Keynote Lecture 2 Targeting the Tumor Microenvironment in Pancreatic Cancer

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1 Keynote Lecture 2 Targeting the Tumor Microenvironment in Pancreatic Cancer E. Gabriela Chiorean, MD University of Washington Fred Hutchinson Cancer Research Center Seattle, Washington, United States

2 Learning Objectives Review key compartments in tumor microenvironment Review immunosuppressive mechanisms in pancreatic cancer (PC) Targeting the tumor microenvironment: Extracellular matrix: Hyaluronic acid Focal adhesion kinase Mesenchymal cells: Pancreas stellate cells Hematopoietic cells: Tumor associated macrophages Myeloid derived suppressor cells: Gr, Mo T regs B regs How to help immunotherapies work in PC?

3 Genetic Progression Model of Pancreatic Cancer Immunosuppressive stroma CDKN2A p16 DNA damage checkpoint Bardeesy N, et al. Nat Rev Cancer. 2002;2(12):

4 Tumor Epithelial Cells and Stroma Interactions in Pancreatic Cancer KRAS FAK PI3K WNT Stromnes IM, et al. Carcinogenesis. 2014;35(7):

5 Prognosis of Desmoplasia in Pancreatic Cancer 24 m vs 9 m 15 m vs 6 m Whatcott C, et al. Clin Cancer Res. 2015;21(15): M, months

Targeting the Tumor-Stroma Interactions in Pancreatic Cancer IDO inhibitors CD40 agonist CCR2 inhibitors CSF1R inhibitors CXCR2 CXCR4 inhibitors FAK FAK inhibitors

6 Targeting the Tumor-Stroma Interactions in Pancreatic Cancer IDO inhibitors CD40 agonist CCR2 inhibitors CSF1R inhibitors CXCR2 CXCR4 inhibitors FAK FAK inhibitors PEGPH20 IDOi CXCR4i Vitamin D receptor therapy FAK, focal adhesion kinase; IDO, indoleamine 2,3 dioxygenase Stromnes IM, et al. Carcinogenesis. 2014;35(7):

gemcitabine-resistant human pancreas cancer xenograft Von Hoff DD, et al.

7 nab-paclitaxel: Preclinical Evidence of Stromal Collapse Immunohistochemistry (IHC) for collagen 1 fibers in a gemcitabine-resistant human pancreas cancer xenograft Von Hoff DD, et al. J Clin Oncol. 2011;29(34): Intratumoral concentration of gemcitabine in human pancreas cancer xenograft

PEGPH20 Degrades Hyaluronan in the Tumor Microenvironment Hyaluronan (HA) Naturally occurring linear polysaccharide and major component of the tumor stroma 1 HA accumulation increases tumor

8 PEGPH20 Degrades Hyaluronan in the Tumor Microenvironment Hyaluronan (HA) Naturally occurring linear polysaccharide and major component of the tumor stroma 1 HA accumulation increases tumor interstitial fluid pressure, which in turn compresses blood vessels and compromises blood flow 2,3 HA accumulation is associated with accelerated tumor growth and is an independent, negative predictor of survival 4 PEGPH20 (pegvorhyaluronidase alfa) A PEGylated form of recombinant human hyaluronidase PH20, which degrades HA and remodels the tumor stroma 1. Minchinton AI, et al. Nat Rev Cancer. 2006;6(8): Thompson CB, et al. Mol Cancer Ther. 2010;9(11): Provenzano PP, et al. Cancer Cell. 2012;21(3): Whatcott C, et al. Clin Cancer Res. 2015;21(15):

9 HALO-202: Phase II Randomized Study of Gem/Nab-Paclitaxel ± PEGPH20 Stage IV PDA PAG PEGPH20 + nab-paclitaxel + Gemcitabine KPS: N=279 N = 279 AG nab-paclitaxel + Gemcitabine Primary Endpoints: PFS Thromboembolic event rate Secondary Endpoints: PFS by HA Level ORR OS Exploratory Endpoints: OS by HA Level DoR DCR (CR+PR+SD) Primary & secondary PFS endpoint: 80% power at 2-sided alpha level of 0.1 CR, complete response; DCR, disease control rate; DoR, duration of response; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PR, partial response; SD, stable disease Hingorani SR, et al. J Clin Oncol. 2017;35(suppl):Abstract 4008.

10 Primary Efficacy Endpoint: PFS Kaplan-Meier Estimate of Progression-Free Survival, % PAG (n = 166 ) AG (n = 113) Events Median PFS 6.0 months 5.3 months HR (95% CI) 0.73 ( ) P value At Risk, n PAG 166 AG 113 PAG AG Study Duration, Months Hingorani SR, et al. J Clin Oncol. 2017;35(suppl):Abstract 4008.

