Anti-PDL1 in combination

50th ASCO Annual Meeting, Chicago

Roche Analyst Event Sunday, 1 June 2014

Welcome and introduction

Karl Mahler Head of Investor Relations, Roche

2

3

Agenda

Welcome and introduction Karl Mahler, Head of Investor Relations, Roche

Realizing the promise of cancer immunotherapy: translating science into medical benefit Ira Mellman, Vice President, Cancer Immunology, Genentech Hy Levitsky, Head, Cancer Immunotherapy Experimental Medicine, pRED ASCO 2014 Roche highlights: setting new standards of care Sandra Horning, Chief Medical Officer and Head Global Product Development Oncology strategy and outlook Daniel O’Day, Chief Operating Officer, Roche Pharmaceuticals

Q&A

,0

5,000

10,000

15,000

20,000

25,000

1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013

Roche oncology: continued sales growth A portfolio of differentiated medicines

4

(CHF mn)

Sales at 2013 exchange rates

10 medicines 14 tumor types 40 indications

Science is continually evolving

Pao & Girard. Lancet Oncol 2011; Johnson, et al. ASCO 2013

KRAS EGFR

Unknown Com

plex

ity

Classification of lung adenocarcinomas

>1 mutated gene 3% MEK1 <1%

NRAS 1% MET 1% PIK3CA

1% BRAF 2% HER2 3%

EGFR (other) 4%

ALK 8% EGFR

17%

KRAS 25%

No oncogenic driver detected

35%

2014 2004 Future

PDL1 positive

5

Global Product Development and Strategy

Oncology Biomarker

Development

Roche’s cancer immunotherapy community Concerted actions while valuing diversity of approaches

Late Stage

gPartnering Roche Partnering

pRED

Hy Levitsky Pablo Umana

Molecule teams

Support function

6

gRED

Ira Mellman

Molecule teams Support function

Cancer immunotherapy today Approved in monotherapy, one cancer type, few patients

7 Control

Medical benefit

Immunotherapy Targeted Therapy

Illustrative Kaplan–Meier curves

Med

ical

ben

efit (

PFS/

OS)

Time 1 2

Cancer immunotherapy in the future Better patient selection, combinations, broader use?

8 Control

Medical benefit

Immunotherapy Targeted Therapy Immuno doublets & combos with targeted therapies

Illustrative Kaplan–Meier curves

?

1 2 3

Realizing the Promise of Cancer Immunotherapy: Translating science into medical benefit (I)

Ira Mellman, Ph.D. Vice President, Cancer Immunology, Genentech

9

Mechanistic basis of cancer immunotherapy

Mellman et al (2011) Nature

CEA-IL2v

anti-PDL1 anti-CSF-1R

Immuno- suppression

vaccines adjuvants anti-CD40

Avastin

Chen & Mellman (2013) Immunity

The cancer immunity cycle strategy Different drugs target distinct steps

Using patient data to understand cancer immunity and find new treatments

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?

Comprehensive approach to biomarker discovery

CD8 IHC Target expression

Gene Expression - iChip

High throughput and comprehensive evaluation of

tumor and immune genes Multiplex Immune IHC

12 marker assay for evaluation of multiple immune cell subsets,

endothelial cells, and tumor cells Enables spatial assessment of

TILs

Spatial assessment of CD8 in response to treatment

Molecular Imaging

Live CD8 T cell PET under development

Dx grade assays for assessment of target expression

On-treatment biomarker profile defines response and lack of response

Responder

Non-responder

0"

2"

4"

6"

8"

10"

12"

14"

16"

PD*L1"

Granzym

e*A"

Granzym

e*B"

Perforin"

EOMES"

IFNg"

CXCL9"

CD8A"

rela%v

e'expression

'(to'BS

L)'

Baseline'

On5Tx'

0"

2"

4"

6"

8"

10"

12"

14"

16"

PD*L1"

Granzym

e*A"

Granzym

e*B"

Perforin"

EOMES"

IFNg"

CXCL9"

CD8A"

rela%v

e'expression

'(to'BS

L)''

Baseline'

On5Tx'

PD-L1 PD-L1

Baseline On-treatment 4 weeks

PD-L1 PD-L1

Baseline On-treatment 6 weeks

Expression of different immune inhibitory factors may not correlate with lack of response to anti-PDL1

Biomarker status

ORRa

RECIST 1.1 PD rate

PD-L2 highb 20% (13/66) 35% (23/66)

PD-L2 lowb 19% (12/63) 46% (29/63)

Allc 21% (36/175) 37% (65/175)

a ORR includes investigator-assessed unconfirmed and confirmed PR/CR by RECIST 1.1. b PD-L2 low/high is defined as patients with tumor PD-L2 level lower/equal to or higher than the median PD-L2 level in all patients. c All patients include PD-L2–high patients, PD-L2–low patients and patients with unknown tumor PD-L2 status. Patients first dosed at 1-20 mg/kg prior to October 1, 2012; data cutoff April 30, 2013.

Summary of Best Response in lung cancer

High tumor PD-L2 expression does not reduce response rate to anti-PDL1

Kohrt et al. SITC 2013

PD-L1 patient immune biomarker analysis guides research and clinical development

cbind(1:nc)

Indication

Mel

anom

a

SCC

NSC

LC

RC

C

Aden

oN

SCLC

Blad

der

TNBC

HER

2+BC

CR

C

HR

+BC

Th17 Signature

Treg Signature

Th2 Signature

Teff Signature

B cell Signature

IB Signature

IFNg Signature

NK cell Signature

APC Signature

Myeloid Signature

Compounds moving into clinic •  Negative regulator NME1 •  Anti-cytokine NME2 •  Positive regulator NME3

Immune marker expression analysis (illustrative) Targets elevated in non-responders

−2 −1.6 −0.67 0.22 1.1 1.6 2

2 1 0 -1 -2

Example: NME1 is a negative regulator discovered from biomarker analysis

0 10 20 30 40 6010

100

1000

10000

Day

Median Tumor Volume (mm3)�

Control �anti-PD-L1 �NME1 �

anti-PD-L1 �+ NME1�

Complete Remission (CR)�

010

2030

4060

10100

1000

10000

Day

Med

ian

Tum

or V

olum

e (m

m3 )�

Con

trol�

anti-

PD-L

1�NM

E1�

anti-

PD-L

1 �

+ NM

E1�

Com

plet

e Re

miss

ion

(CR)�

Negative regulator combines in PD-L1 non-responsive model

Immuno- suppression

1

2

3

4

5

6

7

Accelerate T cell response to antigen

NME3: positive regulator targeting two steps in the cycle – anti-OX40

Anti-PDL1

anti-OX40

Inhibit T regs

anti-OX40

OX40 function and potential in oncology Promote antigen dependent effector T cell activation and T regulatory cell inhibition

Adapted from Nature Rev Immunol. 4:420 (2004).

