Dra. Omayra Reyes, MD. Hematologist- Oncologist. Introduction to Immuno Oncology

Transcription

1 Dra. Omayra Reyes, MD. Hematologist- Oncologist Introduction to Immuno Oncology

2 Disclosure I have no conflicts of interest

3 Objectives Review Basic concepts of onco- immunology. Recognize different mechanisms of action of immunotherapy drugs. Overview of new emerging indications in immunotherapy.

4 History of Immunotherapy Journal of Clinical Oncology

5 The spectrum of available immunotherapies BMC Medicine :73

6 Escape From Immune Surveillance Is a Hallmark of Cancer Evasion of immune detection and destruction is an emerging hallmark of cancer 1 Tumor cells can reprogram cellular metabolism to gain energy Emerging Hallmarks Epigenetics Activated T cells Tumor cells can evade detection and destruction by the immune system Tumor cells divide without control TUMOR Tumor cells invade and metastasize to other tissues Tumor cells sustain proliferative signaling Tumor cells evade growth suppressors Tumor cells resist cell death Tumor cells encourage growth of new blood vessels Established Hallmarks 1. Image adapted from Hanahan D, Weinberg RA. Cell. 2011;144(5):

7 INTRODUCTION TO IMMUNE CHECKPOINTS

8 Immune Checkpoints 1 Activating Receptors Inhibitory Receptors CD27 CD28 CD137 GITR HVEM OX40 T Cell BTLA CTLA-4 LAG-3 PD-1 TIM-3 VISTA The normal physiological function of inhibitory immune checkpoints is to regulate the intensity of the T-cell response during inflammation to limit autoimmunity and collateral tissue damage 1. Adapted from Mellman, Coukos, and Dranoff. Nature. 2011; 480:

9 1. Finn OJ. N Engl J Med. 2008;358: Specific Antigens Induce T Cell Recognition of Tumors 1 Normal Cells Express antigens that do not elicit an immune response Tumor Cells Express both normal antigens and tumor antigens NORMAL CELL TUMOR CELL

10 Immuno-surveillance 1,2 Tumor 1. May KF Jr et al. In: Prendergast GC, Jaffee EM, eds. Cancer Immunotherapy: Immune Suppression and Tumor Growth. 2nd ed. Amsterdam, Netherlands; Elsevier: 2013: Mellman I et al. Nature. 2011;480:

11 Immuno-surveillance 1,2 Tumorspecific antigens Dendritic cell Tumor 1. May KF Jr et al. In: Prendergast GC, Jaffee EM, eds. Cancer Immunotherapy: Immune Suppression and Tumor Growth. 2nd ed. Amsterdam, Netherlands; Elsevier: 2013: Mellman I et al. Nature. 2011;480:

12 Immuno-surveillance 1,2 Tumorspecific antigens Dendritic cells activate naïve T cells in lymph nodes Dendritic cell Tumor 1. May KF Jr et al. In: Prendergast GC, Jaffee EM, eds. Cancer Immunotherapy: Immune Suppression and Tumor Growth. 2nd ed. Amsterdam, Netherlands; Elsevier: 2013: Mellman I et al. Nature. 2011;480:

13 T-cells are Critical for Immune Surveillance and Antitumor Response To be properly activated, a T-cell MUST receive 2 signals 1-2 : Binding of MHC-antigen complex to TCR Binding of a second costimulatory signal This initiates intracellular signaling that activates the T-cell which can then kill infected or cancer cells and/or help support other immune functions 1 4 T cell Costimulation Effector functions Antigen MHC APC 1. Ott PA. Clin Cancer Res. 2013;19(19): Sompayrac L. How the Immune System Works. 4th ed. Oxford, UK: Wiley-Blackwell; Mellman I et al. Nature. 2011;480(7378): Murphy K. Janeway s Immunobiology. 8th ed. New York, NY: Garland Science; 2012.

