Utilizing Immuno-Oncology Therapies in Clinical Practice

Michael Smylie Medical Oncology Cross Cancer Institute CFPC CoI Templates: Slide 2 Disclosure of Financial Support

• This Program is funded through AHS Operational Funding. • This Program has not received financial support. • This Program has not received in-kind support. • Dr. Michael Smylie is presenting at this Program on a voluntary basis. • Potential for conflict(s) of interest: None Disclosures

• GSK Honoraria • International Advisory Panel for Ipilimumab and Nivolumab development • Honoraria: BMS • Honoraria: Roche • Merck Honoraria • “I am not an immunologist” The History of Immunotherapy

Coley’sToxin PD-1 Approved in 1995 IFN-α as melanoma and adjuvant therapy for lung cancer Adoptive melanoma (US) immunotherapy

2 1898 1970s 1970s 1980s 1990s 2011 2015

Immune component to First tumor- spontaneous associated antigen regressions in cloned (MAGE-1) melanoma Ipilimumab approved for advanced melanoma 1998 IL-2 approved for melanoma (US)

Adapted from Kirkwood JM, Ca J Clin. 2012;62:309–335; Garbe C, et al. The Oncologist. 2011;16:2–24; Rosenberg SA. Sci Transl Med. 2012;4:127ps8; Mansh M. Yale J Biol Med. 2011;84:381–389; Hodi FS, et al. N Engl J Med. 2010;363:711–723; Alexandrescu DT, et al. J Immunother. 2010;33:570–590.

4 William Coley Immuno-oncology agents in development for cancer

Cytokines T-cell activation • IL-21 • IL-12 • IL-2 T cell • Interferon TCR Inhibitory checkpoints

MHC Immune checkpoint inhibitors Vaccines • nivolumab (anti-PD1) • T-VEC • MK-3475 (anti-PD1) • Dendritic cells APC • BMS-936559 (anti-PDL1) • MAGE • MPDL3280A (anti-PDL1) • NY-ESO-1 • lirilumab (anti-KIR) • TG1042 (IFN) • Anti-TIM3 • GM-CSF Tumour Ag T-cell Checkpoint Regulation

Activating receptors Inhibitory receptors • T-cell responses are regulated though a complex balance of CTLA-4 inhibitory (“checkpoint”) CD28 and activating signals PD-1 • Tumours can dysregulate OX40 these pathways and TIM-3 consequently, the immune response CD137 LAG-3 • Targeting these pathways is an evolving approach to Agonistic antibodies Antagonistic cancer therapy (blocking) antibodies T-cell stimulation

Adapted from Mellman I, et al. Nature 2011; 480(7378):480-9; Pardoll DM. Nat Rev Cancer 2012; 12(4):252-64. Immuno-oncology: Blocking CTLA-4 and PD-1 Pathways with Monoclonal

Priming Phase Antibodies Effector Phase Periphery Tumour microenvironment

T-cell activation (cytokines, lysis, proliferation, migration to tumour)

TCR TCR MHC MHC +++ + ++ Dendritic B7 CD28 PD-1 PD-L1 Tumour cell cell +++ T cell B7 CTLA-4 T cell ------Anti-PD-1/PD-L1 Anti-CTLA-4 PD-1 PD-L2 - - - Anti-PD-1

CTLA-4 pathway blockade PD-1 pathway blockade Ipilimumab

CTLA-4=cytotoxic T-lymphocyte antigen-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 presentation at ASCO 2013 (Abstract 9012). Ipilimumab Demonstrated ImprovedMDX010 -20 and Long-term Overall Survival vs.

100 gp100 Survival (%)2 Median OS, months 95% CI HR P value ≥2 years ≥3 years 80 Ipilimumab + gp100 10.0 8.5–11.5 0.68 <0.001 19 15 Ipilimumab 10.1 8.0–13.8 0.66 0.003 25 25 gp100 6.4 5.5–8.7 17 10 60

40 Patients Alive (%) Alive Patients 20

0 0 1 2 3 4 Years

• In clinical trials, most AEs associated with ipilimumab were immune-related and were managed using ipilimumab-specific treatment algorithms3 • The most frequently reported irAEs associated with ipilimumab monotherapy (≥10%, all grades) in a phase 3 trial were: diarrhea (28%), pruritus (24%), and rash (19%)1

1. Adapted from Hodi FS, et al. N Engl J Med. 2010;363:711-723. 2. McDermott D, et al. Ann Oncol. 2013;24:2694-2698. 3. Yervoy Risk Evaluation and Mitigation Strategy. https://www.hcp.yervoy.com/pages/rems.aspx. Accessed February 5, 2015. Pooled OS Data Shows Durable, Long-term Survival in Some Patients An OS plateau started at approximately 3 years, with follow-up of up to 10 years in some patients.