Rationale for targeting OX40 in oncology •  Dual mode of action:

Co-stimulation of effector T cells Inhibition of regulatory T cells

•  Reduced risk of toxicity •  Complementary MoA to blocking inhibitory receptors •  Potential to overcome suppressive signals from multiple

inhibitory receptors

Effector T cell

TCR

Antigen Presenting Cell

OX40

OX40L Suppressive

T cell

IFN-γ

OX40 engagement on Treg cells

OX40

OX40L

Treg

OX40

OX40L

Potential for activity in multiple tumor types Pre-clinical efficacy and durability of response OX40 is expressed in a variety of tumors

Anti-OX40 increases intratumor Teff cells while depleting T regs

Colorectal cancer

Breast cancer

control

a-OX40

control

a-OX40

-4-202468101214161820

IFN

-γ F

old

Cha

nge

(Rel

to A

vg C

ontro

l)

day 2 day 9

0 5 10 15 200

20

40

60

Foxp3/CD4(%)

day

controla-OX40

Increase in intratumoral Teff cells (CD4+CD8)

Decrease in intratumoral Treg cells (FoxP3+)

Anti-OX40 can induce durable responses and immunity as a single agent Pre-clinical efficacy and generation of tumor-specific immunity

0 10 20 30 40 500

1000

2000

3000

day

Tum

or V

olum

e (m

m3 ) Control

Anti-mouse OX40

Treatment

Primary Tumor Challenge (EMT6)

0 10 20 30

0

500

1000

1500

2000

dayTu

mor

Vol

ume

(mm

3 ) EMT6 SecondaryCT26 Secondary

EMT6 Primary

Re-challenge (EMT6 or CT26)

No Treatment day day

Chen & Mellman (2013) Immunity

anti-OX40

anti-PDL1

IFN-γ"

OX40

OX40L

CD8 T cell receptor

HLA

PD-1

PD-L1

Tumor cell

T cell

IFNγ

PD-L1 increase

Increase in Teff cells by anti-OX40 may create need to combine with anti-PDL1

Can combination of anti-PDL1 with chemo- and targeted agents extend benefit to more patients?

Immunotherapy+ Targeted Therapy

Control

Targeted Therapy

Hypothetical OS Kaplan Meier curves

•  Agents must be safe in combination with anti-PD-L1

•  Targeted/chemo therapy should not interfere with immune response or immunotherapeutic mechanism of action

Immunotherapy

Combinations may extend the benefit of anti-PDL1 Chemo and targeted therapies

Biomarker analysis in progress to identify combinations with enhanced efficacy

oxaliplatin

0

500

1000

1500

2000

2500

3000

0 5 10 15 20 25

Tu

mo

r V

olu

me

, m

m3

Day

docetaxel

α-PDL1

combo

Dosing Dosing

0

500

1000

1500

2000

2500

3000

0 6 12 16 22 29 36

Tum

or V

olum

e, m

m3

Day

α-PDL1

combo

Control Control

CT26 08-1033O

0 10 20 30 40 500

500

1000

1500

2000

2500

Day

Tum

or V

olum

e (m

m3)

controlGDC-0973 (7.5mg/kg)aPDL1GDC-0973 (3mg/kg) + aPDL1

MEKi

CT26 (Krasmut)

Dosing

Control α-PDL1

α-PDL1/ MEKi

MEKi

Chemotherapy Targeted agent

Recognition of cancer cells in the absence of T cell immunity ImmTACs and bispecifics

1

2

3

4

5

6

7

Recognition of cancer cells by T cells

(CTLs, cancer cells)

ImmTACs Bispecifics

Immune-mobilizing mTCR Against Cancer*

*In colalboaration with Immunocore

T-cell Dependent Bispecific

TCR

Tumor antigen

Cancer cell

T cell Knob into holes full-length IgG

Targeting intracellular tumor markers Targeting extracellular tumor markers

Recognition of cancer cells ImmTACs and bispecifics

PBMC=Peripheral blood mononuclear cell

Examples: B-cell and HER2 bispecifics

Killing of endogenous B-cells by endogenous T-cells in healthy donor PBMCs

Vehicle TBD

Tum

or v

ol. (

% c

hang

e)

TBD efficacy in HER2 tumor mouse model

Days post treatment

Data 1

0 5 10 15 20 250

100

200

300

400

500

600Vehicle (2701-680)Vehicle (2701-657)Vehicle (2701-897)Vehicle (2701-1266)Vehicle (2701-1272)Vehicle (2701-936)Vehicle (2701-1214)4D5-2C11 (2701-572)4D5-2C11 (2701-794)4D5-2C11 (2701-800)4D5-2C11 (2701-1171)4D5-2C11 (2701-834)4D5-2C11 (2701-744)4D5-2C11 (2701-875)

Target 1: 8.0 pM

Target 4: 8.6 pM

Target 3: 70 pM

Target 2: 22 pM

Target 5: 426 pM

% B

cel

l Kill

ing

24 hour assay

pM 0.1 1 10 100 1000 10000

-20

0

20

40

60

80

100

K&H CD19(HD37)/UCHT1 #26975K&H CD20(2H7)/UCHT1 #26975K&H CD22(12F7)/UCHT1 #27608Bisfab huCD79a(7H7)/U #30972Bisfab huCD79b(17A7)/U #33236

pM

% o

f end

o B

depl

etio

n

The cancer immunity cycle Many known targets, and likely many “unknown”

Biomarker analysis will aid in prioritizing targets and combinations

Realizing the promise of cancer immunotherapy: Translating science into medical benefit (II)

Hy Levitsky, MD Head, Cancer Immunology Experimental Medicine, Roche, Pharma Research and Early Development (pRED)

