in lymphoma Catherine Hildyard Haematology Senior Registrar Oxford - - PowerPoint PPT Presentation

Immune checkpoint inhibitors in lymphoma

Catherine Hildyard Haematology Senior Registrar Oxford University Hospitals NHS Foundation Trust

Aims

• How immune checkpoint inhibitors work
• Success of immune checkpoint inhibitors in

Hodgkin lymphoma

• Toxicity profiles of immune checkpoint

inhibitors

• Immune checkpoint inhibitors in non-Hodgkin

lymphoma?

How immune checkpoint inhibitors work

Priming phase: CTLA-4 and PD-1 Effector phase: PD-1 Hude et al. (2017) Haematologica

Pre-determined genetic susceptibility of cHL to PD-1 blockade?

Roemer et al. (2016) J Clin Oncol PD-L1 PD-L2

Unmet clinical need

• Median survival of r/r cHL after failure of ASCT

= 2 years1

• Brentuximab has a 75% response rate after

failure of ASCT but with progression free survival of only 5.6 months2

• Response rate of brentuximab in transplant

ineligible patients is much lower at 30%3

1. Von Tresckow et al. (2014) Leuk Lymphoma 2. Younes et al. (2012) J Clin Oncol 3. Forero-Torres et al. (2012) Oncologist

Nivolumab in Hodgkin: Checkmate 039

• Phase 1 study (Checkmate-039)
• 23 patients
• Relapsed / refractory cHL
• Most had had ASCT and

brentuximab

• 87% had 3 or more lines of Rx

Ansell et al. (2014) NEJM

Nivolumab in Hodgkin: Checkmate 039

• Every patient had some tumour reduction
• 87%: partial response + complete response
• Only 17% (4 pts) had complete response

Ansell et al. (2014) NEJM

Nivolumab in Hodgkin: Checkmate 205

Cohort B n = 80 Cohort A n = 63 Cohort C n = 100

Brentuximab vedotin naïve Brentuximab vedotin before and/or after auto-HSCT Brentuximab vedotin after auto-HSCT Relapsed cHL after autologous (auto)-HSCT nivolumab monotherapy

Primary endpoint

• ORR

Additional endpoints

• DOR
• Duration of CR/PR
• PFS by IRC
• OS
• Safety

Nivolumab 3 mg/kg IV Q2W Treatment until disease progression or unacceptable toxicity

Patients could elect to discontinue nivolumab and proceed to allogeneic SCT

23 months f/up 16 months f/up 19 months f/up

Armand et al. (2018) J Clin Oncol

Best Overall Response by cohort

BV naïve (Cohort A) n=63 BV after auto- HSCT (Cohort B) n=80 BV before and/or after auto-HSCT (Cohort C) n=100 Overall n=243 Objective response, % 65 68 73 69 Best overall response, % Complete remission Partial remission Stable disease Progressive disease Unable to determine 29 37 24 11 13 55 21 8 4 12 61 15 10 2 16 53 19 9 2

• >95% of patients had reduction in tumour burden
• Responses were similar irrespective of BV treatment sequence

Duration of Response by Best Overall Response

0.0 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 3 6 9 12 15 18 Proportion of patients in response DOR (months) 0.2 0.1 CR: Median: 20 months PR: Median: 13 months

Outcomes After Allo-SCT (n=44)

Progression-free survival

Probability of PFS from subsequent allo-HSCT PFS from allo-SCT (days) 0.0 0.3 0.4 0.5 0.6 0.7 0.8 0.9

1.0

0.2 0.1 50 100 150 200

100-day rate 87% 6-month rate 82%

Toxicity post allo-SCT

• But, 5% (2 pts) hyper-acute GVHD

Similar trials with pembrolizumab: Keynote-087 study

Cohort 2 n = 81 Cohort 1 n = 69 BV treated post-ASCT SCT-naïve Failed salvage chemo & BV Cohort 3 n = 60 BV naïve post- ASCT

Chen et al. (2017) J Clin Oncol

Similar trials with pembrolizumab: Keynote-087 study

Cohort 2 n = 81 Cohort 1 n = 69 BV treated post-ASCT SCT-naïve Failed salvage chemo & BV Cohort 3 n = 60 BV naïve post- ASCT

Chen et al. (2017) J Clin Oncol

Similar trials with pembrolizumab: Keynote-087 study

Cohort 2 n = 81 Cohort 1 n = 69 BV treated post-ASCT SCT-naïve Failed salvage chemo & BV Cohort 3 n = 60 BV naïve post- ASCT