1.0 0.9

0.8

0.7 N = 1861 0.6 Median OS, months (95% CI): 11.4 (10.7-12.1)a 0.5 3-year OS rate, % (95% CI): 22 (20-24)a

0.4

Proportion Alive Proportion 0.3 0.2

0.1 Ipilimumab CENSORED 0.0

0 12 24 36 48 60 72 84 96 108 120 Patients at Risk Months Ipilimumab 1861 839 370 254 192 170 120 26 15 5 0

CI, confidence interval; OS, overall survival. aIpilimumab was given at different doses and as different lines of therapy, using different schedules across the 12 studies. 1. Schadendorf D, et al. J Clin Oncol. doi:10.1200/JCO.2014.56.2736. Example of Evolution of Response to CTLA-4 Inhibitor

Screening

Week 12: Initial increase in total tumour burden (mWHO PD) Week 96: Durable & ongoing response without signs of IRAEs

Week 16: Responding

Harmankaya et al. EADO 7th World Congress of Melanoma 2009.

PD-Adaptive Resistance to Immunotherapy

Anti–PD-1

Anti–PD-L1 Tumor cell

Interferons

• PD-L1 can be expressed on tumor cells either endogenously or induced by association with T cells (adaptive immune resistance)[1,2] – PD-1:PD-L1 interaction results in T cell suppression (anergy, exhaustion, death) • In RCC, melanoma, and other tumors, PD-L1 expression has been shown to be associated with adverse clinical/pathologic features, eg, more aggressive disease and shorter survival[3]

1. Topalian SL, et al. Curr Opin Immunol. 2012;24:207-212. 2. Taube JM, et al. Sci Transl Med. 2012;4:127ra37. 3. Thompson RH, et al. Proc Natl Acad Sci USA. 2004;101:17174-17179. Activity of Anti-PD-1 Agents in Solid Tumors [1] Nivolumab Activity (ORR) MK-3475 Activity (ORR)[2] Melanoma: 28% Melanoma: 38% NSCLC: 18% Highest dose: 52% RCC: 27% (assessed by RECIST 1.1 with confirmation by ICR)

Patient with metastatic melanoma

81% of pts with response still on treatment at time of analysis (median followup: 11 mos)

1. Topalian SL, et al. N Engl J Med. 2012;366:2443-2454. 2. Hamid O, et al. N Engl J Med. 2013;369:134-144. Nivolumab vs Dacarbazine: CheckMate Compared to dacarbazine, nivolumab066 decreased risk of death by 57%

2-year survival rate nivolumab 57.7% vs Chemotherapy Obituary dacarbazine 26.7% REST IN PEACE

Overall Survival Hazard ratio for death, 0.43 (95% CI, 0.33-0.57) p<0.001

NIVO DTIC (N=210) (N=208) Median OS, NR 11.2 mo (95% CI) (23.1, NR) (9.6, 13.0) 0.43 HR (95% CI) P<0.001 1.0 (0.33, 0.57) 0.9 0.8 70.7% 0.7 57.7%

Survival 0.6 of of 0.5 Nivolumab 0.4 46.3% 0.3

Probability 0.2 NIVO 26.7% Dacarbazine 0.1 DTIC Dacarbazine 0.0 0 3 6 9 12 15 18 21 24 27 30 1975 - 2010 Months Robert C et al. N Engl J Med 2015:372:320-30; Atkinson V et al. Society for Melanoma Research International Congress, San Francisco, November 18- 21, 2015 15 NIVO Monotherapy: 5-Year OS in Heavily Pretreated Patients (CA209- 003)1,a

o Data from long-term follow-up of phase 1 study 1.0

0.9 All patients (events: 69/107), median and 95% CI: 17.3 (12.5, 37.8) NIVO 3 mg/kg (events: 11/17), median and 95% CI: 20.3 (7.2, NR) 0.8