14 Typical Depiction of Cell-Cell Communication 1,2 To be properly activated, a T cell MUST receive 2 signals: Priming Phase Signal 1 MHC + Ag TCR Dendritic cell CD 80 or 86 CD 28 + T cell CD80 or 86 CTLA-4 - Signal 2 CTLA-4 = cytotoxic T-lymphocyte antigen 4 1. Pardoll DM. Nat Rev Cancer. 2012;12: Ribas A. N Engl J Med. 2012;366:

15 More Realistic Depiction of Cell-Cell Communication 1,2 Dendritic cell T cell 1. Pardoll DM. Nat Rev Cancer. 2012;12: Ribas A. N Engl J Med. 2012;366:

16 Immuno-surveillance 1,2 Tumorspecific antigens Dendritic cells activate naïve T cells in lymph nodes Dendritic cell Tumor Activated T cell Activated T cells migrate back to the tumor 1. May KF Jr et al. In: Prendergast GC, Jaffee EM, eds. Cancer Immunotherapy: Immune Suppression and Tumor Growth. 2nd ed. Amsterdam, Netherlands; Elsevier: 2013: Mellman I et al. Nature. 2011;480:

17 Immuno-surveillance 1,2 Tumorspecific antigens Dendritic cells activate naïve T cells in lymph nodes Dendritic cell Tumor Effector T cells: Recognize tumor through specific TCR/MHC Release lytic enzymes Induce apoptosis Activated T cell Activated T cells migrate back to the tumor 1. May KF Jr et al. In: Prendergast GC, Jaffee EM, eds. Cancer Immunotherapy: Immune Suppression and Tumor Growth. 2nd ed. Amsterdam, Netherlands; Elsevier: 2013: Mellman I et al. Nature. 2011;480:

18 Immuno-surveillance 1-3 Tumorspecific antigens Dendritic cells activate naïve T cells in lymph nodes Dendritic cell Checkpoints Tumor Checkpoints PD-1 Immune checkpoints such as CTLA-4 and PD-1, LAG-3, and TIM-3 function at different phases in the immune response to regulate the duration and level of the T-cell response. CTLA-4 CTLA-4 = cytotoxic T-lymphocyte antigen 4 PD-1 = programmed cell death protein 1 LAG-3 = lymphocyte activation gene 3 TIM-3 = T-cell immunoglobulin and mucin protein 3 Activated T cell Activated T cells migrate back to the tumor Receptor is expressed on the T cell and the ligand on APCs or peripheral tissues May KF Jr et al. In: Prendergast GC, Jaffee EM, eds. Cancer Immunotherapy: Immune Suppression and Tumor Growth. 2nd ed. Amsterdam, Netherlands; Elsevier: 2013: Mellman I et al. Nature. 2011;480: Pardoll DM. Nat Rev Cancer. 2012;12:

19 CTLA-4 Is Thought to Affect the Priming Phase of T-Cell Activation 1 Dendritic cell Inactivated T cell MHC + Ag TCR CD CTLA-4 Priming Phase In healthy tissues, CTLA-4 is thought to function as a dominant off switch broadly shutting down T-cell activity to prevent autoimmunity Pardoll DM. Nat Rev Cancer. 2012;12: Ribas A. N Engl J Med. 2012;366: Topalian SL et al. Curr Opin Immunol. 2012;24:

20 PD-1 Is Thought to Primarily Regulate the Effector Phase of T-Cell Activity 1 Normal Cell Effector T cell MHC + Ag TCR PD-1 Effector Phase In healthy tissues, PD-1 is thought to limit the activity of antigen-specific T cells to prevent collateral tissue damage during infection 1 1. Pardoll DM. Nat Rev Cancer. 2012;12:

21 PD-1 Is Thought to Primarily Regulate the Effector Phase of T-Cell Activity 1 Tumor Cell Effector T cell MHC + Ag TCR PD-1 In cancer, the PD-1 pathway can be exploited by some tumor cells to inactivate T cells 1 1. Pardoll DM. Nat Rev Cancer. 2012;12:

22 TIM-3 Signaling Is Thought to Affect T-Cell Subtype Response Development 1,2 APC (Dendritic Cell) T Cell (Th1, Th17, CD8+) MHC + Ag TCR GAL9 TIM-3 TIM3 is expressed on T helper (Th1, Th17) and CD8+ T cells when bound to its ligand Galectin 9, TIM-3 inhibits T helper 1 (TH1) and Th17 cell responses 1 1. Gao X. PLoS ONE. 2012; 7(2): e30676, doi: /journal.pone Pardoll DM. Nat Rev Cancer. 2012;12:

23 LAG-3: An Antigen Co-receptor Is Thought to Suppress Immune Responsiveness 1 Antigen Presenting Cell T cell MHC + Ag TCR LAG-3 Can engage MHC Class II APCs during antigen presentation Decreased signaling of effector T cells Promotional signals into Treg cells 1. Sierro S et al. Expert Opin Ther Targets. 2011;15(1):

24 HOW CAN TUMORS EVADE THE IMMUNE RESPONSE

25 Several Mechanisms Within the Tumor Microenvironment Contribute to Immunosuppression 1 APC = antigen-presenting cells; BTLA = B- and T-lymphocyte attenuator; CD = cluster of differentiation; CTLA-4 = cytotoxic T-lymphocyte associated protein-4; GITR = glucocorticoid induced tumor necrosis factor-related protein; HVEM = herpes virus entry mediator; LAG-3 = lymphocyte-activation gene 3; MDSC = myeloid-derived suppressor cell; MHC = major histocompatibility complex; PD-4 = programmed death receptor-4; TIM-3 = T-cell immunoglobulin domain and mucin domain-3; Tregs = regulatory T cells; VISTA = V-domain immunoglobulin-containing suppressor of T-cell activation. 1. Davies M. Cancer Manag Res. 2014;6:63 75.

26 Immune Evasion by Loss of Antigen Expression 1,2 Dendritic cells Tumor 1. Pinzon-Charry A et al. Immunol Cell Biol. 2005;83: Ahmad M et al. Cancer Immunol Immunother. 2004;53: Cytotoxic T cells

27 Immune Evasion by Immuno-Suppressive Cytokines and Cells 1,2 Tumor CELLS: MDSC = myeloid derived suppressor cell Treg = regulatory T cell NK cell = natural killer cell Cytokines = secreted immune proteins MDSC T reg Cytokines: Expression of cytokines, such as TGF-, IL- 10, and VEGF, within the tumor microenvironment can suppress T-cell function through different mechanisms. Cytokines Inactivated NK cell Inactivated T cell 1. Zou W. Nat Rev Immunol. 2006;6: Finn OJ. N Engl J Med. 2008;358:

28 Targeting Immune Checkpoints: Releasing the Brake on the Immune System The immune checkpoint pathway is an elaborate series of cellular interactions that prevent excessive T-cell effector activity 1 Inhibitory receptors, such as CTLA-4 and PD-1, downregulate T-cell activity 2 APC = antigen-presenting cell; CTLA-4 = cytotoxic T lymphocyte associated protein-4; LAG-3 = lymphocyte-activation gene 3; MHC = major histocompatibility complex; PD-1 = programmed death receptor-1; PD-L1 = programmed death ligand 1; PD-L2 = programmed death ligand 2; Treg = regulatory T cell. 1. Ott PA. Clin Cancer Res. 2013;19(19): Pardoll DM. Nat Rev Cancer. 2012;12(4):

29 Impact of Immune checkpoints in clinical practice

30 Introduction to Checkpoints Inhibitors

31 Melanoma therapeutics options

32 Ipilimumab (Yervoy ) Click to edit Master title style 32

33 Ipilimumab vs. Ipi+ Glyco 100 vs Glyco 100

34 Ipilimumab, a CTLA-4 Blocking Monoclonal Antibody, Augments T-cell Activation Click to edit Master title style 34

35 The PD-1 Pathway May Be Exploited to Evade the Immune Response 1 TCR Antigen MHC Click to edit Master title style PD-L1 PD-1 PD-L2 Activated cytotoxic T cell Tumor cell The body s immune response can detect and destroy tumor cells through activated T cells and other mechanisms. 2 MHC = major histocompatibility complex; NSCLC = non small cell lung cancer; PD-L1 = programmed death ligand 1; PD-L2 = programmed death ligand 2; TCR = T-cell receptor. 1. Pardoll DM. Nat Rev Cancer. 2012;12(4): Chen DS, Mellman I. Immunity. 2013;39(1):

