2018 KSMO Immune Oncology Forum. Immune checkpoint inhibitors in hematologic. malignancies: evidences and perspectives 서울아산병원종양내과 홍정용

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1 2018 KSMO Immune Oncology Forum Immune checkpoint inhibitors in hematologic malignancies: evidences and perspectives 서울아산병원종양내과 홍정용

2 Contents Introduction Immune checkpoint inhibtors in lymphomas & multiple myeloma Future perspectives

3 Contents Introduction Immune checkpoint inhibtors in lymphomas & multiple myeloma Future perspectives

4 Drugs approved by BTD status (US FDA) in hematological malignancies Blinatumomab CAR-T cell Nivolumab Pembrolizumab Obinutuzumab Brentuximab vedotin Nat Rev Clin Oncol Jan;13(1):25-40.

5 ALL CLL Lymphomas MM naïve Lymphoid progenitor B-lymphocytes T-lymphocytes Plasma cells Hematopoietic stem cell Myeloid progenitor AML Myeloproliferative disorders Neutrophils Eosinophils Basophils Monocytes Platelets Red cells

6 림프종 (lymphoma) 다발성골수종 (Myeloma) 호지킨림프종 (Hodgkin lymphoma) 비호지킨림프종 (non- Hodgkin lymphoma) B 세포림프종 T/NK 세포림프종 미성숙 B 세포림프종 Lymphoblastic lymphoma/leukemia 성숙 B 세포림프종 공격성 (aggressive) 림프종 Diffuse large B-cell lymphoma Burkitt lymphoma Mantle cell lymphoma 지연성 (indolent) 림프종 Follicular lymphoma (G1,2) Marginal zone lymphoma CLL / SLL 미성숙 T 세포림프종 Lymphoblastic lymphoma/leukemia 성숙 T/NK 세포림프종 Peripheral T-cell lymphoma Anaplastic large cell lymphoma Angiommunoblastic lymphoma Extranodal NK-T cell lymphoma Mycosis fungoides

7 CTLA-4 in priming stage & PD-1 in effector stage N Engl J Med Jun 28;366(26):

8 Contents Introduction Immune checkpoint inhibtors in lymphomas & multiple myeloma Future perspectives

9 Rationale of PD 1 blockade in Hodgkin lymphoma Alterations / amplification in chromosome 9p24 Abundance of the PD-1 ligands, PD-L1 and PD-L2 Increased JAK-STAT activity further Induces PD-1 ligand transcription Blood Oct 28;116(17): Clin Cancer Res Mar 15;18(6):

10 Nivolumab in Hodgkin lymphoma Relapsed or Refractory HM (N=105) No autoimmune disease No prior organ or stem cell allograft No prior checkpoint blockade Dose Escalation Nivolumab 1mg/kg 3mg/kg Wks 1,4 then q2w Dose Expansion (3mg/kg) Hodgkin Lymphoma (n=23) NHL/MM NHL/MM (n=69) (n=69) Endpoints Primary Safety and Tolerability Secondary Best Overall Response Investigator assessed Objective Response PET + CT Duration of Response PFS Biomarker studies

11 Phase 1 study (dose expansion) of nivolumab in Hodgkin lymphoma 23 patients with heavily treated R/R Hodgkin s lymphoma Nivolumab 3mg/kg IV Q2W Dramatic validation of scientific hypothesis!! ORR 87%, CR rate 17% Tolerable toxicity profiles N Engl J Med Jan 22;372(4):311-9.

12 Nivolumab for classical HL after failure of both ASCT and BV (CHECKMATE-205 study) 80 patients Nivolumab 3mg/kg IV Q2W ORR 67%, CR rate 9% (IRRC) ORR 73%, CR rate 28% (investigator) Lancet Oncol Sep;17(9):

13 Pembrolizumab for classical HL after BV failure (KEYNOTE-013 study) 31 patients (heavily treated) Pembrolizumab 10mg/kg IV Q2W ORR 65%, CR rate 16% J Clin Oncol Jun 27.[Epub ahead of print]

14 Nivolumab in non-hodgkin lymphoma Relapsed or Refractory HM (N=105) No autoimmune disease No prior organ or stem cell allograft No prior checkpoint blockade Dose Escalation Nivolumab 1mg/kg 3mg/kg Wks 1,4 then q2w Dose Expansion (3mg/kg) Hodgkin Lymphoma (n=23) NHL/MM NHL/MM (n=69) (n=69) Endpoints Primary Safety and Tolerability Secondary Best Overall Response Investigator assessed Objective Response PET + CT Duration of Response PFS Biomarker studies

15 Phase 1 study (dose escalation) of nivolumab in non-hodgkin lymphoma J Clin Oncol Aug 10;34(23):

16 Summary of clinical efficacy of immune checkpoint inhibitors in lymphomas Nat Rev Clin Oncol Jan;13(1):25-40.

17 Who is the best candidate for anti-pd1/pd-l1 Tx in lymphoma (other than HL)? PD-L1 Expression Is Characteristic of a Subset of Aggressive B-cell Lymphomas and Virus-Associated Malignancies EBV-associated lymphomas LMP1 signaling NF-kB signaling PD-L1 overexpressed lymphomas (such as EBV-associated NKTCL) can be good candidates for anti-pd1/pd-l1 treatment PD-L1 overexpression Clin Cancer Res Jul 1;19(13): J Hematol Oncol Oct 13;9(1):109.