0.7

0.6

0.5 5-year OS rate NIVO 3 mg/kg 35% 0.4

0.3 Probability of Survival of Probability 0.2 5-year OS rate all patients 34%

0.1

0.0 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 Number of patients at risk Months All patients 107 86 64 51 49 43 41 36 29 17 15 12 3 1 0 NIVO 3 mg/kg 17 15 11 9 8 7 7 6 6 6 6 6 1 0

aStudy population included patients with advanced melanoma (n = 104), non-small cell lung cancer (n = 122), castrate-resistant prostate cancer (n = 17), renal cancer (n = 34), and colorectal cancer (n = 19). Data shown are for patients with advanced melanoma only2 Database lock October 2015 1. Hodi FS et al. Presented at AACR 2016; abstract CT001. 2. Topalian SL et al. N Engl J Med. 2012;366:2443-2454

16 KEYNOTE-006: Results Co-Primary Endpoint Phase III Pembrolizumab vs Ipilimumab in Ipilimumab-Naive Patients:

PFS at Second Interim Analysis (IA2) OS at Second Interim Analysis (IA2)

Median 6-month 12-month HR Median Rate at 12 HR Treatment arm (95% CI), P Treatment arm P rate, % rate, % (95% CI) (95% CI), mo mo (95% CI) mo Pembrolizumab 0.63 Pembrolizumab 5.5 0.60 NR (NR-NR) 74.1% 0.0005 47% 37.7% <0.0001 Q2W (0.47-0.83) Q2W (n=279) (3.4-7.4) (0.49-0.74) Pembrolizumab 4.1 0.59 Pembrolizumab 0.69 47.4% 36.3% <0.0001 NR (NR-NR) 68.4% 0.0036 Q3W (n=277) (2.9-7.2) (0.48-0.73) Q3W (0.52-0.90) Ipilimumab 2.8 Ipilimumab NR (12.7-NR) 58.2% -- -- 26.4% 17.2% -- -- (n=278) (2.8-2.9)

100 100 90

, % 90 80 Pembrolizumab Pembrolizumab Ipilimumab Q2W Q3W 80 70 (n=277) (n=277)

Survival 60 (n=279) 70

, % Free Free - 50 60 40 Survival 50 30 40 Progression 20 10 30 0 20 0 2 4 6 8 10 12 14 16 18 0 2 4 6 8 10 12 14 16 18

Time (months) Time (months)

17 • Robert C et al. N Engl J Med 2015;372:2521-32; Schachter J et al. Society for Melanoma Research International Congress, San Francisco, November 18-21, 2015 KEYNOTE-006: Final Results for the Secondary Endpoint Phase III Pembrolizumab vs Ipilimumab in Ipilimumab-Naive Patients:

a Ongoing Duration of Response Responders, Median (range), Treatment arm Response n mo b Pembrolizumab 103 NR (1.8 to 22.8+) 69 (67%) Q2W Pembrolizumab 100 NR (2.0 to 22.8+) 60 (60%) 100 Q3W NR (1.1+ to 90 Ipilimumab 37 23 (62%) 80 23.8+) 70 60 74.5% 22.8 50 79.0% 79.3% 70.6% 40 67.6% 30 70.0% 20 10 0 0 2 4 6 8 10 12 14 16 18 20 22 24 Time, months Analysis cutoff date: December 3, 2015; a Assessed per RECIST v1.1 by independent central review; b Patients without progression, death, or new anticancer therapy

Schachter J et al. ASCO Annual Meeting, Abstract # 9504, 2016 18 Resistance: Primary versus Acquired Cancers differ widely in the number of mutations they contain Steps / Mechanism Leading to Sensitivity or Resistance to Immunotherapies

A. Identification of tumour antigen 1. Tumour immunogenicity Tumours must express antigens/be permissive to APCs B. Antigen presentation and T cell activation 2. Antigen presentation / generation of effector T-cells Dendriltic cells APCs harbouring tumour antigen must undergo maturation and be able to present tumour antigen to antigen-specific T cells Naïve T cells C. Activation of T cell 3. The encounter of antigen and PDL1 by tumour- effector specific T-cells functions Exhausted Effector T Tumour-specific effector T cells carry out their cells effector functions

