Advances in Systemic Cancer Therapy Alex A. Adjei

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1 Advances in Systemic Cancer Therapy Alex A. Adjei ESMO Summit Africa February 13, 2017 Cape Town, RSA 2016 MFMER slide-1

2 2016 MFMER slide-2

3 Cancer Cells Adapt to Stress 2016 MFMER slide-3

4 Strategies for Targeting Hallmarks of Cancer 2016 MFMER slide-4

5 Novel Therapeutics Targets - multiple Methods of Inhibiting Targets limited Chemical therapy Small molecule inhibitors Monoclonal Antibodies Chimeric Antibodies Antibody Drug Conjugates Vaccines Adoptive T cell transfer Chimeric Antigen Receptor T-cells RNAi Gene Therapy Viral Therapies Clustered regularly interspaced short palindromic repeats (CRISPR) 2016 MFMER slide-5

6 Targeted Therapeutics 6 ❶ Agents that Target Cell Surface Receptors Endothelial Cell ❺ Anti-angiogenic Agents ❷ Agents that Target Intracellular Signal Transduction Pathways ucleus ❹ Agents that Target Epigenetics ❸ Agents that Target Protein Dynamics Tumor Cell ❻ Agents that Affect Tumor Immunity Immune Cell 2016 MFMER slide-6

7 A typical receptor tyrosine kinase inhibitor of VEGFR-2 VEGF Cell membrane X VEGFR-2 (KDR/Flt-1) Cediranib inhibits RTK activity N O O O N N F N Adapter molecules Endothelial cell X Signal transduction Proliferation and migration Vascular permeability 2016 MFMER slide-7

8 Receptor Tyrosine Kinases 2016 MFMER slide-8

9 Kinase Inhibition by Competing with ATP Binding Domain Goldman JM, Melo JV. N Engl J Med : MFMER slide-9

10 Cancer Targets and their Inhibitors 2016 MFMER slide-10

11 Inhibiting Cyclin-Dependent Kinases 2016 MFMER slide-11

12 Single cyclins Multiple cyclins Cyclin-dependent kinases Yeasts Worms Flies Humans Cdc2/28 Pho85 cdk-1 cdk-2 cdk-4 cdk-5 Cdk1 Cdk2 Cdk4 Cdk5 CDK1 CDK2 CDK3 CDK4 CDK6 CDK5 Ctk1 Kin28 Sgv1/Bur1 Srb10/Ssn3 cdk-11 BO285 CCRK cdk-7 cdk-9 cdk-8 Cdk11 Cdk10 CG7597 Ccrk Cdk7 Cdk9 Cdk8 CDK11 CDK10 CDK13 CDK12 CCRK CDK7 CDK9 CDK8 Malumbres & Barbacid. Nat. Rev. Cancer, 2009 Malumbres et al. Nat Cell Biol, MFMER slide-12

13 Cell Cycle Progression Regulated by GO and STOP SIGNALS growth factors Ras, Raf, Myc, Fos, Jun p18 p19 cdk 4 & 6 PCNA p16 p15 p27 Radiation DNA Damage Chemicals p21 p53 Cyclin H cdk7 p21 P M p27 Rb E2F Cyclin B cdk1 G2 E2F P P Cyclins D Rb P Cyclin Cyclin A A cdk1 cdk1 G1 p107 E2F Cyclin E cdk2 Cyclin A cdk2 p107 E2F S Cyclin Hcdk7 p53 p27 p21 JNCI 92: 376, MFMER slide-13

14 Rationale for Developing a CDK4/6 Inhibitor G0 Growth factors Mitogens CDK4/6 Cyclin D LY p16 Potential Patient Selection (Rb, p16, and cyclin D) M G1 E2F Rb1 DP P Rb1 P P E2F DP G2 Transcription S Cyclin E G1 progression DNA replication P P P Rb1 P P P P P CDK2 Cyclin E Mechanism of Action: Inhibition of CDK4/6 prevents phosphorylation of Rb protein and thereby induces strong G1 arrest in cancer cells Transcription p27 Company Confidential Copyright 2013 Eli Lilly and Company MFMER slide-14

15 Alterations in the CDK4/6-CyclinD-Rb Pathway are Common in Human Cancer MFMER slide-15

16 Cyclin-dependent kinase Inhibitors 2016 MFMER slide-16

17 Palbociclib in ER+, HER- Breast Cancer PD LET (n = 84) LET (n = 81) Number of Events (%) 21 (25) 40 (49) Median PFS, months (95% CI) 26.1 ( ) 7.5 ( ) Hazard Ratio (95% CI) 0.37 ( ) p-value <0.001 Select Treatment-related adverse events Grade 3/4 AEs ( 10%) PD LET LET Neutropenia 61.4% 1.3% Leukopenia 16.9% 0% Anemia 6% 1.3% Fatigue 4.8% 1.3% Thrombocytopenia 1.2% 0% but beyond ER-positive status, CCND1 amplification or loss of the cyclin-dependent kinase inhibitor 2A (p16) did not seem to help to better select patients for treatment benefit. Finn RS et al. (2012) San Antonio Breast Cancer Symposium Abstract S MFMER slide-17

