Novel Treatments for Solid-Organ & Hematologic Malignancies

NOVEL TREATMENTS FOR SOLID ORGAN & HEMATOLOGIC MKDIGOALIGNANCIES Christian Kollmannsberger MD FRCPC

Clinical Professor Div. of Medical Oncology BC Cancer - Vancouver Cancer Centre Dept. of Medicine, University of British Columbia Vancouver, Canada DISCLOSURES

Research Support/P.I. N/A

Employee N/A

Consultant Pfizer, Novartis, Sanofi, Astellas, BMS, Ipsen, Eisai Major Stockholder KDIGON/A Speakers Bureau N/A

Honoraria for presentations Pfizer, Ipsen, Eisai, BMS

Scientific Advisory Board Pfizer, Novartis, Ipsen, Eisai, Sanofi, Astellas, BMS IMMUNOTHERAPY…..IMMUNOTHERAPY ……….IMMUNOTHERAPY…………………. .IMMUNOTHERAPYKDIGO Christian Kollmannsberger MD FRCPC

Clinical Professor Div. of Medical Oncology BC Cancer - Vancouver Cancer Centre Dept. of Medicine, University of British Columbia Vancouver, Canada Immuno-Oncology: A Rapidly Emerging Therapeutic Modality

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1. DeVita BT, Rosenberg SA. N Engl J Med. 2012;366:2207-2214; 2. Kirkwood JM, et al. CA Cancer J Clin. 2012;62:309-335; 3. Murphy JF. Oncology. 2010;4:67-80. Immuno-Oncology: The New World in Oncology

Immuno-oncologic drugs include a broad range of agents:

Ø Monoclonal antibodies Ø Vaccines Ø Cytokines, Ø Oncolytic viruses Ø BispecificKDIGO antibodies / molecules Ø Cellular therapies Ø Antibody-drug conjugates Immuno-Oncology: Major Approaches to Cancer Immunotherapy

• Antibodies • Administer anti-cancer antibodies to patients • Administer antibodies that alter the immune response to the cancer

• T-cells • Cancer vaccinesKDIGO • Change tumor environment so the immune system recognizes and eliminates the cancer (in situ immunization) • Take out T cells, change them so they are specific for the cancer, and give them back to the patient Immuno-Oncology: Monoclonal antibody-based cancer therapeutic strategies

KDIGO Agenda

Ø Checkpoint Inhibition

Ø CAR-T Cell therapy Ø BispecificKDIGO Antibodies Ø Radioimmunoconjugates / Small Molecules T-cell Checkpoint Regulaon

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Tasuku Honjo James Allison

PD-1 CTLA-4 (Programmed cell death protein 1) (cytotoxic T-lymphocyte-associated 2018 Nobel Price Medicine protein-4) T-cell Checkpoint Regulaon

Acvang receptors Inhibitory receptors • T-cell responses are regulated though a complex balance of inhibitory CTLA- CD2 (“checkpoint”) and acvang signals 4 8 PD- • Tumours can dysregulate these OX4 1 pathways and consequently, 0 TIM- the immune response 3 • Targeng these pathways is an CD13 KDIGO LAG- 7 evolving approach to cancer therapy 3 Agonisc anbodies Antagonisc (blocking) anbodies

T-cell smulaon

Adapted from Mellman I, et al. Nature 2011; 480(7378):480-9; Pardoll DM. Nat Rev Cancer 2012; 12(4):252-64. Immune Escape in Cancer

Many tumours escape the immune response by creang an immunosuppressive microenvironment that prevents an eﬀecve antumour response1,2

Recruitment of immunosuppressive Release of immunosuppressive factors cells Factors/enzymes directly or indirectly suppress Tregs MDSCs immune response

Ineﬀecve presentaon Tumour Cells T-cell checkpoint dysregulaon of tumour angens CTLA-4 to the immune system CD28 PD-1 Downregulaon of Suppression KDIGO OX40 B7-1 MHC Expression of APC GITR T cell TIM-3 CD137 BTLA CD27 VISTA Tumour APC HVEM LAG-3 Cell Co-smulatory Co-inhibitory Tumour Microenvironment receptors receptors

The mechanisms tumours use to escape the immune system provide a range of potenal therapeuc targets for cancer APC=angen-presenng cell; MDSC=myeloid-derived suppressor cell; MHC=major histocompability complex; Treg=regulatory T cell.