Effector T cells

D. Encounter of tumour antigen and PDl1 4. The activity and efficacy of tumour-specific immune responses

Memory T cells To be recognized, tumours must display cognate antigen & PDL1, otherwise PD1-mediated immune suppression will not occur

E. Induction of immunological memory 5. The induction of immunological memory In order to sustain anti-tumour immune responses 21 long term, induction of immunological memory must O'Donnell JS, et al. Cancer Treat Rev. 2017;52:71-81. be preserved Immune Escape in Cancer

Many tumours escape the immune response by creating an immunosuppressive microenvironment that prevents an effective antitumour response1,2

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

Ineffective presentation Tumour T-cell checkpoint of tumour antigens Cells dysregulation CTLA-4 to the immune system CD28 PD-1 Downregulation of Suppression OX40 B7-1 MHC Expression of APC GITR T cell TIM-3 CD137 BTLA CD27 VISTA Tumour APC HVEM LAG-3 Cell Co-stimulatory Co- Tumour receptors inhibitory Microenvironment receptors The mechanisms tumours use to escape the immune system provide a range of potential therapeutic targets for cancer

APC=antigen-presenting cell; MDSC=myeloid-derived suppressor cell; MHC=major histocompatibility 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. Overcoming Treatment Resistance

• Dual immune checkpoint Blockage • IDO inhibitors Failed • Enhance tumor Immunogenicity (RT, chemotherapy, 5-AZA) • Depletion of Tregs (anti-OX40, Anti-CTLA- 4, TIM-3, IGIT) • Depletion of MDSC (gemcitabine) • Manipulation of the tumor micro- environment (β-catenin, AKT, CSF-1R, AXL, CXCL2 etc)

23 CA209-067: Study Design

Randomized, double-blind, phase III study to compare NIVO + IPI or NIVO alone to IPI alone

NIVO 1 mg/kg + IPI 3 mg/kg Q3W N=314 for 4 doses then NIVO 3 mg/kg Q2W

Unresectable or Stratify by: Metatastic Treat until Melanoma Randomize • PD-L1 N=316 expression* progression** • Previously 1:1:1 NIVO 3 mg/kg Q2W + or untreated • BRAF status IPI-matched placebo unacceptable toxicity • 945 patients • AJCC M stage

N=315 IPI 3 mg/kg Q3W for 4 doses + NIVO-matched placebo

*Verified PD-L1 assay with 5% expression level was used for the stratification of patients; validated PD-L1 assay was used for efficacy analyses.

**Patients could have been treated beyond progression under protocol-defined circumstances. Overall Survival

NIVO+IPI (N=314) NIVO (N=316) IPI (N=315) Median OS, months 20.0 (17.1– NR 36.9 (29.1–NR) 100 (95% CI) 24.6) 0.55 (0.42– 0.63 (0.48– HR (98% CI) vs. IPI -- 90 0.72)* 0.81) 0.88 (0.69– 73% HR (95% CI) vs. NIVO -- P<0.0001 80 1.12) *P<0.0001 70 74% 64% 60 67% 59% 50

40 45% Percentage PFS of Percentage

Overall Survival (%) Survival Overall 30

20 NIVO+IPI NIVO 10 IPI 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 Months Number of patients at risk: NIVO+IPI 314 292 265 247 226 221 209 200 198 192 170 49 7 0 NIVO 316 292 265 244 230 213 201 191 181 175 157 55 3 0 IPI 315 285 254 228 205 182 164 149 136 129 104 34 4 0 Database lock: Sept 13, 2016 25 Ipilimumab / Nivolumab post primary resistance to pembrolizumab What about me? PD-1 agents In other Cancers

NSCLC Renal Cell Bladder TN Breast Ca MSI Colorectal Glioblastoma Lymphoma Merkel Cell

27 Cancers differ widely in the number of mutations they contain Overall Survival with Nivolumab vs. CheckMate-017 Docetaxel for Pretreated Squamous NSCLC Patients: Phase III, Randomized Study

100 Nivolumab Docetaxel 3 mg/kg 75 mg/m2 90 n = 135 n = 137 80 mOS mo, 9.2 6.0 (95% CI) (7.33, 12.62) (5.29, 7.39) 70 HR=0.62 (0.48, 0.81); P=0.0004 60