29

The cancer-immunity cycle

Chen and Mellman. Immunity 2013

Priming and activation Anti-CTLA4 Anti-CD137 (agonist) Anti-CD27 (agonist) IL-2 IL-12 Anti-CEA IL2v (RG7813) Anti-Cytokine (NME 2) Anti-OX40 (agonist)

Cancer antigen presentation Vaccines (IMA942 & INO-5150) Anti-CD40 (agonist) TLR agonists IFN-α

Release of cancer cell antigens Chemotherapy Radiation therapy Targeted therapy

Killing of cancer cells Anti-PD-L1 Anti-PD-1 IDO inhibitors Neg. Regulator (NME 1) Anti-CSF1R (RG7155) Anti-CEA IL2v (RG7813) Anti-Cytokine (NME 2)

Recognition of cancer cells by T cells CARs T cell bispecifics ImmTACs

Infiltration of T cells into tumors Anti-VEGF Neo-vascular activators

Trafficking of T cells to tumors

tumor

30 clinical preclinical

REDs

1) Inflammatory tumor microenvironment

31

Immuno suppression

Tumor immunity TAM

MDSC

DC Treg

IL-10, TGF-β, CCL-2 … CTL

Th

B NK

IL-2, IFN-γ…

Depletion A

Inhibition B

Switching C

Tumors induce an immunosuppressive environment by recruitment of myeloid cells

Anti-growth factor receptors Targeting lineage antigens

Chemokine receptor blockade Inhibitory receptor agonists

TLR agonists

TLR - toll-like receptor

Anti-CSF1R phase I proof-of-mechanism RG7155 decreases tumor-associated macrophages in patients with various solid tumor types

*pre- vs on-treatment tumor biopsies at 4 weeks, i.e. two cycles of treatment; Mφ – macrophage cell line; CSF1R – colony stimulating factor 1 receptor

Significant reduction of tumor-associated macrophages in 11/13 patients treated in monotherapy and 15/15 patients treated in combination with SoC

Pleural Mesothelioma, 900 mg RG7155

32 Ries et al., Cancer Cell 2014 (in press)

33 Ries et al., Cancer Cell 2014 (in press); * longest follow-up 22 months

Anti-CSF1R phase I proof-of-mechanism in PVNS From model disease to development opportunity

•  Locally aggressive inflammatory joint disorder •  Neoplastic proliferation with overexpression of CSF-1

-100 -90 -80 -70 -60 -50 -40 -30 -20 -10

0 10

Patients who previously failed nilotinib and/or imatinib treatment

Cha

nge

in S

LD a

nd S

UVm

ax v

s ba

selin

e (%

)

% change in SLD vs baseline (MRI)

% change in SUVmax vs baseline (FGD-PET)

PVNS - pigmented villonodular synovitis

900 mg 1,350 mg 2,000 mg 1,000 mg

EORTC RECIST

Patients %

Partial Response 15/18 83

Partial Metabolic Response 15/17 88

Clinically progression-free* 17/18 94

Rapid onset of measurable tumor shrinkage; associated with early functional and symptomatic improvement

2) Tumor targeted antibody-based immunotherapy of cancer

34

ADCC: recruit effector cells

(NK, MØ) via FcgRIIIa

A Support T-cells: supply cytokines and co-stimulatory signals

B

Glycoengineered IgG1s

Antibody-cytokine fusions, co-stimulatory

antibodies

Activate T-cells: stimulate TCR on T cell

C

T cell bispecific antibodies

Macrophage

T cell

Tumor cell NK cell


35



A Support T-cells: supply cytokines and co-stimulatory signals

B



antibodies


C


Macrophage

T cell

Tumor cell NK cell

Obinutuzumab (Gazyva)

Glyco-engineered to better engage immune cells (ADCC = Antibody-Dependent

Cell-mediated Cytotoxicity)

Unequivocal clinical benefit demonstrated in Phase III (CLL) Out-performed Rituxan/Mabthera in H2H Phase III

Glyco-engineered for improved ADCC

Gazyva: first glyco-engineered antibody approved by FDA

36

APPROVED under

breakthrough therapy

designation

Moessner et al., Blood 115 (22), p4393, 2010; Goede et al., N Engl J Med 370, p1101, 2014


37



A



C


Macrophage

T cell

Tumor cell NK cell

Support T-cells: supply cytokines and co-stimulatory signals

B


antibodies

Amplifying T cell responses in the tumor IL-2 variant immunocytokine

•  Ideal combination partner for ADCC competent antibodies such as Herceptin, obinutuzumab

•  Phase I initiated Dec 2013

First truly tumor targeted immunocytokine

IL-2 variant (diminished CD25 binding) to increase number & activity of effector cells vs. immuno-suppressive cells

High binding affinity to CEA for tumor targeting

Inert Fc-part for improved PK & safety

38 CEA – carcinoembryogenic antigen

Klein et al., abstract number 486, AACR April 6-10, 2013, Washington, DC, USA

Tumor-targeted cytokine

High affinity for CEA1 (tumor antigen)

IL2v engineered to boost effector immune cells

1 carcinoembryonic antigen

Increasing T-cells in tumors

CEA-IL2v treated Vehicle

CEA-IL2v increases T-cells & NK cells in tumors

•  Targets to tumors in vivo (preclinical)

•  Synergistic with ADCC mediated therapeutic mAbs (preclinical)

•  Phase 1 initiated Dec 2013

CEA-IL2v

Cells x 106/gm tumor

+-

+-

T-cell

NK

5 10 15 0

Antibody-targeted IL-2 variant Preferentially stimulating immune cells in tumors

39 Nicolini et al., AACR poster 2014, San Diego, Abstract Number: 2579

Two major categories of solid tumors have been observed at diagnosis

20-30 % of patients •  T cell markers •  Expression of chemokines

(attract leukocytes) •  Other immuno-regulatory

factors (PD-L1, IDO, FoxP3)

70-80% of patients •  No lymphocytic infiltrates

rarely clinical response to single agent immunotherapies

Tumor phenotype by T cell staining

Inflamed Non-inflamed

single agent immunotherapies ü 40

Most tumors lack tumor specific T cell infiltrates A potential role for vaccination •  Increase frequency of relevant effector cells

