51 st ASCO Annual Meeting, Chicago. Roche Analyst Event. Sunday, 31 May 2015

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1 51 st ASCO Annual Meeting, Chicago Roche Analyst Event Sunday, 31 May 2015

2 Agenda Welcome Karl Mahler, Head of Investor Relations Oncology strategy and outlook Daniel O Day, Chief Operating Officer, Roche Pharmaceuticals Working along the cancer immunity-cycle: Strategies and new agents Ira Mellman, gred: Ph.D., Vice President, Cancer Immunology, Genentech William Pao, pred: M.D., Ph.D., Global Head Oncology Discovery and Translational Area, Roche ASCO 2015 Roche highlights: Setting new standards, developing combinations Sandra Horning, M.D., Chief Medical Officer and Head Global Product Development Growing importance of molecular information in cancer immunotherapy Garret Hampton, Ph.D., Vice President, Oncology Biomarker Development and Companion Diagnostics Summary and Q&A Karl Mahler, Head of Investor Relations 2

3 Oncology strategy and outlook Daniel O Day Chief Operating Officer, Roche Pharmaceuticals 3

4 Roche oncology: Continued sales growth A portfolio of differentiated medicines CHF m 24,000 22,000 20,000 18,000 16,000 14,000 12,000 10,000 8,000 6,000 4, medicines 16 tumor types 42 indications 2, Sales at 2014 average exchange rates 4

5 Oncology continues to become more complex Science, clinical practice evolving with understanding of disease biology Complexity Unknown >1 mutated gene 3% MEK1 <1% NRAS 1% MET 1% PIK3CA BRAF1% 2% HER2 3% EGFR (other) 4% No oncogenic driver detected 35% ALK 8% EGFR 17% KRAS 25% PD-L1 positive (illustrative) EGFR KRAS Today Pao & Girard. Lancet Oncol 2011; Johnson, et al. ASCO 2013 Classification of lung adenocarcinomas 5

6 Roche s oncology strategy has remained constant Today s presentations highlight the results of our strategy across key programs Follow the science Personalized healthcare Strong portfolio & development Bringing our best minds together Science driven programs Differentiation via biomarkers Experts integrated in R&D Comprehensive pipeline and active partnering Smart trial design Higher certainty of patient benefit: Better for patients and for reimbursement 6

7 Strategy in action - Immunotherapy Perspectives in key franchises Summary 7

8 Strategy into action: Learning loop Comprehensive and scientifically driven strategies crafted by our best minds Research (gred, pred, Chugai & external) Development (early and late) We bring our best scientists & clinicians together for: Partnering (Genentech and Roche) Immunotherapy & Combinations Clinical Insights & Biomarkers (internal and external) Ideation Decision making Quick & efficient pursuit of promising ideas...and we dedicate budget for rapid proof of concept studies (Ph1) 8

9 Atezolizumab (apd-l1, MPDL3280A) strategy Biomarker selection and combinations Our vision: Bringing the potential for transformative benefit to a broad patient population either in mono therapy or combinations Diagnostic selection to identify patients most likely to benefit from atezolizumab as a monotherapy Improve survival using well-tolerated combinations with existing and emerging therapies PD-L1+ (tumor infiltrating immune cells) PD-L1+ (tumor cells) 9

10 Atezolizumab in 2/3L NSCLC (POPLAR) Clinical outcomes correlate with PD-L1 expression ITT n=287 TC3 or IC3 16%* TC2/3 or IC2/3 37%* TC1/2/3 or IC1/2/3 67%* Overall Survival Progression Free Survival TC0 and IC0 32%* HR a HR a In favor of atezolizumab In favor of docetaxel In favor of atezolizumab In favor of docetaxel a = Unstratified HR; * = eligible patient population Spira A. et al, ASCO

11 Atezolizumab strategy: Combinations Scientifically driven strategy that combines with chemo, targeted therapy, and other immunotherapy pred gred Both Priming & activation T cell Trafficking Eliminate M2 Macrophages Anti-CSF-1R Costimulatory antibodies Anti-OX40 (agonist) Antigen presentation APC stimulators Anti-CD40 (agonist) Clinical phase molecules Chen & Mellman (2013) Immunity Antigen release T cell killing T cell infiltration T cell bispecifics Anti-CEA/CD3 TCB Cancer T cell recognition Checkpoint Inhibitors Anti-PD-L1, Anti-TIGIT, IDOi, Anti-OX40 Tumor-targeted cytokines Anti-CEA-IL2v FP Anti-FAP-IL2v FP 11

12 Atezolizumab strategy: Programs by disease Focused strategy: Going deep in diseases where we have strong scientific rationale 15 Roche / Genentech Phase 2 or 3 Studies LUNG 2L+ single-arm Ph2 (x2) 2L+ rand Ph2 and rand Ph3 1L single-agent Ph3 (x2) 1L w/chemo, Avastin Ph3 (x3) BLADDER 2L+ & 1L cis-inel single-arm Ph2 2L+ rand Ph3 Adjuvant Ph3 KIDNEY 1L w/avastin Ph2 1L w/avastin Ph3 BREAST 1L w/abraxane Ph3 12

13 Atezolizumab strategy: Summary Comprehensive, science-driven program Dx + Monotherapy Examples: mrcc (Ph II) mubc (Ph II) 2L mnsclc (Ph II BIRCH, POPLAR, FIR, Ph III OAK ) Dx+ 1L NSCLC (2x: Sq/NSq, Ph III) Dx+ mubc (Ph III) Strategic pillars of our PD-L1 development approach Dx+ Monotherapy Chemotherapy Combinations Combination with Chemotherapy Examples: 1L NSCLC Squamous and Non- Squamous with platinum doublets (x3, Ph III) 1L TNBC with Abraxane (Ph III) Immune Doublets Examples: Loc adv/ metastatic solid tumors with ipilimumab or Interferon alfa-2b (Ph Ib) Combination with anti-csf-1r (Ph Ib) Combination with anti-cd40 (Ph Ib) Combination with Incyte s IDOi (Ph Ib) Combination with anti-ox40 (Ph Ib) Combination with CEA-IL2v (Ph Ib) Combination with Celldex anti-cd27 Immune Doublets Targeted Therapy Combinations Combination with Targeted Therapy Examples: mrcc with Avastin (Ph II) mrcc with Avastin (Ph III) EGFR+ NSCLC w/tarceva (Ph Ib) ALK+ NSCLC w/alectinib (Ph Ib) Solid tumors with Avastin (Ph Ib) Solid tumors w/cobimetinib (Ph Ib) Lymphoma with Gazyva (Ph Ib) 13

14 Strategy in action - Immunotherapy Perspectives in key franchises Summary 14

15 Hematology strategy on track Strong pipeline and programs across key indications Compound Combination Indication P 1 P 2 P 3 Gazyva +chemo GREEN CLL Gazyva +chemo GOYA anhl Gazyva +chemo GADOLIN inhl Gazyva +chemo GALLIUM 1L FL Gazyva +apd-l1 R/R FL Gazyva +apd-l1 anhl venetoclax* +Rituxan MURANO R/R CLL Biosimilars delayed to 2017 * venetoclax in collaboration with AbbVie BR = bendamustine+rituxan venetoclax (Bcl2 inhibitor); polatuzumab vedotin (CD79b ADC) venetoclax +Gazyva CLL14 CLL venetoclax R/R CLL 17p venetoclax +Rituxan/+BR R/R FL venetoclax +Rituxan/Gazyva+chemo 1L anhl venetoclax +BR R/R NHL venetoclax +bortezomib+chemo R/R MM venetoclax +chemo AML polatuzumab +Rituxan/Gazyva ROMULUS NHL polatuzumab +Gazyva/BR polatuzumab +Gazyva/BR R/R FL anhl Data presented at ASCO 15

