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Advances in Cancer Immunotherapy for Solid Tumors Expert Perspectives on The New Data Sunday, June 5, 2016 Supported by an independent educational grant from AstraZeneca Not an official event of the 2016 ASCO Annual Meeting Not sponsored or endorsed by ASCO or the Conquer Cancer Foundation Disclaimer • This slide deck in its original and unaltered format is for educational purposes and is current as of Sunday, June 5, 2016. The content and views presented in this educational activity are those of the authors/presenters and do not necessarily reflect those of Creative Educational Concepts, Inc. or the supporter. • These materials may discuss therapeutic products that have not been approved by the US Food and Drug Administration and off-label uses of approved products. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or employing any therapies or strategies described in this educational activity. Usage Rights • This slide deck is provided for educational purposes and individual slides may be used for personal, non-commercial presentations only if the content and references remain unchanged. • No part of this slide deck may be published or distributed in print or electronic format without prior written permission from Creative Educational Concepts, Inc. Additional terms and conditions may apply. Learning Objectives 1. Evaluate the principles of tumor immunology and the mechanisms of action of current and emerging cancer immunotherapies used in solid tumors. 2. Appraise the latest clinical trial data regarding emerging cancer immunotherapies in SCCHN, NSCLC, mesothelioma, gastric cancer, melanoma, and other solid tumors, including use of both monotherapy and combination regimens. 3. Explore the role of biomarkers in patient selection to improve targeted use of immune checkpoint inhibitors. 4. Identify practical strategies for using current and emerging cancer immunotherapies, including prevention, early detection, and management of immune-related adverse effects. Cancer Immunotherapy in Solid Tumors Current Concepts Jeffrey S. Weber, MD, PhD Deputy Director Laura and Isaac Perlmutter Cancer Center Professor of Medicine NYU Langone Medical Center New York, New York Disclosures • I consult for and have received less than $10000 dollars per annum from BMS, Merck, Genentech, AstraZeneca, GSK, Novartis, Nektar Therapeutics, Medivation, Celldex Therapeutics, cCAM, CytomX, Lion Bioscience, Incyte and EMD Serono for membership on advisory boards • I hold equity in Celldex, CytomX and cCAM • I am not a member of any speakers’ bureau • My institution, but not me personally, received research support from BMS, Merck, GSK, Novartis and AstraZeneca • My laboratory receives research support from Mirati Therapeutics and Acetylon Pharmaceuticals, Inc. New Era in Cancer Therapy Harnessing The Immune System Reproduced from Immunity, Vol. 39, Daniel S. Chen and Ira Mellman, Oncology Meets Immunology: The Cancer Immunity Cycle, Page 2, Copyright 2013, with permission from Elsevier via Copyright Clearance Center. Activation of Antitumor T-Cells Two Signals Required Tumor or epithelial cells No T cell proliferation 1 APC’s (dendritic cells, macrophages) T cell proliferation 2 1 Sharma P, et al. Science. 