•  Change character of immune response: functional differentiation

•  Alter lymphocyte trafficking

•  Generate long-lived immunologic memory

41 Drive cancer antigen-specific T cells into tumors

3) Tumor vaccines and immunoadjuvants Providing specificity and memory to combination immunotherapy

42

Delivery Vehicle

(platform)

APC Activators

Antigen(s)

Naked Peptides DNA/RNA Nano-particles

Normal Cancer Antigen Discovery

Activators of innate immunity (“adjuvants”)

CD40 agonist mAb

DC

Exploiting complementary strengths with our partners to co-develop combination assets

Tumor targets Vaccine platforms/ Immuno-adjuvants

Enable & expand T-cells

XPresident Antigen discovery

platform

Tumor derived

peptides

Vaccine platforms

T-cell bi-specific antibodies

Cancer vaccines strategy at Roche Incorporating rich antigen portfolio into alternative targeting platforms

43

Immunocheckpoint inhibitors

Co-stimulatory antibodies

Anti-CD40 agonistic IgG2 mAb Compelling combination partner for cancer immunotherapy

44

CD40 agonist

IgG2 mAb

Immune checkpoints

T-cell agonists

iTME targets Cancer vaccines

ADCC competent antibodies

Multiple immune doublet opportunities

Seeking Synergy

NME 3: blocking immune checkpoints

NME 2

+

NME 2

+

NME 2:

+

antigen presenting cell activation

+

therapeutic vaccine:

+

tumor antigen specific T cell priming

NME 4: depleting suppressive macrophages

45

NME 1 NME 1: T and NK cell amplification

+ +

Numbering of NMEs is for illustrative purposes only

The immunotherapist’s dilemma ....circa 2014

46

ASCO 2014 Roche highlights: Setting new standards of care

Sandra Horning, M.D. Executive Vice President Chief Medical Officer and Head Global Product Development

47

48

Update on immunotherapy and bladder cancer results Lung: Tarceva +/- Avastin, alectinib

Colorectal: Avastin and anti-VEGF/Ang2

Melanoma: cobimetinib in combination with Zelboraf Hematology: Bcl-2i and polatuzumab ADC (CD79b)

Agenda Setting new standards of care

Cancer immunotherapy at Roche Pipeline overview

49

Anti-PDL1 trials

Start planned for 2014

Stimulator

Inhibitor

Phase I Anti-PDL1 Solid tumors

Anti-PDL1+Avastin Solid tumors

Anti-PDL1+cobimetinib Solid tumors

Anti-PDL1+Zelboraf Met. Melanoma

Anti-PDL1+Tarceva NSCLC

Anti-PDL1 + immune m. Solid tumors

Anti-PDL1 + Gazyva Heme tumors

CSF1R huMAb

CEA IL-2v

Phase II Anti-PDL1

NSCLC (Dx+) Anti-PDL1

NSCLC Anti-PDL1+Avastin

Renal Anti-PDL1

Bladder

Anti-PDL1 NSCLC 2/3 L

Phase III

Anti-PDL1 Bladder

Pre-clinical

ImmTAC

Neg. Regulator NME 1

Anti-cytokine NME 2

T-cell bispecific

IMA 942

Note: Anti-PDL1 is listed as MPDL3280A in clinicaltrials.gov

Anti-OX40

Anti-CD40

INO-5150

Urothelial bladder carcinoma (UBC) High unmet need for patients with advanced disease

50

•  US: 74, 690 new cases/year1

-  5% metastatic, 20% muscle invasive

•  Metastatic UBC prognosis:

–  5-year OS ~5%2

•  US: no therapies approved for patients who relapse on cisplatin-based chemo

1 Siegel R, CA Cancer J Clin 2014; 64:9-29. 2 http://seer.cancer.gov/statfacts/html/urinb.html (Feb. 2014)

Galsky et. al. 2013

New therapies in RCC, prostate and bladder cancer

UBC

RCC

Prostate cancer

No.

of d

rugs

app

rove

d by

FD

A

Year

MPDL3280A (anti-PDL1) in metastatic UBC Response by PD-L1 IHC status

•  2 complete responses in the IHC 2 / 3 cohort •  16 of 17 responding patients had ongoing responses at the time of data cut-off

51 * Patients with complete responses. Patients with a CR had < 100% reduction of the target lesions due to lymph node target lesions. All lymph nodes returned to normal size as per RECIST v1.1.IC; tumor-infiltrating immune cells.Best response is not known for 7 patients. Diagnostic PD-L1-positive: IHC 2 (≥ 5% but < 10% ICs); IHC 3 (≥ 10%. ), PD-L1 negative: IHC 0 (< 1% of Ics) and IHC 1 (≥ 1% but < 5%). Patients dosed by Nov 20, 2013 with a baseline tumor assessment. Clinical data cut-off was Jan 1, 2014.

PD-L1 IHC (n)

ORR (95% CI)

Dx+ vs Dx- ORR

(95% CI) IHC 3 (n=10) 50% (22-78)

43% (26-63) IHC 2 (n=20) 40% (21-64)

IHC 1 (n=23) 13% (4-32) 11% (4-26)

IHC 0 (n=12) 8% (0.4-35)

MPDL3280A (anti-PDL1) in metastatic UBC Treatment related adverse events

52 Clinical data cutoff Jan 1, 2014. Includes events occurring in 3 or more patients. Additional grade 3 or 4 events included thrombocytopenia and decreased blood phosphorous.