16 HER2 franchise outlook Complete portfolio of innovative drugs 2nd line mbc Xeloda + lapatinib Kadcyla (EMILIA) Biosimilar launch (EU) 1st line mbc Herceptin + chemo Herceptin & Perjeta + chemo (CLEOPATRA) Kadcyla & Perjeta (MARIANNE) Adjuvant BC Herceptin + chemo Herceptin sc + chemo (HannaH) Herceptin & Perjeta + chemo (APHINITY) Kadcyla (KATHERINE) Neoadjuvant BC Herceptin + chemo (NOAH) 1 Herceptin & Perjeta + chemo (Neosphere, Tryphaena) Kadcyla & Perjeta (KRISTINE) Kadcyla & Perjeta (KAITLIN) Established standard of care New standard of care Trials in progress 16

17 HER2 franchise: Perjeta commercial uptake strong CHFm Perjeta US Neoadj Approval Perjeta Cleopatra OS Readout NEOSPHERE OS Data at this ASCO 2,200 Kadcyla 2,000 Perjeta Herceptin 1,800 1,600 0 Q3 Q4 Q1 Q2 Q3 Q4 Q Next Milestone: ebc readout (APHINITY) in

18 Avastin franchise Continues to be the most studied molecule at ASCO Continued growth fueled by recent launches in cervical, ovarian cancers CHFm 7,000 6,000 5,000 4,000 3,000 2,000 1, Avastin Mesothelioma data presented at ASCO 2015 Sales at 2014 average exchange rates 18

19 Strategy in action - Immunotherapy Perspectives in key franchises Summary 19

20 ASCO 2015: Roche highlights More than 275 abstracts, Avastin most quoted drug Potential improvements on current standard of care: Cobimetinib / Zelboraf in 1L skin cancer (targeted therapies) Alectinib in 2L ALK mutated lung cancer New treatment options: Atezolizumab in 2L lung cancer (vs chemo) Atezolizumab combinations with chemo in lung and TNBC Avastin in mesothelioma Gazyva in R/R indolent NHL Several filings resulting from data presented at the meeting Collaborations: Zelboraf with Plexxikon; Cobimetinib iwith Exelixis; Alectinib with Chugai, Gazyva with Biogen Idec; Kadcyla with ImmunoGen 20

21 Roche s oncology strategy has remained constant Today s presentations highlight the results of our strategy across key programs Follow the science Personalized healthcare Strong portfolio & development Bringing our best minds together Science driven programs Differentiation via biomarkers Experts integrated in R&D Comprehensive pipeline and active partnering Smart trial design Higher certainty of patient benefit: Better for patients and for reimbursement 21

22 Working along the cancer immunity-cycle: Strategies and new agents I Ira Mellman Vice President, Cancer Immunology, Genentech 22

23 The renaissance of immunotherapy is a revolution for cancer patients 23

24 Early data suggests that anti-pd-l1/pd-1 is active across a wide range of tumor types Renal cancer Lung cancer Bladder cancer Breast cancer Head & Neck cancer Melanoma Broad activity but only subset of patients benefit ORR ~10-30% Hodgkin s lymphoma Most patients will need biomarker selection and combination therapy: Strategy now supported by clinical results

25 Using patient data to understand cancer immunity-cycle Atezolizumab Phase 1 data: Urothelial bladder cancer patients Change in sum of longest diameters (SLD) from baseline (%) Time on study (days) Complete response Partial response Stable disease Progressive disease 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? Powles et al., Nature 2014

26 Combinations of immunotherapeutics Increasing response rates & benefit by keeping cancer immunity-cycle turning 4 Trafficking of T cells to tumors (CTLs) Priming and activation (APCs & T cells) 3 Avastin Anti-OX40 Anti-CD27* Anti-CTLA4* 5 Infiltration of T cells into tumors (CTLs, endothelial cells) T cell bispecifics ImmTacs Cancer antigen presentation (dendritic cells/apcs) 2 6 Recognition of cancer cells by T cells (CTLs, cancer cells) vaccines Anti-CD40 Anti-PD-L1/PD-1 Anti-TIGIT Anti-OX40 (Treg) Anti-CSF-1R IDO inhibitor Anti-CEA-IL2v Genentech/Roche programs *Partnered programs Chen & Mellman (2013) Immunity Release of 1 cancer cell antigens (Immune and cancer cells) 7 Killing of cancer cells (Immune and cancer cells) 26

27 IDO (indoleamine di-oxygenase) A suppressor of effector T cells Adaptive expression of PD-L1 Adaptive expression of IDO IDO IFNg-mediated up-regulation of tumor PD-L1 IFNg-mediated up-regulation of tumor IDO Kynurenine Tryptophan Shp-2 Shp-2 MAPK" PI3K pathways" MAPK" PI3K pathways" T cell suppression

28 Pre-clinical data shows promising activity for IDO inhibition (GDC-0919) Plasma kynurenine decrease T regulatory cells decrease T effector cells show increased proliferation & CTL function Enhanced anti-tumor efficacy with anti-pd-l1 and anti CTLA4 Tumor volume (mm 3 ) Anti-PD-L1 control 20 Day IDOi Anti-PD-L1 + IDOi Ongoing studies Phase 1a (GDC-0919) Phase 1b combination (GDC atezolizumab) Phase 1b combination (INCB atezolizumab) GDC-0919 in collaboration with NewLink; INCB in collaboration with Incyte 28

29 TIGIT A second potent negative regulator of T cell responses Tumor cell or DC Human and murine tumor-infiltrating CD8 + T cells express high levels of TIGIT PVR 100nm CD226 ITAM 2 ITIM 1 1nm TIGIT ITIM 3 Antibody co-blockade of TIGIT and PD-L1 elicits tumor rejection in preclinical models TIGIT selectively limits the effector function of chronically stimulated CD8 + T cells T cell TIGIT interacts with CD226 in cis and disrupts CD226 homodimerization Competes with CD226 for PVR Disrupts CD226 activation Directly inhibits T cells in cis TIGIT=T cell immunoreceptor with Ig and ITIM domains 29

30 TIGIT atigit and apd-l1 combination effective in PD-L1 non-responsive model Tumor cell or DC nm CD226 ITAM 2 PVR ITIM T cell 1 1nm TIGIT ITIM 3 Median tumor volume (mm 3 ) Control Anti-PD-L1 TIGIT Complete remission (CR) Anti-PD-L1 + TIGIT Competes with CD226 for PVR Disrupts CD226 activation Directly inhibits T cells in cis Day 30

31 Elevated expression of TIGIT by T cells in human cancer supports combination with atezolizumab Lung squamous cell carcinoma CD3ε Tumor Normal ρ=0.82 TIGIT/CD3ε ratio TIGIT Johnson et al (2014) Cancer Cell 31

