Checkpoint Inhibition in Hodgkin s Lymphoma John Kuruvilla, MD & Rob Laister, PhD

Checkpoint Inhibition in Hodgkin s Lymphoma John Kuruvilla, MD & Rob Laister, PhD

Disclosures for Rob Laister Research Support Employee Consultant Major Stockholder Speakers Bureau Honoraria Scientific Advisory Board Leukemia and Lymphoma Society US, Rasch Foundation, CCSRI N/A N/A N/A N/A Celgene, Janssen, Jazz Pharmaceuticals, Seattle Genetics, N/A

Disclosures for John Kuruvilla Research Support Employee Consultant Major Stockholder Speakers Bureau Honoraria Scientific Advisory Board Leukemia and Lymphoma Society US, Rasch Foundation Roche, N/A Abbvie, BMS, Gilead, Janssen, Roche N/A N/A Abbvie, Amgen, BMS, Celgene, Gilead, Roche, Janssen, Lundbeck, Merck Seattle Genetics, Lymphoma Canada (Chair) I don t understand the purpose of the World Cup of Hockey I will likely discuss all sorts of off-label use of agents as well as investigational agents

The Cancer Immunity Cycle - To understand the genesis of immune checkpoint inhibitors, it behooves us to understand the process by which immune cells target cancer cells. Adapted from Hughes, 2016, Trends in Immuno., 37, 462-476

The Cancer Immunity Cycle 1) Tumour cell turnover/ death results in the release of tumour antigens that are captured, taken up and processed by dendritic cells. Adapted from Hughes, 2016, Trends in Immuno., 37, 462-476

The Cancer Immunity Cycle 2) These dendritic cells migrate to lymph nodes where they prime naïve T-cells to have anti-cancer activity. Adapted from Hughes, 2016, Trends in Immuno., 37, 462-476

The Cancer Immunity Cycle 3) These activated effector T-cells travel to and infiltrate into the tumour where they kill cancer cells. Adapted from Hughes, 2016, Trends in Immuno., 37, 462-476

What are Immune Checkpoints? Adapted from Hughes, 2016, Trends in Immuno., 37, 462-476 and Pardoll, 2012, Nat Rev Can, 5, 252-265

What are Immune Checkpoints? Adapted from Hughes, 2016, Trends in Immuno., 37, 462-476 and Pardoll, 2012, Nat Rev Can, 5, 252-265

What are Immune Checkpoints? - Oncogenic pathways in HL cells express cell surface ligands that bind to and shut down T-cell function Adapted from Hughes, 2016, Trends in Immuno., 37, 462-476 and Pardoll, 2012, Nat Rev Can, 5, 252-265

What are Immune Checkpoints? Surface of Cancer Cell (Ligand) Surface of T-cell (Receptor) Adapted from Pardoll, 2012, Nat Rev Can, 5, 252-265 -there are numerous ligand/receptor interactions between T-cells and tumour cells that can positively or negatively regulate T-cell function -these interactions are used in normal T-cell biology to control the duration and amplitude of immune responses -cancer cells can express inhibitory ligands to evade the immune system

What are Immune Checkpoints? Cancer Cell T-cell Adapted from Pardoll, 2012, Nat Rev Can, 5, 252-265 -upon binding there respective ligands, PD-1 and CTLA4 transmit negative regulatory signals into the T-cell thereby compromising its anti-tumour activity.

Regulation of PD-1 Ligands in Hodgkin Lymphoma -what drives PD-L1 expression in Hodgkin lymphoma? 9p24 amplified - 9p copy gain has been reported in HL and MLBCL - the PD-L1 and PD-L2 genes are located in close proximity to each other on chromosome 9p24 Adapted from Green, et al., 2010, Blood, 116, 3268-3277

Regulation of PD-1 Ligands in Hodgkin Lymphoma -there is an association between 9p24 amplification and increased levels of PD-L1 in HL Adapted from Green, et al., 2010, Blood, 116, 3268-3277

Regulation of PD-1 Ligands in Hodgkin Lymphoma -9p24 amplification also increases JAK2 levels which drive PD-L1 expression through JAK/STAT signaling. Adapted from Green, et al., 2010, Blood, 116, 3268-3277

Regulation of PD-1 Ligands in Hodgkin Lymphoma -with a limited number of cases, 9p24 amplification appears to results in a trend towards worse outcome in patients with early stage unfavourable(es-u) and advanced stage(as) HL Adapted from Green, et al., 2010, Blood, 116, 3268-3277 and Roemer, et al., 2016 JCO, 34, 2690-2697

Regulation of PD-1 Ligands in Hodgkin Lymphoma AP-1 EBV -EBV can also promote PD-L1 expression through JAK/STAT singnaling and the transcription factor AP1 Adapted from Green, et al., 2010, Blood, 116, 3268-3277 and Green et al., 2012, Clin Can Res, 18, 1611-1618

Immune Checkpoint Inhibitors Cancer Cell T-cell Adapted from Pardoll, 2012, Nat Rev Can, 5, 252-265 - Several mechanisms have been identified by which Hodgkin lymphoma cells up-regulate factors that result in immune system evasion. - What can we do about it?

