The renaissance of immunotherapy is a revolution for cancer patients and for oncology

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

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The renaissance of immunotherapy is a revolution for cancer patients

Traditional drug development Is linear development path the best approach?

Research

Generate Hypothesis

Late Development

Verify Hypothesis

Early Development

Test Hypothesis Launch

Marketing

Cancer immunotherapy requires a cyclical “learning organization”

Research

Early Development

Post-Launch

Late Development

Cancer Immunotherapy Strategy Group

(CITS)

PII 1/2L Dx+ ORR FIR

BIRCH

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

PIII 2L+ Dx+/- vs. Doce OS OAK

PII Dx+ ORR

Cancer immunotherapy at Genentech/Roche Pipeline overview

Anti-PDL1 trials

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 solid tumors

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

IDO (GDC-0919)

Anti-CD40

CSF1R huMAb PVNS

Trial planned

Anti-PDL1 NSCLC 1L Dx+

Mechanistic basis of cancer immunotherapy

Mellman et al (2011) Nature 2011 Dec 21;480(7378):480-9

Immuno-supression

The Cancer Immunity Cycle Immunosuppression is the rate limiting step to effective anti-tumor immunity

•  PD-1/PD-L1 interaction inhibits T cell activation, attenuates target killing: prevents overstimulation of T cells during acute virus infection

•  A large percentage of tumors also up-regulate PD-L1 and evade killing by T cells

•  Blocking PD-1 binding restores effector T cell activity

IFNγ-mediated up-regulation of

tumor PD-L1

Shp-2

PD-­‐L1/PD-­‐1  inhibits    tumor  cell  killing  

“Adaptive expression” of PD-L1

MAPK"PI3K

pathways"

or tumor-infiltrating immune cells

Targeting immuno-supression PD-1/PD-L1 pathway

Targeting PD-L1 produces dramatic responses in many cancers (lung)

64-year-old male with squamous NSCLC s/p R lobectomy; cisplatin + gemcitabine, docetaxel, erlotinib; PD-L1 positive

Hospital Universitario Vall d´Hebron (Cruz/Tabernero).

Post C12 (Week 36) Baseline Post C2 (Week 6)

Herbst et al. MPDL3280A Anti-PDL1 Phase I ASCO 2013

Patients with clinical benefit rarely progress

Herbst et al., (2013) J Clin Oncol. 31, (suppl; abstr 3000)

Chan

ge in

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onge

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eter

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) Fro

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asel

ine,

%

100

50

-50

0 21 42 63 84 105

Time on Study (Days)

0

126 147 168 189 210 231 252 273 294 315 336 357 378 399 420

-100

441

20 mg/kg (n = 39)

Patients dosed at 1-20 mg/kg prior to Aug 1, 2012 with at least 1 post-baseline evaluable tumor assessment; data cutoff Feb 1, 2013.

New Lesions Discontinued Study

PD-L1 positive kidney cancer patient with rapid response to MDL3280A

Baseline

Carolina BioOncology Institute (Powderly)

After 4 weeks

51-year-old male with RCC s/p L nephrectomy, sunitinib, XRT T9, temsirolimus

Cho et al., (2013) J Clin Oncol. 31, (suppl; abstr 4505)

Baseline

CD8 PD-L1 PD-L1

Biomarkers*at*baseline:*

On-Tx

CD8$PD&L1$

Biomarkers*at*week*4*post*C1D1:*

Biomarkers at baseline

Baseline

CD8 PD-L1 PD-L1

Biomarkers*at*baseline:*

On-Tx

CD8$PD&L1$

Biomarkers*at*week*4*post*C1D1:*Biomarkers at week 4 post C1D1

MPDL3280A Phase Ia response correlates with expression of PD-L1 on tumor infiltrating cells (bladder cancer)

PD-L1 IHC (IC) ORR, Best Response % (95% CI)

ORR, Best Response % (95% CI)

IHC 3 (n = 10) 60% (27, 85) 52% (34, 69)

IHC 2 (n = 23) 48% (27, 68)

IHC 1 (n = 24) 17% (6, 37) 14% (6, 28)

IHC 0 (n = 12) 8% (0, 35)

!100$!90$!80$!70$!60$!50$!40$!30$!20$!10$0$10$20$30$40$50$60$70$80$90$

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a$a$a$

Summary of ORR in UBC

12 Powles et al (2014)  Nature  Nov  26;515(7528):558-­‐62

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?