32 OX40 exhibits a dual mechanism of action Promote antigen dependent effector T cell activation and T regulatory cell inhibition Primary Tumor Challenge (EMT6) Antigen Presenting Cell TCR OX40L OX40 engagement on T reg cells OX40L OX40 T reg OX40L Tumor volume (mm 3 ) Control Anti-mouse OX40 OX40 Effector T cell IFN-γ Day Adapted from Nature Rev Immunol. 4:420 (2004) 32

33 Increase in T effector cells by aox40 may create need to combine with apd-l1 anti-ox40 OX40L OX40 IFN-γ" T cell IFNγ PD-L1 increase PD-1 anti-pd-l1 (or IDOi) CD8 T cell receptor HLA PD-L1 Tumor cell

34 Promising pre-clinical efficacy of an aox40/apd-l1 combination model Tumor Volume (mm 3 ) Tumor volume (mm 3 ) !!!!!!!!!!!!!!!!!!!!!!!anti&OX40! anti-ox40!!!!!!!!!!!!!!!!!control! Day day Tumor Volume (mm 3 ) Tumor volume (mm 3 ) Day day anti%pd%l1* anti-pd-l1 control* Tumor Volume (mm 3 ) Tumor volume (mm 3 ) anti%ox40*+*anti%pd%l1* anti-ox40 + anti-pd-l Day day Jeong Kim et al. AACR 2015 Ongoing studies Phase 1a (MOXR0916) Phase 1b combination (MOXR atezolizumab) Planned (MOXR GDC-0919) MOXR0916 = anti-ox40

35 Combinations with chemotherapy Induced inflammation & antigen release may enhance atezolizumab efficacy 4 Trafficking of T cells to tumors (CTLs) Priming and activation (APCs & T cells) 3 5 Infiltration of T cells into tumors (CTLs, endothelial cells) Cancer antigen presentation (dendritic cells/apcs) 2 6 Recognition of cancer cells by T cells (CTLs, cancer cells) Chemotherapy Vaccines Chen & Mellman (2013) Immunity Release of 1 cancer cell antigens (Immune and cancer cells) 7 Killing of cancer cells (Immune and cancer cells) 35

36 Combinations may extend the benefit of apd-l1 Preclinical synergy with selected chemo and targeted therapies Oxaliplatin chemotherapy MEKi targeted therapy 3000 Oxaliplatin 2500 CT O CT26 (Kras mut ) 2500 Control apd-l Control MEKi apd-l1 Tumor volume, mm 3 Tumor Volume, mm Tumor volume, mm 3 Tumor Volume (mm3) combo 500 apd-l1/ MEKi Day Dosing Dosing control Day GDC-0973 (7.5mg/kg) apdl1 GDC-0973 (3mg/kg) + apdl1

37 Combinations with chemotherapy appear to extend the benefit of atezolizumab in NSCLC patients Change in Sum of Largest Diameters from Baseline (%) Atezolizumab + carboplatin/paclitaxel CR/PR (n=3) SD (n=2) PD (n=0) Atezolizumab + carboplatin/ pemetrexed CR/PR (n=9) SD (n=1) PD (n=1) Atezolizumab + carboplatin/nab-paclitaxel CR/PR (n=8) SD (n=4) PD (n=1) Time on study (days) Chemotherapy can promote Th1-type inflammation in tumors Liu et al. ASCO 2015

38 Strategic vision: Lead by developing best-in-class combination therapies Priming & activation anti-cea-il2v anti-fap-il2v anti-ox40 anti-ctla4* anti-cd27* anti-cytokine 2 Antigen presentation anti-cd40 IMA942 vaccine* oncolytic viruses* neo-epitope vaccine 3 1 Antigen release Pro-inflammatory EGFRi ALKi BRAFi MEKi Chemo BTKi HDAC 4 Immunosuppression 7 T cell trafficking Cancer cell killing atezolizumab anti-ox40 anti-csf-1r IDOi* anti-tigit IDO/TDO TDO 6 5 T cell infiltration anti-vegf anti-ang2/vegf Cancer cell recognition anti-cea/cd3 TCB anti-cea-il2v FP anti-her2/cd3 anti-cd20/cd3 anti-fap-il2v FP ImmTAC* Clinical development Preclinical development * Partnered projects Combinations with immunotherapies acd40 Vaccines, Oncolytic Viruses actla4 aox40 acd27 acea/fap-il2v T Cell Bispecifics ImmTACs Planned IDOi acsf1r atigit Planned Cytokines, anti-cytokines Combinations with other agents avegf EGFRi ALKi BRAFi MEKi BTKi acd20 aher2 Chemo HDAC A2V Partnered external combo Internal combo Planned

39 Working along the cancer immunity-cycle: Strategies and new agents II William Pao, M.D., Ph.D. Global Head Oncology Discovery and Translational Area, Roche pred 39

40 Cancer immunotherapy at pred Distinct MoAs with potential for combinations Macrophage acsf-1r acea-il2v FP acea/cd3 TCB acd40 First antibody shown to eliminate tumorassociated macrophages Designed to amplify immune response First anti-tumor T-cell engager from Roche to enter clinical trials Best/first in class immuno-activating Ab Proof of biological activity established in rare disease (PVNS) Novel recombinant immunocytokine with superior safety, PK, and tumor targeting Best-in-class TCB platform Activates antigen presenting cells to jumpstart adaptive immunity 40

41 Tumor-associated macrophages A promising new target in oncology 41

42 Emactuzumab (acsf-1r) Proof of biological activity shown in PVNS* Clinical benefit Patients % Emactuzumab Phase I data: PVNS Each color represents a patient Objective response 24/28 86 Complete response 2/28 7 Partial metabolic response Clinically progression-free 24/ /28 96 Change in sum of longest diameters from baseline % Time from baseline (days) *PVNS - pigmented villonodular synovitis, emactuzumab = anti-csf-1r (RG7155) CSF1R Inhibition with Emactuzumab in Locally Advanced Diffuse-type Tenosynovial Giant Cell Tumors of the soft tissue: a phase 1, dose escalation and expansion study, Cassier P. et al. (2015), Lancet Oncology, in press 42

43 Oral presentation on Mon 1 Jun; abstract #3005 Emactuzumab: Elimination of tumor-associated macrophages in solid tumors phase I data Depletion of CSF-1 dependent macrophages in solid tumors Macrophages suppress T cell proliferation in vitro % Change from baseline macrophage coverage (IHC) RG7155 plus Paclitaxel RG7155 monotherapy Proof of biological activity in wide range of tumor types Potentially synergistic with atezolizumab Phase I combination study: dose escalation with atezolizumab ongoing No severe immune-related AE reported to date Multiple extensions to start Q atezolizumab = anti-pd-l1 (MPDL3280A) Gomez-Roca, CA: Phase I study of RG7155, a novel anti-csf1r antibody, in patients with advanced/metastatic solid tumors, 2015 ASCO 43

44 Tumor targeted IL2v cytokine fusion proteins A platform to amplify and activate immune effectors in tumors Mechanism of Action Binds to target to deliver novel variant of IL-2 to the tumor Recruits killer T and Natural Killer (NK) cells to the tumor Features IL-2v Compared to standard IL-2-based therapy, it shows: Superior expansion of immune effectors Less activation of suppressive T-cells Better tolerability Better tumor targeting IL2v interleukin-2 variant Novel tumor-targeted, engineered IL-2 variant (IL-2v)-based immunocytokines for immunotherapy of cancer: Christian Klein et al., ASH, 2013, Blood 122 (21),