36 Other targets Activating Receptors Inhibitory Receptors CD27 Click to edit Master title BTLA style CD28 CD137 GITR HVEM OX40 T Cell CTLA-4 LAG-3 PD-1 TIM-3 VISTA The normal physiological function of inhibitory immune checkpoints is to regulate the intensity of the T-cell response during inflammation to limit autoimmunity and collateral tissue damage 1. Adapted from Mellman, Coukos, and Dranoff. Nature. 2011; 480:

37 The PD-1 Pathway May Be Exploited to Evade the Immune Response 1 TCR Antigen MHC Click to edit Master title style PD-L1 PD-1 PD-1 PD-L1 PD-L2 Activated cytotoxic T cell PD-L2 Tumor cell The body s immune response can detect and destroy tumor cells through activated T cells and other mechanisms. 2 Emerging research has identified the programmed death receptor-1 (PD-1) as a key immune checkpoint pathway involved in inhibiting the T-cell mediated immune response. 1 Tumor cells can downregulate T-cell activity by exploiting the PD-1 checkpoint pathway through expression of the PD-1 ligands, PD L1 and PD L2; the primary PD-1 ligand expressed on tumor cells is PD-L1. 1 MHC = major histocompatibility complex; NSCLC = non small cell lung cancer; PD-L1 = programmed death ligand 1; PD-L2 = programmed death ligand 2; TCR = T-cell receptor. 1. Pardoll DM. Nat Rev Cancer. 2012;12(4): Chen DS, Mellman I. Immunity. 2013;39(1):

38 The PD-1 Pathway May Be Exploited to Evade the Immune Response 1 TCR Antigen MHC Click to edit Master title style PD-1 PD-L1 Activated cytotoxic T cell PD-L2 Tumor cell The body s immune response can detect and destroy tumor cells through activated T cells and other mechanisms. 2 Emerging research has identified the programmed death receptor-1 (PD-1) as a key immune checkpoint pathway involved in inhibiting the T-cell mediated immune response. 1 Tumor cells can downregulate T-cell activity by exploiting the PD-1 checkpoint pathway through expression of the PD-1 ligands, PD L1 and PD L2; the primary PD-1 ligand expressed on tumor cells is PD-L1. 1 PD-L1 and PD-L2 engage the PD-1 receptor on T cells in order to inactivate them, which may allow tumor cells to evade the immune response. 1 MHC = major histocompatibility complex; NSCLC = non small cell lung cancer; PD-L1 = programmed death ligand 1; PD-L2 = programmed death ligand 2; TCR = T-cell receptor. 1. Pardoll DM. Nat Rev Cancer. 2012;12(4): Chen DS, Mellman I. Immunity. 2013;39(1):

39 The PD-1 Pathway May Be Exploited to Evade the Immune Response 1 TCR Antigen MHC Click to edit Master title style PD-1 PD-L1 PD-L2 Inactivated cytotoxic T cell Tumor cell The body s immune response can detect and destroy tumor cells through activated T cells and other mechanisms. 2 Emerging research has identified the programmed death receptor-1 (PD-1) as a key immune checkpoint pathway involved in inhibiting the T-cell mediated immune response. 1 Tumor cells can downregulate T-cell activity by exploiting the PD-1 checkpoint pathway through expression of the PD-1 ligands, PD L1 and PD L2; the primary PD-1 ligand expressed on tumor cells is PD-L1. 1 PD-L1 and PD-L2 engage the PD-1 receptor on T cells in order to inactivate them, which may allow tumor cells to evade the immune response. 1 MHC = major histocompatibility complex; NSCLC = non small cell lung cancer; PD-L1 = programmed death ligand 1; PD-L2 = programmed death ligand 2; TCR = T-cell receptor. 1. Pardoll DM. Nat Rev Cancer. 2012;12(4): Chen DS, Mellman I. Immunity. 2013;39(1):

