pre-treatment clinical stage (N=18) N (%) Yes 7 (39) No 11 (61) Tumor pathologic response after neoadjuvant anti-pd-1 (N=17) Resected Tumors 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Major pathologic response Minor or no response 0 10 20 30 40 50 60 70 80 90 100 Percent Pathologic Response <10% residual viable tumor cells defines major pathologic response per Pataer et al. JTO 2012 39% (95% CI 20-61% ) of per protocol patients, 7 of 18, had <10% residual viable tumor at resection 1 patient had a pathologic complete response Forde et al, ESMO 2016

CA184-029: IPILIMUMAB IN ADJUVANT MELANOMA OVERALL SURVIVAL Patients Alive (%) 100 90 80 70 60 50 40 30 20 10 0 Ipilimumab Placebo Deaths/patients 162/475 214/476 HR (95.1% CI) a 0.72 (0.58, 0.88) Log-rank P value a 0.001 65% 54% 0 1 2 3 4 5 6 7 8 O N Number of patients at risk 162 475 431 369 325 290 199 62 4 214 476 413 348 297 273 178 58 8 a Stratified by stage provided at randomization. Years Ipilimumab Placebo Eggermoint et al, ESMO 2016

PIPELINE RATIONALE The immune system is built on homeostatic mechanisms which can turn it on and off as appropriate Tumors exploit normal homeostatic mechanisms of the immune system to protect themselves from immune attack Our strategy works to reset the balance in favor of the immune system, and to initiate new responses that counteract the tumor s protection

AT THE FOREFRONT OF SCIENCE EXPLORING A DIVERSITY OF MECHANISMS At Bristol-Myers Squibb, we have a vision for the future of cancer care that is focused on Immuno-Oncology (I-O). We will continue to build upon our past discoveries and advance our current research. Bristol-Myers Squibb remains inspired by the broad potential of I-O and driven by the many patients with advanced cancer with an unmet medical need. ^ Some of the pathways described are under investigation as part of a collaboration between Bristol-Myers Squibb and other companies. * Pathways are listed by primary mechanisms. Secondary mechanisms may exist. 24

AT THE FOREFRONT OF SCIENCE EXPLORING EFFECTOR T-CELL MECHANISM Broad Portfolio Effector T Cell Mechanisms Activating CD137 GITR OX40 Inhibitory CTLA4 PD1 Lag3 TIGIT *Targets are listed by primary mechanisms. Secondary mechanisms may exist.

CD137: POTENTIATES INNATE AND ADAPTIVE IMMUNITY* CD137, or 4-1BB, is an activating receptor found on both T cells and natural killer (NK) cells 17,18 The presence of CD137 appears to be a marker for tumor reactivity the ability to react to tumor antigen and mount an immune response 19 Based on preclinical data, activation of CD137 signaling can stimulate both cytotoxic T-cell and NK-cell activity and generate a lasting memory response 20,21 The CD137 pathway is currently under investigation in Phase I and Phase II trials for advanced solid tumors and hematologic malignancies EFFECTOR T CELL MECHANISMS: Activating Pathways 26

LAG-3: IMPLICATED IN BOTH T-CELL EXHAUSTION AND SUPPRESSION Lymphocyte-activation gene 3 (LAG-3) is an immune checkpoint receptor expressed on the surface of both activated cytotoxic T cells and regulatory T cells (Tregs) 43,44 The presence and activity of LAG-3 steadily increases with exposure to tumor antigen, leading to T-cell exhaustion. Tregs expressing LAG-3 also gather at tumor sites and show potent suppression of cytotoxic T cells 43,45-47 In preclinical studies, inactivation of LAG-3 allowed T cells to regain cytotoxic function 48 The LAG-3 pathway is under investigation in Phase I and Phase II trials for advanced solid tumors and hematologic malignancies EFFECTOR T CELL MECHANISMS: Inhibitory Pathways 27

AT THE FOREFRONT OF SCIENCE EXPLORING EFFECTOR NK-CELL MECHANISM Broad Portfolio NK Cell Mechanisms Activating SLAMF7 CD137 Inhibitory KIR *Targets are listed by primary mechanisms. Secondary mechanisms may exist.

KIR: REGULATES THE FIRST RESPONDERS OF IMMUNE DEFENSE NK CELL MECHANISMS: Inhibitory Pathways Killer cell immunoglobulin-like receptors (KIRs) are immune checkpoint receptors expressed on the surface of natural killer (NK) cells. Data suggest they may also be expressed on cytotoxic T cells 6,7 Inhibitory KIRs stop NK cells from killing normal cells, and tumor cells subvert this process to evade NK cell-mediated recognition and destruction 6,8 In preclinical studies, blockade of inhibitory KIRs has been shown to help restore NK cell-mediated immune activity 9,10 The KIR pathway is currently under investigation in Phase I trials for advanced solid tumors and hematologic malignancies 29

AT THE FOREFRONT OF SCIENCE EXPLORING TUMOR-CELL TARGET MECHANISM Broad Portfolio Tumor Cell Targeted Pathways BCR-ABL CXCR4 BET Fucosyl-GM1 HER2 Mesothelin Glypican-3 Tumor cells *Targets are listed by primary mechanisms. Secondary mechanisms may exist.

CXCR4: GUIDES TUMOR-CELL MIGRATION TUMOR CELL TARGETED PATHWAYS CXCR4 is a G-protein-coupled receptor in the CXC chemokine receptor family found on the surface of T cells and other immune cells. 104,105 Binding of CXCR4 to its ligand CXCL12 directs the migration and recruitment of immune cells 106,107 The CXCR4 pathway is one of the most common chemokine receptors expressed in cancer, where it plays a key role in tumor-cell proliferation, migration, metastasis, invasion, and survival 108-111 Preclinical data suggest that inhibition of the CXCR4 pathway promotes the accumulation of cytotoxic T cells and impairs tumor-cell migration 112 The CXCR4 pathway is currently under investigation in Phase I/II trials for advanced solid tumors 31

NEED TO THINK DIFFERENTLY More than 110 Phase III clinical studies: With 15 molecules and considering only combinations of 2 drugs Avoid patients are over or undertreated TRANSLATIONAL RESEARCH SHOULD BE MUCH MORE LINKED TO CLINICAL RESEARCH

FOLLOWING THE PATIENT JOURNEY WITH INNOVATIVE CLINICAL TRIAL DESIGN WITH THE FRACTION * PROGRAM Innovative and Efficient Trial Design I-O therapy naive Patients with advanced NSCLC PDL1+ PDL1- Nivolumab monotherapy Innovative design to efficiently evaluate I-O combos for delivery of transformational effects I-O therapy experienced Nivo + X Combo Nivo + Y Combo Ability to explore potential benefits across range of NSCLC patients Nivo + Z Combo New Nivo Combo Novel Combo X+Y Triple Combo New treatment options provided throughout the patients journey *Fast Real-time Assessment of Combination Therapy in Immuno-ONcology Program

CONCLUSIONS Immunocheckpoint targets led the way to select and develop effective therapies. Combination therapy studies are ongoing to increase the outstanding results to a broader population patients Research is running much faster than ever and «personalized medicine» is needed in order to speed the process, maximize the benefits and minimize the risks Innovation in protocol design is needed