45 Oral poster presentation on Saturday 30 May; abstract # 3016* acea-il2v phase I data Tumor targeting and intra-tumoral T cell activation CEA-IL2v tumor accumulation shown in 4/4 patients with CEA+ tumors Baseline C1D2 C1D5 CEA +ve NSCLC CRC FDG-PET/CT 89 Zr-CEA-IL2v-PET/CT Increased CD8 densities and CD8:CD4 ratio confirm intra-tumoral immune activation at doses 20 mg CD8 density (cells/mm 2 ) CD8:CD4 Ratio baseline (BL) 4d p.1. CEA-IL2v dose baseline (BL) 4d p.1. CEA-IL2v dose acea-il2v is an ideal combination partner for atezolizumab: Phase I combination starting CEA - carcinoembryonic antigen; *Quantitative data from 2 CEA-ve patients pending, no tumor uptake on visual assessment *Schellens, Jan H. M. et al., CEA- targeted engineered IL2: Clinical confirmation of tumor targeting and evidence of intra tumoral immune activation; 2015 ASCO 45

46 afap-il2v: A complementary approach targeting tumor stroma FAP staining Parameter CEA-IL2v FAP-IL2v Target cell Target expression Cancer cells (CEA) Target density Medium Indications Tumor stromal cells (FAP) Heterogeneous Homogeneous Mainly GI indications: GC, PaC, CRC High Very broadly expressed: High expression in e.g. H&N, sq NSCLC, BC FAP-IL2v phase I start: planned in 2015 FAP fibroblast-activation protein 46

47 T cell engaging therapies in development CAR T cells versus T cell bispecific antibodies Engineered T cells (CARS) T cell engaging bispecific antibodies BITE 1:1 format 2:1 format ü High interest, outstanding clinical efficacy with CD19 CARs in hematology û Activity associated with high toxicity û Challenging manufacturing and regulatory processes Potency ü ü ü ü ü ü ü Long half-life û ü ü ü ü ü ü Differentiation of high vs low antigen expressing cells ü ü ü ü ü 47

48 CEA-TCB: First 2:1 T cell bispecific in the clinic Targets CEA-expressing tumors to induce localized T cell-mediated killing High avidity binding to tumor antigen Mechanism of Action Binds T cells and tumor cells simultaneously Results in T cell activation/proliferation and killing of tumor cells Does not require MHC:peptide complex presentation by tumor cells T cell engagement independent of specificity and activation status CD3e T cell engagement Low affinity Inert, engineered Fc region Features Entry into human study started in Dec 2014 Combination with IL2v & PD-L1 planned early in clinical development Broad, early pipeline of several TCBs addressing solid & hematological malignancies 48

49 CEA-TCB: Novel mode of action From poorly inflamed to highly inflamed tumors Control CEA-CD3 Intravital two-photon imaging 24 h after CEA-CD3 therapy. Red: Tumor cells (LS174T RFP). Green: Human T cells Recruits new T cells and/or expands pre-existing ones Induces T cell re-localization from tumor periphery to tumor bed Activates intra-tumor T cells to become differentiated towards effector memory phenotype Bacac M. et al., submitted 49

50 Roche cancer immunotherapy pipeline Abundant opportunities for combinations pred gred Both Priming & activation T cell Trafficking Eliminate M2 Macrophages Anti-CSF-1R Costimulatory antibodies Anti-OX40 (agonist) Antigen presentation APC stimulators Anti-CD40 (agonist) Clinical phase molecules Antigen release T cell killing T cell infiltration T cell bispecifics Anti-CEA/CD3 TCB Cancer T cell recognition Checkpoint Inhibitors Anti-PD-L1, Anti-TIGIT, IDOi, Anti-OX40 Tumor-targeted cytokines Anti-CEA-IL2v FP Anti-FAP-IL2v FP Chen & Mellman (2013) Immunity 50

51 Cancer immunotherapy program growing strongly Compound Combination Indication Phase 1 Phase 2 Phase 3 apd-l1 Mono +Tarceva +chemo +Avastin+chemo Lung cancer apd-l1 Mono Bladder cancer apd-l1 apd-l1 Mono +Avastin +Zelboraf +Zelboraf+cobimetinib Renal cancer Melanoma apd-l1 Mono +Avastin +cobimetinib +ipilimumab +IFN alfa-2b +acd40 +aox40 +acsf-1r +acea-il2v FP Solid tumors apd-l1 +Avastin+FOLFOX Colorectal cancer apd-l1 apd-l1 acsf-1r Mono +Gazyva Mono +chemo Mono +acd40 Hematology Triple neg. breast cancer Solid tumors acea-il2v FP Mono Solid tumors afap-il2v FP Mono Solid tumors aox40 Mono Solid tumors acea/cd3 TCB Mono Solid tumors IDO Mono Solid tumors IDO (Incyte)* +apd-l1 Solid tumors Varlilumab (Celldex)* +apd-l1 Solid tumors Study ongoing Study imminent * External collaboration 51

52 ASCO 2015 Roche highlights: Setting new standards, developing combinations Sandra Horning, M.D. Chief Medical Officer and Head Global Product Development 52

53 Agenda Setting new standards, developing combinations Cancer immunotherapy Roche program update Atezolizumab in lung cancer Atezolizumab in bladder cancer Targeted therapies and combinations Alectinib in ALK-positive lung cancer Cobimetinib + Zelboraf in melanoma Kadcyla, Perjeta, Herceptin in HER2+ breast cancer Hematology Gazyva in NHL 53

54 Roche cancer immunotherapy program apd-l1 Solid tumors apd-l1+chemo Solid tumors apd-l1+lenalidomide** MM apd-l1+tarceva NSCLC apd-l1+zelboraf Melanoma apd-l1+cobimetinib Solid tumors apd-l1+avastin Solid tumors apd-l1 + Gazyva R/R FL / anhl apd-l1+avastin+chemo Solid tumors apd-l1+zelboraf+cobi** Melanoma acsf-1r Solid tumors acea-il2v FP Solid tumors aox40 Solid tumors acea/cd3 TCB Solid tumors Status as at May 31, 2015 Phase I ü ü ü ü ü IDO Solid tumors apd-l1+ipilimumab Solid tumors apd-l1+ifn-alfa Solid tumors apd-l1+acd40 Solid tumors apd-l1+aox40** Solid tumors apd-l1+acsf-1r** Solid tumors apd-l1+acea-il2v FP** Solid tumors apd-l1** tba apd-l1** tba apd-l1** tba apd-l1** tba apd-l1** tba NME** tba ** Phase II apd-l1 NSCLC (Dx+) apd-l1 2/3L NSCLC apd-l1+avastin 1L Renal apd-l1 1/2L Bladder apd-l1 trials NMEs monotherapy Immune doublets 2015 readout expected Study start in 2015 ü Data at ASCO 2015 ü ü Phase III apd-l1 2/3L NSCLC apd-l1** 2/3L Bladder apd-l1+avastin+chemo** 1L non sq NSCLC apd-l1+chemo** 1L non sq NSCLC apd-l1+chemo** 1L sq NSCLC apd-l1** 1L non sq NSCLC (Dx+) apd-l1** 1L sq NSCLC (Dx+) apd-l1+chemo** 1L TNBC apd-l1+avastin** 1L RCC apd-l1** Adjuvant MIBC (Dx+) apd-l1** tba 54