•  Safety profile in bladder cohort consistent with safety in overall phase I population •  No new safety signals identified in the bladder cohort

All Grade n (%)

Grade 3/4 n (%)

All 39 (57%) 3 (4%) Decreased Appetite 8 (12%) 0 Fatigue 8 (12%) 0 Nausea 8 (12%) 0 Pyrexia 6 (9%) 0 Asthenia 5 (7%) 1 (2%) Chills 3 (4%) 0 Influenza-like illness 3 (4%) 0 Lethargy 3 (4%) 0

MPDL3280A (anti-PDL1) in locally advanced and metastatic UBC: next steps in development

53

Phase II

Anti-PDL1 1200 mg IV Q3 weeks

Locally Advanced or Metastatic UBC

N=330

In preparation, expect start in 2014

Phase III

Phase I

•  Phase I results warrant move into pivotal studies

•  Results observed to date suggest higher response rate in PD-L1+ patients

Primary end-point:

•  Overall Response Rate

FPI: Q2 2014

Breakthrough therapy designation


Anti-PDL1 in metastatic non-small cell lung cancer (mNSCLC)

54

Primary end-point: ORR FPI Q2 2013 Data in-house end ‘14

Primary end-point: OS

FPI Q3 2013 Enrollment complete

54

All comers 2,3L NSCLC n = 850

Docetaxel 75 mg/m2 IV Q3 wk

Anti-PDL1 1200 mg IV Q3 wk

OAK: Phase III 2/3L mNSCLC

Primary end-point: OS

FPI Q1 2014

FIR: Phase II Dx-positive advanced mNSCLC

PDL1-positive NSCLC n = 130


All comers 2,3L NSCLC n = 287

Docetaxel 75 mg/m2 IV Q3 wk

Anti-PDL1 1200 mg IV Q3 wk

POPLAR: Phase II 2/3L mNSCLC

BIRCH: Phase II Dx-positive advanced mNSCLC

PDL1-positive NSCLC n = 300


Primary end-point: ORR

FPI Q1 2014


Phase III trials in first line NSCLC in preparation


Negative control (293)

Positive control (293-PDL1)

Positive tissue control (Placenta)

Available lab tests

PD-L1+ Trophoblasts

Roche/Genentech

Proprietary reagent

CONFIDENTIAL INFORMATION – DO NOT COPY OR FORWARD

20

GNE/Spring PD-L1 IHC reagent – potential for BIC Dx

Hartmut Koeppen (GNE) Spring Bio Ventana

GNE/Spring PD-L1 IHC • good sensitivity • highly specific • no background

Negative control (293)

Positive control (293-PDL1)

Positive tissue control (Placenta)

ProSci #4059

27A2

SP142 (GNE/Spring)

293 cells:

PD-L1 low

PD-L1 med

PD-L1 high

PD-L1 IHC (pAb)

PDL1 IHC dynamic range:

Non-specific background

PD-L1 in trophoblasts

Commercial*1*

Commercial*2*

Roche/Genentech*Proprietary*reagent*

MPDL3280A (anti-PDL1) diagnostic program Development of the right assay

55

Three pillars of the successful IHC test:

•  Sensitivity: Detects signal from a few cells

•  Specificity: Detects PD-L1 protein only

•  Precision: Reproducibly assigns cases to well-defined categories (IHC 0,1,2,3)

MPDL3280A (anti-PDL1) development Readouts over the next 12 months

56 Outcome studies are event driven, timelines may change

Study Indication Readout

Anti-PDL1 as single agent

Phase I New tumor type First readout

Lung Follow-up data

Renal Follow-up data

Bladder Follow-up data

Melanoma Follow-up data

Phase II (FIR) NSCLC (PD-L1+) First readout

Phase II (POPLAR) 2/3L NSCLC First readout

Anti-PDL1 in combination

Phase Ib Multiple tumor types First readout

57

Update on Immuno-oncology and Bladder cancer results Lung: Tarceva +/- Avastin, alectinib




Hanahan and Weinberg, 2011 | Cell 144:646, 2011.

Sustaining proliferative signaling Evading growth

suppressors

Avoiding immune destruction

Enabling replicative immortality

Tumor-promoting inflammation

Activation invasion & metastasis

Inducing angiogenesis

Genome instability & mutation

Resisting cell death

Deregulating cellular energetics

10 HALLMARKS OF CANCER

Alectinib

aPD-L1

Avastin

Tarceva

TARGETING MULTIPLE HALLMARKS TO ADDRESS:

HETEROGENEITY COMPLEXITY RESISTANCE

Lung cancer disease area Targeting multiple hallmarks of cancer

58

Tarceva plus Avastin in EGFR+ mNSCLC Japanese study JO25567

59

l  Primary endpoint： Progression free survival

l  Secondary endpoint： Overall survival, Objective Response (Response Rate, Disease Control Rate, Response Duration), QOL, Safety

l  Exploratory： Biomarker analysis

l  Stratification: Gender, stage, smoking status, EGFR mutation type

Study conducted by Chugai

•  Non-squamous NSCLC Stage IIIB / IV or postop. recurrence

•  Chemo naïve, PS 0-1 •  Active EGFR mutation

– exon 19 del or L858R without T790M

N=150 Tarceva 150 mg daily

Tarceva 150 mg daily + Avastin15mg/kg q3W

PD

PD

R

A+T T

Median PFS (months) 16.0 9.7

Hazard ratio 0.54 [0.36;0.79]

P=0.0015, log rank test

Tarceva plus Avastin in EGFR+ mNSCLC Japanese study JO 25567

60

Superior efficacy of A+T combination compared to Tarceva single agent in EGFR+ patients

Progression Free Survival

75 72 69 64 60 53 49 38 30 20 13 8 4 4 0 77 66 57 44 39 29 24 21 18 12 10 5 2 1 0

0 0

1.0

T A+T Number at risk Time (months)

4 8 12 2 6 10 14 18 22 26 16 20 24 28

0.2

0.4

0.6

0.8

PFS

prob

abili

ty

9.7 16.0

A+T T


Alectinib in ALK+ve NSCLC Brain-penetrant ALKi with promising efficacy & safety

61

-100

0

-30

CRPRSDNE

Bes

t C

hang

e fr

om B

asel

ine

in S

ize

of T

arge

t Le

sion

s (%

)

Crizotinib–naïve ALK-positive patients post-chemotherapy

1 Seto et al, Lancet Oncology, Vol. 14, p. 590-598, 2013. 2 Gadgeel et al, WCLC 2013. 3 Ou et al, WCLC, 2013

•  Filed in Japan in Oct. 2013 •  Global Phase I/II study expected to

readout in 2014 •  Start of Phase III in 2014


Study results Crizotinib-naive1

Overall Response Rate

93.5%

Crizotinib-failures2

Overall Response Rate CNS Objective Response Rate3

54.5% 52%

Breakthrough therapy

designation

Next steps

62





Avastin in KRAS wt met. colorectal cancer Impact of the CALGB study

63

•  Cetuximab failed to demonstrate survival benefit over Avastin •  Avastin survival benefit in metastatic colorectal cancer in 1L, 2L and TML1-3

