Haemato-Oncology ESMO PRECEPTORSHIP PROGRAMME IMMUNO-ONCOLOGY. Development and clinical experience Monique Minnema, hematologist

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1 Haemato-Oncology ESMO PRECEPTORSHIP PROGRAMME IMMUNO-ONCOLOGY Development and clinical experience Monique Minnema, hematologist

2 Consultancy for disclosures Amgen, Celgene, Jansen Cilag, BMS, Takeda

3 Immune Response Within the Tumor Microenvironment Hodgkin Lymphoma Aberrant cytokine expression attracts immunosuppressive and pro-cancer growth cells Chromosomal amplification of 9p24.1 enhances PD-L1/L2 expression and immune escape Non-Hodgkin Lymphoma Inhibitory ligand expression suppresses tumor-associated T-cell function In DLBCL, inactivation of β2-mg and CD58 is observed in 50% of cases, and leads to reduced immune recognition

4 Single Agent Activity of PD-1/PD-L1 Blockade in Relapsed/Refractory Cancer Overall response rate (%) No of patients HL B-NHL T-NHL Hodgkin Lymphoma Non-Hodgkin Lymphoma Melanoma NSCLC SCLC TNBC Ovary RCC High PD-L1 Low PD-L1 Urothelial Atezolizumab Pembrolizumab Nivolumab MMR-deficient MMR-proficient Colorectal Gastric Esophageal HNSC HCC

5 Classical Hodgkin Lymphoma Reed-Sternberg cell in an extensive inflammatory background

6 PD-L1 Expressie in chl NHL 1. 87% (33 of 38 cases) of primary chl show PD-L1 expression by the Reed-Sternberg cells 2. 11% (7 of 66 cases) of primary non-hodgkin lymphomas show PD-L1 expression by the neoplastic B-cells Chen BJ et al. Clin Cancer Res. 2013;19:

7 Chromosome 9p24.1 mutations in 97% chl 9p24.1/PD-L1/PD-L2 mutations increase PD-L1 expression (EBV+ too!) Roemer M et al. JCO; Apr 11, 2016.

8 CheckMate 205: Study Design, Cohorts A and B Phase 2 study conducted in Europe and North America Cohort A n = 63 BV naïve post-asct ASH 2016: Primary disclosure Minimum follow-up 9 months Cohort B n = 80 BV treated post-asct EMA approval Nov 2016 ASH 2016: Update Minimum follow-up 12 months Nivolumab 3 mg/kg IV Q2W Treatment until disease progression or unacceptable toxicity Patients could elect to discontinue nivolumab and proceed to allogeneic (allo) HSCT Primary endpoint ORR by IRRC Additional endpoints Duration of response Duration of CR/PR PFS by IRRC OS Safety 1. Younes A et al. Lancet Oncol 2016;17:

9 Antibody drug conjugate/adc EMA approval October relapsed or refractory Hodgkin Lymphoma - Anaplastic Large Cell Lymphoma (type of T cell NHL

10 Lancet Oncol 2016;17:

11 Baseline Characteristics Characteristic BV naïve post-asct Cohort A (n = 63) BV post-asct Cohort B (n = 80) 1 Age, median (range), years 33 (18 65) 37 (18 72) Male, n (%) 34 (54) 51 (64) ECOG performance status, n (%) (63) 23 (37) 42 (53) 38 (48) Previous lines of therapy, median (range) Prior BV therapy after ASCT, n (%) Treatment between ASCT and nivolumab, n (%) Systemic cancer therapy Radiotherapy only Neither 2 (2 8) 0 12 (19) 8 (13) 43 (68) 4 (3 15) 80 (100) 80 (100) Younes A et al. Lancet Oncol 2016;17:

12 Best Change in Target Lesions Cohort A and B: Nivolumab Post-ASCT B A ** * ** *** * 75 ***** *** ****************************** ************** * ****************** ***************** 100 Asterisks ( * ) represent responders 95% and 93% of evaluable patients showed a reduction in tumor burden

13 Progression-Free Survival by Best Response B A

14 tumour biopsy samples from 45 patients

15 Pembrolizumab na BV failure

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17 Pembroluzimab in relapsed Hodgkin

18 PFS and OS

19 IO in relapsed Hodgkin Lymphoma CR rate is low (9-16%), but PR/SD can be durable and prolong survival in phase II studies EMA approval Nivolumab after ASCT and BV Pembrolizumab after BV (ASCT not obligatory, 2017)

20 Single agent Nivolumab in NHL Patients (CA ): Best Overall Response B-Cell Lymphoma* (n=29) Follicular Lymphoma (n=10) DiffuseLarge B-Cell Lymphoma (n=11) T-Cell Lymphoma (n=23) Mycosis Fungoides (n=13) Peripheral T-Cell Lymphoma (n=5) Primary Mediastinal B-Cell Lymphoma(n=2) Objective Response Rate, n (%) Complete Responses, n (%) Partial Responses, n (%) Stable Disease, n (%) 8 (28) 2 (7) 6 (21) 14 (48) 4 (40) 1(10) 3 (30) 6 (60) 4 (36) 1 (9) 3 (27) 3 (27) 4 (17) 0 (0) 4(17) 10 (43) 2 (15) 0 (0) 2 (15) 9 (69) 2 (40) 0 (0) 2 (40) 0 (0) 0 (0) 0 (0) 0 (0) 2 (100)