40 Checkpoint Inhibitors in Oncology Click to edit Master title style 40

41 What to treat? Click to edit Master title style 41

42 FDA-Approved Checkpoints Inhibitors Click to edit Master title style 42

43 PD-L1 Testing Helps to Inform an Appropriate Treatment Decision in NSCLC PD-L1 expression level is measured using TPS, the percentage of viable tumor cells staining for PD-L1 (0% 100%). 1 PD-L1 expression level can be interpreted as no expression (TPS <1%), expression (TPS 1%), or high expression (TPS 50% 100%). 1 Click to edit Master title style A minimum of 100 viable tumor cells are required to determine PD-L1 positivity in tissue samples, with 2 tissue slides recommended for analysis. 1 Examples of Staining Results 2 <1% 1% 50% 100% No PD-L1 expression PD-L1 expression High PD-L1 expression Stains are 40X magnification; reproduced with permission of Dako Denmark A/S, a subsidiary of Agilent Technologies, Inc., Santa Clara, California, USA. All rights reserved. IHC = immunohistochemistry; NSCLC = non small cell lung cancer; PD-L1 = programmed death ligand 1; TPS = tumor proportion score. 1. PD-L1 IHC 22C3 pharmdx IVD [package insert]. Dako. P03951_04/SK / Dako Denmark A/S. PD-L1 IHC 22C3 pharmdx Interpretation Manual. 43

44 Real progression vs pseudo progression Pseudo progression vs real progression: Asymptomatic PD-L1 expression High mutational burden Smoking burden KRAS mutation Click to edit Master title style 44

45 Click to edit Master title style 45

46 Click to edit Master title style

47 The Breadth of iraes Click to edit Master title style 47

48 Managing Adverse Reactions Monitor patients for signs and symptoms of pneumonitis. Evaluate suspected pneumonitis with radiographic imaging. Based on the severity of the adverse reaction, withhold or discontinue the drug and administer corticosteroids as recommended below. For any Grade 1 (mild) adverse reaction, manage with supportive care, monitor patients, and continue treatment with therapy. Refer to the NCI- CTCAE guidelines for grading the severity of an adverse reaction. 1 Pneumonitis Grade 2 Grade 3 or 4 or recurrent Grade 2 Click to edit Master title style Withhold the drug and administer corticosteroids (initial dose 1 to 2 mg/kg/day prednisone or equivalent followed by a taper) Permanently discontinue the drug and administer corticosteroids (see prednisone dose above) CTCAE = Common Terminology Criteria for Adverse Events; NCI = National Cancer Institute. 1. National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Bethesda, MD: National Cancer Institute NIH Publication Updated version CTCAE v4.03, June 14, Resume treatment WHEN Adverse reaction remains at Grade 1 or less following corticosteroid taper over at least 1 month Permanently discontinue the drug WHEN Any life-threatening adverse reaction (excluding endocrinopathies controlled with hormone replacement therapy, or hematologic toxicity in patients with classical Hodgkin lymphoma) occurs Persistent Grade 2 or 3 adverse reactions (excluding endocrinopathies controlled with hormone replacement therapy) do not improve to Grade 0 1 within 12 weeks after last dose Inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks Any Grade 3 (severe) treatment-related or immune-mediated adverse reaction recurs 48

49 Managing Adverse Reactions (continued) Monitor patients for signs and symptoms of colitis. Based on the severity of the adverse reaction, withhold or discontinue the drug and administer corticosteroids as recommended below. For any Grade 1 (mild) adverse reaction, manage with supportive care, monitor patients, and continue treatment with the drug. Refer to the NCI-CTCAE guidelines for grading the severity of an adverse reaction. 1 Colitis Grade 2 or 3 Grade 4 Click to edit Master title style Withhold the drug and administer corticosteroids (initial dose 1 to 2 mg/kg/day prednisone or equivalent followed by a taper) Permanently discontinue the drug and administer corticosteroids (see prednisone dose above) CTCAE = Common Terminology Criteria for Adverse Events; NCI = National Cancer Institute. 1. National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Bethesda, MD: National Cancer Institute NIH Publication Updated version CTCAE v4.03, June 14, Resume treatment WHEN Adverse reaction remains at Grade 1 or less following corticosteroid taper over at least 1 month Permanently discontinue WHEN Any life-threatening adverse reaction (excluding endocrinopathies controlled with hormone replacement therapy, or hematologic toxicity in patients with classical Hodgkin lymphoma) occurs Persistent Grade 2 or 3 adverse reactions (excluding endocrinopathies controlled with hormone replacement therapy) do not improve to Grade 0 1 within 12 weeks after last dose Inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks Any Grade 3 (severe) treatment-related or immune-mediated adverse reaction recurs 49

