Atezolizumab Oncology Development Pediatric Oncology Subcommittee of the

Oncologic Drugs Advisory Committee (ODAC) Raphaël Rousseau, M.D., Ph.D.

Global Head, Pediatric Oncology Drug Development Group Genentech, a member of the Roche Group

South San Francisco

1

Outline

• Introduce Roche/Genentech Pediatric Oncology Team

• Cancer Immunotherapy

• Atezolizumab Mechanism of Action

• Atezolizumab Adult Development

• Key Differences Between Adult and Pediatric Cancers

• Atezolizumab Pediatric Development

• Next Steps

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Genentech/Roche Pediatric Oncology Doing Now What Children Need Next

Provide children with unmet medical needs with innovative, safe, life-saving therapies

• Ensure early access to drugs for children with high unmet medical needs • Improve pediatric patient care through pediatric product labeling • Fulfill pediatric regulatory obligations to enable timely registrations

31 dedicated individuals and growing. Research Scientists, Pediatric Oncologists, Clinical Pharmacologists, Safety Specialists, Regulatory, etc.

Team

Goals

Vision

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Cancer Immunotherapy Checkpoint Inhibitors are Key Activators of Anti-cancer Immunity

Chen DS, Mellman I. Immunity. 2013.

Cancer antigen presentation

Priming and activation

Recognition of cancer cells by T cells

4

2

3

4

5

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Lymph node Blood vessel

Tumor

Release of cancer cell antigens 1 7 Killing of cancer cells

Trafficking of T cells to tumors

Infiltration of T cells into tumors

Cancer Immunotherapy Checkpoint Inhibitors are Key Activators of Anti-cancer Immunity

Chen DS, Mellman I. Immunity. 2013.

Release of cancer cell antigens

Cancer antigen presentation

Priming and activation

Recognition of cancer cells by T cells

5

1

2

3

4

5

6

7

Lymph node Blood vessel

Tumor

Killing of cancer cells

PD-L1 / PD-1 Pathway Atezolizumab (aPD-L1)

Trafficking of T cells to tumors

Infiltration of T cells into tumors

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Atezolizumab Mechanism of Action Humanized mAB inhibits binding of PD-L1 to PD-1 & B7.1

1. Akbari. Mucosal Immunol. 2010; 2. Matsumoto. Biochem Biophys Res Commun. 2008.

• Inhibiting PD-L1/PD-1 and PD-L1/B7.1 interactions can restore antitumor T-cell activity and enhance T-cell priming

• Atezolizumab leaves the PD-L2/PD-1 interaction intact, maintaining immune homeostasis and potentially preventing autoimmunity

Tumor cell

T cell PD-L1

PD-1

B7.1

PD-1 B7.1

anti PD-L1

T cell

Dendritic cell

PD-1

B7.1

PD-1 B7.1

PD-L2 PD-L1

anti PD-L1

• ~ 5000 patients have received atezolizumab across clinical trials, as of February 2016

• The key safety risks associated with atezolizumab are immune-related events – Events include pneumonitis, hepatitis, colitis, endocrinopathies, and other

immune-related events including meningitis / encephalitis, motor and sensory neuropathy, and pancreatitis

– Immune-related events are generally grade 1 and 2 in nature and manageable with dose interruption and supportive care, including the use of systemic corticosteroids, where appropriate

• The safety profile appears similar between tumor types and suggests independence from the level of PD-L1 expression

• No apparent dose related trends in the incidence of AEs

Atezolizumab Adult Development Acceptable Safety Profile Across Tumor Types

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Atezolizumab Adult Development Demonstrates Activity Across Tumor Types

Non-small cell lung cancer

Small cell lung cancer

Renal cell cancer

Prostate cancer

Colorectal cancer

Myelo dysplastic syndrome Multiple myeloma

Acute myeloid leukemia

Triple-negative breast cancer

Melanoma

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Metastatic urothelial cancer (FDA approval May 2016)

Atezolizumab Adult Development Overall Survival Benefit in Patients with Non Small Cell Lung Cancer

9 Smith D, et al. ASCO 2016 [abstract 9028]

Atezolizumab vs. Docetaxel for Patients with Previously Treated NSCLC (POPLAR)

100

80

60

40

20

0 0 3 6 9 12 15 18 21 24 27

Time (months)

Ove

rall

Surv

ival

(%) Docetaxel

Atezolizumab

Censored

Median 9.7 months (95% CI, 8.6 -12.0)

Median 12.6 months (95% CI, 9.7 -16.0)

HR 0.69 (95% CI, 0.52 - 0.92)

P value = 0.011

Minimum follow-up = 12 months

N = 287 Intent to Treat

Atezolizumab Adult Development Demonstrates Activity Across Subgroups of PD-L1 Expression Levels

