The renaissance of immunotherapy is a revolution for cancer patients. Ira Mellman, Ph.D. Vice President, Cancer Immunology, Genentech

Transcription

1 The renaissance of immunotherapy is a revolution for cancer patients Ira Mellman, Ph.D. Vice President, Cancer Immunology, Genentech 1

2 This presentation contains certain forward-looking statements. These forward-looking statements may be identified by words such as believes, expects, anticipates, projects, intends, should, seeks, estimates, future or similar expressions or by discussion of, among other things, strategy, goals, plans or intentions. Various factors may cause actual results to differ materially in the future from those reflected in forward-looking statements contained in this presentation, among others: 1 pricing and product initiatives of competitors; 2 legislative and regulatory developments and economic conditions; 3 delay or inability in obtaining regulatory approvals or bringing products to market; 4 fluctuations in currency exchange rates and general financial market conditions; 5 uncertainties in the discovery, development or marketing of new products or new uses of existing products, including without limitation negative results of clinical trials or research projects, unexpected side-effects of pipeline or marketed products; 6 increased government pricing pressures; 7 interruptions in production; 8 loss of or inability to obtain adequate protection for intellectual property rights; 9 litigation; 10 loss of key executives or other employees; and 11 adverse publicity and news coverage. Any statements regarding earnings per share growth is not a profit forecast and should not be interpreted to mean that Roche s earnings or earnings per share for this year or any subsequent period will necessarily match or exceed the historical published earnings or earnings per share of Roche. For marketed products discussed in this presentation, please see full prescribing information on our website All mentioned trademarks are legally protected. 2

3 The renaissance of immunotherapy is a revolution for cancer patients

4 Early data suggests that anti-pd-l1/pd-1 is active across a wide range of tumor types Melanoma: FDA approval NSCLC (squamous): FDA approval, 2 nd line Renal cell carcinoma Breast cancer (e.g. TNBC) Metastatic bladder cancer Head & neck cancer Hodgkin's lymphoma Response rates are modest, at ~10-30% Broad activity but most patients do not benefit from single agent therapy

5 Using patient data to understand cancer immunity cycle MPDL3280A Phase 1 Data: Urothelial Bladder Cancer Patients Progressive Disease (PD) Why do many patients not respond? No pre-existing immunity? Stable disease (SD) What combinations will promote PRs & CRs? Insufficient T cell immunity? Multiple negative regulators? Monotherapy durable responses (PR/CR) What are the drivers of single agent response? How can PRs be enhanced to CRs? Insufficient T cell immunity? Multiple negative regulators?

6 The cancer immunity cycle Immunosuppression as the rate limiting step to effective anti-tumor immunity α-ctla4 (ipilumumab) Immunosuppression α-pd-l1/pd-1 (multiple) Chen & Mellman (2013) Immunity

7 Combinations of immunotherapeutics Increasing response rates by keeping cancer immunity cycle turning * = Genentech/Roche programs α-ctla4* α-ox40* α-cd27* α-cd137 α-gitr α-vegf-a* vaccines* α-cd40* α-pdl1*/pd1 α-lag-3 α-tigit* α-kir α-ox40* (Treg) α-ctla4* (Treg) α-csf1r* IDO inhibitor* Chen & Mellman (2013) Immunity

8 IDO (indoleamine di-oxygenase) Another suppressor of effector T cells Adaptive expression of PD-L1 Adaptive expression of IDO IDO IFNγ- mediated up- regulation of tumor PD- L1 IFNγ- mediated up- regulation of tumor IDO Inhibition of effector T cell function Shp-2 Shp-2 MAPK" PI3K pathways" MAPK" PI3K pathways" Georgia Hatzivassiliou, Yichin Liu

9 IDO mediates T cell suppression by reducing extracellular tryptophan and increasing kynurenine Dendritic cells Tumor cells Macrophages Free tryptophan high low IDO* IFNg activates IDO expression Kynurenine mtor ñ Uncharged Tryptophanol-tRNA arylhydrocarbon receptor Promote translation GCN2 kinase Stress response suppressive cytokines *TDO (tryptophan dioxygenase) is a second related target to IDO Suppress T effectors FoxP3 Enhance T reg