50 Managing Adverse Reactions (continued) Monitor patients for signs and symptoms of hypophysitis (including hypopituitarism and adrenal insufficiency) and for hyperglycemia or other signs and symptoms of diabetes. Monitor patients for changes in thyroid function (at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders. Based on the severity of the adverse reaction, manage patients as recommended below. For any Grade 1 (mild) adverse reaction, manage with supportive care, monitor patients, and continue treatment with the drug. Refer to the NCI-CTCAE guidelines for grading the severity of an adverse reaction. 1 Resume treatment Hypophysitis Click to edit Master title style Grade 2 Grade 3 or 4 Withhold the drug and administer corticosteroids and hormone replacement as clinically indicated Withhold or discontinue the drug and administer corticosteroids and hormone replacement as clinically indicated CTCAE = Common Terminology Criteria for Adverse Events; NCI = National Cancer Institute. 1. National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Bethesda, MD: National Cancer Institute NIH Publication Updated version CTCAE v4.03, June 14, WHEN Adverse reaction remains at Grade 1 or less following corticosteroid taper over at least 1 month Permanently discontinue WHEN Any life-threatening adverse reaction (excluding endocrinopathies controlled with hormone replacement therapy, or hematologic toxicity in patients with classical Hodgkin lymphoma) occurs Persistent Grade 2 or 3 adverse reactions (excluding endocrinopathies controlled with hormone replacement therapy) do not improve to Grade 0 1 within 12 weeks after last dose Inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks Any Grade 3 (severe) treatmentrelated or immune-mediated adverse reaction recurs 50

51 Managing Adverse Reactions (continued) Monitor patients for signs and symptoms of hypophysitis (including hypopituitarism and adrenal insufficiency) and for hyperglycemia or other signs and symptoms of diabetes. Monitor patients for changes in thyroid function (at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders. Based on the severity of the adverse reaction, manage patients as recommended below. For any Grade 1 (mild) adverse reaction, manage with supportive care, monitor patients, and continue treatment with the drug. Refer to the NCI-CTCAE guidelines for grading the severity of an adverse reaction. 1 Resume treatment Hypophysitis Hypothyroidism Hyperthyroidism Type 1 diabetes Click to edit Master title style Grade 2 Grade 3 or 4 Administer replacement hormones Withhold the and administer corticosteroids and hormone replacement as clinically indicated Withhold or discontinue the drug and administer corticosteroids and hormone replacement as clinically indicated Manage with thionamides and beta-blockers as appropriate Administer insulin for type 1 diabetes and withhold KEYTRUDA and administer anti-hyperglycemics in patients with severe hyperglycemia CTCAE = Common Terminology Criteria for Adverse Events; NCI = National Cancer Institute. 1. National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Bethesda, MD: National Cancer Institute NIH Publication Updated version CTCAE v4.03, June 14, WHEN Adverse reaction remains at Grade 1 or less following corticosteroid taper over at least 1 month Permanently discontinue WHEN Any life-threatening adverse reaction (excluding endocrinopathies controlled with hormone replacement therapy, or hematologic toxicity in patients with classical Hodgkin lymphoma) occurs Persistent Grade 2 or 3 adverse reactions (excluding endocrinopathies controlled with hormone replacement therapy) do not improve to Grade 0 1 within 12 weeks after last dose Inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks Any Grade 3 (severe) treatmentrelated or immune-mediated adverse reaction recurs 51