Chen et al. (2017) J Clin Oncol

Patients with a drug-related AEs (≥10%), serious AEs (≥1%), or AEs leading to discontinuation (≥1%) Overall population (N = 243) Any grade Grade 3–4

Drug-related AE, % Fatigue 23 1 Diarrhea 15 1 Infusion-related reaction 14 Rash 12 1 Nausea 10 Pruritus 10 Drug-related serious AE, % Infusion-related reactions 2 <1 Pneumonitis 1 Drug-related AEs leading to discontinuation, % Pneumonitis 2 Autoimmune hepatitis 1 1

Case study

• 35 year old man
• cHL diagnosed 2y ago, stage IIIA
• 6xABVD – PR
• 3 months later – progressive disease
• 2xIVE – very good PR
• 1xIVE and ASCT
• 8 months later – progressed
• BV 3 courses: PR
• BV further 2 courses: PD prior to allo-SCT
• Commenced pembrolizumab on trial

PD-1 inhibitors are not without significant toxicity

Shortly after 3rd infusion:

• Admitted with urinary retention
• Ascending paraesthesia
• Developed paraplegia and tingling

in both arms

• Intractable hiccoughs
• MRI performed

Rx commenced: high dose steroids, IVIG and plasma exchange

Phase 1 data for PD-1 inhibitors in NHL

• Phase 1 trial of nivolumab
• r/r B cell and T cell NHL

Lesokhin et al. (2016) J Clin Oncol

Preliminary phase 2 data for PD-1 inhibitors in DLBCL: checkmate 0139

• Nivolumab in DLBCL relapsed post auto-SCT or

ineligible for auto-SCT

• 161 patients

ASCT failed/ ineligible ORR (%) ASCT failed (n= 87) 10.3 ASCT ineligible (n=34) 2.9 ClinicalTrials.gov Identifier: NCT02038933

Why are PD-1 inhibitors less effective in DLBCL than cHL?

Green et al. (2010) Blood

PMBCL

PMBCL – a promising subtype?

• Pembrolizumab for up to 2 years or until disease

progression/unacceptable toxicity

• 81% patients had decrease in target lesions
• OR 41%, CR 12%
• DOR 2.3 to 22.5 months

Zinzani et al. (2017) Blood

PCNSL and PTL

Nayak et al. (2017) Blood

• Copy number gain and PD-L1/2 over-expression in PCNSL and PTL

Epstein-Barr virus (EBV)+ NHL

• Increased PD-L1 expression in EBV+ NHL:

– PTLD: 60% – Plasmablastic lymphoma: 44% – Primary effusion lymphoma: 50% – Extra-nodal NK/T-cell lymphoma: 67%

NK/T-cell lymphoma and PD-1 inhibition

• 7 patients with r/r NKTCL treated with

pembrolizumab

• All patients responded: 5 CR, 2 PR
• 5 patients remained in remission after a

median f/u of 6 months

• Radiological CR correlated with clearance of

EBV DNA

• “Pseudo-progression” seen in some patients

Kwong et al. (2017) Blood

Enhancing efficacy of PD-1 inhibitors with combination therapy?

• BV-treated tumour cells may undergo

“immunogenic cell death”1

• Similar responses can also be induced by

chemotherapy and radiotherapy

• Checkmate 436 study2: nivolumab +

brentuximab in r/r DLBCL and PTCL

1. Gardai et al. (2015) Cancer Res (abstract) 2. ClinicalTrials.gov Identifier: NCT02581631

Checkmate 436 case study

• 67 year old woman with PTCL: no response to

4x CHOP-14

• Escalated to IVEx2: CR, consolidated by

autograft

• Relapse 14 months later: severe itch, fatigue,

cough, diarrhoea

• Symptoms improved after 1 cycle of

checkmate 436

PET scans pre and post checkmate 436

Summary

• PD-1 inhibitors are very effective in cHL:
• Success both in relapse post-ASCT and in transplant

ineligible patients

• Durable responses with CR and even with PR
• Different toxicity profile from conventional chemotherapy
• Some questions remain to be answered
• PD-1 inhibitors have not yet found a niche in NHL:
• Low activity in r/r DLBCL as monotherapy – ?role for

combination therapy

• Some subtypes may be more responsive (PMBCL,

PCNSL/PTL, EBV+)

Thank you Questions?

catherine.hildyard@ouh.nhs.uk

PDL1 expression as a biomarker?

Younes et al. (2016) Lancet Oncol