10 Early combination data shows promising efficacy Phase I/II study of INCB plus ipilimumab in melanoma Percent change in tumor burden Best percent change in tumor burden Gibney et al. ASCO 2014

11 TIGIT Model of TIGIT regulation of T cell responses 100nm CD226 ITAM Disrupts CD226 ac7va7on Tumor cell or DC PVR 2 ITIM 1 Competes with CD226 for PVR 1nm TIGIT ITIM 3 Directly inhibits T cell in cis Human and murine tumor-infiltrating CD8 + T cells express high levels of TIGIT Antibody coblockade of TIGIT and PDL1 elicits tumor rejection in preclinical models TIGIT selectively limits the effector function of chronically stimulated CD8 + T cells TIGIT interacts with CD226 in cis and disrupts CD226 homodimerization T cell

12 TIGIT TIGIT and PD-L1 combination effective in PD-L1 non-responsive model 100nm CD226 ITAM Disrupts CD226 ac7va7on Tumor cell or DC PVR 2 ITIM 1 T cell Competes with CD226 for PVR 1nm TIGIT ITIM 3 Directly inhibits T cell in cis Median Tumor Volume (mm 3 ) Median Tumor Volume (mm 3 ) Control anti-pd-l1 NME1 Control Control anti-pd-l1 Anti-PD-L1 NME1 TIGIT Complete Remission (CR) Day Anti-PD-L1 anti-pd-l1 + TIGIT + NME Day 1000 anti-pd-l1 + NME1 100 Complete Remission (CR) 10

13 OX40 function and potential in oncology Promote antigen dependent effector T cell activation and T regulatory cell inhibition OX40 engagement on T reg cells Primary Tumor Challenge (EMT6) Antigen Presenting Cell TCR OX40L OX40 Effector T cell IFN-γ OX40L OX40 T reg OX40L Tumor Volume (mm 3 ) Treatment day Control Anti-mouse OX40 Adapted from Nature Rev Immunol. 4:420 (2004).

14 Increase in Teff cells by anti-ox40 may create need to combine with anti-pdl1 anti-ox40 OX40L OX40 IFN-γ" T cell IFNγ PD-L1 increase PD-1 anti-pdl1 CD8 HLA PD-L1 Tumor cell Chen & Mellman (2013) Immunity Jul 25;39(1):1-10 T cell receptor

15 Anti-OX40 combined with anti-pdl1 in the MC38 model Tumor Volume (mm 3 ) !!!!!!!!!!!!!!!!!!!!!!!anti&OX40!!!!!!!!!!!!!!!!!!control! day Tumor Volume (mm 3 ) day anti%pd%l1* control* Jeong Kim et al. AACR 2015 Tumor Volume (mm 3 ) anti%ox40*+*anti%pd%l1* day PD-L1 Expression Tumor Myeloid Granulocyte CD4+T CD8+T

16 Combination with Avastin Increasing response rates by keeping cancer immunity cycle turning α-vegf-a Chen & Mellman (2013) Immunity

17 Increases in CD8+ T cell infiltration and vasculature changes with treatments in RCC Pretreatment Post Avastin Post Avastin + apd-l1 CD8 (T cells) CD31 (vasculature) Sznol et al. ASCO GU

18 Anti-PDL1 in combination with Avastin Anti-VEGF combination: preclinical data Combination of anti-pdl1 and Avastin (Ph1 data in renal cancer) Cloudman melanoma 2000 a-pd-l Control a-vegf Tumor Volume, mm a-pd-l1 + a-vegf Day Sznol et al. ASCO GU

19 Combinations with chemotherapy Induced inflammation & antigen release may enhance anti-pdl1 efficacy Chemotherapy Chen & Mellman (2013) Immunity