55 Biomarker development for atezolizumab PD-L1 expression on different cell types PD-L1 expression on immune cells (IC) and tumor cells (TC) IC Score PD-L1 staining TC Score PD-L1 staining IC3 IC 10% TC3 TC 50% IC2 IC 5% and < 10% TC2 TC 5% and < 50% IC1 IC 1% and < 5% TC1 TC 1% and < 5% IC0 IC < 1% TC0 TC < 1% Assessed by immunohistochemistry using SP142, a sensitive and specific proprietary monoclonal antibody assay against PD-L1 Immune cell staining Tumor cell staining Gettinger S. et al, ASCO

56 Atezolizumab clinical program in 2/3L NSCLC Breakthrough designation in PD-L1+ patients Primary end-point: FIR Phase II PD-L1-selected mnsclc n=138 atezolizumab 1200 mg IV Q3 weeks ORR Data at ASCO POPLAR Phase II All comers 2/3L mnsclc n=287 PD-L1 stratified atezolizumab 1200 mg IV Q3 weeks docetaxel OS Interim data at ASCO Final data in H mg/m2 IV Q3 weeks BIRCH Phase II PD-L1-selected mnsclc n=667 atezolizumab 1200 mg IV Q3 weeks ORR Data in Q OAK Phase III atezolizumab All comers 2/3L mnsclc n=1100 PD-L1 stratified 1200 mg IV Q3 weeks docetaxel OS Data expected mg/m2 IV Q3 weeks Note: Atezolizumab (Anti-PD-L1) is listed as MPDL3280A in clinicaltrials.gov mnsclc = metastatic Non Small-Cell Lung Cancer 56

57 Atezolizumab in 2/3L NSCLC (POPLAR) Clinical outcomes correlate with PD-L1 expression ITT n=287 TC3 or IC3 16%* TC2/3 or IC2/3 37%* TC1/2/3 or IC1/2/3 67%* Overall survival Progression-free survival TC0 and IC0 32%* HR a HR a In favor of atezolizumab In favor of docetaxel In favor of atezolizumab In favor of docetaxel a = unstratified HR; * = eligible patient population Spira A. et al, ASCO

58 Atezolizumab in 2/3L NSCLC (POPLAR) Overall survival correlates with PD-L1 expression TC1/2/3 or IC1/2/3 TC0 or IC0 Not Reached (11.0, NE) 9.1 mo (7.4, 12.8) 9.7 mo (6.7, 11.4) 9.7 mo (8.6, 12.0) Final POPLAR and BIRCH read-outs in H2 15 Phase III (OAK) in all comers (stratified by PD-L1 expression): Data in 2016 a = Unstratified HR Spira A. et al, ASCO

59 Atezolizumab + chemotherapy in 1L NSCLC (Ph1) Well tolerated with no unexpected toxicities 4-6 cycles maintenance C atezolizumab 15mg/kg IV q3w+ carboplatin q3w + paclitaxel q3w atezolizumab Treat to PD or loss of clinical benefit 1L NSCLC n=37 D atezolizumab 15mg/kg IV q3w+ carboplatin q3w + pemetrexed q3w atezolizumab +/- pemetrexed Treat to PD or loss of clinical benefit E atezolizumab 15mg/kg IV q3w+ carboplatin q3w + nab-paclitaxel q1w atezolizumab Treat to PD or loss of clinical benefit The addition of atezolizumab to standard 1L chemotherapy was well tolerated throughout the course of treatment, including maintenance therapy, with no unexpected toxicities No autoimmune renal toxicity or pneumonitis was observed Liu S. et al, ASCO

60 Atezolizumab + chemotherapy in 1L NSCLC (Ph1) Efficacy unrelated to PD-L1 expression Arm C, n=5 Arm D, n=12 Arm E, n=13 atezolizumab + carboplatin/paclitaxel atezolizumab + carboplatin/pemetrexed atezolizumab + carboplatin/nab-paclitaxel ORR (95% CI) 60% (19-92) 75% (45-93) 62% (33-83) Change in Sum of Largest Diameters from Baseline (%) CR/PR (n=3) SD (n=2) PD (n=0) CR/PR (n=9) SD (n=1) PD (n=1) CR/PR (n=8) SD (n=4) PD (n=1) Time on study (days) ORR across all arms = 67% (48-82) CR = complete response; PR = partial response; SD = stable disease; PD = progressive disease Liu S. et al, ASCO

61 Atezolizumab phase III program in 1L NSCLC Developing combinations, building on predictive PD-L1 biomarker Study Indication Treatment arms Combination studies All comers (PD-L1 subgroup analysis) Primary completion* GO29436 n=1200 Non-squamous Atezo + Carbo + Pac Atezo + Carbo + Pac + Avastin Carbo + Pac + Avastin 2017 (PFS) GO29537 n=550 Non-squamous Atezo + Carbo + Nab-pac Carbo + Nab-pac 2017 (PFS) GO29437 n=1200 Squamous Atezo + Carbo + Pac Atezo + Carbo + Nab-pac Carbo + Nab-pac 2017 (PFS) Monotherapy studies PD-L1 Selected GO29431 n=400 Non-squamous Atezo Cis or Carbo + Pem 2017 (PFS) GO29432 n=400 Squamous Atezo Cis or Carbo + Gem 2017 (PFS) * Outcome studies are event driven, timelines may change, OS endpoint included for all studies Atezo=atezolizumab; Carbo=Carboplatin; Pac=Paclitaxel; Nab-pac= Nab-paclitaxel; Cis=Cisplatin; Pem=Pemetrexed; Gem=Gemcitabine Note: Atezolizumab (Anti-PD-L1) is listed as MPDL3280A in clinicaltrials.gov ` 61

62 Atezolizumab in 2L UBC (Ph1) ORR correlates with PD-L1 expression Atezolizumab responses by PD-L1 biomarker status PD-L1 IHC n=87 ORR, % (95% CI) IC3 (n=12) 67% (35, 90) IC2 (n=34) 44% (27, 62) 50% (35, 65) IC3 IC2 IC1 IC0 IC1 (n=26) 19% (7, 39) IC0 (n=15) 13% (2, 40) 17% (7, 32) Response rates correlate with PD-L1 status; 20% CR in IHC2/3 Responses observed with visceral metastases: 38% RR in IHC2/3 Well tolerated with 5% Gr3/4 immune-related adverse events UBC = urothelial bladder Cancer; IC = immune cells; ORR = overall response rate Petrylak D. et al, ASCO

63 Atezolizumab in 2L UBC (Ph1) Survival correlates with PD-L1 expression Overall survival Survival a N = 92 IC2/3 n = 48 IC0/1 n = 44 Not Reached (95% CI, 9.0-NE) OS Median OS (range) 1-y survival (95% CI) Not reached (1 to 20+ mo) 57% (41-73) 8 mo (1 to 15+ mo) 38% (19-56) IC2/3 IC0/1 7.6 mo (95% CI, 4.7-NE) PD-L1 is a predictive biomarker for ORR, PFS and OS in 2L bladder cancer Phase II study (NCT ) in 1/2L bladder: Read-out H Phase III studies in 2/3L bladder and high risk muscle invasive bladder after cystectomy (adjuvant) started in 2015 Petrylak D. et al, ASCO

64 Agenda Setting new standards, developing combinations Cancer immunotherapy Roche program update Atezolizumab in lung cancer Atezolizumab in bladder cancer Targeted therapies and combinations Alectinib in ALK-positive lung cancer Cobimetinib + Zelboraf in melanoma Kadcyla, Perjeta, Herceptin in HER2+ breast cancer Hematology Gazyva in NHL 64