Immune Checkpoint Inhibitors Cancer Cell T-cell Adapted from Pardoll, 2012, Nat Rev Can, 5, 252-265 Target Biological Function Antibody CTLA4 Inhibitory Receptor Ipilimumab Tremelimumab PD1 Inhibitory Receptor Nivolumab Pembrolizumab PD-L1 Inhibitory Ligand Durvalumab Avelumab

Immune Checkpoint Inhibitors Cancer Cell T-cell Adapted from Pardoll, 2012, Nat Rev Can, 5, 252-265 PD-L1 PD-1 PDB ID: 4ZQK

Immune Checkpoint Inhibitors PD-L1 PD-1 PDB ID: 4ZQK PD-1 Fab fragment of Pembrolizumab PDB ID: 5JXE

Immune Checkpoint Inhibitors Target Biological Function Antibody CTLA4 Inhibitory Receptor Ipilimumab Tremelimumab PD1 Inhibitory Receptor Nivolumab Pembrolizumab PD-L1 Inhibitory Ligand Durvalumab Avelumab Fab fragment of Pembrolizumab PD-1 -the current immune checkpoint inhibitors are antibodies targeting either the inhibitory ligands or their receptors thus blocking their interaction and preventing the transmission of a negative regulatory signal into the T-cell.

Immune Checkpoint Inhibitors PD-L1 PD-1 PDB ID: 4ZQK -some potential downsides to the use of therapeutic antibodies in the clinic are their limited tumour penetration, lack of oral bioavailability, immunogenicity and cumbersome production.

Immune Checkpoint Inhibitors PD-L1 PD-1 PDB ID: 4ZQK -the development of small molecules inhibiting PD-1/PD-L1 interactions is currently underway.

Next Steps: Immune Checkpoint Combinations Target Biological Function Antibody CTLA4 Inhibitory Receptor Ipilimumab Tremelimumab PD1 Inhibitory Receptor Nivolumab Pembrolizumab PD-L1 Inhibitory Ligand Durvalumab Avelumab - checkpoint inhibitors have impressive clinical activity (Nivolumab, 87% ORR in rrhl; Ansell et al., NEJM, 2015) - what are the strategies to combine them with other agents to turn some of those PRs into CRs?

Next Steps: Immune Checkpoint Combinations Checkpoint Inhibitors +? Adapted from Chen and Mellman, 2013, Immunity, 39, 1-10

Next Steps: Immune Checkpoint Combinations Checkpoint Inhibitors + Checkpoint Inhibitors Adapted from Chen and Mellman, 2013, Immunity, 39, 1-10

Next Steps: Immune Checkpoint Combinations Direct on-target HL inhibition ADC (Vedotin) JAK2 inhibitors Chemotherapy Radiation Checkpoint Inhibitors Adapted from Chen and Mellman, 2013, Immunity, 39, 1-10 +

Next Steps: Immune Checkpoint Combinations Cytokines IL-2 IL-12 Checkpoint Inhibitors + Adapted from Chen and Mellman, 2013, Immunity, 39, 1-10

Next Steps: Immune Checkpoint Combinations Checkpoint Inhibitors + Cell-Cell Interactions BiTEs CARs Adapted from Chen and Mellman, 2013, Immunity, 39, 1-10

Next Steps: Immune Checkpoint Combinations Checkpoint + Inhibitors Immune modulators Lenalidomide CC-122 Adapted from Chen and Mellman, 2013, Immunity, 39, 1-10

Next Steps: Immune Checkpoint Combinations - Activated T-cells need the appropriate vasculature to enter the tumour micro-environment and carry out their cytotoxic activities. -VEGFR signalling can contribute to aberrant tumour vascularization Adapted from Hughes, 2016, Trends in Immuno., 37, 462-476

Next Steps: Immune Checkpoint Combinations - VEGFR inhibitors in combination with checkpoint inhibitors, may allow greater numbers of effector T-cells into the tumour micro-environment. Adapted from Hughes, 2016, Trends in Immuno., 37, 462-476

Checkpoint Inhibitors Question #1 Which of the following mechanisms have been associated with enhanced expression of the PD-1 ligands? 1. 9p24 amplification 2. CHK1 and CHK2 activation 3. JAK/STAT signalling 4. T-cell ambivalence 5. Answers 1 and 3

Ready for prime time in 2014?

