Immunoteràpia en el Limfoma de Hodgkin

Immunoteràpia en el Limfoma de Hodgkin A. Sureda Servei d Hematologia Institut Català d Oncologia - Hospitalet SCHH. Barcelona, 22 de juny de 2016

OS from relapse after an ASCT. The experience of the LWP EBMT/GITMO 1.00 0.80 0.60 39.5% (95% CI: 35-44) at 3 years OS 0.40 29.7% (95% CI: 25-34) at 5 years 0.20 0.00 0 12 24 36 48 60 72 84 96 Months from relapse Median follow-up of survivors 50 months (75% of cases > 34 months) Martínez et al, Ann Oncol 2013 The European Group for Blood and Marrow Transplantation The European Group for Blood and Marrow Transplantation

Ongoing Phase II Study of Brentuximab Vedotin PFS Per Investigator 5 Year Follow-up Progression free survival Overall median PFS = 9.3 mo (95% CI: 7.1, 12.2) PFS, progression-free survival; mo, months; ITT intention to treat; PD, progressive disease Chen R, et al. ASH 2015, Poster presentation from Abstract #2736

Introduction Classical Hodgkin lymphoma (chl) is characterized by expression of PD-L1 and PD-L2 on malignant Reed Sternberg cells and on inflammatory cells in the tumor microenvironment PD-L1 expression in chl frequently occurs in the setting of genetic amplication of the 9p24.1 locus Prognosis for patients with relapsed chl is poor PD-L1 expression in chl Copy Gain Amplication PD-L1/L2 copy gains and amplication visible by FISH Chen BJ, et al. Clin Cancer Res. 2013;19:3462 3473. Ansell SM, et al. N Engl J Med. 2015;372:311 319. 4

Institut Institut Català Català d Oncologia d'oncologia

PD-1/PD-L1 Blockade Recognition of tumour by T cell through MHC/antigen interaction mediates IFNγ release and PD-L1/2 upregulation on tumour Nivolumab is a fully human immunoglobulin G4 monoclonal antibody targeting the programmed death-1 (PD-1) immune checkpoint pathway IFNγR IFNγ MHC T cell receptor T-cell receptor MHC Tumour cell PD-L1 PD-L2 PD-1 Shp-2 PI3K NFκB Other T cell Shp-2 CD28 PD-1 B7 PD-L1 Dendritic cell PD-1 PD-1 PD-L2 PD1 Receptor Blocking Ab WCLC 2013 Institut Institut Català Català d Oncologia d'oncologia

Phase 1 Study (CA209-039) Clinical Outcomes From Extended Follow-up Study design Relapsed or Refractory HL (N = 105) No autoimmune disease No prior organ or stem cell allografting No prior checkpoint blockade Dose Escalation Nivolumab 1 mg/kg 3 mg/kg Weeks 1 and 4, then every 2 weeks Non-Hodgkin lymphoma (n = 13) Dose Expansion (3 mg/kg) Hodgkin Hodgkin lymphoma (n Lymphoma = 23) (n=23) Non-Hodgkin lymphoma (n = 69) Endpoints Primary Safety and tolerability Secondary Best overall response Investigator assessed Objective response Duration of response Progression-free survival (PFS) Biomarker studies August 2012 June 2014 April 2015 Median 40 weeks 76 weeks Follow-up August 2015 101 weeks 7

Baseline Characteristics Characteristic chl (n = 23) Age, median (range) 35 (20 54) Histology, n Nodular sclerosing 22 Mixed cellularity 1 Prior autotransplant, n (%) 18 (78) Prior brentuximab vedotin, n (%) 18 (78) Number of prior therapies, median (range) 5 (2 15) 8