Avastin+ chemo

Cetuximab+ chemo

HR P value

OS 29.0 29.9 0.925 0.34

PFS 10.8 10.4 1.04 0.55

Untreated KRAS wt

advanced or mCRC

N=1’142 Cetuximab+FOLFOX or

FOLFIRI q2w

Avastin+FOLFOX or

FOLFIRI PD

PD

R

Primary endpoint: Overall survival 90% powered to detect a HR of 0.80 (2-sided α=0.05), assumption: OS 22 months to 27.5 months, Δ=5.5 months

Study design Results

1Hurwitz, et al. NEJM 2004; 2Giantonio et al, JCO, 2007, 3 D. Arnold et al, JCO, 2012

64

CrossMAb: bispecific anti-VEGF & Ang2 antibody Neutralizing two complementary angiogenic factors

VEGF Ang2

Phase II trial design

1L mCRC

N=140

Avastin + mFOLFOX-6

A2V + mFOLFOX-6

Induction Up to 8 Cycles (16

wks)

Maintenance until PD, max. 24

mon

Avastin + 5-FU/LV

A2V + 5-FU/LV

Open Label Safety Run-in

2 Cycles (4 wks)

CrossMAb + mFOLFOX-6 N = 6 -18

Primary endpoint: Median progression free survival (mPFS) Secondary endpoints: Safety & tolerability, RECIST ORR, OS & duration of

response, PK

CrossMAb is listed as RO5520985 in clinicaltrials.gov

ASCO 2014: Manuel Hidalgo, abstract #2525

65

Update on Immuno-oncology and bladder cancer results Lung: Tarceva +/- Avastin, alectinib




Cobimetinib plus Zelboraf Encouraging results of phase I in BRAF+ve mMelanoma

66

BRAFi-naïve patients

Presented at EADO May 7, 2014 1Applicable to PFS

Readout of Phase III trial co-BRIM expected later in 2014

BRAFi− naïve (n = 63)

Vem-Progression (n = 66)

Patients with events1 33 (52.4%) 58 (87.9%)

Median PFS (months) 13.7 2.8

95% CI for Median PFS 10.1 − 17.5 2.6 − 3.4

Response rate 87.3% 15.2%

% pts alive at 1 year 83% 32%

95% CI for 1 year survival 73-93 19-45

13.7m

67



Melanoma: Cobimetinib in combination with Zelboraf Hematology: Bcl-2i and polatuzumab ADC (CD79b)


Strategies beyond great medicines Hematology

68

MabThera

BCL-2i

ADCs ADC 79b

ADC 22

Replace

Extend

Replace and extend

CLL11 GOYA

GALLIUM GADOLIN

Murano (CLL) Romulus (NHL)

Chemo

MabThera

BCL-2i

ADCs ADC 79b

ADC 22

Phase Ib CLL(G+Bcl-2i)

Gazyva Gazyva

Med

ical

val

ue

Bcl-2 i. in collaboration with AbbVie (ABT-199)

B-cell hematologic malignancies A portfolio addressing multiple drug targets

Adapted from Zenz et al, Nature Reviews Cancer, 2010, p. 37-50

Rituxan Gazyva

GDC-0199

polatuzumab ved.

69

Anti CD22 ADC

Rituximab (375 mg/m2) + ADC (2.4 mg/kg) administered in every 21-day cycles

ROMULUS: Phase II head to head study in NHL Study design

70

Randomize 1:1

Anti-CD22 ADC + RTX

polatuzumab vedotin + RTX

polatuzumab vedotin + RTX

Anti-CD22 ADC + RTX

PD

PD

•  R/R FL, n= 41

•  2/3+L DLBCL, n= 81

FL: follicular lymphoma, DLBCL: diffuse large B-cell lymphoma

Morschhauser, F., ASCO 2014, abstract #8519

ROMULUS: Phase II head to head study in NHL Promising results for polatuzumab

71

Polatuzumab ved. selected for late stage development based on high level of anti-tumor activity

Morschhauser, F., ASCO 2014, abstract #8519

polatuzumab ved.+rituximab in FL

Regimen R/R DLBCL R/R FL

polatuzumab vedotin + rituximab

ORR = 56% CR = 15%

ORR = 70% CR = 40%

anti-CD22 ADC + rituximab

ORR = 57% CR = 24%

ORR = 62% CR = 10%

Max

% c

hang

e tu

mor

dec

reas

e fro

m B

L

Bcl-2 inhibitor (GDC-0199) single agent in R/R CLL Encouraging responses across patient subgroups

72 In collaboration with AbbVie (ABT-199). J.F. Seymour, ASCO 2014, abstract # 7015

R/R CLL: relapsed/refractory chronic lymphocytic leukemia.

Responses

All n (%) n = 78

del (17p) n (%) n = 19

F-Refractory n (%) n =41

IGHV Unmutated

n (%) n =24

Overall response 60 (77) 15 (79) 31 (76) 18 (75)

Complete response 18 (23) 5 (26) 9 (22) 7 (29)

Partial response* 42 (54) 10 (53) 22 (54) 11 (46)

Stable disease 10 (13) 2 (11) 7 (17) 2 (8)

Disease progression 2 (3) 1 (5) 1 (3) 2 (8)

D/C Prior to first (W6) assessment

6 (8) 1 (5) 2 (5) 2 (8)

Median PFS for patients treated at or above 400 mg has not been reached.

Bcl-2 inhibitor (GDC-0199)+R in R/R CLL Efficacy in combining with an anti-CD 20 antibody

73 In collaboration with AbbVie (ABT 199). Shuo Ma, ASCO 2014, abstract #7013, R: rituximab. MRD: minimal residual disease (PB or BM)

Best % change from baseline in Lymphocyte Count

* Evaluable pts have reached the month 7 bone marrow assessment, discontinued, or progressed on therapy

Response Evaluable* n=25

Response rate 21 (84%)

Complete response 9 (36%)

Partial response 12 (48%)

Stable disease 1 (4%)

Disease progression 1 (4%)

Discontinued prior to assessment 2 (8%)

•  High level of complete response and MRD (6/8 CR, 75%) •  Results supported move into phase III (MURANO) study in R/R CLL