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NSCLC – POPLAR Study

Tumor Cell % of PD-L1- expressing cells Score

≥50% TC3

TC0 <1% TC1 ≥1% and <5% TC2 ≥5% and <50%

Immune Cell % of PD-L1- expressing cells Score

≥10% IC3

IC0 <1% IC1 ≥1% and <5% IC2 ≥5% and <10%

In favor of docetaxel

0.69

0.88

0.59

0.50

0.45

In favor of atezolizumab

N = 287 Intent to Treat

0.2 1 2 Hazard Ratio

Overall Prevalence

Proportion Subgroup

16% TC3 or IC3

TC0 and IC0 32%

TC1/2/3 or IC1/2/3 68%

TC2/3 or IC2/3 37%

Smith D, et al. ASCO 2016 [abstract 9028]

Antigen release

T cell recognition

T cell killing

Mutational Load Adult cancers

Pediatric cancers

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Adult cancers

Presence of Tumor Resident T cells Pediatric cancers

LB Alexandrov et al. Nature, 1-7 (2013).

Cancer Immunotherapy Biomarkers of Tumor Immunity in Adult vs Pediatric Cancers

1 7

6

5 Infiltration of T cells into tumors

PD-L1 Expression

Adult cancers Pediatric cancers

1000

100

10

1.0

0.1

0.01

0.001

Som

atic

mut

atio

n pr

eval

ence

(n

umbe

r mut

atio

ns p

er m

egab

ase)

Tumor

Mutational Load

Adult cancers Pediatric cancers

Cancer Immunotherapy Mutational Load Across Adult and Pediatric Tumor Types

LB Alexandrov et al. Nature, 1-7 (2013)

1000

100

10

1.0

0.1

0.01

0.001

Som

atic

mut

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n pr

eval

ence

(n

umbe

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egab

ase)

* Additional Publications: Lung adenocarcinoma: McGranahan N, Furness AJS, Rosenthal R, et al. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science 10.1126/science.aaf490 (2016). Melanoma: McGranahan N, Furness AJS, Rosenthal R, et al. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science 10.1126/science.aaf490 (2016)┃Snyder A, Makarov V, Merghoub T. et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N. Engl. J. Med. 2014;371:2189-2199┃Van Allen EM, Miao D, Schilling B, et al. Genomic correlates of response to CTLA-4 blockade in metastatic melanoma. Science 2015;350:207-21┃Hugo W, Zaretsky JM, Sun L, et al. Genomic and transcriptomic features of response to anti-PD-1 therapy in metastatic melanoma. Cell 2016;165:35-44. Lung-small cell: McGranahan N, Furness AJS, Rosenthal R, et al. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science 10.1126/science.aaf490 (2016). Colon: 1. Le D. T., Uram J. N., Wang H. et al. PD-1 blockade in tumors with mismatch-repair deficiency. N. Engl. J. Med. 2015;372:2509-2520.

Tumor

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Antigen release

1

PD-L1 Expression

Adult cancers Pediatric cancers

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Cancer Immunotherapy PD-L1 Expression in Adult and Pediatric Tumors

PD-L1 / PD-1 Pathway Atezolizumab (aPD-L1)

Tumor T cell recognition

T cell killing 7

6

Rhabdomyosarcoma

Colon Cancer

Presence of Tumor Resident T cells

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Cancer Immunotherapy Evidence of Pre-existing Immune Infiltrate in Adult and Pediatric Tumors

Adult cancers Pediatric cancers Tumor

5 Infiltration of T cells into tumors

Colon Cancer

Rhabdomyosarcoma

Pediatric Biomarker Development

• Unselected pediatric population chosen for Phase I to ensure: – We did not prematurely exclude any children who could potentially benefit – We could collect robust data to optimize our biomarker understanding and development

• Planned evaluation of CD8+ T-cell infiltration PD-L1 expression, and antigen-specific T-cell responses in addition to other immune markers

• Biomarker findings will be utilized to guide amendments to the current protocol, and to the design of future studies

Atezolizumab Pediatric Development Broad Spectrum Biomarker Research Ongoing

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Atezolizumab Pediatric Development Proactive Study Evaluating Multiple Tumor Types

• Age <30 yrs • Relapsed, refractory pediatric

solid tumors • No known curative options • IHC PD-L1 expression not required

Atezolizumab IV q3 weeks while experiencing clinical benefit Dose: < 18 years = 15 mg/kg * ≥18 years = 1200 mg

Primary Endpoints: • PK • Safety • Efficacy: ORR (CR or PR), PFS

Secondary Efficacy Endpoints:

• DOR • OS

Phase I/II: Single Arm Study Designed to Evaluate the Safety, Tolerability, Pharmacokinetics, Immunogenicity & Preliminary Efficacy

16 IHC= Immunohistochemistry; PK=Pharmacokinetics; ORR= Overall Response Rate; CR= Complete Response; PR=Partial Response; PFS= Progression Free Survival; DOR= Duration of Response; OS= Overall Survival. * Maximum pediatric dose 1200mg.

