Download Biomarker-driven indication and patient selection in the ICONIC trial

Biomarker-driven indication and patient selection in
the ICONIC trial
Beth Trehu, MD, FACP
© 2017 Jounce Therapeutics
Page
Biomarker-driven indication and patient selection in the ICONIC trial
•
•
•
How a translational science platform can optimize clinical
development in immuno-oncology
Use of preclinical data to prioritize clinical indications
Linking preclinical biomarkers to patient enrichment strategies in early
clinical development
© 2017 Jounce Therapeutics
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Jounce Translational Science Platform
Comprehensive Interrogation of the TME to Develop a Sustainable Innovative Pipeline
Patient enrichment
strategies
using predictive
biomarkers
Comprehensive
interrogation
of the TME
Sustainable
immunotherapy
pipeline
Identifying optimal immune
cell targets and developing
new immunotherapies
© 2017 Jounce Therapeutics
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JTX-2011: Agonist Monoclonal Antibody that Targets ICOS
ICOS: T cell Surface Protein Receptor with Strong Target Rationale
• Key clinical observations support ICOS as a target for cancer
immunotherapy
• Significant anti-tumor activity seen in preclinical studies
• Preclinical data supports use as both a single agent and in
combination
• Potential predictive biomarkers identified for patient enrichment
strategies
© 2017 Jounce Therapeutics
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Clinical Data Supports ICOS as Immunotherapy Target
Chen et al, PNAS (2009);
Carthon et al, Clin Can Res (2010);
Tang et al, Canc Immunol Res (2013)
• Monitoring immune system changes in pre- and post-Yervoy™-treated patients
• Sustained upregulation of ICOS on CD4(+) lymphocytes in responding patients
Founders’ data suggest that ICOS activates an
immune-based anti-tumor response
© 2017 Jounce Therapeutics
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JTX-2011 Dual Mechanism
Shifts Balance of T Cells Towards Anti-tumor Activity
APC
NK cell
JTX-2011
1st signal
ICOS
TCR
↑ICOS
↑↑ IFN-γ
↑↑ IFN-γ
X
T regulatory cell
T effector cell
Activation of T eff
Reduction of T regs
Dual mechanism of action
© 2017 Jounce Therapeutics
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Single Agent Development of JTX-2011
Supported by Long-Lasting Response in Preclinical Tumor Models
Anti-ICOS
Control
1400
1/10
1200
7/10
1200
1000
1000
800
800
600
600
400
400
200
200
0
Tumor free /
animals treated
Sa1/N Tumors
0
10
20
30
40
0
10
20
30
40
Days post-inoculation of tumor cells
A n im a ls c u r e d o f t u m o r s a r e
im m u n e t o t u m o r r e -c h a lle n g e
3
0
T u m o r v o lu m e (m m )
Tumor volume (mm3)
1400
Animals “cured”
from Sa1/N
studies rested for
10 weeks
1500
N o p r io r
tre a tm e n t
1000
500
A n im a ls p re v io u s ly
c u re d b y a n ti-IC O S
0
0
10
20
30
40
D a y s a fte r tu m o r r e - c h a lle n g e
© 2017 Jounce Therapeutics
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Combination Development of JTX-2011 with Anti-PD-1
Supported by Enhanced Anti-tumor Activity in Preclinical Models
Control antibody
Anti-PD-1
2000
2000
1500
1500
0/10
Tumor free /
animals treated
6/10
1000
1000
500
500
Tumor volume (mm3)
CT26 Tumors
0
0
0
10
20
30
0
40
10
20
30
40
D a y s P o s t - In o c u la t i o n
D a y s P o s t - In o c u la t i o n
Anti-ICOS + Anti-PD-1
Anti-ICOS
2000
2000
1/10
8/10
1500
1500
1000
1000
500
500
0
0
0
10
Days
20
30
40
0
10
20
30
40
Days
tumor
a y s Pcells
o s t - In o c u la t i o n
P o s t - In o c u la
t i o n post-inoculation of D
© 2017 Jounce Therapeutics
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Patient Selection Strategy Supported by Mouse Models
Better Efficacy in Tumors Expressing Higher Levels of Intra-Tumoral ICOS
B16/SIY
LLC1
T
0
2+
Tumor
ICOS IHC
Score
Single Agent
Efficacy
Combination Efficacy
(+ anti-PD-1)
Sa1/N
3+
++++
ND
B16-SIY
2+
+++
++++
MC38
1+
+
+++*
CT26
CT26
1+
1+
+
+
++++
EMT6
EMT6
1+
1+
+
+
+/-
LLC1
LLC1
0
0
--
+
++++ ≥70% tumor regression
*Intra-tumoral levels of ICOS+ T cells increases post PD-1 treatment
© 2017 Jounce Therapeutics
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Patient Enrichment:
Patients with High ICOS on Tumor T cells May be More Likely to Respond
Tumor cells
(gold)
