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.