2015. Cytokines Antitumor T-Cell Response How It Happens 3 Perforin granzyme Cytokines (IL-2) Resting T cell Tumor 1 T-cell clonal Tumor antigen expansion Activated T cell TCR MHC B7 Dendritic cell 2 CD28 Lymph node Immune Checkpoints Inhibitory and Stimulatory Effects Immune Checkpoints How Are They Defined? • Immune checkpoints modulate the duration and amplitude of the physiologic adaptive immune response. • Immune checkpoint signals can be ‘hijacked’ by cancer cells to allow for tumor growth that is unchecked by the immune system. • PD-L1, which binds PD-1, has been found to be expressed by almost all types of cancers. • Antibodies that target immune checkpoints can be used to “disinhibit” T cell responses against cancer. Immune Checkpoint Blockade CTLA-4 and PD-1/PD-L1 Inhibitors Reproduced from N Engl J Med, Antoni Ribas, MD, PhD, Tumor Immunotherapy Directed at PD-1, Vol. 366, Page 2518. Copyright © 2012 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society via Copyright Clearance Center. Tumor Rejection in Mice Anti-CTLA-4 mAb and GM-CSF Vaccine Hamster IgG 300 BL6/GM + Hamster IgG Anti-CTLA4 BL6/GM + Anti-CTLA4 200 100 Day 4 Post-Challenge Van Elsas A, et al. J Exp Med. 1999. 50 40 30 0 20 (0/5) 10 Mean Tumor Area (mm2) 400 Does Ipilimumab Cure Melanoma? Proportion Alive Long-Term OS Data 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Median OS (95% CI): 11.4 mos (10.7–12.1) 3-year OS Rate (95% CI): 22% (20–24%) Ipilimumab CENSORED 0 Patients at Risk Ipilimumab 1861 12 24 36 48 839 370 254 192 60 72 84 96 108 120 170 120 26 15 5 0 Months Hodi S, et al. ECC. 2013; Schadendorf D, et al. J Clin Oncol. 2015. Clinical Challenge When to Hold ‘em, When to Fold ’em? • Unique patterns of response are seen with checkpoint inhibitory immunotherapies − Traditional RECIST response with regression at week 12 − Slow response with prolonged SD followed by response − Progression followed by regression, with or without the development of new disease − Mixed response with regression in some disease and development of new disease followed by regression of the new disease Clinical Challenge (cont.) When to Hold ‘em, When to Fold ’em? • It is acceptable to continue therapy past week 12 with checkpoint inhibition if: − No decrease in performance status − No worsening of labs by more than one grade − No symptomatic worsening of disease − No major increase in disease burden (>50%) • I suggest getting an interim scan 6 weeks after continuing • If there is worsening of any of the above, or another 25% worsening in disease burden, time to fold ’em! • Otherwise, hold ’em and continue to week 24 Immune Checkpoint Blockade irAEs and Outcomes • Preclinical melanoma tumor models using CTLA-4 knock-outs have demonstrated enhanced immunemediated tumor rejection AND immune related depigmentation, but not irAEs as seen in patientsa • Although still somewhat controversial, irAEs do not seem to correlate with response;b,c irAEs do seem to correlate with response with PD-1 and PD1/CTLA-4 combinationsb-e but poorly with CTLA-4 blockade aloneb,c JS, et al. J Clin Oncol. 2012; bSpain L, et al. Cancer Treat Rev. 2016; cHorvat TZ, et al. J Clin Oncol. 2015; dDowney SG, et al. Clin Cancer Res. 2007; eFreeman-Keller M, et al. Clin Cancer Res. 2016. aWeber irAEs General Issues • Infections and other etiologies should be ruled out or deemed unlikely as contributing to the irAEs. • Most irAEs occur during the first 3-4 months. − Late irAEs, however, also can occur (eg, one episode has been seen at month 47 during maintenance phase of therapy). − Each irAE has different kinetics of onset and some can wax and wane, particularly colitis. • Steroids can be used to manage almost all irAEs. − Prolonged steroid tapers are required Weber JS, et al. J Clin Oncol. 2012; Weber JS, et al. ASCO. 2015; Weber JS, et al. J Clin Oncol. 2015. irAEs Colitis Focal Active Colitis Ulceration in Descending Colon Alterations in Crypt Epithelium Maker AV, et al. Ann Surg Oncol. 