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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


  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 Cohort B Cohort C n = 63 n = 80 n = 100 Primary endpoint • ORR Nivolumab 3 mg/kg Brentuximab Brentuximab Brentuximab IV Q2W vedotin naïve vedotin vedotin before Treatment until Additional after and/or after disease progression or endpoints auto-HSCT auto-HSCT unacceptable toxicity • DOR • Duration of CR/PR Patients could elect to discontinue nivolumab and • PFS by IRC proceed to allogeneic SCT • OS • Safety 19 months 23 months 16 months f/up f/up f/up Armand et al. (2018) J Clin Oncol

  9. Best Overall Response by cohort BV before and/or BV after auto- BV naïve after Overall HSCT (Cohort A) auto-HSCT (Cohort B) n=63 (Cohort C) n=243 n=80 n=100 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

  10. Duration of Response by Best Overall Response 1.0 0.9 Proportion of patients in response 0.8 0.7 CR: Median: 20 months 0.6 0.5 0.4 0.3 PR: Median: 13 months 0.2 0.1 0.0 0 3 6 9 12 15 18 DOR (months)

  11. Outcomes After Allo-SCT (n=44) Progression-free survival 1.0 0.9 100-day rate 0.8 87% 6-month rate Probability of PFS from 0.7 subsequent allo-HSCT 82% 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 50 100 150 200 PFS from allo-SCT (days)

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

  13. Similar trials with pembrolizumab: Keynote-087 study Cohort 1 Cohort 2 Cohort 3 n = 69 n = 81 n = 60 SCT-naïve Failed BV treated BV naïve salvage post-ASCT post- chemo & ASCT BV Chen et al. (2017) J Clin Oncol

  14. Similar trials with pembrolizumab: Keynote-087 study Cohort 1 Cohort 2 Cohort 3 n = 69 n = 81 n = 60 SCT-naïve Failed BV treated BV naïve salvage post-ASCT post- chemo & ASCT BV Chen et al. (2017) J Clin Oncol

  15. Similar trials with pembrolizumab: Keynote-087 study Cohort 1 Cohort 2 Cohort 3 n = 69 n = 81 n = 60 SCT-naïve Failed BV treated BV naïve salvage post-ASCT post- chemo & ASCT BV Chen et al. (2017) J Clin Oncol

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

  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: NCT02038933

  21. Why are PD-1 inhibitors less effective in DLBCL than cHL? Green et al. (2010) PMBCL 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: NCT02581631

  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? catherine.hildyard@ouh.nhs.uk

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

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