Think Differently: Challenges in Immunotherapy

SITC CICT: Challenges and Solutions

April 5th 2013

Daniel S. Chen MD PhD

Associate Group Director
Anti-PDL1 Global Development Leader
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Presenter Disclosure Information: 2

Daniel S. Chen

<YOUR NAME HERE>

The following relationships exist related to this presentation:

Employee of Genentech, a member of the Roche Group

I will not be discussing the off-label usage of any Genentech or Roche

approved drugs

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What’s Up with Immunotherapy?

Unlike most traditional anti-cancer therapy…

…Immunotherapy relies on the

function of immune cells

Chemotherapy
(tubulin stabilizing agent epothilone)
Prota 2013

Oncogene Target
(bRAF mutated melanoma)
Hsieh 2012
Tumor Cell Target
(Her2neu expressing breast cancer)

Mellman et al. 2011

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Relying on an Intact Immune System

Need to understand a complex network

of cells, compartments and cytokines

BMC Genomics 2008

Bodenmiller, Nature BioTech 2012

CD8 FoxP3

Smith, BioTechniques 2012

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Immunotherapy vs Targeted Therapy

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Drug Development Cycle

33-6
-6 Years
Years 66-7
-7 Years
Years 11-2
-2 Years
Years

Target FDA Lg-

Drug Pre- Clinical Trials scale
ID Discovery Clinical Review
MFG
IND NDA
Post Marketing
Phase I Phase II Phase III Phase IV

5,000-10,000 compounds 5 compounds 1 FDA Approval

Duration: 10-15 Years

Cost: >1 billion US Dollars

• Dose & schedule

• Biologic plausibility • Safety
• Pre-clinical activity • PD biomarkers
• Biomarker ID • Estimate efficacy
• Acceptable tox • Evaluate predictive biomarker
• Confirm efficacy
• Validate predictive biomarker

DiMasi 2003
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Drug Development Cycle: Pre-clinical

33-6
-6 Years
Years 66-7
-7 Years
Years 11-2
-2 Years
Years

Target FDA Lg-

Drug Pre- Clinical Trials scale
ID Discovery Clinical Review
MFG
IND NDA
Post Marketing
Phase I Phase II Phase III Phase IV

5,000-10,000 compounds 5 compounds 1 FDA Approval

Duration: 10-15 Years

Cost: >1 billion US Dollars

• Biologic plausibility
• Pre-clinical activity
• Biomarker ID
• Acceptable tox

Complex biology/biomarkers
Challenging pre-clinical models
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 How Well Do Pre-clinical Models 8

Predict Human Immunobiology?

• Intact immune system required
• Limited syngeneic models
• Immunogenicity of antigens
• Tumor immune microenvironment differences?
• Intrinsic vs adaptive immune suppression
• Variability in models
• Genetic diversity vs human tumors

Dillow 2010 Human breast cancer

Irving et al (Genentech) Ruffell et al 2012

Kowanetz et al (Genentech) Huseni et al (Genentech)

Complex biology/biomarkers
Challenging pre-clinical models
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 Drug Development Cycle: 9

Early Clinical Development

33-6
-6 Years
Years 66-7
-7 Years
Years 11-2
-2 Years
Years

Target FDA Lg-

Drug Pre- Clinical Trials scale
ID Discovery Clinical Review
MFG
IND NDA
Post Marketing
Phase I Phase II Phase III Phase IV

5,000-10,000 compounds 5 compounds 1 FDA Approval

Duration: 10-15 Years

Cost: >1 billion US Dollars

• Dose & schedule

• Safety
• PD biomarkers

Starting dose
Dose and schedule
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Immunotherapy Dose and Schedule 10

Can Be Challenging
Starting Dose:
•MABEL vs NOAEL
•Minimal efficacious dose
•Maximum tolerated dose
Schedule:
Persistent immune activation may
complicate identification of a schedule www.dlsweb.rmit.edu.au

•Single dose?
•4 doses
•Dose for 1 year?
•Dose until PD or CR?
•Tx duration confounded by
pseudoprogression
Endpoint: Long term OS
•Long time to endpoint
•May require large studies to evaluate
the tail on the curve Hodi et al 2010

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 Drug Development Cycle: 11

Clinical Development
33-6
-6 Years
Years 66-7
-7 Years
Years 11-2
-2 Years
Years

Target FDA Lg-

Drug Pre- Clinical Trials scale
ID Discovery Clinical Review
MFG
IND NDA
Post Marketing
Phase I Phase II Phase III Phase IV

5,000-10,000 compounds 5 compounds 1 FDA Approval

Duration: 10-15 Years

Cost: >1 billion US Dollars

• Estimate efficacy
• Evaluate predictive biomarker

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Biomarkers: Non-invasive
PFS
Adjuvant OS
Time 0 Years
Metastatic Cancer Natural History Death
Location Primary Metastatic

1L 2L 3L

Kurdziel et al 2007

Njemini et al 2007

• Obvious advantages to being able to easily

assess a dynamic immune related biology
• Challenge related to whether tumor biology
is adequately reflected in blood
• Use of imaging as a biomarker for
immunotherapy will likely require additional
Gattinoni et al 2011
technology development
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Biomarkers: Tumor Tissue

PFS
Adjuvant OS
Time 0 Years
Metastatic Cancer Natural History Death
Location Primary Metastatic
1L 2L 3L

Dynamic immune environment

Differences between archival and met
Changes in immunogenicity
Changes following SOC therapy
Changes following immunotherapy

Representative IHC images

Metastatic samples likely to be limited
to a small core bx
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1NME Drug Development

33-6
-6 Years
Years 66-7
-7 Years
Years 11-2
-2 Years
Years

Target FDA Lg-

Drug Pre- Clinical Trials scale
ID Discovery Clinical Review
MFG
IND NDA
Post Marketing
Phase I Phase II Phase III Phase IV

5,000-10,000 compounds 5 compounds 1 FDA Approval

Duration: 10-15 Years

Cost: >1 billion US Dollars

• Dose & schedule

• Biologic plausibility • Safety
• Pre-clinical activity • PD biomarkers
• Biomarker ID • Estimate efficacy
• Acceptable tox • Evaluate predictive biomarker
• Confirm efficacy
• Validate predictive biomarker

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2NME Drug Development

33-6
-6 Years
Years 66-7
-7 Years
Years 11-2
-2 Years
Years

Target FDA Lg-

Drug Pre- Clinical Trials scale
ID Discovery Clinical Review
MFG
IND NDA
Post Marketing
Phase I Phase II Phase III Phase IV

5,000-10,000 compounds 5 compounds 1 FDA Approval

Duration: 10-15 Years

Cost: >1 billion US Dollars

• Dose & schedule of the combo: multiple potential MTDs

• Strong combo rationale • Safety: distinguish from monotx?
• Pre-clinical combo activity • PD biomarkers for combo
@ tolerable doses • Estimate efficacy in multiarm study
• Non-overlapping organ • Evaluate predictive biomarker for 1 or both
tox
• Biomarkers for combo • Confirm efficacy- contribution?
activity • Validate predictive biomarker
• Both drugs available
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2NME Drug Development

33-6
-6 Years
Years 66-7
-7 Years
Years 11-2
-2 Years
Years

Target FDA Lg-

Drug Pre- Clinical Trials scale
ID Discovery Clinical Review
MFG
IND NDA
Post Marketing
Phase I Phase II Phase III Phase IV

5,000-10,000 compounds 5 compounds 1 FDA Approval

Duration: 10-15 Years

Cost: >1 billion US Dollars

Combinations that show high activity with good

safety in early testing should be accelerated in
their development

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