Powles et al (2014)  Nature  Nov  26;515(7528):558-­‐62

Comprehensive approach to biomarker discovery

Multi-parametric immunofluorescence

T-Cell Receptor Repertoire

Genentech ImmunoChip

Mutliplex cytokine assay

Multi-channel fluorescence activated

cell sorting

Molecular Imaging

On-treatment biomarker profile defines response and lack of response

Responder

Non-responder

0"

2"

4"

6"

8"

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Baseline On-treatment 4 weeks

PD-L1 PD-L1

Baseline On-treatment 6 weeks

Herbst et al (2014) Nature Nov 27;515(7528):563-7

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

Compounds moving into clinic •  Negative regulator NME1 •  Positive regulator: OX40

Targets elevated in non-responders

Activating receptors Inhibitory receptors

OX40*

CD27*

TIGIT

B7H4

TIM-3

PD-1*

BTLA

VISTA

LAG-3*

CD96

CD226 2B4

NKG2D

HVEM

ICOS

GITR

2B4

CTLA-4*

CD137*

CD28

T cell

T"cell"stimulation"

Example: NME1 is a negative regulator discovered from biomarker analysis

0 10 20 30 40 6010

100

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Control �anti-PD-L1 �NME1 �

anti-PD-L1 �+ NME1�

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Negative regulator combines in PD-L1 non-responsive model

Immuno- suppression

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Accelerate T cell response to antigen

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 •  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

Treg

OX40L OX40L

OX40

OX40L

OX40

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

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day 2 day 9

0 5 10 15 200

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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

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m3 ) Control

Anti-mouse OX40

Treatment

Primary Tumor Challenge (EMT6)

0 10 20 30

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500

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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 Jul 25;39(1):1-10

anti-OX40

anti-PDL1 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

IFN-γ"

OX40L

OX40

IFNγ-­‐mediated  up-­‐regulation  of  tumor  PD-­‐L1  

Shp-2

Adaptive expression of PD-L1

MAPK"PI3K

pathways"

IFNγ-­‐mediated  up-­‐regulation  of  

tumor  IDO  

Inhibition  of  effector  T  cell  

function  

Shp-2

MAPK"PI3K

pathways"

Adaptive expression of IDO

IDO  

Georgia Hatzivassiliou, Yichin Liu

IDO (indoleamine di-oxygenase) Another suppressor of effector T cells

Free tryptophan

mTOR

Promote translation

high

Enhance T reg

arylhydrocarbon receptor

FoxP3

Kynurenine

IDO*

Tumor cells

IFNγ activates IDO expression

Suppress T effectors

Uncharged Tryptophanol-tRNA

GCN2 kinase

Stress response

low

suppressive cytokines

Dendritic cells Macrophages

*TDO (tryptophan dioxygenase) is a second related target to IDO

IDO mediates T cell suppression by reducing extracellular tryptophan and increasing kynurenine

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Recognition of cancer cells by T cells (CTLs, cancer cells)

ImmTACs Bispecifics

Not all patients may have pre-existing immunity: ImmTACs and bispecific antibodies as alternatives to CAR-T cells

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

Recruiting T cells to cancer cells ImmTACs and bispecific antibodies

Chen & Mellman (2013) Immunity Jul 25;39(1):1-10

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Recognition of cancer cells by T cells (CTLs, cancer cells)

ImmTACs Bispecifics

Cancer antigen presentation

(dendritic cells/APCs) Vaccines: •  Endogenous •  Exogenous

Not all patients may have pre-existing immunity: Patient data defines a path to rational vaccines

Structural analysis suggests that only some mutations will be accessible to T cell receptors

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REPS1! AQLPNDVVL!

