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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 Page 2 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 Page 3 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 Page 4 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 Page 5 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 Page 6 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 Page 7 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 Page 8 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 Page 9 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 Page 10 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 Page 11 Indication Selection & Patient Enrichment: ICOS RNA expression in TCGA Highest ICOS Levels in Head and Neck and Lung Cancers © 2017 Jounce Therapeutics Page 12 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 Page 13 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 Page 14 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 Page 15 Mutations: Triple Negative Breast Cancer © 2017 Jounce Therapeutics Page 16 Smoking: Non-Small Cell Lung Cancer © 2017 Jounce Therapeutics Page 17 Viral Status: Head and Neck Squamous Cell Carcinoma © 2017 Jounce Therapeutics Page 18 ICOS is expressed on a small subset of PDL1 low NSCLC tumors © 2017 Jounce Therapeutics Page 19 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 Page 20 Thank you! © 2017 Jounce Therapeutics Page 21