11 Secondary Endpoint: PFS HA-High Kaplan-Meier Estimate of Progression-Free Survival, % At Risk, n PAG AG 100 PAG PAG AG Study Duration, Months (n = 49) AG (n = 35) Events Median PFS 9.2 months 5.2 months HR (95% CI) 0.51 ( ) P value Hingorani SR, et al. J Clin Oncol. 2017;35(suppl):Abstract 4008.

12 Other Phase II and III Clinical Trials With PEGPH20 HALO-301 Phase III 2 Gemcitabine/nab-Paclitaxel + PEGPH20 vs placebo HA-High Phase II FOLFIRINOX ± PEGPH20 3 µg/kg q 2 w SWOG S Unselected population - DSMB stopped study for futility 04/ Why? - PEGPH20 dose less frequent? - Drug interaction? - More toxicity and less chemo exposure? DSMB, Data and Safety Monitoring Board 1. National Institutes of Health NCT Accessed on 26 September 2017.

13 Stroma Remodeling With Vitamin D Receptor Ligand Calcipotriol Deactivates Pancreas Stellate Cells Sherman MH, et al. Cell. 2014;159(1):80-93.

14 Stroma Remodeling With FAK Inhibition CTL CD8+ FOXP3 T reg Jiang H, et al. Nature Med (8):

15 Immunosuppressive Stroma in Pancreatic Cancer CD45 staining Clark CE, et al. Cancer Res. 2007;67(19):

16 Immunosuppressive Mechanisms in PC Genetic factors: Few somatic mutations vs 1000s (MSI-H) Physical factors: High interstitial pressure and dense stroma Cellular factors: Immunosuppressive cells: Granulocytic > Monocytic MDSCs M2 TAMs T reg, B reg Molecular factors: Immunosuppressive cytokines IDO CCL2 CXCL12 GM-CSF TGFβ MDSC, myeloid-derived suppressor cells; MSI-H, high-frequency microsatellite instability

17 Mutation Burden From TCGA BioPortal mutations Borazanci E, et al. Clin Cancer Res. 2017;23(7):

18 PD-1 Inhibition in MSI-H Non-CRC Cancers MSI-high dmmr n = 86 Le DT, et al. Science. 2017;357(6349):

19 Therapy of T-Cell Poor & T-Cell Inflamed Tumors Differ Substantially Therapy to bring T cells into tumors Followed by anti PD-1 Therapy with anti PD-1 In concert with agents to inhibit suppressive cells & cytokines Gajewski TF, et al. Curr Opin Immunol. 2013;25(2):

20 Remodeling Stroma to Enhance Response to Immune Therapies PEGPH20 HA-High extracellular matrix protects cancer cells from immune cell surveillance 1 Remodels the tumor stroma and allows infiltration of cytotoxic T lymphocytes, NK cells 2 Enhances antibody access (2-3x) 2,4 Enhanced IDO-ST mediated tumor regression 3 Enhanced PD-1 inhibitor mediated tumor regression 4 FAK inhibition synergizes with chemo and immunotherapies Vitamin D Receptor therapy Calcipotriol (ligand) reduces inflammation, fibrosis 5 Paricalcitol (modified Vitamin D): Allows T cell entry into tumors CD40 agonist allows infiltration with M1 macrophages and T cells, 6 converts M2 to M1, activates CD8 nab-paclitaxel/gemcitabine: Depletes collagen Generates neo-antigens, depletes MDSCs, T regs BX: IHC immune cells 1. Dick SJ, et al. Science. 1983;220(4598): Singha NC, et al. Mol Cancer Ther. 2015;14(2): Manuel ER, et al. Cancer Immunol Res. 2015;3(9): Rosengren S, et al. AACR 2016, abstract Sherman MH, et al. Cell. 2014;159(1): Beatty GL, et al. Science. 2011;331(6024):

21 Baseline After 2 cycles: Gem/nab-P + Nivolumab New liver metastases Phase Ib Trial After 6 cycles: Nivo alone (> cycle 2) Complete response in liver mets Gemcitabine + nab-paclitaxel + Nivolumab 1 st line metastatic PC Available at: NCT Accessed: September 28, 2017