65 Alectinib in ALK+ NSCLC after crizotinib failure Strong efficacy in two phase 2 studies Results from P2 US and Global Studies Overall and CNS Response Rates 46% All (n=87) 69% 13% Measurable CNS disease (n=16) 50% All (n=122) 57% 20% Measurable CNS disease (n=16) ORR CR All (n=69) Alectinib, next generation, brain penetrant ALK inhibitor Two P2 studies (global and US) show high systemic and CNS response rates in crizotinib-failed patients Median PFS: 8.9m & 6.3m (global & US study, respectively) Good tolerability with minimal dose modifications Final duration of response and PFS results expected in H US Study Global Study Ou S-H. et al, ASCO 2015; Gandhi L. et al, ASCO

66 Alectinib in ALK+ NSCLC after crizotinib failure Excellent CNS disease control Measureable CNS responses in global study Day 6 Day 87 Both global and US studies show high ORR (57-69%) in measureable CNS disease; disease control rates % Median duration of response in measureable CNS disease was 10.3 months in the global study Filing planned 2015 Global phase III study in 1L ALK+ NSCLC (Alex) on-going: alectinib vs crizotinib Ou S-H. et al, ASCO 2015; Gandhi L. et al, ASCO

67 Cobimetinib+Zelboraf in Melanoma (cobrim) Update confirms benefit in BRAF V600 + patients Orphan disease designation Progression free survival HR = 0.58 ( ) Zelboraf + Cobimetinib (n = 247) Zelboraf + Placebo (n = 248) % ORR % CR Median PFS Median DoR in months m 12.3m Median PFS of ~1 year in Cobimetinib + Zelboraf arm with longer follow-up (14.2 m) OS data not yet mature Filed in US and EU ORR = overall response rate; CR = complete response; PR = partial response; DoR = duration of response Larkin J. et al, ASCO

68 Cobimetinib+Zelboraf in Melanoma (BRIM7) Phase I update shows strong efficacy Overall survival BRAF inhibitor naive (n=63) Zelboraf- Progressors (n=66) Zelboraf Progressors (N=66) ORR% CR% mpfs (m) mos (m) yr OS% yr OS% Vem prog Naive Time (months) Two-year survival rate demonstrates benefit of cobimetinib + Zelboraf Projected 28.5 m median OS compares to historical 13.6 m with Zelboraf alone Results show importance of combination vs sequential use of targeted therapy in melanoma CR = complete response; PR = partial response; SD = stable disease; PD = progressive disease Pavlick A. et al, ASCO

69 Kadcyla + Perjeta in 1L HER2+ mbc (MARIANNE) Non-inferior PFS for Kadcyla or Kadcyla + Perjeta Median PFS (m) HR vs H+T HR vs K Previously untreated HER2+mBC n=1092 1:1:1 Herceptin + docetaxel (H+T) (8 mg/kg LD then 6 mg/kg or 75 mg/m2 q3w) OR Herceptin + paclitaxel (H+T) (4 mg/kg LD then 2 mg/kg + 80 mg/m2 qw) Kadcyla + placebo (K) (3.6mg/kg mg LD then 420 mg q3w) Kadcyla + Perjeta (K+P) (3.6mg/kg mg LD then 420 mg q3w) p= p= K and K + P achieved non-inferiority but not superiority to H + T Addition of Perjeta to Kadcyla did not improve PFS Kadcyla was better tolerated and maintained health-related quality of life for a longer duration Ellis P. et al, ASCO

70 Perjeta + Herceptin in HER2+ ebc (NEOSPHERE) 5yr follow-up shows lasting benefit in neoadjuvant setting neoadjuvant Herceptin+docetaxel (H+T) n=107 Perjeta+Herceptin+docetaxel (P+H +T) n=107 Perjeta+Herceptin n=107 S U R G E R Y pcr adjuvant FEC q3 w x 3* + Herceptin PFS, DFS P + H + T (n=107) H + T (n=107) Events PFS year PFS 86% 81% HR 0.69 ( ) Events DFS 15 (14.9%) 18 (17.5%) Perjeta+docetaxel n=96 5-year DFS 84% 81% HR 0.60 ( ) Perjeta + Herceptin + docetaxel PFS and DFS benefit of neoadjuvant Perjeta + Herceptin + docetaxel - despite identical adjuvant therapy No new safety concerns with longer follow-up APHINITY adjuvant study results in 2016 pcr endpoint Achievement of tpcr (ITT analysis of all patients) reduced risk of PFS (HR = 0.54) Results support pcr as an earlier indicator of benefit FEC = 5-fluorouracil, Epirubicin, Cyclophosphamide; pcr = pathologic complete response; PFS = progression free survival; DFS = disease free survival Gianni L. et al, ASCO 2015 * PT arm also received docetaxel q3w X 4 70

71 HER2 franchise outlook Complete portfolio of innovative drugs 2nd line mbc Xeloda + lapatinib Kadcyla (EMILIA) Biosimilar launch (EU) 1st line mbc Herceptin + chemo Herceptin & Perjeta + chemo (CLEOPATRA) Kadcyla & Perjeta (MARIANNE) Adjuvant BC Herceptin + chemo Herceptin sc + chemo (HannaH) Herceptin & Perjeta + chemo (APHINITY) Kadcyla (KATHERINE) Neoadjuvant BC Herceptin + chemo (NOAH) 1 Herceptin & Perjeta + chemo (Neosphere, Tryphaena) Kadcyla & Perjeta (KRISTINE) Kadcyla & Perjeta (KAITLIN) Established standard of care New standard of care Trials in progress APHINITY, KRISTINE results in 2016 NEOSPHERE update ASCO

72 Agenda Setting new standards, developing combinations Cancer immunotherapy Roche program update Atezolizumab in lung cancer Atezolizumab in bladder cancer Targeted therapies and combinations Alectinib in ALK-positive lung cancer Cobimetinib + Zelboraf in melanoma Kadcyla, Perjeta, Herceptin in HER2+ breast cancer Hematology Gazyva in NHL 72

73 Hematology franchise A broad portfolio of innovative drugs Breakthrough therapy designation for venetoclax in R/R CLL 17p Compound Combination Indication P 1 P 2 P 3 Gazyva +chemo GREEN CLL Gazyva +chemo GOYA anhl Gazyva +chemo GADOLIN inhl Gazyva +chemo GALLIUM 1L FL Gazyva +apd-l1 R/R FL Gazyva +apd-l1 anhl venetoclax* +Rituxan MURANO R/R CLL Biosimilars delayed to 2017 * venetoclax in collaboration with AbbVie BR = bendamustine+rituxan venetoclax (Bcl2 inhibitor); polatuzumab vedotin (CD79b ADC) venetoclax +Gazyva CLL14 CLL venetoclax R/R CLL 17p venetoclax +Rituxan/+BR R/R FL venetoclax +Rituxan/Gazyva+chemo 1L anhl venetoclax +BR R/R NHL venetoclax +bortezomib+chemo R/R MM venetoclax +chemo AML polatuzumab +Rituxan/Gazyva ROMULUS NHL polatuzumab +Gazyva/BR polatuzumab +Gazyva/BR R/R FL anhl Data presented at ASCO 73