18 Abemaciclib in HR+ breast cancer Patnaik et al. Cancer Discovery MFMER slide-18

19 Ribociclib in HR+ breast cancer Hortobagyi et al. MONALEESA-2 ESMO 2016 Copenhagen 2016 MFMER slide-19

20 Future Outlook Inhibiting both CDK4 and CDK6 likely results in increased toxicity Cdk4 mice are viable - Cdk6 mice are viable Palbo/Ribo CDK4 CycD1 Abema CDK6 CycD3 Cdk4/6 double knockout mice die during embryonic development Eliminating CDK4 (or Cyclin D1) is sufficient to cure HER2+ breast tumors in mice Eliminating CDK6 (or Cyclin D3) is efficient in Notch+ leukemias in mice CDK4 specific inhibitors may be efficient against breast (epithelial?) cancers with reduced toxicity CDK6 specific inhibitors could be efficient against specific hematopoietic neoplasias with reduced toxicity? 2016 MFMER slide-20

21 Cancer occurs when something goes wrong with our genes DNA is the building block of a gene. Genes are stored in the chromosome A C T T G A G C 2016 MFMER slide-21

22 Gene Mutation 2016 MFMER slide-22

23 Chromosomal Aberrations 2016 MFMER slide-23

24 Genome Alterations Identified by NGS Meyerson et al, Nat Rev Gen MFMER slide-24

25 Driver Genes as Cancer Targets EGFR EML4-ALK Erlotinib, Gefitinib, Afatinib, Osimertinib Crizotinib, Alectinib, Ceritinib Bcr-abl HER2-neu B-raf Ret Hedgehog Ros-1 Imatinib, dasatinib,ponatinib Trastuzumab, perzutumab Vemurafenib, dabrafenib Vandetanib, cabozantinib Vismodegib Crizotinib 2016 MFMER slide-25

26 MET Inhibitors Peters and Adjei, Nat Rev Clin Oncol MFMER slide-26

27 MET and Exon 14 Splice Mutations 2016 MFMER slide-27

28 Slide MFMER slide-28

29 Lung Adenocarcinoma with MET Exon 14 splice mutations 2016 MFMER slide-29

30 Crizotinib for MET Exon 14 Mutations Slide MFMER slide-30

31 Slide MFMER slide-31

32 Genomics-based Therapy is Part of the future Future Directions 2016 MFMER slide-32

33 Current Hot Study Designs Baskets and Umbrellas 2016 MFMER slide-33

34 Umbrella Trial - Lung Master Protocol MFMER slide-34

35 Basket Trial NCI MATCH 2016 MFMER slide-35

36 2016 MFMER slide-36

37 2016 MFMER slide-37

38 Molecular Aberrations Being Targeted 2016 MFMER slide-38

39 Molecular Aberrations Being Targeted 2016 MFMER slide-39

40 Early Cancer Therapeutics Program at Mayo Clinic 2016 MFMER slide-40

41 Paramyxovirus The Measles Virus Negative stranded RNA virus nm Attenuated vaccine strain-edmonston strain 2016 MFMER slide-41

42 MV-NIS 2016 MFMER slide-42

43 Experiment of Nature Tumor Responses Following Incidental Viral Infection Mayo Clinic Proceedings DOI: ( /j.mayocp ) 2016 MFMER slide-43

44 Best Clinical Response 2016 MFMER slide-44

45 T-VEC: An HSV-1 Derived Oncolytic Immunotherapy Designed to Produce Both Local and Systemic Effects 2016 MFMER slide-45

46 T-VEC Responses in Injected and Uninjected Sites 2016 MFMER slide-46

47 Secondary Endpoint : Time to treatment Failure Durable Response rate 5.7% vs 26.4 % 2016 MFMER slide-47

48 Immune Modulation 2016 MFMER slide-48

49 Elements of an Anitbody Drug Complex (ADC) 2016 MFMER slide-49

50 The Mesothelin Protein 2016 MFMER slide-50

51 Mesothelin is highly expressed in many cancers 2016 MFMER slide-51

52 Mesothelin-Antibody Drug Conjugate : Anetumab Ravtansine 2016 MFMER slide-52

53 Clinical Activity of Anetumab Ravtansine 2016 MFMER slide-53

54 Mesothelin Expression in Cancer 2016 MFMER slide-54

55 Ravtansine in Advanced/Recurrent Malignancies 2016 MFMER slide-55

56 Two Types of Immune Responses Provide Extended Protection 1 Adaptive Immunity CANCEROUS CELLS Innate Immunity Physical Barriers The immune response can be divided into 2 types 1 Innate immune response Nonspecific and immediately available to fight a large range of pathogens Does not generate long-term protective immunity (immunologic memory) Adaptive immune response Specific response developed during lifetime as an adaptation to infection by pathogens Does generate immunologic memory, which confers life-long protection against reinfection with the same pathogen The innate and adaptive immune systems communicate with one another 1,2 1. Murphy K. Janeway s Immunobiology. 8th ed. New York, NY: Garland Science; Sompayrac L. How the Immune System Works. 4th ed. Oxford, UK: Wiley-Blackwell; MFMER slide-56

