Checkpoint Inhibition in Hodgkin’s Lymphoma John … · Checkpoint Inhibition in Hodgkin’s Lymphoma . ... (Nivolumab, 87% ORR in rrHL; ... Slide 1 Author: User

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

Research Support Leukemia and Lymphoma Society US, Rasch Foundation, CCSRI

Employee N/A

Consultant N/A

Major Stockholder N/A

Speakers Bureau N/A

Honoraria Celgene, Janssen, Jazz Pharmaceuticals, Seattle Genetics,

Scientific Advisory Board N/A

Disclosures for Rob Laister

Research Support Leukemia and Lymphoma Society US, Rasch Foundation Roche,

Employee N/A

Consultant Abbvie, BMS, Gilead, Janssen, Roche

Major Stockholder N/A

Speakers Bureau N/A

Honoraria Abbvie, Amgen, BMS, Celgene, Gilead, Roche, Janssen, Lundbeck, Merck Seattle Genetics,

Scientific Advisory Board 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

Disclosures for John Kuruvilla

The Cancer Immunity Cycle

Adapted from Hughes , 2016, Trends in Immuno., 37, 462-476

- To understand the genesis of immune checkpoint inhibitors, it behooves us to understand the process by which immune cells target cancer cells.



1) Tumour cell turnover/ death results in the release of tumour antigens that are captured, taken up and processed by dendritic cells.



2) These dendritic cells migrate to lymph nodes where they prime naïve T-cells to have anti-cancer activity.



3) These activated effector T-cells travel to and infiltrate into the tumour where they kill cancer cells.

What are Immune Checkpoints?

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





- Oncogenic pathways in HL cells express cell surface ligands that bind to and shut down T-cell function


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

Surface of Cancer Cell (Ligand)

Surface of T-cell (Receptor)



Cancer Cell T-cell

-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

Adapted from Green, et al., 2010, Blood, 116, 3268-3277

-what drives PD-L1 expression in Hodgkin lymphoma ?

- 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

9p24 amplified



-there is an association between 9p24 amplification and increased levels of PD-L1 in HL



-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 and Roemer, et al., 2016 JCO, 34, 2690-2697

-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 Green et al., 2012, Clin Can Res, 18, 1611-1618

-EBV can also promote PD-L1 expression through JAK/STAT singnaling and the transcription factor AP1

EBV AP-1


Cancer Cell T-cell

- 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

Target Biological Function Antibody CTLA4 Inhibitory Receptor Ipilimumab

Tremelimumab

PD1 Inhibitory Receptor Nivolumab Pembrolizumab

PD-L1 Inhibitory Ligand Durvalumab Avelumab

PD-1 PD-L1

PDB ID: 4ZQK



Cancer Cell T-cell

PD-1 PD-L1

PDB ID: 4ZQK

PDB ID: 5JXE

PD-1

Fab fragment of Pembrolizumab



-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.


Tremelimumab



Fab fragment of Pembrolizumab

PD-1


-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.

PD-1

PD-L1

PDB ID: 4ZQK


-the development of small molecules inhibiting PD-1/PD-L1 interactions is currently underway.

PD-1

PD-L1

PDB ID: 4ZQK

Next Steps: Immune Checkpoint Combinations


Tremelimumab



- 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?


Checkpoint Inhibitors + ?

Adapted from Chen and Mellman, 2013, Immunity, 39, 1-10


Checkpoint Inhibitors

Checkpoint Inhibitors +



Direct on-target HL inhibition ADC (Vedotin) JAK2 inhibitors Chemotherapy

Radiation



+


Cytokines IL-2

IL-12



+



Cell-Cell Interactions BiTEs CARs


+


Immune modulators Lenalidomide

CC-122



+



- 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



- VEGFR inhibitors in combination with checkpoint inhibitors, may allow greater numbers of effector T-cells into the tumour micro-environment.

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 – 2 discontinuations were study drug related (pancreatitis, myelodysplastic syndrome)

Ansell ASH 2015

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

Median PFS (95% CI): NA (18.6–NA)

Time, Months

Prop

ortio

n of

Pat

ient

s With

out P

rogr

essi

on

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 3 6 9 12 15 21 27 18 No. Patients at Risk

24

23 20 13 12 11 8 1 0 5 11

• Median follow-up: 101 wks, Median PFS not reached Ansell ASH 2015

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


C205: Overall Response rate IRRC Waterfall Plot of best response


C205: Change in tumour burden in patients treated beyond PD


C205: PFS by IRRC


C205: Drug-related AEs in ≥ 10% of patients


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 follow-up

• 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

• ?

Documents

Checkpoint Inhibition in Hodgkin’s Lymphoma John … · Checkpoint Inhibition in Hodgkin’s Lymphoma . ... (Nivolumab, 87% ORR in rrHL; ... Slide 1 Author: User