2005. T-Cell Tumor Immunity Adaptive Resistance Chen L, Han X. J Clin Invest. 2015. PD-1 Pathway Mechanisms of Immune Suppression Chen L, Han X. J Clin Invest. 2015. PD-1 Pathway Mechanisms of Immune Suppression B16BL6 Melanoma Antibody Rx + Cellular Vaccine MC38 Colon Cancer Antibody Rx Only 3000 2000 1000 0 0 10 20 30 Days 40 50 anti-PD-1 1/12 Tumor Free 3000 2000 1000 0 0 2000 1000 0 0 10 20 30 Days 40 50 20 30 Days 40 50 9/12 Tumor Free 3000 2000 1000 0 0 10 20 30 Days 40 50 75 50 25 0 B Untreated GVAX αCTLA-4 GVAX αCTLA-4/αPD-1 100 0 25 50 Days 75 100 100 Percent survival 0/12 Tumor Free 10 anti-PD-1+ anti-CTLA-4 Tumor Volume (mm³/2) Tumor Volume (mm³/2) anti-CTLA-4 3000 A Percent survival 0/12 Tumor Free Tumor Volume (mm³/2) Tumor Volume (mm³/2) mlgG 125 Untreated FVAX αCTLA-4 FVAX αPD-1 FVAX αCTLA-4/αPD-1 75 50 25 0 0 25 50 75 Days 100 125 Korman A, et al. J Immunol. 2007; Selby M, et al. ASCO. 2013; Curran, et al. PNAS USA. 2010. Nivo + Ipi vs Ipi in Advanced Melanoma OS at 2 Years of Follow-Up Probability of Overall Survival All Randomized Patients 1.0 NIVO + IPI (N=95) IPI (N=47) NR NR (11.9‒NR) Median OS, months (95% CI) 0.9 0.8 64%0.74 (0.43‒1.26)* HR (95% CI) *Exploratory endpoint: NR = not reached 73% 0.7 0.6 65% 0.5 54% 0.4 0.3 0.2 0.1 NIVO + IPI IPI 0.0 0 3 Number of Patients at Risk NIVO + IPI 95 82 IPI 47 41 6 9 12 77 36 74 33 69 29 15 18 21 24 27 30 67 27 65 26 63 25 57 22 6 3 0 0 Months 30/47 (64%) of patients randomized to IPI crossed over to receive any systemic therapy at progression Postow M, et al. AACR. 2016. CTLA-4 Blockade Durable Responses in Fraction of Patients Ipilimumab induces durable objective responses in a small fraction of patients leading to an OS plateau, but no shift of the early portion of the OS curve. “Hypothetical” Patients Alive ICB + Complementary TX PD-1/PD-L1 Blockade CTLA-4 Blockade 1 2 3 Years Ott PA, et al. Clin Cancer Res. 2013. 4 Boosting Antitumor Immunity Targeting Four Nodes Node 1 Blocking Immune Suppression PGE2 MDSC Adenosine NKG2A KIR TGF-β TREG Immature dendritic cell Arginase-1 HIF-1α VEGF CCL2 IDO IL-10 Tie2 IL-13 CSF1 IL-23 Smyth MJ, et al. Nat Rev Clin Oncol. 2016. M2 Paracrine effect STAT3 activators CTLA-4 PD-1 LAG-3 TIM-3 BTLA VISTA/ PD-1H TIGIT CD96 Inhibitory Node 2 Inducing Immunogenic Cancer-Cell Death Conventional therapy TRAIL-R agonists • Radiotherapy • Chemotherapy (eg, anthracycline, oxaliplatin) Oncogene inhibitors HDAC inhibitors Chemokines to attract CTL and TH1 Smyth MJ, et al. Nat Rev Clin Oncol. 2016. p53 rescue Vaccines to generate CTL and TH1 Proteasome inhibitors Node 3 Enhancing APC Function/Adjuvanticity STING activator TLR agonists Type I IFN GM-CSF Smyth MJ, et al. Nat Rev Clin Oncol. 2016. SIRPα antagonists CD40 agonists α-GalCer or α-C-GalCer Node 4 Enhancing T/Macrophage Effector Activity ICOS CD28 CD137 OX40 GITR CD27 IL-2 IL-15 IL-21 α-B7-H5 α-B7-H6 α-B7-H4 α-B7-H3 α-CD73 α-CD47 α-CD200 CD30 HVEM DNAM-1 CD28H Agonistic Smyth MJ, et al. Nat Rev Clin Oncol. 2016. FcγR CD40 Checkpoint Blockade Current Concepts and Future Prospects • Checkpoint blockade is a major advance in cancer treatment that is supported by extensive murine preclinical data. • Multiple checkpoints and agonists regulate antitumor immunity, and their modulation is clinically feasible. • Unique kinetics of response is associated with checkpoint inhibitory therapy. • irAEs typify checkpoint inhibition and may be associated with benefit. • Strong scientific rationale for novel combinations raises the hope for cures in multiple different cancers. Thank you! Please visit us at: www.ceconcepts.com