57 Mechanisms involved in adaptive T cell-mediated immunity against tumors and in its modulation exerted by CTLA-4 and PD-1/PD-L MFMER slide-57

58 The the anti-tumor immune response Chen and Mellman, Immunity. 25;39(1): MFMER slide-58

59 Immune Regulation via Costimulatory and Coinhibitory (Checkpoint) Receptors Multiple costimulatory and coinhibitory interactions regulate T- cell responses 1 Signaling via costimulatory molecules (eg, CD28, GITR) activates T cells 1,2 Signaling via coinhibitory (or checkpoint) molecules (eg, CTLA-4, PD-1, LAG-3) inhibits T-cell activation 1,2 Costimulatory Receptors Coinhibitory Receptors Image reprinted from Mellman I et al. Nature. 2011;480(7378): Pardoll DM. Nat Rev Cancer. 2012;12(4): Mellman I et al. Nature. 2011;480(7378): MFMER slide-59 41

60 Physiological Roles of Immune Checkpoint Pathways (cont) CTLA-4 pathway 1,2 Inhibits the activation of naïve and memory T cells at the lymph nodes, suppressing broad immune responses throughout the body CD80 CD28 DC MHC CD80 TCR CTLA-4 Naïve T cell - PD-1 pathway 1,2 Acts at sites of inflammation and tumor immunosuppression, inhibiting tumor-specific immune responses Tumor Cell PD-L1 PD-1 T cell - Images adapted from Pardoll DM. Nat Rev Cancer. 2012;12(4): Pardoll DM. Nat Rev Cancer. 2012;12(4): McDermott DF, Atkins MB. Cancer Medicine. 2013;2(5): MFMER slide-60 42

61 Physiological Roles of Immune Checkpoint Pathways (cont) TIM-3 immune checkpoint receptor Functions specifically to limit the duration and T m ce a ll gnitude of T-cell responses 1,2 DC GAL9 TIM3 T cell - LAG-3 immune checkpoint receptor Enhances the function of Tregs and can inhibit effector CD8+ T cells 2 DC MHC T cell TCR Signal 1 LAG3 - Image adapted from Pardoll DM. Nat Rev Cancer. 2012;12(4): GAL9 = galectin Anderson AC et al. Cancer Immunol Res. 2014;2(5): Pardoll DM. Nat Rev Cancer. 2012;12(4): MFMER slide-61 43

62 Physiological Roles of Costimulatory Pathways OX40-mediated costimulation 1,2 Promotes T-cell activation, survival, proliferation, and cytokine production DC OX40L OX40 T cell + GITR-mediated costimulation 2,3 Enhances proliferation and effector function of naïve T cells DC GITR-L GITR T cell + Image adapted from Pardoll DM. Nat Rev Cancer. 2012;12(4): Pardoll DM. Nat Rev Cancer. 2012;12(4): Schaer DA et al. J Immunother Cancer. 2014;2:7. 3. Bakdash G et al. Front Immunol. 2013;4: MFMER slide-62 44

63 Management of cancer in the post-anti-pd-1/l1 era Anti-PD-1/anti-PD-L1 Bring T cells into tumors: + anti-ctla4 + immune activating antibodies or cytokines + TLR agonists or oncolytic viruses + IDO or macrophage inhibitors + targeted therapies Generate T cells: Vaccines TCR engineered ACT CAR engineered ACT 2016 MFMER slide-63

64 Checkpoint Inhibitors are Expensive Pembrolizumab ($15,000/3 wks) Nivolumab ($14,000/4 wks) Ipilimumab q3wks x 4 doses ($120,000) Nivolumab + Ipilimumab = you do the math MFMER slide-64

65 HOW THE HECK DO THEY GET THOSE NAMES FOR ALL THESE ANTIBODIES? 2016 MFMER slide-65

66 Monoclonal Antibodies in Cancer Fab Fc Murine Ab momab Chimeric Mouse-Human Ab ximab Humanized Ab zumab Human Ab mumab 17-1A Cetuximab Bevacizumab Panitumumab 2016 MFMER slide-66

67 Nomenclature of Monoclonal Antibodies -mab monoclonal antibody -mo-mab mouse mab -xi-mab chimeric mab -zu-mab humanized mab -mu-mab human mab -tu-xx-mab tumor-directed xx mab -li-xx-mab immune-directed xx mab -ci-xx-mab cardiovascular-directed xx mab -vi-xx-mab virus-directed xx mab Ipilimumab; pembrolizumab; atezolizumab 2016 MFMER slide-67

68 MFMER slide-68