Multiple Tumor Types: Known or Expected PD-L1 Pathway

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Atezolizumab Pediatric Development Gated Study Design

Gate 1 PK/ Safety Check

PK/Safety Additional Response Assessment Efficacy Confirmation

iMATRIX (Phase I/II) Pivotal

Further gates for futility Gate 2 Initial Response

Assessment

Gate 3 Additional Response

Assessment Initial Response

Assessment

• First 5 patients enrolled ≥2 years of age

• Minimum of 20 patients

• Early PK and Safety Evaluation

• Will occur when tumor type cohort reaches ~10 patients

• Decision will be made whether or not to continue enrollment in that tumor type based on disease-specific criteria (for most tumor types 2 – 3/10 need to show an objective response)

• Retrospective biomarker analysis

Investigational sites: 24 sites (ITCC, EU, Israel), 10 sites (POETIC, US).

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Atezolizumab Pediatric Development Gated Study Status

PK/Safety Additional Response Assessment Efficacy Confirmation

Pivotal

Initial Response Assessment

As of June 1, 2016:

Total Patients Enrolled 67

Median Age 14 years

Age Range 2 – 29 years

Wilms’ Tumor, Rhabdomyosarcoma, Hodgkin Lymphoma, Non-Hodgkin Lymphoma, Soft Tissue Sarcoma, Osteosarcoma, Ewing Sarcoma & Neuroblastoma

• First Patient In (FPI), November 2015 • iDMC, March 2016 • iDMC, May 2016 • Preliminary Pharmacokinetic Data: exposure in pediatric

patients is similar to exposure in adult patients - No recommended dose modifications at this time

• Robust Safety Monitoring Plan Ongoing - No study conduct changes recommended by iDMC at

this time

iMATRIX (Phase I/II)

iDMC = independent Data Monitoring Committee.

Gate 1 PK/ Safety Check Further gates for futility Gate 2

Initial Response Assessment

Gate 3 Additional Response

Assessment

Cancer Immunotherapy Future Opportunities

Chen DS, Mellman I. Immunity. 2013.

Release of cancer cell antigens Chemotherapy, Radiation therapy Targeted therapy (BRAFi or MEKi)

Cancer antigen presentation Vaccines, IFN-a, GM-CSF

Anti-CD40 (agonist) TLR agonist

Priming and activation Anti-PD-L1, Anti-PD-1, Anti-CTLA-4

Anti-CD137 (agonist), Anti-OX40 (agonist) Anti-CD27 (agonist), IL-2, IL-12

Trafficking of T cells to tumors

Infiltration of T cells into tumors Anti-VEGF

Recognition of cancer cells by T cells

CAR-T cells

Killing of cancer cells Anti-PD-L1, Anti-PD-1

IDO inhibitors 1

2

3

4

5

6

7

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Continue to collaborate and utilize latest research findings to support and prioritize the development of new therapies for children with high unmet needs

Lymph node Blood vessel

Tumor

iMATRIX Trial Concept

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Ph3 – Disease 1 ADULT Ph1/2 Studies Ph3- Disease 2 Ph3 – Disease 3

Preclinical

assessment for pediatric use

PEDIATRIC Tumor A

PEDIATRIC Tumor B

PEDIATRIC Tumor C

Efficacy Signal/Safety? P2 Cohort Expansion Yes

No

Efficacy Signal/Safety? P2 Cohort Expansion Yes

No

Efficacy Signal/Safety? P2 Cohort Expansion Yes

No

PEDIATRIC Ph1 Study

Molecule #1 Study

Molecule #2 Study

Molecule #3 Study

Cross Tumor

PK & Safety Assessment

Match Promising Molecules to Pediatric Patients with High Unmet Needs

Key Conclusions & Next Steps

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• Atezolizumab is a humanized, monoclonal antibody which binds to PD-L1 to restore the anti-tumor immunity mediated by T cells

• Atezolizumab is well tolerated and demonstrates clinical efficacy across tumor types & subgroups in adults

• Voluntary pediatric study of atezolizumab is ongoing as part of our iMATRIX platform which matches promising molecules to pediatric patients with high unmet medical needs

- Rigorous and consistent PK, safety and efficacy assessment - Comprehensive biomarker evaluation - Strong collaboration with academic consortium and health

authorities

THANK YOU

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Increase in CD8 T Cells in Pseudoprogressing On-treatment Brain Lesions

Scale bars represent 50 µm

CD

8 P

D-L

1

TC0; IC0 TC0; IC0 TC0; IC0 TC0; IC0 TC0; IC0 TC0; IC1

Pre-Treatment On-Treatment with Atezo

Bx1 Bx2 Bx3 Bx4 Bx5 Bx6

0

5

10

15

20

0 1 2 3 4 5 6

%C

D8

Pos

itive

are

a in

Tu

mor

CN

Patient Biopsies

CD8 IHC Quantification Across Samples Bx1. brain Bx2. thigh Bx3. small bowel Bx4. brain (Responding lesion) Bx5. brain (Responding lesion) Bx6. small bowel (Non- Responding lesion)

OHSU Collaboration: Single Patient IND 23