1. Bremnes RM et al. J Thorac Oncol. 2011;6:824-833. 2. Jadus MR et al. Clin Dev Immunol. 2012:160724. . Mulple Potenal I-O Targets to Acvate the Immune System

• Antumour response is a net balance of complex inhibitory and smulatory interacons between APC, T cell, and tumour1-6 • Mulple potenal I-O targets, such as: – T-cell co-smulatory receptors – T-cell checkpoint/inhibitory receptors – APC – Microenvironment KDIGO • Modulaon of these targets by I-O therapies may acvate the immune system to eliminate the tumour

1. Baruah P, et al. Immunobiology. 2012;217(7):669-675; 2. Hemon P, et al. J Immunol. 2011,186:5173-5183; 3. Pardoll DM. Nat Rev Cancer. 2012;12:252-264; 4. Kirkwood JM, et al. CA Cancer J Clin. 2012;62:309-335; 5. Zang X, et al. PNAS. 2007;104(49):19458-19463; 6. Leitner J. Eur J Immunol. 2009;39:1754-1764. . Immuno-oncology: Blocking CTLA-4 and PD-1 Pathways with Monoclonal Anbodies Priming Phase Eﬀector Phase Periphery Tumour microenvironment

T-cell acvaon (cytokines, lysis, proliferaon, migraon to tumour)

TCR MHC TCR MHC + + + KDIGO+ + + Dendric B7 CD28 PD-1 PD-L1 Tumour cell cell T cell B7 CTLA-4 + + + T cell ------An-PD-1/PD-L1 An-CTLA-4 PD-1 PD-L2 - - - An-PD-1

CTLA-4 pathway blockade PD-1 pathway blockade

CTLA-4=cytotoxic T-lymphocyte angen-4; PD-1=programmed cell death 1; PD-L1/2=PD ligand 1/2; TCR=T cell receptor. Adapted from Wolchock J, et al. Oral presentaon at ASCO 2013 (Abstract 9012). Immunotherapy in Melanoma Nivolumab Improved Overall Survival vs. Dacarbazine CHECKMATE-066 100 90 80 1-yr OS 73% Nivolumab (n = 210) 70 60 50 HR 0.42 (99.79% CI, 0.25–0.73; P < 0.0001) 1-yr OS 42% 40 (Boundary for stascal signiﬁcance 0.0021) 30 Paents Surviving (%) KDIGO Median OS Paents who died, n/N Dacarbazine (n = 208) 20 mo (95% CI) Nivolumab 50/210 NR 10 Dacarbazine 96/208 10.8 (9.3–12.1) 0 0 3 6 9 12 15 18 Months Follow-up since randomizaon: 5.2–16.7 months. Paents at Risk Nivolumab 210 185 150 105 45 8 0 Dacarbazine 208 177 123 82 22 3 0

Robert C et al. N Engl J Med. 2015 Jan 22;372(4):320-30 Immunotherapy in NSCLC Nivolumab as 2nd-line Treatment for Non-squamous NSCLC 100 Nivolumab Docetaxel 90 (n = 292) (n = 290)

80 mOS, mo 12.2 9.4 70 HR = 0.73 (96% CI: 0.59, 0.89); P = 0.0015 60

50 1-yr OS rate = 51%

OS (%) 40 1-yr OS rate = 39% 30 KDIGO Nivolumab 20

10 Docetaxel 0 0 3 6 9 12 15 18 21 24 27

Number of Paents at Risk Time (months) Nivolumab 292 232 194 169 146 123 62 32 9 0

Docetaxel 290 244 194 150 111 88 34 10 5 0

Borghaei et al N Engl J Med. 2015. Immunotherapy in Metastatic Bladder Cancer Pembrolizumab in platinum-refractory Bladder Cancer

Keynote 045

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Bellmunt et al ASCO GU 2018 Immunotherapy in Metastatic Kidney Cancer Second-line Therapy after TKI Failure