22 Baseline After 2 cycles: Gem/nab-P + Nivolumab: Progression After 6 cycles: Nivo alone (> Cycle 2) PR

Phase I/II Study of FOLFIRINOX + CCR2i in Locally Advanced

cancer Depletion of TAM in tumors Decreased mobilization

response rate TAM, tumor-associated macrophages; RR,

23 Phase I/II Study of FOLFIRINOX + CCR2i in Locally Advanced Pancreatic Cancer RR 50% in locally advanced pancreas cancer Depletion of TAM in tumors Decreased mobilization of CCR2+ monocytes in peripheral blood Adequate safety 49% response rate TAM, tumor-associated macrophages; RR, response rate Nywening TM, et al. Lancet Oncol. 2016;17(5):

24 Effect of FOLFIRINOX Plus CCR2 Inhibitor on TAM in the Tumor Microenvironment Tumor-associated macrophages CD8 T cells CD4 T cells Regulatory T cells Nywening TM, et al. Lancet Oncol. 2016;17(5):

25 Phase I CD40 Agonist With Gemcitabine in Metastatic Pancreas Cancer Beatty GL, et al. Science. 2011;331(6024):

26 CD40-Activated Tumor-Infiltrating Macrophages Mediate Tumor Regression and Deplete Stroma Beatty GL, et al. Science. 2011;331(6024):

27 PEGPH20 + IDO Inhibition Controls KPC Pancreas Tumor Growth KPC, LSL-Kras G12D/+ ;LSL-Trp53 R172H/+ ;Pdx-1-Cre mouse model Manuel ER, et al. Cancer Immunol Res. 2015;3(9):

28 Chiorean EG, et al FDA-approved PCRT Phase II Study of PEGPH20 + Pembrolizumab in Refractory Metastatic HA-High PC N = 35 PFS: 3m 6 m PEGPH20 Days 1, 8, 15 + Pembrolizumab Day 1 PEGPH20 Days 1, 8, 15 + Pembrolizumab Day 1 PEGPH20 Days 1, 8, 15 + Pembrolizumab Day 1 P D Cycle 1 (weeks 1-3) Cycle 2 (weeks 4-6) Cycle 3 (weeks 7-9) NSAIDs will be used to manage MSE if tolerable Steroids will be used only for intolerable MSE All patients will receive LMWH Biopsy HA/PD-L1 level Immunological biomarkers: IHC immune cells, RNA seq, flow, genomics Blood: Cytokine, flow cytometry Biopsy HA Immunological biomarkers: IHC, flow Blood: Cytokine, flow Biopsy (if possible) Blood

29 FAK Inhibition + Anti-PD-1 CTL CD8+ FOXP3 T reg Jiang H, et al. Nature Med (8):

30 Summary of Microenvironment Targeted Therapies Class Target Combination Strategies Examples HA inhibitor Hyaluronic acid chemotherapy Anti-PD-1 PEGPH20 FAK inhibitor CTF inhibitor Vit D receptor analog Focal adhesion kinase (FAK) Connective tissue factor (CTF) Pancreas stellate cells (PSC) chemotherapy Anti-PD-1 VS4718 chemotherapy FG3019 chemotherapy Anti-PD-1 Paricalcitol CD40 agonists TAM, CD4 chemotherapy Anti-PD-1 RO IDO inhibitors CD8, T reg, tolerant DC chemotherapy Anti-PD-1 Indoximod, Epacadostat CCR2 inhibitors TAM-M2 chemotherapy PF , CCX872 CSF1R inhibitors TAM-M2 Anti-PD-1 PLX3397, ARRY382 CXCR2 inhibitors Gr-MDSCs chemotherapy Anti-PD-1 AZD5069 CXCR4 inhibitors Mo-MDSCs, chemotaxis T cells Anti-PD-L1 BTK inhibitors B reg chemotherapy Anti-PD-1/PD-L1 Ibrutinib Ulocuplumab, BL-8040, Plerixafor

31 Conclusions Tumor epithelial cells (TEC) and the microenvironment are interconnected and create an immune-privileged and drug-resistant sanctuary tumor development and progression treatment resistance Combined targeting: - TEC with chemotherapy (or molecularly targeted agents when strong genomic driver) - Microenvironment with stromaand immune-targeting therapies

Future Perspectives in mpca. Michel Ducreux, MD, PhD Gustave Roussy Villejuif, France

Future Perspectives in mpca. Michel Ducreux, MD, PhD Gustave Roussy Villejuif, France Future Perspectives in mpca Michel Ducreux, MD, PhD Gustave Roussy Villejuif, France Number of Novel Therapies and Targets in Pancreatic Cancer Are Expanding Garrido-Laguna I, et al. Nat Rev Clin Oncol.