Select Treatment-Related Adverse Events Adverse Event chl (n = 23) Any Grade, n (%) Resolved, % Gastrointestinal 4 (17) Diarrhea 3 (13) 100 Colitis 1 (4) 100 Hepatic 2 (9) ALT increased 1 (4) 100 AST increased 1 (4) 100 Blood alkaline phosphatase increased 1 (4) 0 Pulmonary 1 (4) Pneumonitis 1 (4) 100 Skin 5 (22) Rash 4 (17) 100 Pruritus 3 (13) 100 Pruritic rash 1 (4) 100 Skin hypopigmentation 1 (4) 0 Endocrine disorders Hyperthyroidism 4 (17) 75 Hypersensitivity/infusion reaction 2 (9) Bronchospasm 1 (4) 100 Infusion-related reaction 1 (4) 100 All AEs were Grade 1/2 except colitis and pneumonitis which were Grade 3 There were no Grade 4 or Grade 5 AEs and no treatment-related deaths 9

Select Treatment-Related Adverse Events Adverse Event chl (n = 23) Any Grade, n (%) Resolved, % Gastrointestinal 4 (17) Diarrhea 3 (13) 100 Colitis 1 (4) 100 Hepatic 2 (9) ALT increased 1 (4) 100 AST increased 1 (4) 100 Blood alkaline phosphatase increased 1 (4) 0 Pulmonary 1 (4) Pneumonitis 1 (4) 100 Skin 5 (22) Rash 4 (17) 100 Pruritus 3 (13) 100 Pruritic rash 1 (4) 100 Skin hypopigmentation 1 (4) 0 Endocrine disorders Hyperthyroidism 4 (17) 75 Hypersensitivity/infusion reaction 2 (9) Bronchospasm 1 (4) 100 Infusion-related reaction 1 (4) 100 All AEs were Grade 1/2 except colitis and pneumonitis which were Grade 3 There were no Grade 4 or Grade 5 AEs and no treatment-related deaths 10

Response Rates Best Objective Response chl (n = 23) n (%) 95% CI Objective response rate 20 (87) 66.4 97.2 CR 5 (22) 7.5 43.7 PR 15 (65) 42.7 83.6 SD 3 (13) 11

Best Response 25 SD (13%) PR (65%) CR (22%) Percent Change in Tumor Burden 0 25 50 75 100 Patients (n = 23) On treatment, ongoing response Off treatment without disease progression a Progressive disease, following response or stable disease a Maximum clinical benet, transplant, or toxicity 12

Durability of Response Percent Change From Baseline in Target Lesions/Tumor Burden 100 50 0 50 On treatment, ongoing response Off treatment without progression Progressive disease, following response or stable disease 100 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102 108 114 Time Since First Treatment Date, Weeks First occurrence of new lesion 13

Duration of Response Probability of Patients in Response 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 Median DOR (95% CI): NA (15.5 NA) 0.0 0 3 6 9 12 15 18 21 24 No. Patients at Risk Time, Months 18 15 12 10 9 7 4 2 0 Median follow-up: 101 wks Median DOR not reached 14

Responding Patients Patients 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 First CR First PR Death Ongoing response 0 8 16 24 32 40 48 56 64 72 80 88 96 104 112 PFS Responders Time, Weeks On treatment, ongoing responses 15

Responding Patients Patients 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 First CR First PR Death Ongoing response 0 8 16 24 32 40 48 56 64 72 80 88 96 104 112 PFS Responders Time, Weeks On treatment, ongoing responses 13 patients off treatment without disease progression 6 with maximum clinical benet 5 proceeded to transplant 2 discontinued for toxicity 16

Responding Patients Patients 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 First CR First PR Death Ongoing response 0 8 16 24 32 40 48 56 64 72 80 88 96 104 112 PFS Responders Time, Weeks On treatment, ongoing responses 13 patients off treatment without disease progression 6 with maximum clinical benet 5 proceeded to transplant 2 discontinued for toxicity Disease progression following initial response 17

Progression-Free Survival Proportion of Patients Without Progression 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Median PFS (95% CI): NA (18.6 NA) 0 3 6 9 12 15 18 21 24 27 Time, Months No. Patients at Risk 23 20 13 12 11 11 8 5 1 0 Median follow-up: 101 wks Median PFS not reached 18