50 12-month OS rate=42% OS (%) OS 40 c 18-month OS rate=28% 30 Nivolumab 20 12-month OS rate=24% 18-month OS rate=13% Docetaxel 10 0 0 3 6 9 12 15 18 21 24 27 30 33 Time (mos) Number of Patients at Risk Nivolumab 135 113 86 69 57 51 37 25 14 6 0 0 Docetaxel 137 104 69 46 33 22 17 11 7 3 1 0 Minimum follow-up for survival: 18 months

Based on August 2015 DBL. • NivolumabSymbols refer decreasedto censored observations. risk of death by 41% vs. docetaxel at 1 year and 38% at 18 months • Nivolumab significantly improved median overall survival by 3.2 months vs. docetaxel.

Reckamp K et al. Presented at World Lung Conference. 2015; Based on August 2015 DBL; symbols refer to censored observations. Pembrolizumab Significantly Improved OS vs. Docetaxel for Pretreated PD-L1-Positive NSCLC Patients

Keynote-010: PD-L1-Positive (>50%) Squamous and Non-Squamous NSCLC 100

90 80 Pembrolizuma Pembrolizumab b Docetaxel 70 2 mg/kg 10 mg/kg (n = 2343) 60 (n = 344) (n = 346) 50

OS (%) OS mDoR, mo 40 6 (range) Not reached Not reached 30 Pembrolizumab 2 mg/kg mOS, mo 20 Pembrolizumab 10 mg/kg 14.9 17.3 8.2 Median follow-up: (95% CI) 10 Docetaxel 13.1 months (IQR 8.6-17.7) HR for 2 mg/kg mOS vs. docetaxel = 0.71 (95% CI 0·58–0·88); 0 p=0·0008 0 5 10 15 20 25 HR for 10 mg/kg mOS vs. docetaxel = 0·61 (0·49–0·75); p<0·0001 Time (months)

mDoR = median duration of response; mOS = median overall survival Note: pembrolizumab has not yet been approved from the treatment of NSCLC in Canada 1. Herbst RS et al. Lancet. 2015 Dec 18. pii: S0140-6736(15)01281-7. 30 PD-1 Inhibitors: Pembrolizumab ⎮ Nivolumab

Health Canada Approval Health Canada Approval:

• Pembrolizumab is indicated for the NivolumabActivatedis indicated T for the treatment treatment of patients with Metastatic of adultcell patients with locally advanced non-small cell lung carcinoma or metastatic non-small cell lung cancer (NSCLC) whose tumours express (NSCLC) with progression on or after PD-L1 (as determined by a validated platinum-based chemotherapy. Patients test) and who have disease with EGFR or ALK genomic tumour progression on or after aberrations should have disease platinumcontaining chemotherapy. progression on a therapy for these Patients with EGFR or ALK genomic aberrations prior to receiving tumour aberrations should have nivolumab. disease progression on authorized therapy for these aberrations prior to receiving pembrolizumab

31• KEYTRUDATM pembrolizumab. Product Monograph. Merck Canada Inc. May 19, 2015. Canada News Wire. Bristol-Myers Squibb Press Release, September 25, 2015; www.fda.gov Accessed October 2, 2015. OPDIVO, nivolumab. Canadian Product Monograph. Bristol-Myers Squibb Canada Inc. September 24, 2015 •

KEYNOTE (KN)-024: Improved Overall Survival for PD-L1 ≥ 50%

Brahmer et. al., WCLC 2017 Conclusions

• Immune checkpoint inhibitors are making a major impact on cancer survivals and quality of life • Potentially curative in some patients • Need biomarkers to accurately predict who will benefit from immune therapy • Immune therapy is costly • Cancer treatment is evolving to a more personalized approach • Therapy is evolving to combination therapy (What combination) • Toxicity is substantial Immune Related Adverse Events (irAE): The Elephant in the Room

36 Identification of Immune-related Adverse Events

• Immune related adverse events occur as a consequence of an activated immune system targeting normal tissues • Immune-related side effects are diagnosed by exclusion: rule out side effects with other etiologies (eg, infection, neoplasm, metabolic causes, or other medications) • Consider that immune-related adverse events may be worsened by non-immune-related side effects (eg, infection could trigger an acute adrenal dysfunction) • Skin and the gastrointestinal system are the most frequently affected areas, but immune-related side effects can affect the hepatic, neurologic, endocrine, or any organ system • Vigilance and patient education is paramount irAEs Observed With Novel Immune Therapy