CD4(+) T cells
expressing ICOS
target within human
tumors (green)
T regulatory cells
(red and green)
© 2017 Jounce Therapeutics
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An Integrated Approach to Understanding ICOS in the Context of Immune
Oncology Landscape
Collaborations with premier Institutions
1000s of human tumors interrogated
Integrated TCGA and Internal Data Analysis
Adaptive immune cells
Innate immune cells
Stromal cells
© 2017 Jounce Therapeutics
Pinpointing patients
for our clinical trials
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Indication Selection & Patient Enrichment: ICOS RNA expression in TCGA
Highest ICOS Levels in Head and Neck and Lung Cancers
© 2017 Jounce Therapeutics
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Indication Selection & Patient Enrichment
ICOS Immunohistochemistry (IHC)
1
ICOS protein levels within high ICOS indications vary across
individual patients
None
1+
2+
3+
100
%Tumors
2
ICOS protein levels vary across
indications
(n=94)
50
Re
na
Br l
ea
Bl st
ad
d
Ov er
ar
Pr ian
os
St tate
om
ac
h
Co
Me lo
lan n
om
a
TN
BC
Lu
HN ng
SC
C
0
None (0)
Low (1+)
Medium (2+)
(n=204)
High (3+)
© 2017 Jounce Therapeutics
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ICONIC: Adaptive, Biomarker-Driven Clinical Study
Phase 2 Preliminary Efficacy Proof-of-Concept
Phase 1
Phase 2
Safety, PK and PD
Preliminary Efficacy
Enriched for pts with high ICOS
expression
All-comers, no enrichment for ICOS expression
Dose escalate to anticipated clinically effective dose
NSCLC
A
Single Agent
Dose
Escalation
C
Single
agent
HNSCC
Any solid tumor type
New indications based on
emerging science*
PK/PD Expansions
Pivotal
NSCLC
B
Combo
with nivolumab
Dose
Escalation
D
PK/PD Expansions
Trials
HNSCC
Combo
TNBC
with
Nivolumab
Melanoma
Gastric
New indications based
on emerging science*
* Additional indications, including niche indications, identified
through our Translational Science Platform
© 2017 Jounce Therapeutics
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An Integrated Approach to Understanding ICOS in the Context of Immune
Oncology Landscape
Is ICOS expression higher in patients with specific mutations? (e.g KRAS, BRAF or BRCA)?
•
Genetic testing routinely done in the clinic in some indications
Is ICOS expression higher in smoking patients?
•
There is suggestion that lung cancer patients with smoking history respond better to antiPD1/PDL1.
Does viral status matter in indications with known viral associations?
•
Virally infected tumors tend to be more immunogenic and viral testing is common in clinic
Is ICOS expression higher in tumors non responsive to anti-PD-1/L1?
•
Can we understand if potential ICOS patients are also positive for Bmx for
these therapies?
Are there other tumor types/contexts with high ICOS expression?
•
Do integrative analyses of tumor samples provide additional
suggestions?
© 2017 Jounce Therapeutics
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Mutations: Triple Negative Breast Cancer
© 2017 Jounce Therapeutics
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Smoking: Non-Small Cell Lung Cancer
© 2017 Jounce Therapeutics
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Viral Status: Head and Neck Squamous Cell Carcinoma
© 2017 Jounce Therapeutics
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ICOS is expressed on a small subset of PDL1 low NSCLC tumors
© 2017 Jounce Therapeutics
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ICONIC: Adaptive, Biomarker-Driven Clinical Study
Phase 2 Preliminary Efficacy Proof-of-Concept
Phase 1
Phase 2
Safety, PK and PD
Preliminary Efficacy
All-comers, no enrichment for ICOS expression
Dose escalate to anticipated clinically effective dose
Enriched for pts with high ICOS
expression
NSCLC
A
Single Agent
Dose
Escalation
C
Single
agent
HNSCC
Any solid tumor type
PK/PD Expansions
New indications based on
emerging science*
Pivotal
Trials
NSCLC
B
Combo
with nivolumab
Dose
Escalation
HNSCC
D
PK/PD Expansions
Combo
TNBC
with
Nivolumab
Melanoma
Gastric
* Additional indications, including niche indications, identified
through our Translational Science Platform
New indications based
on emerging science*
© 2017 Jounce Therapeutics
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Thank you!
© 2017 Jounce Therapeutics
Page 21