1.0 Median OS, months (95% CI) 0.9 Nivolumab 25.0 (21.8–NE) 0.8 Everolimus 19.6 (17.6–23.1) 0.7 0.6 Nivolumab 0.5 0.4 HR (98.5% CI): 0.73 (0.57–0.93) 0.3 P = 0.0018 Everolimus 0.2 KDIGO 0.1 Overall Survival (Probability) OverallSurvival(Probability) 0.0 0 3 6 9 12 15 18 21 24 27 30 33 No. of patients at risk Months Nivolumab 410 389 359 337 305 275 213 139 73 29 3 0 Everolimus 411 366 324 287 265 241 187 115 61 20 2 0

Motzer et al NEJM 2015 I-O Therapies have the Potenal to be Used as Monotherapy or Part of Combinaon Regimens

Plus Plus chemotherapy radiotherapy

KDIGOI-O therapy

Plus I-O therapy targeted therapy Immunotherapy in Metastatic Kidney Cancer Nivolumab/Ipilimumab as First-line Treatment for Metastatic RCC Checkmate 214

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Motzer et al NEJM 2018 Immunotherapy in Metastatic Kidney Cancer Avelumab/Axitinib as First-line Treatment for Metastatic RCC

Javelin Renal 101 100 Median PFS (95% CI), months 90 Avelumab + Axitinib 13.8 (11.1, NE) Sunitinib 7.2 (5.7, 9.7) 80 Stratified HR, 0.61 (95% CI: 0.475, 0.790) 70 P < .0001

60 50 40 30 KDIGO Progression-freesurvival,% 20

10 0 0 2 4 6 8 10 12 14 16 18 20 22 24 Months

PD-L1 inhibitor plus VEGF-TKI Combination

Motzer et al ESMO 2018 Developments in Immunotherapy Across Oncology Multiple targets for checkpoint inhibitor

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Mellman et al. Nature 2011 Immuno-Oncology: Toxicity - The Tiger is Out of the Cage

KDIGO Checkpoint Inhibitor Toxicity

Can affect ANY organ system Endocrine § Hypo- or hyperthyroidism Eye § Adrenal insufficiency Skin § Uveitis § Hypophysitis § Dermatitis exfoliative § Iritis § Vitiligo § Alopecia Pulmonary § Pneumonitis (< 5% incidence) Hepatic Toxicity Management is § Hepatitis, autoimmune TEAM WORK Cardiac KDIGO § Myocarditis

Gastrointestinal § Colitis Neurologic § Neuropathy § Guillain-Barre § Myasthenia gravis–like syndrome Renal § Nephritis If not vigilant, may result in more serious immune-related AEs Immune-related Adverse Events with Checkpoint Inhibition

Most frequent toxicities in monotherapy Drug Target Phase of study (any grade) Grade 3 Grade 4 Ipilimumab CTLA‑4 I, II, III Gastrointestinal 7.6% <0.5% Dermatologic 1.5% <0.3% Grade 3-4 Nivolumab PD‑1 or PD‑L1 I, II, III Rash <1.0% Pembrolizumab Pruritus 0.0 - 1.0% Atezolizumab Diarrhoea 0.2-2.6% Durvalumab Fatigue 1.0-7.0% KDIGOPneumonitis 0.0-1.0% Headache 0.0 - 0.4% Asthenia 0.4 – 2.0% Dyspnea 0.3 – 7.0% Anemia 0.0 – 3.0%

PD-1 Monotherapy

Hodi FS, et al. N Engl J Med 2010; 363(8):711-23. Ribas A et al., ASCO 2014 oral presentaon, J Clin Oncol 32:5s, 2014 (suppl; abstr LBA9000). Topalian S, et al. J Clin Oncol. 2014. Long et al., SMR. 2014; Herbst et al., Nature Volume: 515, Pages:563–567. Larkin J et al., N Engl J Med 2015; ePub ahead of print. May 31, 2015. Robert C et al. N Engl J Med. 2015 Jan 22;372(4):320-30. Brahmer J et al. N Engl J Med 2015; ePub ahead of print. June 17, 2015. Paz-Arez L et a., Oral presentaon. Presented at ASCO 2015. Spira AI, et al: Presented at ASCO 2015; Oral Presentaon. Garon EB et al. N Engl J Med 2015; 372:2018-2028. Immune-related Adverse Events with Checkpoint Inhibition