52 Managing Adverse Reactions (continued) Monitor patients for changes in liver or renal function and for signs and symptoms of infusion-related reactions. Based on the severity of the adverse reaction, withhold or discontinue the drug and administer corticosteroids as recommended below. For any Grade 1 (mild) adverse reaction, manage with supportive care, monitor patients, and continue treatment with the drug. Refer to the NCI-CTCAE guidelines for grading the severity of an adverse reaction. 1 Hepatitis Withhold and administer Click to edit corticosteroids Master (initial dose title 0.5 to style AST/ALT >3 to 5x ULN or total bilirubin >1.5 to 3x ULN AST/ALT >5x ULN or AST/ALT increases 50% relative to baseline and lasts 1 week in patients with liver metastasis who begin treatment with Grade 2 elevation of AST/ALT or total bilirubin >3x ULN 1 mg/kg/day [Grade 2] or 1 to 2 mg/kg/day [Grade 3] prednisone or equivalent followed by a taper) Permanently discontinue and administer corticosteroids (see prednisone dose above) ALT = alanine aminotransferase; AST = aspartate aminotransferase; CTCAE = Common Terminology Criteria for Adverse Events; NCI = National Cancer Institute; ULN = upper limit of normal. 1. National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Bethesda, MD: National Cancer Institute NIH Publication Updated version CTCAE v4.03, June 14, Resume treatment WHEN Adverse reaction remains at Grade 1 or less following corticosteroid taper over at least 1 month Permanently discontinue WHEN Any life-threatening adverse reaction (excluding endocrinopathies controlled with hormone replacement therapy, or hematologic toxicity in patients with classical Hodgkin lymphoma) occurs Persistent Grade 2 or 3 adverse reactions (excluding endocrinopathies controlled with hormone replacement therapy) do not improve to Grade 0 1 within 12 weeks after last dose Inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks Any Grade 3 (severe) treatmentrelated or immune-mediated adverse reaction recurs 52

53 Managing Adverse Reactions (continued) Monitor patients for changes in liver or renal function and for signs and symptoms of infusion-related reactions. Based on the severity of the adverse reaction, withhold or discontinue the drug and administer corticosteroids as recommended below. For any Grade 1 (mild) adverse reaction, manage with supportive care, monitor patients, and continue treatment with the drug. Refer to the NCI-CTCAE guidelines for grading the severity of an adverse reaction. 1 Hepatitis Nephritis Infusionrelated reaction Withhold the drug and administer Click to edit corticosteroids Master (initial dose title 0.5 to style AST/ALT >3 to 5x ULN or total bilirubin >1.5 to 3x ULN AST/ALT >5x ULN or AST/ALT increases 50% relative to baseline and lasts 1 week in patients with liver metastasis who begin treatment with Grade 2 elevation of AST/ALT or total bilirubin >3x ULN Grade 2 Grade 3 or 4 Grade 3 or 4 1 mg/kg/day [Grade 2] or 1 to 2 mg/kg/day [Grade 3] prednisone or equivalent followed by a taper) Permanently discontinue the drug and administer corticosteroids (see prednisone dose above) Withhold the drug and administer corticosteroids (initial dose 1 to 2 mg/kg/day prednisone or equivalent followed by a taper) Discontinue the drug and administer corticosteroids (see prednisone dose above) Stop infusion and permanently discontinue the drug ALT = alanine aminotransferase; AST = aspartate aminotransferase; CTCAE = Common Terminology Criteria for Adverse Events; NCI = National Cancer Institute; ULN = upper limit of normal. 1. National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Bethesda, MD: National Cancer Institute NIH Publication Updated version CTCAE v4.03, June 14, Resume treatment WHEN Adverse reaction remains at Grade 1 or less following corticosteroid taper over at least 1 month Permanently discontinue WHEN Any life-threatening adverse reaction (excluding endocrinopathies controlled with hormone replacement therapy, or hematologic toxicity in patients with classical Hodgkin lymphoma) occurs Persistent Grade 2 or 3 adverse reactions (excluding endocrinopathies controlled with hormone replacement therapy) do not improve to Grade 0 1 within 12 weeks after last dose Inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks Any Grade 3 (severe) treatmentrelated or immune-mediated adverse reaction recurs 53