Bcl-2 inhibitor (GDC-0199) +R in R/R CLL Encouraging duration of response

74 In collaboration with AbbVie (ABT-199). Shuo Ma ASCO 2014, abstract # 7013

R/R CLL: relapsed/refractory chronic lymphocytic leukemia. SE: safety expansion

Months on Study

ABT-

199 C

ohor

t Dos

e

0 5 10 15 20 25

200 mg

300 mg

400 mg

500 mg

600 mg

400 mg SE

Most patients are still progression-free, even those on lower doses

Months on study

ABT

-199

coh

ort d

ose

Bcl-2 inhibitor (GDC-0199) Safety update

75

•  No further clinical TLS1 cases since program restart (120 new patients treated)

•  New revised monitoring agreed with FDA: –  No hospitalization for low/ medium risk patients –  Hospitalization for high risk patients2: at treatment initiation and

first escalation one week later

In collaboration with AbbVie (ABT-199). 1TLS: Tumor lysis syndrome. 2High risk is currently defined at those patients who have large tumors (10+ cm) and those patients who have tumors 5-10 cm and high circulating lymphocyte counts

Bcl-2 (GDC-0199) development Next steps

76 In collaboration with AbbVie (ABT-199)

Outcome studies are event driven, timelines may change. R=rituximab, G=obinutuzumab, B=bendamustine

Study Indication Status Readout (exp.)

CLL

Phase II 17p del Enrolment complete 2015

Phase III combo with R (MURANO) R/R CLL Enrolling 2016

Phase III combo with Gazyva 1L CLL Start planned in 2014 2017 and beyond

NHL

Phase II + R, +BR Follicular lymphoma Start planned in 2014 2016

Phase Ib/II +R-/G- CHOP DLBCL Start planned in 2014 2016

Roche hematology pipeline Broad range of indications and approaches

77

1  Approved in US, submitted in EU

Phase II Bcl-2 inh (GDC 199)

CLL R/R 17p del

polatuzumab ved. (CD 79b) NHL

pinatuzumab ved. (CD22) NHL

Erivedge AML

Phase III

Registration

Gazyva DLBCL

Gazyva iNHL relapsed

Gazyva iNHL front-line

Bcl-2 inh. (GDC 199) CLL R/R

Gazyva1 CLL

Phase I Bcl-2 inh (GDC 199) + Gazyva

CLL

LSD1 inh (RG6016) AML

MDM2 (RG738) AML

ADC (RG7598) multiple myeloma

Bcl-2 inh (GDC 199) AML

RG 7845 heme tumors

ChK1 inh (RG7741) lymphoma

Bcl-2 inh (GDC 199) Multiple myeloma

Bcl-2 inh (GDC 199) NHL

New Molecular Entity

Additional Indication

Oncology strategy and outlook

Daniel O’Day Chief Operating Officer, Roche Pharmaceuticals

78

,0

5,000

10,000

15,000

20,000

25,000

1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013

Roche oncology: continued sales growth A portfolio of differentiated medicines

79

(CHF mn)

Sales at 2013 exchange rates

10 medicines 14 tumor types 40 indications

Evolution of science and market in oncology Increasing competition and scientific complexity

1995 Today 2006

73 Key Players

Oncogenic Mutations & Emerging Immunotherapy

30% of Industry Pipelines

Disease Subsets

Anatomic Diseases

Little Competition

Increasing complexity in science

Increasing market competition

80

81

Roche strategy in oncology

Summary

Key success factors in the new environment

•  Integrated biomarker expertise

•  Top tier scientific talent

Best Science Innovative Business Model

•  Tailored approaches to access

Smart Development

•  First or best in class •  Shift paradigms in

development •  Leverage Combinations

82

Best science: integrated biomarker expertise

Generics

Differentiation

MedTech

OTC

Prem

ium

for i

nnov

atio

n

Dia Pharma

Focus

Personalized Healthcare at Roche •  Supports development of medically

differentiated therapies

•  PHC strategy applied to vast majority of pipeline molecules

•  Leverage fully integrated biomarker and diagnostic expertise

83

Best science: need top tier scientists

Strong foundation in science key to guide decisions

ALK Bcl-2 BCR BRAF CD20 CD22 CD79b CD40 EGFR HER2 Hormone HP IDO IGFR1 Immuno JAK MAPK MDM2 MEK OX40 NaPi2b PARP PI3K VEGF

ALK

Bcl-2

BCR

BRAF

CD20

CD22

CD79

b

CD40

EGFR

HER2

Horm

one

HP

IDO

IGFR

1

Imm

uno

JAK

MAP

K

MD

M2

MEK

OX4

0

NaP

i2b

PARP

PI3K

VEGF

Strategy 1: Try everything

•  High cost approach

Strategy 2: Focus on the most promising combinations

•  Requires scientific expertise and smart development

Hypothetical Example MoAs

84

Source: Evaluate Pharma, Decision Resources, Roche internal analysis Note: *Market shares represent either % sales of target product relative to sales competing products in similar indications or patient shares

Smart development: aim at first and best in class Focus on most promising molecules

85

Market share*

Years post launch

cabazitaxe

nilotinib

axitinib

pazopanib

dasatinib

temsirolimus Ziv-aflibercept

ofatumumab lapatinib afatinib nab-paclitaxel panitumumab

enzalutamide

ipilimumab abiraterone

Kadcyla

crizotinib

Zelboraf

Perjeta

Second-in class products Incrementally better products Breakthrough / Best in class

Major Oncology Drug Launches

Smart development: paradigm shift I Adaptive clinical trials: “Learning on the go”

86

Past

Present / Future

•  Small phase I è Proof-of-concept in phase II è Large phase III •  Similar path for each new indication

Ph I Ph II Ph III

Ph I

Time/trial size

Pivotal ph II/III – indication 1



•  Large phase I, proof-of-concept for multiple indications è Multiple pivotal phase II/III with adaptive trial design

Smart development: paradigm shift I Learning on the go in PD-L1

87

Past

Example – PDL1 NSCLC diagnostic approach

•  Small phase I è Proof-of-concept in phase II è Large phase III •  Similar path for each new indication

Ph I Ph II Ph III

Time/trial size

PII 1/2L Dx+ ORR FIR

BIRCH

PII 2L+ Dx+/- vs. Doce OS POPLAR

PIII 2L+ Dx+/- vs. Doce OS OAK (GO28915, N=850)

(GO28754, N=400)

(GO28753, N=300)