Overall Survival Proportion of Patients Alive 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 OS (N=23) 1 Year OS rate, % (95% CI) 91 (69.5 97.8) 1.5 Years OS rate, % (95% CI) 83 (60.1 93.1) 0 3 6 9 12 15 18 21 24 27 30 Time Since First Dose, Months No. Patients at Risk 23 23 23 22 21 21 18 17 7 2 0 19

CheckMate 205: Overall Study Design Relapsed/refractory chl after ASCT Newly diagnosed advanced-stage chl Cohort A Cohort B Cohort C Cohort D Brentuximabvedotin naïve Posttransplant brentuximab vedotin The same inclusion criteria as cohort B. Now enrolling Registrational trial for regulatory approval Additionally, brentuximab vedotin prior to ASCT was allowed. Stop treatment if persistent CR for 1 year, if relapse, reinitiate nivo Engert A et al. EHA 2016

CheckMate 205: Study Design, Cohort B Registrational phase 2 study conducted in Europe and North America Inclusion criteria Prior ASCT Brentuximab vedotin Relapsed/refractory chl Single-arm Nivolumab 3 mg/kg (every 2 weeks) Treatment until disease progression or unacceptable toxicity Minimum follow-up: 6 months Primary endpoint ORR assessed by IRRC a Secondary and other endpoints IRRC-assessed DOR for complete and partial remission Investigator-assessed ORR and DOR IRRC-assessed PFS OS Safety QoL Biomarkers Patients could elect to discontinue nivolumab and proceed to allogeneic hematopoietic stem cell transplantation a Per the 2007 International Working Group (IWG) criteria. IRRC = independent radiologic review committee Engert A et al. EHA 2016

CheckMate 205B Baseline Characteristics Characteristic Age, median (range) <65 years Patients (N = 80) 37 (18 72) 77 (96) Sex Male 51 (64) ECOG performance status 0 1 Previous lines of therapy, a median (range) 5 lines of therapy 42 (53) 38 (48) 4 (3 15) 39 (49) Previous radiation therapy 59 (74) Previous ASCT 1 2 80 (100) 74 (93) 6 (8) Prior brentuximab vedotin therapy after ASCT 80 (100) No response to prior brentuximab vedotin 43 (54) Data shown as n (%) unless indicated otherwise a Excluding high-dose preparative regimen prior to ASCT Engert A et al. EHA 2016

CheckMate 205B Response Rates Objective response rate, n (%) 95% CI Best overall response, n (%) Complete remission Partial remission Stable disease Progressive disease Unable to determine IRRC (N = 80) 53 (66) 55 76 7 (9) 46 (58) 18 (23) 6 (8) 3 (4) Investigator (N = 80) 58 (73) 61 82 22 (28) 36 (45) 18 (23) 3 (4) 1 (1) Patients with no prior response to most recent brentuximab vedotin treatment IRRC (N = 43) Investigator (N = 43) Objective response rate, n (%) 31 (72) 35 (81) Engert A et al. EHA 2016

Time to and Durability of Response by IRRC Responders: PR + CR (n = 53) Median time to response, months (range) Median duration of response, months (95% CI) Patients with ongoing response, n/n (%) Censored with ongoing response First partial response First complete response Transplant 2.1 (1.6 5.7) 7.8 (6.6 NE) 33/53 (62%) 0 8 16 24 32 40 48 56 Weeks Engert A et al. EHA 2016

CheckMate 205 Progression-Free and Overall Survival 1.0 0.8 98.7% OS (3/80 events) Probability of event 0.6 0.4 0.2 76.9% PFS (24/80 events) 0 PFS per IRRC assessment 0 3 6 9 12 Months Median follow-up (range) 8.9 months (1.9 11.7) Median PFS (95% CI) 10.0 months (8.41 NA) PFS rate at 6 months (95% CI) 76.9% (65% 85%) Median OS Not reached OS rate at 6 months (95% CI) 98.7% (91% 100%) Engert A et al. EHA 2016