Endocrine Skin • Hypophysitis • Skin rash or (headache,visual pruritus changes, weakness) • Thyroiditis with hyper/hypothryroidism*

Hepatic • Abnormal LFTs (eg, AST, ALT, Pulmonary total bilirubin) • Pneumonitis*

Gastrointestinal (GI) Neurologic • Diarrhea • Sensory or motor • Bloody stool neuropathy • Fever • Myositis • Constipation (rarely) • Cerebral vasculitis • Demyelination, central/peripheral

*more common with anti-PD-1 MABs If not vigilant, may result in more serious immune-mediated side effects. Immune-related Side Effects: Occurrence

Common occurrences Less common occurrences • Skin • Liver – eg, rash and pruritus – eg, hepatitis or abnormal liver function tests • Gastrointestinal tract • Endocrine system – eg, diarrhea/colitis – eg, hypophysitis, hypopituitarism, adrenal dysfunction,thyroid etc • Neurologic – eg, neuropathies and Guillain- Barré syndrome (GBS) • Other – eg, uveitis, arthritis, pancreatitis, and toxic epidermal necrolysis (TEN) Nivolumab vs Nivolumab + Ipilimumab vs Ipilimumab: CheckMate-067

Ipilimumab Nivolumab Nivolumab + Adverse Event (N=311) (N=313) Ipilimumab (n=313) Any Adverse Event Grade 3 173 (55.6%) 136 (43.5%) 215 (68.7%) or 4 n (%)

Treatment-related adverse 85 (27.3%) 51 (16.3%) 172 (55%) event: n (%)(Grade 3 or 4) Diarrhea 19 (6.1%) 7 (2.2%) 29 (9.3%) Fatigue 3 (1.0%) 4 (1.3%) 13 (4.2%) Pruritus 1 (0.3%) 0 6 (1.9%) Of the patients who Colitis 27 (8.7%) 2 (0.6% 24 (7.7%) discontinued the Hepatic 5 (1.6%) 8 (2.6%) 59 (18.8%) NIVO + IPI combination due to Immune modulatory agents, treatment-related including topical agents, to AEs, 67.5% (81/120) 55.9% 47% 83.4% manage adverse events developed a response

Secondary 5.1% 0.6% 6.1% immunosuppressive agents (e.g., infliximab) Treatment-related adverse event leading to 41 (13.2) 16 (5.1%) 92 (29.4) discontinuation

Larkin J et al. N Engl J Med 2015; May 31 DOI:10.1056/NEJMoa1504030 40 Time to Onset of imAEs Observed With Ipilimumab

Weeks to Symptoms for imAEs With 10 mg/kg ipilimumab Immune-mediated Side Effect Expected Time (imAE) to Onset of imAE Skin-related imAEs After 2 to 3 weeks Gastrointestinal and hepatic imAEs After 6 to 7 weeks Endocrinologic imAEs After an average of 9

Lebbé C, et al. Presented at: Perspectives in Melanoma XII. October 8–10, 2008;weeks Baltimore, MD; abstract O-015. Kaehler KC, et al. Semin Oncol 2010;37(5):485-498. Time to Resolution of Grade 3/4 Treatment-related Select AEs

1.0 Resolved, n/N (%)

0.9 Median (95% Treated with CI) Overall IMM

0.8 Endocrine 15.1 (4.6, NA) 13/21 9/16 (56.3)

a (61.9)

0.7 AEs Gastrointesti 3.6 (2.0, 4.3) 69/73 62/65 (95.4)

Grade 3/4 Grade nal (94.5) ith 0.6 Hepatic 4.3 (3.1, 5.6) 74/76 52/52 (100) (97.4)

0.5 Pulmonary 4.5 (0.3, 10.1) 6/6 (100) 5/5 (100) Related Select Select Related

- Renal 1.9 (0.4, 3.6) 7/7 (100) 4/4 (100) 0.4 Skin 3.9 (2.1, 6.1) 27/33 23/29 (79.3) (81.8) • Most treatment-related select AEs 0.3 resolved, except endocrinopathies Treatment that required long-term hormone

