Immune checkpoint inhibitors in lymphoma. Catherine Hildyard Haematology Senior Registrar Oxford University Hospitals NHS Foundation Trust

Transcription

1 Immune checkpoint inhibitors in lymphoma Catherine Hildyard Haematology Senior Registrar Oxford University Hospitals NHS Foundation Trust

2 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?

3 How immune checkpoint inhibitors work Priming phase: CTLA-4 and PD-1 Effector phase: PD-1 Hude et al. (2017) Haematologica

4 Pre-determined genetic susceptibility of chl to PD-1 blockade? PD-L1 PD-L2 Roemer et al. (2016) J Clin Oncol

5 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

6 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

7 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

8 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

9 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, % Best overall response, % Complete remission Partial remission Stable disease Progressive disease Unable to determine >95% of patients had reduction in tumour burden Responses were similar irrespective of BV treatment sequence

10 Proportion of patients in response Duration of Response by Best Overall Response CR: Median: 20 months PR: Median: 13 months DOR (months)

11 Probability of PFS from subsequent allo-hsct Outcomes After Allo-SCT (n=44) Progression-free survival day rate 87% 6-month rate 82% PFS from allo-sct (days)

12 Toxicity post allo-sct But, 5% (2 pts) hyper-acute GVHD

13 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

14 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

15 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

16 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

17 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

18 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

19 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

20 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: NCT

21 Why are PD-1 inhibitors less effective in DLBCL than chl? PMBCL Green et al. (2010) Blood

22 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

23 PCNSL and PTL Copy number gain and PD-L1/2 over-expression in PCNSL and PTL Nayak et al. (2017) Blood

24 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%

25 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

26 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: NCT

27 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

28 PET scans pre and post checkmate 436

29 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+)

30 Thank you Questions?

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32 PDL1 expression as a biomarker? Younes et al. (2016) Lancet Oncol