CheckMate 205B Adverse Events Total patients with an event (%) Any grade Grade 3 4 Any AE 79 (99) 32 (40) Treatment-related AE 72 (90) 20 (25) Treatment-related AE leading to discontinuation: Autoimmune hepatitis Increased ALT and AST Multi-organ failure* 3 (4) 1 1 1 2 (3) 1 1 0 Treatment-related serious AE 5 (6) 0 Treatment-related death 0 0 Serious AEs (SAEs) included pyrexia, tumor progression, arrhythmia, infusion reaction, septic meningitis, and pneumonia ( 4% each) *One patient experienced a grade 5 SAE of multi-organ failure due to Epstein Barr virus positive T-cell lymphoma Engert A et al. EHA 2016

CheckMate 205B Treatment-Related AEs in 10% of Patients a Fatigue Infusion-related reaction Rash Pyrexia Arthralgia Nausea Diarrhea Any grade Grade 3 4 Pruritus a Within 30 days of last dose 0 20 40 Patients (n) 60 80 Engert A et al. EHA 2016

CheckMate 205B Select AEs (immune-related, any cause) Skin Gastrointestinal Hypersensitivity/infusion reaction Endocrine Hepatic Pulmonary Renal Any grade Resolved Grade 3 4 0 20 40 60 80 Patients (n) Drug-related pneumonitis reported in 2 patients (grade 2 and grade 3) between rst dose and 35 days after last dose Majority of events were manageable, with resolution occurring when immune-modulating medications were administered Engert A et al. EHA 2016

OPDIVO (Nivolumab) OPDIVO (nivolumab) is indicated for the treatment of patients with chl that has relapsed or progressed after ASCT and post-transplantation BV. This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verication and description of clinical benet in conrmatory trials. Institut Institut Català Català d Oncologia d'oncologia

The PD-1 and PD-L1/L2 Pathway to Be Continued PD-1 is an immune checkpoint receptor 1 Binding of PD-1 by its ligands PD-L1 or PD-L2 leads to downregulation of T-cell function 1 This mechanism is usurped by many tumors 1 PD-1 blockade through mab therapy can restore effective anti-tumor immunity 2,3 Pembrolizumab is a humanized anti-pd1 mab with activity in multiple malignancies 4,5 1. Keir ME et al. Annu Rev Immunol. 2008; 2. Pardoll DM. Nat Rev Cancer. 2012; 3. Topalian et al. N Engl J Med. 2012. 4. Garon et al. N Engl J Med. 2015; 5. Robert et al. Lancet. 2014. Institut 30 Institut Català Català d Oncologia d'oncologia

KEYNOTE-087: Study Design Cohort 1 (N = 60) R/R chl who progressed after ASCT and subsequent BV therapy Cohort 2 (N = 60) R/R chl who failed salvage chemotherapy, ineligible for ASCT and failed BV therapy Pembrolizumab 200 mg Q3W Progressive Disease Survival Follow-Up Cohort 3 (N = 60) R/R chl who failed ASCT and not treated with BV post transplant CT scans repeated Q12W PET repeated at W12, W24, to conrm CR or PD, and as clinically indicated Primary end point: ORR (central review) Secondary end points: ORR (investigator review), PFS, OS Prespecied interim analysis, based on investigator-assessed response, performed after 30 patients in all 3 cohorts reached rst response assessment Chen R et al. EHA 2016 31

Baseline Characteristics Characteristic (N = 30 in each cohort) Cohort 1 Progressed after ASCT and subsequent BV therapy % Cohort 2 Failed salvage chemotherapy, ineligible for ASCT and failed BV therapy % Cohort 3 Failed ASCT and not treated with BV post transplant % Age, median (range) 36 (19-64) 33 (20-71) 30 (18-67) Age >65 0 20 3 Lines of systemic therapy, median (range) 5 (3-12) 4 (1-10) 3 (2-10) Primary refractory 23 50 50 Prior radiation therapy 47 27 43 Bulky lymphadenopathy 7 10 3 Baseline B symptoms 23 20 23 Bone marrow involvement 0 10 3 Prior brentuximab failure 100 100 40 Bulky disease was dened as a mass larger than a third of transthoracic diameter at any level of thoracic vertebrae, or single site of disease in any area that is 10 centimeters or greater in diameter. Patients received BV therapy prior to transplant. Data cutoff: April 8, 2016 Chen R et al. EHA 2016 32