(GO28625, N=130)

PII Dx+ ORR

2014 2013 •  Data from Phase Ia NSCLC, FIR and

POPLAR can be used to modify BIRCH and OAK before they read out

Smart development: paradigm shift II Surrogate end-points: fast readout of clinical efficacy

88

True clinical outcome

Disease Surrogate endpoint

Intervention

Good surrogate endpoint in the causal pathway of the disease

Neo-adjuvant treatment

Pre-surgery, 4-6 cycles

SURGERY Adjuvant treatment

Post-surgery up to 1 year

PCR: Pathological Complete Response –

Absence of cancer cells

Eg Early Breast Cancer PCR Eg Hematology MRD

Smart development: paradigm shift II Surrogate end-points with Perjeta and Gazya

89

True clinical outcome

Disease Surrogate endpoint

Intervention

Good surrogate endpoint in the causal pathway of the disease

E.g. early breast cancer (Perjeta) PCR

PCR: Pathological Complete Response – Absence of cancer cells •  US approval for

Perjeta Sept 2013

E.g. hematology (Gazyva) MRD

MRD: Minimal Residual Disease

•  Provided strong confidence in results earlier

Smart development: paradigm shift III Disease area approaches – hematology example

Pre-clinical Phase I Phase II Phase III

Polatuzumab vedotin anti-CD79b-ADC

Gazyva

ADC (RG7598)

MabThera/Rituxan

GDC-0199* BCL-2 inhibitor

MDM2 antagonist

Anti-PDL1

ADC=Antibody-Drug Conjugate; AML=Acute Myeloid Leukemia; CLL=Chronic Lymphocytic Leukemia; NHL=Non-Hodgkin’s Lymphoma; *Co-development molecule with AbbVie

Approved

RG7845

T-Cell Dependent Bi-specific (TDB) AB, PIM,

CD44, Others

Erivedge

NHL

MM

NHL, CLL, MM, AML

NHL, CLL approved

CLL approved in US; ongoing in NHL

AML and solid tumors

Heme Malignancies & solid tumors

Heme malignancies

Heme malignancies

AML, solid tumors

90

Smart development: leverage combinations 26 disclosed combinations in 9+ tumor types

91

Lung cancer Avastin Tarceva Ph2 Anti-PDL1 Tarceva Ph2 Pictilisib (PI3Ki) Avastin Ph1

Breast cancer Perjeta Herceptin Perjeta Herceptin Kadcyla Perjeta Ph3 Kadcyla Perjeta Ph3 Perjeta Herceptin Ph2, 3 Perjeta Herceptin Ph3 GE-anti-HER3 Perjeta Ph1

Colon cancer Anti-PDL1 Avastin Ph1

Melanoma Cobimetinib Zelboraf Ph3 Anti-PDL1 Zelboraf Ph1 Gastric, brain, kidney and others

Perjeta Herceptin Ph3 Anti-PDL1 Avastin Ph2 Cobimetinib AKT inh Ph1 Cobimetinib Pictilisib (PI3Ki) Ph1 GE-anti-HER3 Tarceva Ph1

Leukemia Bcl2 inh Gazyva Ph1 Bcl2 inh Rituxan Ph1 Bcl2 inh Rituxan (+B) Ph1, 3

Lymphoma Anti-CD22 ADC Rituxan Ph2 Anti-CD79b ADC Rituxan Ph2 Bcl2 inh Rituxan (+B) Ph1

Solid tumors Hematological tumors

ü ü

ü Studies read out/filed/approved

Locally advanced solid tumors Anti-PDL1 Cobimetinib Ph1 Anti-HER3/EGFR Cobimetinib Ph1

Innovative business models: tailored access Developed markets - access through innovative pricing

Pack based pricing Value based pricing

Need for data from healthcare systems

Undifferentiated $$ by vial

Today Future

Combinations

Indication based

+

Episode-of-care based

Personalized Reimbursement Models

92

Note: Incremental patients treated are current estimates based upon available new patient starts data through YE 2013

Differential pricing

>1,900 more patients treated

since 2013

Access to the public reimbursement

+

Patient assistance programs

>24,000 more patients treated

since 2011

Partnership with Cancer Foundation, Ministry of

Health

+

17

Innovative business models: tailored access Developing markets – multiple approaches

Examples of approaches

•  Multiple approaches to ensure access to medicines in emerging markets

•  No ‘one-size fits all’ solution – depends on market characteristics and segments

Key success factors in the new environment

•  Integrated biomarker expertise

•  Top tier scientific talent

Best Science Innovative Business Model

•  Tailored approaches to access

Smart Development

•  First or best in class •  Shift paradigms in

development •  Leverage Combinations

94

95

Roche strategy in oncology

Summary

Tumor microenvironment Angiogenic signaling

Antibody-drug conjugates

Cell death “apoptosis“

HER2 signaling

PI3K/AKT/mTOR

Cancer immunotherapy Activating immune system

Comprehensive approach to cancer… Multiple ways to target cancer

96

Multiple assets require disease area strategies

Total 40 55

…enabling a disease area approach Focused and distinct projects per disease area

97

Tumor type Global incidence

(%)

Late stage projects

Early stage projects

Colorectal & gastric 22 2 8

Lung 13 7 7

Breast 11 11 8

Ovarian/GYN 8 3 1

Hematology 7 7 15

Skin 2 4 4

Other 25 6 12

2014: Key upcoming oncology readouts

98 Outcome studies are event driven, timelines may change

Compound Indication Readout

cobimetinib (MEKi) Met. melanoma Ph III (co-BRIM)

Kadcyla & Perjeta HER2+ mBC (1 Line) Ph III MARIANNE

alectinib (ALKi) NSCLC Ph II

anti-HER3 EGFR DAF Head and neck, colorectal cancer Ph II (MEHGAN, DARECK)

anti-PDL1 Solid tumors Ph I/II updates

Oncology strategy summary

99

2 Smart clinical development: •  Delivering first and/or best in class medicines •  Making smart development decisions and trial designs •  Using a disease area approach and leveraging combinations

1 Best science: •  Leveraging our top oncology talent to focus on the most promising

molecules and combinations

3 Innovative business models: •  Tailoring approaches to ensure access in both developed and

developing markets

Doing now what patients need next

Anti-PDL1 in combination

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