74 Second positive readout for Gazyva GADOLIN in Rituxan-refractory inhl CLL11: Ph III Chronic Lymphocytic Leukemia (CLL) Primary end-point: 1L CLL n=781 Gazyva + chlorambucil Rituxan + chlorambucil chlorambucil PFS Approved in Q GADOLIN: Ph III Recurrent Indolent NHL (inhl) Rituxan-refractory inhl n=411 bendamustine Induction Gazyva + bendamustine CR, PR, SD Maintenance Gazyva q2mo x 2 years PFS Data at ASCO 2015 GOYA: Ph III 1L Diffuse Large B-cell Lymphoma (DLBCL) Front-line DLBCL (aggressive NHL) n=1418 Gazyva + CHOP Rituxan + CHOP PFS Trial to continue until 2016 GALLIUM: Ph III 1L Indolent NHL (inhl) 1L inhl n=1401 Induction Gazyva + CHOP or Gazyva + CVP or Gazyva + bendamustine Rituxan + CHOP or Rituxan or Rituxan + bendamustine CR, PR Maintenance Gazyva q2mo x 2 years Rituxan q2mo x 2 years In collaboration with Biogen Idec CHOP=Cyclophosphamide, Doxorubicin, Vincristine and Prednisone; CVP=Cyclophosphamide, Vincristine and Prednisolone PFS Enrollment complete Q Data expected

75 Gazyva in Rituxan-refractory inhl (GADOLIN) Significant PFS improvement achieved IFR-assessed PFS OS HR a = 0.55 ( ) not reached 14.9m PFS significantly prolonged by independent (HR=0.55) and investigator (HR 0.52) assessment Median PFS was ~ doubled by investigator assessment (29 versus 14 months) OS data immature Filing planned in 2015 a = Stratified HR Sehn L. et al, ASCO

76 Setting new standards, developing combinations Driven by the breadth of our portfolio Launched portfolio chemo CSF-1R CEA-IL2v anti-ox40 atezolizumab Immunotherapy portfolio CEA-CD3 IDO/TDO anti-cd40 alectinib cobimetinib venetoclax Targeted combinations approved Chemotherapy combinations approved Roche combinations in trials Chemotherapy combinations in trials NMEs to be filed soon 76

77 Growing importance of molecular information in cancer immunotherapy Garret Hampton, Ph.D. Vice President, Oncology Biomarker Development and Companion Diagnostics 77

78 Personalized healthcare A cornerstone of our strategy Diagnostics Pharma Molecule Dx Gazyva CLL Right patient right drug Alectinib ALK+ NSCLC Atezolizumab PD-L1+ NSCLC Atezolizumab PD-L1+ UBC Venetoclax 17p- CLL 4 of 5 BTD were enabled by having a Dx that identified patients most likely to benefit > 60% of current drugs in our development portfolio have a companion diagnostic 78

79 Oncology is evolving More complex science with better patient outcomes Disease heterogeneity in lung cancer Overall survival in EGFR mut + lung cancer HER2 ALK Fusions EGFR KIF5B-RET ROS1 Fusions NRAS BRAF KRAS PIK3CA MET Amplification AKT1 PD-L1 expression MAP2K1 Unknown MET splice site PFS probability Number at risk Erlotinib Chemo Erlotinib (n = 86) Chemotherapy (n = 87) HR 0.37 (95% CI ); log-rank p < Time (months) Rosell et al. (2012) The Lancet 79

80 Biomarker discovery and development at Genentech/Roche Understand disease biology Develop new technologies Biomarker prevalence Prognostic significance Subsets of unmet need Pipeline opportunities Dx hypotheses Disease Technology Multiplex assays Real-time Dx Monitoring Identify biomarkers Pharmacodynamic Predictive Response surrogate Resistance (innate/acquired) Therapeutics Define diagnostic endpoints Companion Dx endpoints Response surrogates 80

81 Predictive markers tissue staining for PD-L1 Cancer and/or immune cell expression of PD-L1 can correlate with clinical benefit Tumor type n % of PD-L1 positive (immune cells) % of PD-L1 positive (tumor cells) NSCLC RCC Melanoma HNSCC PD-L1+ (immune cells) Gastric CRC Pancreatic Bladder cancer PD-L1+ (tumor cells) Herbst et al (2014) Nature 81

82 Patient selection enriches for benefit PD-L1-selected lung (TC & IC) and bladder cancer (IC) PD-L1 TC staining TC 50% TC 5% and < 50% TC 1% and < 5% TC < 1% Score TC3 TC2 TC1 TC0 PD-L1 IC staining IC 10% IC 5% and < 10% IC %1 and < 5% IC < 1% Score IC3 IC2 IC1 IC0 Lung cancer: Survival hazard ratio* TC3 or IC TC2/3 or IC2/ TC1/2/3 or IC1/2/ TC0 and IC0 ITT (N = 287) Hazard Ratio a In favor of atezolizumab In favor of docetaxel Overall survival Bladder cancer: Overall survival* IC2/3 IC0/1 + Censored Median OS Not Reached (95% CI, 9.0-NE) Median OS 7.6 mo (95% CI, 4.7-NE) Time (months) * Monotherapy data 82

83 Using patient data to understand cancer immunity-cycle Atezolizumab Phase 1 data: Urothelial bladder cancer patients Change in sum of longest diameters (SLD) from baseline (%) Time on study (days) Complete response Partial response Stable disease Progressive disease 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? Powles et al., Nature

84 Biomarker discovery and development Integral part of the cancer immunotherapy learning organization Research (gred, pred, Chugai & external) Development (early and late) Cancer Immunotherapy Committee Partnering (Genentech and Roche) Clinical Insights & Biomarkers (internal and external) 84

85 Combination with Avastin Increasing response rates by keeping cancer immunity-cycle turning On-treatment biopsies show absence of T cells in tumor bed before and after treatment with PD-L1 Lack of T cell infiltration may limit response to checkpoint inhibitors Pre-treatment On-treatment (week 6) Patient 1 CD8 CD8 Anti-VEGF CD8 CD8 Patient 2 Herbst et al. (2014) Nature Chen & Mellman (2013) Immunity 85

86 Combination with Avastin Increased T cell infiltration and clinical activity On-treatment biopsies show increased infiltrate and reduction in tumor vasculature Combination regimen benefits most patients irrespective of PD-L1 status CD8 (T cells) CD31 (vasculature) Pre-treatment Avastin Avastin + apd-l1 Change in sum of largest diameters from baseline (%) IHC 3 IHC 0 IHC 0 IHC 1 PR SD PD IHC 1 IHC 0 IHC 0 IHC 1 IHC 0 Discontin Time on study (days) Phase 2 in RCC ongoing (n= 300); Phase 3 initiated Sznol et al. ASCO GU

87 Clinical data guides combinations Identifying potentially synergistic combinations Myeloid signature associated with lack of response to atezolizumab in bladder cancer Th2 and Myeloid signature by response group. Red: PD; Black: SD; Blue: CR/PR. Complementary mechanisms of action to enhance benefit from immunotherapies Immune marker expression (illustrative) Th2 signature Myeloid signature: IL1B, Myeloid IL8, signature CCL2 N=15 CR/PR Indication Expression Melanoma SCC NSCLC RCC N=23 N=20 N=15 cbind(1:nc) Adeno NSCLC Bladder TNBC HER2+BC CRC HR+BC PD SD CR/PR Myeloid Signature APC Signature NK cell Signature IFNg Signature IB Signature B cell Signature Teff Signature Th2 Signature Treg Signature Th17 Signature Expression N=23 N=20 N=15 P=0.01 PD SD CR/PR Anti-PD-L1 Anti-CSF-1R Progressive disease Tumor associated macrophages 30 Phase I combination study of anti-csf-1r and atezolizumab ongoing 87