NIVO + IPI N = 547 Category, % Any grade Grade 3–4 Rash 17 3 Diarrhea/colitis 10 5 Hepatitis 7 6 Nephritis and renal dysfunction 5 2 Pneumonitis 4 2 Hypersensitivity/infusion reaction 1 0 Hypothyroidism KDIGO 19 <1 Hyperthyroidism 12 <1 Adrenal insufficiency 8 3 Hypophysitis 5 3 Thyroiditis 3 <1 Diabetes mellitus 3 1

• 60% of patients treated with NIVO + IPI required systemic corticosteroids for an adverse event • 30% of patients required high dose steroids • Secondary immunosuppression with infliximab (3%) and mycophenolic acid (1%) was reported

PD-1 / CTLA-4 Combination Motzer et al NEJM 2018 Immuno-Oncology: Antibody-Drug Conjugates

Step 1: mAb component of ADC binds to tumor antigen

Step 2: ADC-antigen complex undergoes receptor-mediated endocytosis

Step 3: Lysosomes fuse with late endosomes and release the KDIGO active cytotoxin Step 3: Cytotoxin interferes with critical cellular machinery resulting in cell apoptosis

Courtesy of Seattle Genetics / Agensys Immuno-Oncology: Antibody-Drug Conjugates

Agent Indication Antigen Cytotoxin Brentuximab Hodgkin’s lymphoma, Anaplastic CD30 Monomethyl ADCs in clinical large cell lymphoma auristatin E (MMAE) practice Trastuzumab Her2+ metastatic breast cancer HER2 Mertansine (DM1) emtansine

Agent Indication Antigen Cytotoxin Glembatumumab Hodgkin’s lymoma, advanced GPNMB Monomethyl breast cancer auristatin E (MMAE) Lorvotuzumab MultipleKDIGO myeloma, solid tumors CD56 Mertansine (DM1) ADCs in clinical mertansine development Indatuximab Multiple Myeloma CD138 Mertansine (DM4) ravtansine AGS-16C3F-15-3 Kidney Cancer ENPP3 Monomethyl auristatin F (MMAF) Enfortumab Bladder Cancer Nectin-4 Monomethyl Vedotin auristatin E (MMAE) Immuno-Oncology: Enfortumab Vedotin in Metastatic Bladder Cancer

Enfortumab Vendotin with metastatic urothelial cancer Enfortumab Vendotin with metastatic urothelial cancer Patient Characteristics (n = 112) Toxicity (n = 112)

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Well tolerated

Heavily Pretreated Rosenberg et al ASCO 2018 Immuno-Oncology: Enfortumab Vedotin in Metastatic Bladder Cancer

Enfortumab Vendotin with metastatic urothelial cancer Response rate (n = 112)

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Rosenberg et al ASCO 2018 Immuno-Oncology: Antibody-Drug Conjugates – Open Questions

Ø What is the best target ? Potential targets for ADCs § highly expressed with limited heterogeneity across the tumour § low normal tissue expression § minimal antigen shedding to prevent the Ab binding to its target within the circulation § Ab should be well internalised by receptor- mediated endocytosis Ø What is best used as “payload”? KDIGO Ø Can the linker technology be improved ? Diamantis et al Br J Cancer 2016 § Influences ADC’s pharmacokinetics, efficacy Ø How to best give ADC’s : § Stable, does not release the cytotoxic before § schedule reaching its target, is well internalised § duration of treatment Ø Combinations ? Immuno-Oncology: Antibody-Drug Conjugates and Checkpoint Blockade

Ø T-DM1 increases TILs in human primary breast CA Ø T-DM1 induces infiltration by effector T cells in murine breast tumors

KDIGO § Enhanced T-cell response § Reversal of CI resistance § Significant preclinical activity

Potential synergy of ADC’s with Immunotherapy e.g. CI

Muller et al Sci Transl Med 2016 Immuno-Oncology: Antibody-Drug Conjugates

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And many more ……… Immuno-Oncology: Chimeric Antigen Receptor Therapy (CAR T cells)

• Adoptive Cell transfer first in the 80”s • Autologous tumor-infiltrating lymphocytes in melanoma • Gene-transfer techniques were developed in the 1990s to redirect the specificity of T cells with the use of T-cell receptors • CARs are engineered receptors • Graft a defined specificity onto an immune effector cell (T-cell) KDIGO• Augment T-cell function