ADPGK! ASMTNRELM!

FLU-NP! ASNENMETM!

Copine-1! SSPDSLHYL!

H60! SSVIGVWYL!

PA RM DY

Immunogenic solvent-exposed mutation

Non-immunogenic mutation in MHC groove

Yadav et al (2014) Nature Nov 27;515(7528):572-6

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Mutated peptides predicted to be immunogenic induce CD8 T cell responses upon immunization

+ - + - + - + - + - + -0.0

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peptide + adjuvantadjuvant

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Prime/boost immunization elongated peptides + anti-CD40 + pIC

T cell response measured 7d after boost (MHCI dextramer staining)

+   -­‐   +   -­‐   +/-­‐   +/-­‐  Prediction of

immunogenicity

Anchor residue gain of function

Yadav et al (2014) Nature Nov 27;515(7528):572-6

Promise for a PHC vaccine? Immunization with antigenic peptides regresses growth of established MC38 tumors

Dose Groups● 01 − untreated control

02 − d1: anti−CD40 50µg + pIC 100µg, IP injection. d10: anti−CD40 50µg + pIC 100µg, IP injection. (n=10)03 − d1: anti−CD40 50µg + pIC 100µg + 3Xpeptide mix 100µg, IP injection. d10: 3Xpeptide mix anti−CD40 50µg + pIC 100µg, IP injection. (n=10)

Control

Adj

Adj+ Peptides

Immunization

14−0584: mutated MHCI MC38 peptide vaccine; MC−38 Raw and LME Fit Tumor Volume

Day

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Yadav et al (2014) Nature Nov 27;515(7528):572-6

Anti-PDL1/PD1 Anti-OX40

IDOi (GDC-0919) LM & SM NMEs

Anti-CTLA4 Anti-OX40 SM NMEs

Vaccines •  Endogenous •  Exogenous

Building a portfolio based on the emerging appreciation of the cancer immunity cycle

Anti-VEGF

Chen & Mellman (2013) Immunity Jul 25;39(1):1-10

Substantial investment in developing PD-L1 combinations with in house and partnered molecules

Last updated: 3 Dec 2014 Sources: TrialTrove, company presentations, clinicaltrials.gov P ✔

Partnered external combo Internal combo

Roche/GNE (PD-L1 inhibitor)

BMS (PD-1 inhibitor)

Merck (PD-1 inhibitor)

AZ (PD-L1 inhibitor)

Imm

unot

hera

pies

aCD40 ✔ Vaccines P P P P aCTLA-4 P ✔ P ✔ aOX40 ✔ ✔ aCD27 P P a4-1BB/CD137 ✔ P GITRi ✔ aCEA-IL2v ✔ T Cell Bispecifics ✔ ImmTACs P aPDL1/PD1 ✔ aLAG-3 ✔ IDOi ✔, P P P P aKIR ✔ aCSF1R ✔ P Cytokines, anti-cytokines ✔ ✔ ✔ P

Oth

er

aVEGF ✔ P P aAng-2-VEGF ✔ VEGF TKI P P EGFRi ✔ P P ✔ ALKi ✔ P P BRAFi ✔ P P P MEKi ✔ P P P BTKi ✔ P P aCD20 ✔ aHER2 ✔ P Chemo ✔ ✔ ✔ XRT ✔ ✔

Genentech’s competitive advantage: Lead the field by focusing on the science

•  Identification and validation of new targets & combinations based on our

understanding of cancer immunity cycle

•  An ever-expanding patient biomarker database

•  Diverse, innovative portfolio

•  Leverage small molecule expertise

•  Leverage oncology expertise

•  A uniquely integrated team, from Research to Late Stage…and back

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