Proportion of Patients W Patients of Proportion 0.2 replacement therapy - Median time to resolution of 0.1 grade 3/4 AEs was <5 weeks, excluding endocrinopathies, and 0.0 there were no notable differences 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63 66 69 72 75 78 81 84 87 90 93 96 in resolution rates for select AEs overall vs those that required IMM Time to Resolution From AE Onset (Weeks)

aPatients who have not yet resolved; at time 0, 100% have not had resolution. Resolution is shown over time 42 Immune-related Side Effects Management General Considerations

• Delaying the introduction of corticosteroid use or other immunosuppressive therapy may allow the development of severe immune-related side effects and/or life-threatening complications • Immune-related side effect treatment is dependant on severity – Grade 12 immune-related side effects are treated symptomatically, with intensified frequency of monitoring – Persistent grade 12 immune-related side effects should be managed as grade 34 immune-related side effects – Grade 34 immune-related side effects should be treated with corticosteroids, tapered over ≥4 weeks • After immune-related side effect resolution, tapering of corticosteroid to prevent rebound of events is based on clinical judgment of the improvement of the immune-related side effect, and recommended to be performed over at least 4 weeks • Patients should not receive narcotics for symptomatic treatment; narcotic use should be avoided as it may mask immune-related side effect symptoms Immune-related Adverse Events Requiring Immediate Treatment

• Immune-related side effects (or toxicities) can initially present with common symptoms that may rapidly progress to more serious complications – It is important to recognize symptoms early and address them according to the provided management guidelines • The following immune-related side effects should be addressed immediately – Diarrhea, blood in stool, constipation, fever (gastrointestinal immune-related side effects) – Headache, visual-field defects, fatigue/weakness, coma (endocrinopathy immune-related side effects) – Muscle weakness (neurological immune-related side effects) – Elevations in liver function tests (LFTs) (eg, AST, ALT, total bilirubin) in the absence of clinical symptoms (hepatotoxicity immune-related side effects) Management of severe irAEs

• Corticosteroids are highly effective for the majority of IR-AEs. • Various management algorithms exist, but in the case of severe (or life- threatening) toxicity, methylprednisolone 2mg/kg or prednisone 1-2 mg/kg is recommended. • Steroids should be tapered slowly over a period of not less than 5 weeks, with periodic clinical/biochemical reassessments. • Little to no data regarding the efficacy of non-steroid immunosuppressive agents (anti-TNF agents are the best studied, and are effective for steroid-refractory colitis/diarrhea). • Use your algorithms! • Need your go to specialists! Management of PD-1 Inhibitors Adverse Effects

PD-1 Inhibitor DOSE MODIFICATIONS

Withhold PD-1 Inhibitor & Permanently Discontinue PD-1 Inhibitor If: Possible Use of Steroids Grade 2 pneumonitis • Inability to reduce • Any life-threatening steroid dose to 10 mg adverse reaction Grade 2 or 3 colitis or less of prednisone • Grade 3 or 4 pneumonitis or equivalent per day Symptomatic hypophysitis • Grade 3 or 4 nephritis within 12 weeks Grade 2 nephritis Grade 3 hyperthyroidism • AST or ALT > 5 x ULN or • Persistent Grade 2 AST or ALT > 3-5 x ULN or total total bilirubin > 3 x ULN* or 3 adverse Bilirubin > 1.5-3 x ULN • Grade 3 or 4 infusion- reactions that do related reactions not recover to Grade Other severe or Grade 3 reaction hyperthyroidism 0-1 within 12 weeks • Any severe or Grade 3 after last dose of treatment-related adverse PD-1 inhibitor reaction that recurs Resume in patients whose adverse reaction recover to Grade 0-1

For patients with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT increases by ≥ 50% relative to baseline and lasts for at least 1 week; ULN, upper limit of normal

KEYTRUDATM pembrolizumab. Product Monograph. Merck Canada Inc. May 19, 2015. 46 Conclusions

• Immune checkpoint inhibitors are making a major impact on cancer survivals and quality of life • Potentially curative in some patients • Need biomarkers to accurately predict who will benefit from immune therapy • Immune therapy is costly • Cancer treatment is evolving to a more personalized approach • Therapy is evolving to combination therapy • Toxicity is substantial CASE 1: METASTATIC DISEASE TREATED WITH CTLA-4/PD-1 INHIBITOR (THE GOOD)

33-year-old male from Kamloops, British Columbia.