20 Inflammation is necessary for response Inflamed Can responses be improved? Non-inflamed Can we convert these to responsive? 20-30% patients T cells present in tumor Chemokines present (attract leukocytes) Tumor phenotype by T cell staining 70-80% patients Lack lymphocytic infiltrates Responsive to single agent immunotherapies Non-responsive to single agent immunotherapies 20

21 Combinations with chemotherapy extend the benefit of anti-pdl1 Pre-clinical data Tumor Volume, mm oxaliplatin Control α-pdl1 combo Platinum chemo increases number of CD8+ cells in animal models Compelling chemo+pd-l1 combination efficacy observed in phase 1 studies Broad phase 3 combination program initiated in 1L NSCLC and TNBC Day Dosing Phase 1 chemo combination data to be presented at ASCO 2015

22 Not all patients may have pre-existing immunity: monitoring & promoting T cell responses ImmTACs and bispecific antibodies Recognition of cancer cells by T cells (CTLs, cancer cells) ImmTACs Bispecifics 1 7

23 Recruiting T cells to cancer cells ImmTACs and bispecific antibodies Targeting intracellular tumor markers Targeting extracellular tumor markers Cancer cell Tumor antigen TCR Knob into holes full-length IgG T cell Immune-mobilizing mtcr Against Cancer* T-cell Dependent Bispecific *In colalboaration with Immunocore

24 Not all patients may have pre-existing immunity: monitoring & promoting T cell responses Vaccines Cancer antigen presentation (dendritic cells/apcs) 2 6 Vaccines: Endogenous Exogenous 1 7 Chen & Mellman (2013) Immunity

25 Anti-PDL1 Phase Ia: indication response rates correlate with mutation frequency Schumacher and Schreiber (2015) Science

26 Structural analysis suggests that only some mutations will be accessible to T cell receptors Immunogenic solvent-exposed mutation Non-immunogenic mutation in MHC groove A S N E N M E T M S S V I G V W Y L Pà A Rà M Dà Y REPS1! ADPGK! FLU-NP! AQLPNDVVL! ASMTNRELM! ASNENMETM! Copine-1! SSPDSLHYL! H60! SSVIGVWYL! Yadav et al (2014) Nature 26

27 Promise for a PHC vaccine? Immunization with antigenic peptides regresses growth of established MC38 tumors : mutated MHCI MC38 peptide vaccine; MC-38 Overlay Fits Tumor Volume Dose 01 untreated control Control Adj d1: anti CD40 50µg + pic 100µg, IP injection. d10: anti CD d1: anti CD40 50µg + pic 100µg + 3Xpeptide mix 100µg, IP Control Adj Adj+ Peptides Tumor Volume ( mm 3 ) : : mutated MHCI MC38 MC38 peptide peptide vaccine; vaccine; MC 38 MC-38 Raw and LME Fit Tumor Volume Raw and LME Fit Tumor Volume Adj+peptides Immunization Day Yadav et al (2014) Nature

28 Strategic vision: lead by developing best in class combination therapies Priming & activation anti-cea-il2v anti-ox40 anti-ctla4 3 anti-cd27* anti cytokine CD38* Chen & Mellman (2013) Immunity 2 Antigen presentation anti-cd40 IMA942 vaccine* oncolytic viruses* 1 Antigen release EGFRi ALKi BRAFi MEKi Chemo FGFR1* BTKi HDAC 4 Immunosuppression 7 T cell trafficking 6 T cell killing anti-ox40 anti-csf-1r anti-cea-il2v IDO inhibitor* TIGIT IDO1/TDO inhibitor* 5 T cell infiltration avegf Cancer T cell recognition anti-her2-cd3 anti-cd20-cd3 ImmTAC* Clinical development Combinations with immunotherapies acd40 Vaccines, Oncolytic Viruses actla-4 aox40 acd27 acea-il2v T Cell Bispecifics ImmTACs Planned IDOi acsf1r atigit Planned Cytokines, anti-cytokines Combinations with other agents avegf acd38 FGFR1 EGFRi ALKi BRAFi MEKi BTKi acd20 aher2 Chemo HDAC A2V Preclinical development * Partnered projects Planned Partnered external combo Internal combo

29 Doing now what patients need next