18 Who is the best candidate for anti-pd1/pd-l1 Tx in lymphoma (other than HL)? Recent strong early clinical signal of pembrolizumab in NK/T-cell lymphoma - Seven patients with relapsed/refractory NKTCL - Overall response rate 100 % (7/7), complete response rate 71% (5/7) - Complete response was sustained after a median follow-up of 6 months Strong early clinical signal of pembrolizumab in relapsed/refractory NKTCL Blood Apr 27;129(17):

19 Ongoing combination studies with PD1 or PD-L1 inhibitors in lymphoma Target Drug Combo Combo target NCT identifier PD-1 Nivolumab Urelumab Ipilimumab lirilumab Ibrutinib Brentuximab vedotin PD-1 Pembrolizumab Rituximab Ibrutinib Idelalisib PD-L1 Durvalumab Ibrutinib Tremelimumab AZD9150 Lenalidomide Rituximab PD-L1 Atezolizumab Obinutuzumab Lenalidomide Polatuzumab vedotin Anti-CD137 Ab Anti-CTLA4 Ab Anti-KIR Ab BTK inhibitor Anti-CD30 ADC Anti-CD20 Ab BTK inhibitor PI3K inhibitor BTK inhibitor Anti-CTLA4 Ab ASO inhibitor IMiDs Anti-CD20 Ab Anti-CD20 Ab IMiDs Anti-CD79b ADC NCT NCT NCT NCT NCT NCT NCT NCT NCT NCT NCT NCT NCT NCT NCT NCT

20 Adverse events using PD-1 inhibitors in lymphomas Lancet Oncol May;16(5):e

21 Adverse events using PD-1 inhibitors in lymphomas Excellent side-effect profiles!! No MTDs in multiple phase 1 studies of lymphoid malignancies Mainstay of management Short term immunosuppression with corticosteroid and reversal of hormone deficiency Lancet Oncol May;16(5):e

22 Quick summary Dramatic validation of scientific hypothesis of PD-1 inhibitor in Hodgkin lymphoma (Nivo, Pembro) Need response improvement of PD-1 inhibitors in non-hodgkin lymphoma (Nivo ORR of 20~40%) EBV-positive NHLs (such as NKTCL) shows strong early clinical signal of immune checkpoint inhibitors (Pembro ORR 50~100%) No unexpected safety signals in lymphoma

23 Immune checkpoint inhibitor in MM

24 Immune checkpoint inhibitor in MM Bristol-Myers Squibb (BMS) announced that the FDA has placed a clinical hold on 3 combination trials evaluating its programmed death- 1 (PD-1) inhibitor nivolumab (Opdivo) in patients with relapsed/refractory multiple myeloma. In July, Merck, which has developed pembrolizumab, announced that the FDA s decision applied to KEYNOTE-183, KEYNOTE-185, and KEYNOTE-023.

25 Changes of MM treatment options 대체 / 보완 추가 중요성감소 US-FDA approved six new drugs in MM during 5 years

26 Immune checkpoint inhibitors in lymphoma & MM Hodgkin lyphoma Non- Hodgkin lymphoma Multiple myeloma

27 Contents Introduction Immune checkpoint inhibtors in lymphomas & multiple myeloma Future perspectives

28 Drugs approved by BTD status (US FDA) in hematological malignancies Blinatumomab CAR-T cell Nivolumab Pembrolizumab Obinutuzumab Brentuximab vedotin Nat Rev Clin Oncol Jan;13(1):25-40.

29 General structure of Bispecific T-cell Engager (BiTE) Cancer Res Jun 15;69(12):

30 General structure of chimeric antigen receptor (CAR) CAR (chimeric antigen receptor) T-cell activation domains + antigen recognition moieties Nat Rev Clin Oncol May;10(5):

31 Schema of anti-cd19 CAR T-cell therapy engineered T cell manufacturing. Nat Rev Cancer Aug 23;16(9):

32 CAR T-cell Therapy in hematologic malignancies In August 2017, this first-in-class therapy (CTL019) was approved by the FDA for the treatment of children and young adults with relapse or refractory B-ALL. In October 2017, KTE-C19 was also approved by the FDA for the treatment of adults with relapse or refractory DLBCL.

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35 Future perspectives of Immune checkpoint inhibitors in lymphoma & MM Possible replacement of hematopoietic stem cell transplantation.. Novel combinations.. Hodgkin lyphoma Multiple myeloma Non- Hodgkin lymphoma Promising in some subtypes Possible promising combo partner with CAR-T & BsAb Tx Possibly, limited role in MM

36 Take Home Message 1. Great success of immune checkpoint inhibitor in Hodgkin lymphoma and some subtypes of non-hodgkin lymphoma 2. Possible replacement of stem cell transplantation in Hodgkin lymphoma 3. Promising combo partners with CAR-T cell therapy and bispecific antibody treatment in non-hodgkin lymphoma 4. Still limited role in multiple myeloma