Diagnosis and excision; pT4aN2a melanoma of the right forearm, BRAF V600E Nov 2011 mutation positive

Dec 2012 Received 1 month high-dose interferon; discontinued for intolerance

May 2015 Recurrence in right lung and pleura; palliative pleur-X thoracic cathether inserted, draining 2-3 L/day

May 2015 to Combination dabrafenib/trametinib; excellent partial response; cathether September 2015 removed

October 2015 Increasing dyspnea; re-staging scan demonstrates progressive disease, thoracic catheter re-inserted

November 2015 Assessed for second line immunotherapy Case 1: Metastatic Disease Treated with ctla-4/PD-1 Inhibitors

November 2015: began therapy with CTLA-4 / PD-1 inhibitor

. ECOG 1??

. Draining 3 L pleural fluid/24 h

. Sodium 116

. Albumin 20

. LDH 860 Case 1: Metastatic Disease Treated with CTLA-4/PD-1 Inhibitors

Week 52:

Before Week 6 ECOG 0 Treatment . Ongoing response to therapy . No significant treatment- related adverse events (progressive poliosis) Case 2: Metastatic Disease Treated with PD-1 Inhibitors (The Bad) 36-year-old male from Edmonton, Alberta.

Presented with right post-auricular lesion. pT3aN1a after WLE and right neck node June 2013 dissection.

Completed 1 week adjuvant high-dose interferon prior to discontinuation for August 2013 poor tolerance.

Diagnosed with a solitary gallbladder metastasis, cholecystectomy with partial November 2015 hepatectomy confirms M1 disease.

February 2016 Post-operative re-staging scans demonstrate metastatic disease.

March 2016 Initiated combination anti-CTLA-4/PD-1 therapy Immune-related adverse events secondary to ctla-4/pd-1 inhibition

Grade 2 diarrhea, grade 2 dermatitis (treatment held)

Cycle 1 +21 d +21 d May 2016 April 2017 March (pre-cycle 2) (April 2016) 2016 CASE 3: ANCA-POSITIVE DISEASE FOLLOWING TREATMENT WITH CTLA4/PD1 INHIBITORS (THE UGLY)

66-year-old female from Edmonton, Alberta.

Diagnosis and excision; pT2aN3 melanoma of the upper back, BRAF V600K May 2012 mutation positive

Dec 2012 Received 1 month high-dose interferon; discontinued for intolerance

June 2016 Recurrence with biopsy-confirmed, distant subcutaneous nodules (M1a)

Enrolled to a phase III RCT comparing 2 dosing regimens of combination July 2016 ipilimumab/nivolumab. First dose July 25, 2016 CASE 3: ANCA-POSITIVE DISEASE FOLLOWING TREATMENT WITH CTLA4/PD1 INHIBITORS

66-year-old female from Edmonton, Alberta.

Day15 Assessment in advance of cycle 2 therapy, admitted for hydration, investigation, 6 day history of immunosuppressive steroids headache behind left eye CASE 3: ANCA-POSITIVE DISEASE FOLLOWING TREATMENT WITH CTLA4/PD1 INHIBITORS

66-year-old female from Edmonton, Alberta.

UAH nephrology consulted; renal biopsy organized. Corticosteroid supplemented + 31 days with Rrituximab (anti-CD20 mAb) CASE 3: ANCA-POSITIVE DISEASE FOLLOWING TREATMENT WITH CTLA4/PD1 INHIBITORS

66-year-old female from Edmonton, Alberta.

+ 84 days Put onR corticosteroid taper; stable GFR, pulmonary symptoms have resolved Safety Summary Significant Toxicity

NIVO + IPI NIVO (N=313) IPI (N=311) Patients Reporting (N=313) Event, % Any Grade Any Grade Any Grade Grade 3–4 Grade 3–4 Grade 3–4 Treatment-related 95.5 55.0 82.1 16.3 86.2 27.3 adverse event (AE) Treatment-related AE leading to 36.4 29.4 7.7 5.1 14.8 13.2 discontinuation Treatment-related 0 0.3 0.3 *Onedeath* reported in the NIVO group (neutropenia) and one in the IPI group (cardiac arrest).

• 67.5% of patients (81/120) who discontinued the NIVO + IPI combination due to treatment-related AEs developed a response Less Jeeez…. Toxicity

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