Best Overall Response, Investigator Review Cohort 1 Progressed after ASCT and subsequent BV therapy n (%) Cohort 2 Failed salvage chemotherapy, ineligible for ASCT and failed BV therapy n (%) Cohort 3 Failed ASCT and not treated with BV post transplant n (%) % (95% CI) % (95% CI) % (95% CI) Overall response rate 73 (54-88) 83 (65-94) 73 (54-88) Complete remission 27 (12-46) 30 (15-49) 30 (15-49) Partial remission 47 (28-66) 53 (34-72) 43 (26-63) Stable disease 17 (6-35) 7 (1-22) 13 (4-31) Progressive disease 10 (2-27) 7 (1-22) 13 (4-31) One patient in Cohort 2 had no assessment. The patient had symptomatic deterioration, with subsequent clinical progression. For complete remission, a residual mass was permitted for patients who were negative on PET scanning. Data cutoff: April 8, 2016 Chen R et al. EHA 2016 33

Best Overall Response, Investigator Review Primary Refractory Disease N = 37 % (95% CI) Overall response rate 78 (62-90) Complete remission 35 (20-53) Partial remission 43 (27-61) Stable disease 11 (3-25) Progressive disease 8 (2-22) Dened as failure to achieve complete or partial remission to frontline therapy For complete remission, a residual mass was permitted for patients who were negative on PET scanning. Data cutoff: April 8, 2016 Chen R et al. EHA 2016 34

Treatment Exposure: Cohort 1 Progressed after ASCT and subsequent BV therapy 0 5 10 15 20 25 30 35 40 Weeks Data cutoff: April 8, 2016 * Treatment Ongoing Complete Response Partial Response Progressive Disease Last Dose Median number of treatment cycles: 9 (range, 4-13) 19 patients who responded were still on pembrolizumab treatment Chen R et al. EHA 2016 35

Treatment Exposure: Cohort 2 Failed salvage chemotherapy, ineligible for ASCT and failed BV therapy Data cutoff: April 8, 2016 * Treatment Ongoing Complete Response Partial Response Progressive Disease Last Dose 0 5 10 15 20 25 30 35 40 Weeks Median number of treatment cycles: 9 (range, 1-13) 13 patients who responded were still on pembrolizumab treatment Chen R et al. EHA 2016 36

Treatment Exposure: Cohort 3 Failed ASCT and not treated with BV * Treatment Ongoing Complete Response Partial Response Progressive Disease Last Dose 0 5 10 15 20 25 30 35 40 45 Data cutoff: April 8, 2016 Weeks Median number of treatment cycles: 9 (range, 4-14) 21 patients who responded were still on pembrolizumab treatment Chen R et al. EHA 2016 37

Treatment-Related Adverse Events 5% of patients Total Population N = 90 % Any grade Pyrexia 13 Diarrhea 10 Neutropenia 8 Fatigue 8 Cough 8 Hypothyroidism 7 Dry skin 6 Nausea 6 AEs of Clinical Interest Total Population N = 90 % Rash, all grade 1 4 Pneumonitis, all grade 2 2 Colitis, grade 3 1 Four patients (4%) experienced grade 3/4 AEs No treatment related deaths were observed Two discontinuations due to treatment-related AEs (pneumonitis and infusion reaction) Includes erythematous rash. Data cutoff: April 8, 2016 Chen R et al. EHA 2016 38

Comments The advent of check point inhibitors (nivolumab, pembrolizumab) will be changing the therapeutic landscape of patients with relapsed / refractory HL High response rates / durable remissions Manageable toxicity prole The impact on SCT indications / toxicities remains to be seen All data in relapsed / refractory patients support a quick clinical development to earlier phases of the disease Institut Institut Català Català d Oncologia d'oncologia