21 Safety & tolerability of pembrolizumab in patients with relapsed/refractory primary mediastinal large B-cell lymphoma Pier Luigi Zinzani et al, Blood 2017

22 pembrolizumab in RR PMLBCL 17 patients ORR was 41% (7/17); 35% SD median FU of 11.3 months, median duration of response was not reached, OS 100%

23 PD-1 blockade with nivolumab in relapsed/refractory primary central nervous system and testicular lymphoma Lakshmi Nayak et al Blood 2017 Genetic analysis reveals frequent 9p24.1/PD-L1/PD-L2 copy number alterations and increased expression of the PD-1 ligands in PCNSL and PTL. 5 patients 4 CR 1 PR

24 IO in NHL; Combo strategy & targeted therapy; BTK inhibitor & monoclonal antibodies; anti CD20 & lenalidomide/imid & anti CTLA4 antibodies & etc

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26 Response assessment in patients receiving immune modulating agents, including immune checkpoint inhibitors 4 principles 1. Confirmation of progression via a subsequent scan to detect delayed responses 2. Measuring new lesions to include them into the total tumor volume 3. Accounting for durable stable disease as benefit 4. Treating beyond conventional progression if the clinical situation allows

27 Pseudo progression In melanoma; 5% : early pseudoprogression 3% : delayed pseudoprogression Lymphoma;?, < 10%

28 Immunologists nightmare or dream? Combining IO and allogeneic stemcell transplantation Allogeneic T cell responses can cure leukemia and lymphoma

29 Allogeneic SCT in HL Cure due to; 1. Graft versus lymphoma effect Mortality due to; 1. Relapse 2. Infections 3. Graft versus host disease; donor T cells attack healthy tissue of patient

30 Nivolumab AFTERallo SCT 20 patients, (10 history of acute GVHD) All 6 cases of acute GVHD occurred within 1 week after the first infusion of nivolumab All 6 patients who presented with agvhd had a prior history of agvhd There was no flare of chronic GVHD Key Points PD-1 blockade provides durable disease control PD-1 blockade is associated with 30% acute GVHD Charles Herbaux et al. Blood 2017;129:

31 Nivolumab BEFOREallo SCT EMA-approved prescribing information for nivolumab includes a warning for complications after post-nivolumab allo HSCT, including TRM and agvhd Checkmate 205 & 139 Characteristic Patients (N = 49) Age, median (min max) years 31 (18 61) Male, n(%) 27(55) No. of therapies prior to nivolumab, median (min max) 4 (2 9) Prior auto-hsct, n(%) 48 (98)

32 TRM and agvhd: Historical Context n Regimen 100-day incidence of TRM 100-day incidence of agvhd 49 MAC/RIC CheckMate 039/ G3 4 G MAC EBMT 1 G3 4 G RIC EBMT 1 G3 4 G RIC/non-MAC CIBMTR 2 15 G3 4 G RIC EBMT 3 11 G RIC SFGM-TC 4 Any grade RIC b MDACC 5 15 G Incidence (%) Incidence (%) Direct comparisons should not be made across studies due to differences in patient populations and procedures a 3-month cumulative incidence; b Gemcitabine (800 mg/m 2 ), fludarabine (4 doses of 33 mg/m 2 ), and melphalan (2 doses of 70 mg/m 2 ). CIBMTR = Center for International Blood and Marrow Transplant Research; SFGM-TC = French Society of Bone Marrow Transplantation and Cellular Therapy; MDACC = MD Anderson Cancer Center; JSHCT = Japan Society for Hematopoietic Cell Transplantation. 1 Sureda A, et al. J Clin Oncol 2008;26:455 62; 2 Devetten MP, et al. Biol Blood Marrow Transplant 2009;15:109 17; 3 Robinson SP, et al. Haematologica 2009;94:230 8; 4 Marcais A, et al. Haematologica 2013;98: ; 5 Anderlini P et al. Biol Blood Marrow Transplant 2016;22:

33 Incidences of TRM and agvhd after 6 months were comparable with historical analyses in chl G2-4 agvhd was 36%, and TRM was 16% Nivolumab treatment does not appear to preclude allo-hsct Caution for early or severe GVHD warrants appropriate monitoring No association between nivolumab concentration at transplantation and severe GVHD or TRM was found 33

34 Take home messages Hodgkin Lymphoma prototype for IO therapy with 2 EMA approvals Complete remissions are rare, clinical benefit good Other lymphoma types; future Side effects; comparable with solid oncology Combinations with allogeneic SCT is possible