• Removal of Patient’s peripheral-blood T cells • In vitro activation and genetic modification • Expansion of the T cells • Infusion of the cells back into the patient

Tran E et al. N Engl J Med 2017;377:2593-2596 Immuno-Oncology: Chimeric Antigen Receptor Therapy (CAR T cells)

• CAR T cells engraft after reinfusion • Undergo extensive proliferation in the patient • Each CAR T cell can kill many tumor cells • CAR T cells may promote immune surveillance to prevent tumor recurrence through • Antigen release, • Assisting tumor infiltrating lymphocytes to attack tumors KDIGO• By their own persistence

CH June, M Sadelain. N Engl J Med 2018;379:64-73 Immuno-Oncology: Responses to CAR T Treatment

• Outstanding activity in refractory lymphoma • Lymphocytic leukemias • Multiple myeloma

KDIGO Currently explored in solid malignancies

CH June, M Sadelain. N Engl J Med 2018;379:64-73 Immuno-Oncology: Response to CAR-T Cell Therapy

Patient with recurrent DLBCL post-SCT treated with anti- CD19 CAR T cells KDIGO Ongoing Complete Response 15+ months in a patient with chemo-refractory PMBCL

Kochenderfer Blood 2012; Kochenderfer JCO 2015; Kochenderfer ASH 2014 Immuno-Oncology: Potential Targets in Solid Tumor Oncology

KDIGO Studies ongoing

Jackson et al Nat Rev Clin Oncol. 2016. Immuno-Oncology: Toxicity of CAR T Treatment

Distinct and significant KDIGO toxicity profile

CH June, M Sadelain. N Engl J Med 2018;379:64-73 Immuno-Oncology: Bispecific Antibodies

Recruiting of T cells or natural killer (NK) cells to tumors is achieved by entities that bind to tumor cell surface antigens as well as to immune cells.

BsAbs with ‘two- target’ functionality can interfere with multiple surface receptors or ligands associated, for example with cancer, proliferation or KDIGOinflammatory processes.

Walsh et al Nat Biotechnol. 2010 Immuno-Oncology: Bispecific Antibodies - Blinatumomab

Blinatumomab: bispecific antibody consisting of a pair of anti-CD19 and anti-CD3 antibody fragments with a small-molecule linker

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Batlevi et al Nature Rev Clin Oncol 2016 Immuno-Oncology: Bispecific Antibodies – Ongoing Studies

Larger number of studies ongoing

Hematologic malignancies and KDIGO solid tumors

Batlevi et al Nature Rev Clin Oncol 2016 Immuno-Oncology: Radioimmunoconjugates

177Lu-J5911 PSMA therapy in castration resistant metastatic prostate cancer:

• PSMA = Prostate-specific membrane antigen

• Cell membrane protein

• Upregulated in almost all prostate cancers

KDIGO • Also expressed in duodenal mucosa, proximal renal tubules, and salivary glands

• J591 anti-PSMA is radiolabeled with lutetium-177 Immuno-Oncology: Radioimmunoconjugates/Small Molecules

177Lu-PSMA-617 PSMA therapy in castration resistant metastatic prostate cancer:

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• Antibodies exhibit poor permeability • Development of small molecules for In solid tumors and slow clearance targeting the extracellular domain of from the circulation prostate-specific membrane antigen (PSMA) Immuno-Oncology: Radioimmunoconjugates

177Lu-PSMA-617 PSMA therapy in castration resistant metastatic prostate cancer:

PSA response after 12 weeks best PSA response from baseline

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Highly active Hofman et al Lancet Oncol 2018 Immuno-Oncology: Radioimmunoconjugates/Small Molcules

177Lu-PSMA-617 PSMA therapy in castration resistant metastatic prostate cancer:

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Baseline Cycle 1 Cycle 2 Cycle 3 Cycle 4 Novel Treatments on Oncology: Conclusions

Ø Immunotherapy is revolutionizing Oncology and the way we treat patients Ø Immunotherapy is rapidly becoming standard of care in a variety of malignancies Ø CTLA-4 and PD-1 inhibitors are currently used

Ø “Cure” in metastatic disease now seems feasible and on the horizon Ø Side effects are an importantKDIGO issue and can affect any and all organ systems Ø Management of side effect is a team sport including a broad variety of specialists

Ø Innumerable open questions remain