88 Roche and FMI will innovate together Exclusive development of immunotherapy panel Tumor profiling with RNA sequencing Mutation-load and neo-antigen discovery xplot of Te, Th2 and Myeloid signature by response group. Red: PD; Black: SD; Blue: CR/PR. Teff signature 3 N=20 N=15 Indication Immune marker expression (illustrative) SD CR/PR Expression Melanoma SCC NSCLC RCC Adeno NSCLC Bladder cbind(1:nc) Th2 signature Myeloid Signature APC Signature NK cell Signature IFNg Signature IB Signature B cell Signature Teff Signature Th2 Signature Treg Signature Th17 Signature P=0.01 PD SD CR/PR Expression Myeloid signature: IL1B, IL8, CCL2. Myeloid signature N=23 N=20 N=15 N=23 N=20 N=15 TNBC HER2+BC CRC HR+BC PD SD CR/PR Progressive disease Predictive biomarkers & new combinations 30 Identifying immunogenic mutations by structure-guided algorithms Schumacher and Schreiber (2015) Science Yadav et al (2014) Nature 88

89 Our vision for cancer immunotherapy A personalized approach to treatment *Evaluate tumor: Is the tumor inflamed? Y Inflamed N Non-Inflamed Strong PD-L1 Weak PD-L1 No PD-L1 No identifiable immune targets Are T cells at tumor periphery? MHC loss? No T cells? No identifiable immune targets Tx with apd-l1/pd-1 Are suppressive myeloid cells present? IDO/kyneurinin expressed? Chemo+ Atezolizumab Avastin+ Atezolizumab Tumor antigen expression? Antigen experienced? Chemo+ Atezolizumab Anti-CSF-1R+ Atezolizumab IDOi+ Atezolizumab T cell BiSpecific+ Atezolizumab Anti-OX40+ Atezolizumab *Hypothetical algorithm 89

90 Patient journey tomorrow Bridging comprehensive testing and drug development Molecular monitoring Patient care R&D insights Clinical decision Comprehensive testing 90

91 Summary and Q&A Karl Mahler Head of Investor Relations, Roche 91

92 Summary Skin cancer cobimetinib + Zelboraf: Ph III (cobrim) in 1L BRAF+ mm; PFS & biomarker update Filed in 2014 cobimetinib + Zelboraf: Ph Ib (BRIM7) in BRAF+ mm; OS update Lung cancer alectinib: two Ph II in 2L ALK+ NSCLC Filing in 2015 Atezolizumab (anti-pdl1): POPLAR, COMBO, FIR Discuss filing 2015 Avastin: mesothelioma Discuss filing 2015 Bladder cancer Atezolizumab (anti-pdl1): Ph I update in bladder Discuss filing 2015 Breast cancer Kadcyla: Ph II (ADAPT) neoadjuvant 12 weeks HER2+ HR+ BC Kadcyla + Perjeta: Ph III (MARIANNE) in 1L HER2+ mbc Herceptin + Perjeta: Ph II (NEOPSPHERE) in neoadjuvant HER2+ BC Approved in US, filed in EU Avastin + Letrozole: Ph III (CALGB40503) in 1L HR+ mbc Hematology Gazyva: Ph III (GADOLIN) in R/R inhl Filing 2015 Venetoclax: Ph I in R/R NHL and R/R MM BTD: Filing 2015 in 17p CLL depleted 92

93 Cancer immunotherapy: Encouraging early data in monotherapy across various cancer types Range across various studies NSCLC 2L ORR range mpfs range mos* range Prevalence Un-stratified ~ 15% ~ 3 m ~ 9-11 m Stratified 40-45% ~ 6-8 m Not reached ~20-30% Range across various studies Bladder 2L ORR range mpfs range mos range Prevalence Stratified 25-45% ~ m Not reached ~30% * Comparisons based on publicly available competitor data sets. Significant limitations with these cross-trial comparisons; significant variability in baseline population demographics further limit conclusions Note: CheckMate 057 2L+ non-squamous NSCLC trial was stopped early because the study met its OS endpoint 93

94 Cancer immunotherapy: Still many open questions Immunity Review T Cell Trafficking Antigen Presentation What are the factors affecting T-cell infiltration? Biology How can we convert unresponsive tumors into responsive tumors? Immunosuppression Can we modulate / monitor T-cell responses? Biomarker/ Tools Indication/ Patient pop. Therapy Efficacy/ Safety Figure 1. The Cancer-Immunity Cycle The generation of immunity to cancer isa cyclic process thatcan be self propagating, leading to an accumulation ofimmune-stimulatory factors thatin principle should amplify and broaden T cell responses. The cycle is also characterized by inhibitory factors that lead to immune regulatory feedback mechanisms, which can halt the development or limit the immunity. This cycle can be divided into seven major steps, starting with the release of antigens from the cancer cell and ending with the killing of cancer cells. Each step is described above, with the primary cell types involved and anatomic location of the activity listed. Abbreviations are as follows: APCs, antigen presenting cells; CTLs, cytotoxic T Can we create a personalized immunotherapy paradigm? lymphocytes. to (step 4) and infiltrate the tumor bed (step 5), specifically recognize and bind to cancer cells through the interaction between its T cell receptor (TCR) and its cognate antigen bound to MHCI (step 6), and kill their target cancer cell (step 7). Killing of the cancer cell releases additional tumor-associated antigens (step 1 again) to increase the breadth and depth of the response in subsequent revolutions of the cycle. In cancer patients, the Cancer- Immunity Cycle does not perform optimally. Tumor antigens may not be detected, DCs and T cells may treat antigens as self rather than foreign thereby creating T regulatory cell responses rather than effector responses, T cells may not properly home to tumors, may be inhibited from infiltrating the tumor, or (most importantly) factors in the tumor microenvironment might suppress those effector cells that are produced (reviewed by Motz and Coukos, 2013). The goal of cancer immunotherapy is to initiate or reinitiate a self-sustaining cycle of cancer immunity, enabling it to amplify and propagate, but not so much as to generate unrestrained autoimmune inflammatory responses. Cancer immunotherapies Can we convert an unresponsive tumor to a responsive one? dampen or arrest the antitumor immune response, the most effective approaches will involve selectively targeting the ratelimiting step in any given patient. Amplifying the entire cycle may provide anticancer activity but at the potential cost of unwanted damage to normal cells and tissues. Many recent clinical results suggest that a common rate-limiting step is the immunostat function, immunosuppression that occurs in the tumor microenvironment (Predina et al., 2013; Wang et al., 2013). Initiating Anticancer Immunity: Antigen Release, Presentation, and T Cell Priming Attempts to activate or introduce cancer antigen-specific T cells, as well as stimulate the proliferation of these cells over the last 20 What influences durability of response? years, have led to mostly no, minimal or modest appreciable anticancer immune responses. The majority of these efforts involved the use of therapeutic vaccines because vaccines can be easy to deploy and have historically represented an approach that has brought enormous medical benefit (reviewed by Palucka and Banchereau, 2013). Yet, cancer vaccines were limited on two accounts. First, until recently, there was a general lack of 94