Nivo phase 1: Treatment-Related Serious Adverse Events Adverse Event, n (%) chl (n = 23) Any Grade Grade 3 4 Any event 3 (13) 2 (9) Lymph node pain 1 (4) 0 (0) Pancreatitis 1 (4) 1 (4) Myelodysplastic syndrome 1 (4) 1 (4) 3 patients discontinued due to adverse events Ansell ASH 2015 2 discontinuations were study drug related (pancreatitis, myelodysplastic syndrome)

Response Rates Best Objective Response chl (n = 23) n (%) 95% CI Objective response rate 20 (87) 66.4 97.2 CR 5 (22) 7.5 43.7 PR 15 (65) 42.7 83.6 SD 3 (13) Ansell ASH 2015

Progression-Free Survival Proportion of Patients Without Progression 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Median PFS (95% CI): NA (18.6 NA) 0 3 6 9 12 15 18 21 24 27 Time, Months No. Patients at Risk 23 20 13 12 11 11 8 5 1 0 Ansell ASH 2015 Median follow-up: 101 wks, Median PFS not reached

Question #2 Early signals from PD1 inhibition look promising (safe and effective). How would you proceed if you were in charge of development? 1. I m in it to win it who needs a phase II trial? Fire up a phase 3 in the relapsed/refractory setting (palliative) 2. Let s generate some revenue I love single arm phase 2 trials. Pathway to a quick approval and I ll figure out a phase 3 later 3. Split the difference? Maybe an adaptive design phase 2-3 or a randomized phase 2 design is the way to go? 4. I can t believe these drugs work RR-H. We need to build studies with heavy biology. 5. Combo combo combo. CR rate is low and I want to build a more effective regimen. What else is in the pipeline?

Keynote 13 Moskowitz JCO 2016

K13: Baseline Characteristics Moskowitz JCO 2016

K13: Overall Response and Waterfall Plot Moskowitz JCO 2016

K13: PFS Median F/U of surviving patients 17.6m Moskowitz JCO 2016

K13: AEs (Any grade in 3 patients) ASH 2015

Checkmate 205 cohort B Prior ASCT and post-asct BV Younes Lancet Oncol 2016

C205:Baseline Characteristics Younes Lancet Oncol 2016

C205: Overall Response rate IRRC Waterfall Plot of best response Younes Lancet Oncol 2016

C205: Change in tumour burden in patients treated beyond PD Younes Lancet Oncol 2016

C205: PFS by IRRC Younes Lancet Oncol 2016

C205: Drug-related AEs in 10% of patients Younes Lancet Oncol 2016

Summary: Nivolumab and Pembrolizumab in RR-cHL Safe and active Profile of both drugs appears remarkably similar Differences may relate to patient populations, trial design and assessment along with length of followup ROLE TODAY: post ASCT and BV failure Post ASCT failure or in ASCT ineligible? What s next? Combinations Registration trials

Nivolumab Trials in HL Checkmate 205 other cohorts not yet published Ipilimumab, Brentuximab Vedotin and Nivolumab Brentuximab and Nivolumab (older or RR HL, NHL) Ibrutinib and Nivolumab Ipilimumab and Nivolumab post ASCT (high risk, NHL)

Pembrolizumab Trials in HL Keynote 087 (the bigger phase 2) presented, not published AFM13 (bispecific anti-cd30/cd16) and Pembrolizumab Lenalidomide and Pembrolizumab Post ASCT Pembrolizumab Pembrolizumab with ibrutinib or idelalisib (inhl)

Keynote 204 in RR-HL

Question #3 PD1 inhibition is a standard therapy in RR-cHL. Where do you see the best fit for these therapies? 1. First line localized higher risk 2. First line advanced stage 3. RR potentially curative (peri-asct) 4. RR non-curative 5. Special groups (ie. elderly)

Summary anti-pd1 antibodies in RR-cHL Significant activity with favourable toxicity profile Various strategies being evaluated Combinations Earlier in the disease course Best use of these agents remains unknown Biology not well defined?