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? PD-L1 PD-L2 Roemer et al. (2016) J Clin Oncol
Unmet clinical need Median survival of r/r chl after failure of ASCT = 2 years 1 Brentuximab has a 75% response rate after failure of ASCT but with progression free survival of only 5.6 months 2 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 Relapsed chl after autologous (auto)-hsct nivolumab monotherapy Cohort A n = 63 Brentuximab vedotin naïve Cohort B n = 80 Brentuximab vedotin after auto-hsct Cohort C n = 100 Brentuximab vedotin before and/or after auto-hsct Nivolumab 3 mg/kg IV Q2W Treatment until disease progression or unacceptable toxicity Primary endpoint ORR Additional endpoints DOR Patients could elect to discontinue nivolumab and proceed to allogeneic SCT Duration of CR/PR PFS by IRC OS Safety 19 months f/up 23 months f/up 16 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 29 13 12 16 Partial remission 37 55 61 53 Stable disease 24 21 15 19 Progressive disease 11 8 10 9 Unable to determine 0 4 2 2 >95% of patients had reduction in tumour burden Responses were similar irrespective of BV treatment sequence
Proportion of patients in response Duration of Response by Best Overall Response 1.0 0.9 0.8 0.7 0.6 CR: Median: 20 months 0.5 0.4 0.3 0.2 PR: Median: 13 months 0.1 0.0 0 3 6 9 12 15 18 DOR (months)
Probability of PFS from subsequent allo-hsct Outcomes After Allo-SCT (n=44) Progression-free survival 1.0 0.9 0.8 0.7 0.6 100-day rate 87% 6-month rate 82% 0.5 0.4 0.3 0.2 0.1 0.0 0 50 100 150 200 PFS from allo-sct (days)
Toxicity post allo-sct But, 5% (2 pts) hyper-acute GVHD
Similar trials with pembrolizumab: Cohort 1 n = 69 Keynote-087 study Cohort 2 n = 81 Cohort 3 n = 60 BV treated post-asct SCT-naïve Failed salvage chemo & BV BV naïve post- ASCT Chen et al. (2017) J Clin Oncol
Similar trials with pembrolizumab: Cohort 1 n = 69 Keynote-087 study Cohort 2 n = 81 Cohort 3 n = 60 BV treated post-asct SCT-naïve Failed salvage chemo & BV BV naïve post- ASCT Chen et al. (2017) J Clin Oncol
Similar trials with pembrolizumab: Cohort 1 n = 69 Keynote-087 study Cohort 2 n = 81 Cohort 3 n = 60 BV treated post-asct SCT-naïve Failed salvage chemo & BV 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 0 Rash 12 1 Nausea 10 0 Pruritus 10 0 Drug-related serious AE, % Infusion-related reactions 2 <1 Pneumonitis 1 0 Drug-related AEs leading to discontinuation, % Pneumonitis 2 0 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 Shortly after 3 rd 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 toxicity
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? PMBCL Green et al. (2010) Blood
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 Copy number gain and PD-L1/2 over-expression in PCNSL and PTL Nayak et al. (2017) Blood
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 study 2 : 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