54 NCI-CTCAE Guidelines for Grading Select Adverse Reactions 1 The table lists NCI-CTCAE guidelines for grading the severity of select adverse reactions that may be associated with KEYTRUDA (pembrolizumab) a Pneumonitis Grade 1 Grade 2 Grade 3 Grade 4 Symptomatic; medical intervention Severe symptoms; limiting self-care ADL; Click to edit Master title style indicated; limiting instrumental ADL oxygen indicated Life-threatening respiratory compromise; urgent intervention indicated (eg, tracheotomy or intubation) Colitis Hypothyroidism Asymptomatic: clinical or diagnostic observations only; intervention not indicated Abdominal pain; mucus or blood in stool Symptomatic; thyroid replacement indicated; limiting instrumental ADL Severe abdominal pain; change in bowel habits; medical intervention indicated; peritoneal signs Severe symptoms; limiting self-care ADL; hospitalization Indicated Life-threatening consequences; urgent intervention indicated Life-threatening consequences; urgent intervention indicated Hyperthyroidism Symptomatic; thyroid suppression therapy indicated; limiting instrumental ADL Severe symptoms; limiting self-care ADL; hospitalization indicated Life-threatening consequences; urgent intervention indicated Endocrine disorders other Asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated Moderate; minimal, local, or noninvasive intervention indicated; limiting age-appropriate instrumental ADL Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of existing hospitalization indicated; disabling; limiting self-care ADL Life-threatening consequences; urgent intervention indicated Infusion-related reaction Mild transient reaction; infusion interruption not indicated; intervention not indicated Therapy or infusion interruption indicated but responds promptly to symptomatic treatment (eg, antihistamines, NSAIDs, narcotics, IV fluids); prophylactic medications indicated for 24 hours Prolonged (eg, not rapidly responsive to symptomatic medication and/or brief interruption of infusion); recurrence of symptoms following initial improvement; hospitalization indicated for clinical sequelae Life-threatening consequences; urgent intervention indicated ADL = activities of daily living; CTCAE = Common Terminology Criteria for Adverse Events; IV = intravenous; NCI = National Cancer Institute; NSAIDs = nonsteroidal anti-inflammatory drugs. a Grade 5 means death. 1. National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Bethesda, MD: National Cancer Institute NIH Publication Updated version CTCAE v4.03, June 14,

55 Click to edit Master title style Insights Into Advanced Microsatellite Instability-High (MSI-H)/ Mismatch Repair Deficient (dmmr) Cancers 55

56 Relationship between MSI status and immunologic response dmmr tumors are characterized by a high mutational load lymphocyte infiltration exceptional candidates for immune checkpoint blockade Click to edit Master title style Clin Cancer Res; 22(4);

57 MSI-H/dMMR Occurs in a Variety of Different Cancers 1 Click to edit Master title style The estimated frequency of MSI-H and dmmr varies across tumors. dmmr = mismatch repair deficient; MSI-H = microsatellite instability-high. 1. Dudley JC, et al. Clin Cancer Res. 2016;22(4):

58 MSI-H/dMMR Frequency in Various Published Studies Across Stages I IV 1 Click to edit Master title style Colorectal cancer 13% (n=1,066) Endometrial cancer 33% (n=446) 22% (n=543) dmmr = mismatch repair deficient; MSI-H = microsatellite instability-high. 1. Dudley JC, et al. Clin Cancer Res. 2016;22(4):

59 MSI-H/dMMR Frequency in Various Published Studies Across Stages I IV: Tumors With Frequency at or Below 5% 1 Renal cell cancer Click to edit Master title style Breast cancer Sarcoma Bladder cancer Prostate cancer Pancreatic cancer dmmr = mismatch repair deficient; MSI-H = microsatellite instability-high. 1. Dudley JC, et al. Clin Cancer Res. 2016;22(4):

60 MSI-H/dMMR Has Also Been Observed in Other Types of Cancers, but the Frequency Has Not Been Well Characterized 1,a Small cell lung cancer Biliary cancer Click to edit Master title style Thyroid cancer Esophageal cancer Small intestinal cancer Gastric/GE junction cancer Retroperitoneal adenocarcinoma a MSI-H has also been observed in the cancers on the slide, but the frequency has not been well characterized. dmmr = mismatch repair deficient; GE = gastroesophageal; MSI-H = microsatellite instability-high. 1. Dudley JC, et al. Clin Cancer Res. 2016;22(4):

61 Click to edit Master title style 61

62 Summary Immunologic checkpoint blockade with antibodies that target (CTLA-4) and (PD-1/PD-L1) have demonstrated Click to promise edit Master in a variety title of style malignancies. Treatment with both CTLA-4 and PD-1/PD-L1 blockade is associated with a unique pattern of adverse events called immune-related adverse events, and occasionally, unusual kinetics of tumor response are seen. 62

63 Thanks! Click to edit Master title style Questions?