Immuntherapie maligner Lymphome. Mathias Witzens-Harig Medizinische Klinik V Universität Heidelberg

Immuntherapie maligner Lymphome Mathias Witzens-Harig Medizinische Klinik V Universität Heidelberg 20.02.2016

Immuntherapie maligner Lymphome Allogene Stammzelltransplantation Antikörper, z.b. Rituximab Bispezifische Antikörper, z.b. Blinatumomab Immunmodulatoren (IMiDs), z.b. Lenalidomid Checkpointinhibitoren CAR T-Zellen

Nivolumab in Patients (Pts) With Relapsed or Refractory Classical Hodgkin Lymphoma (R/R chl): Clinical Outcomes From Extended Follow-up of a Phase 1 Study (CA209-039) Stephen M. Ansell, MD, PhD, 1 Philippe Armand, MD, PhD, 2 John Timmerman, MD, 3 Margaret A. Shipp, MD, 2 M. Brigid Bradley Garelick, MD, 4 Lili Zhu, MS, 5 Alexander M. Lesokhin, MD 6 1 Mayo Clinic, Rochester, MN, USA; 2 Dana-Farber Cancer Institute, Boston, MA, USA; 3 Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA, USA; 4 Bristol-Myers Squibb, Wallingford, CT, USA; 5 Bristol-Myers Squibb, Princeton, NJ, USA; 6 Memorial Sloan Kettering Cancer Center, New York, NY, USA

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 amplification of the 9p24.1 locus Prognosis for patients with relapsed chl is poor PD-L1 expression in chl Copy Gain Amplification PD-L1/L2 copy gains and amplification 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. 5

Nivolumab Mechanism of Action Nivolumab is a fully human immunoglobulin G4 monoclonal antibody targeting the programmed death-1 (PD-1) immune checkpoint pathway IFN, interferon; MHC, major histocompatibility complex; PI3K, phosphoinositide 3-kinase. 6

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 (%) Gastrointestinal 4 (17) Resolved, % 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

Treatment-Related Serious Adverse Events Adverse Event, n (%) chl (n = 23) Any Grade Grade 3 4 Any event 3 (13) 2 (9) Lymph node pain 1 (4) 0 (0) Pancreatitis 1 (4) 1 (4) Myelodysplastic syndrome 1 (4) 1 (4) 3 patients discontinued due to adverse events 2 discontinuations were study drug related (pancreatitis, myelodysplastic syndrome) 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 benefit, 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

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 benefit 5 proceeded to transplant 2 discontinued for toxicity Disease progression following initial response 14

Treatment Status Status chl (n = 23) n (%) Completed treatment 20 (87) Maximum clinical benefit 6 (26) CR 4 (17) PR 2 (9) Transplant 5 (22) Disease progression 6 (26) Patient request a 1 (4) Study drug toxicity b 2 (9) Continuing treatment 3 (13) a Lymph node pain; b pancreatitis, myelodysplastic syndrome 15

Retreatment With Nivolumab Pretreatment 6 weeks posttreatment Progression when therapy stopped 6 weeks post-second course of therapy 16

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 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

Conclusions With longer follow-up, treatment with nivolumab in patients with chl indicated: Consistent and manageable adverse event profile Both CRs and PRs were durable In the one patient that was retreated post-progression, a second response was achieved Long-term therapy (up to 2 yr) appears feasible and is associated with durable responses, and encouraging PFS and OS These data support the further investigation of nivolumab in patients with chl in a larger, ongoing phase 2 study, CHECKMATE 205 20

Best Overall Response NHL Objective Response Rate, n (%) Complete Responses, n (%) Partial Responses, n (%) Stable Disease n (%) B-Cell Lymphoma* (n=29) 8 (28) 2 (7) 6 (21) 14 (48) Follicular Lymphoma (n=10) Diffuse Large B-Cell Lymphoma (n=11) 4 (40) 1 (10) 3 (30) 6 (60) 4 (36) 1 (9) 3 (27) 3 (27) T-Cell Lymphoma (n=23) Mycosis Fungoides (n=13) Peripheral T-Cell Lymphoma (n=5) 4 (17) 0 (0) 4 (17) 10 (43) 2 (15) 0 (0) 2 (15) 9 (69) 2 (40) 0 (0) 2 (40) 0 (0) *includes other B-cell lymphoma (n=8) includes other cutaneous T-cell lymphoma (n=3) and other non-cutaneous T-cell lymphoma (n=2)

Sustained Remissions Following Chimeric Antigen Receptor Modified T Cells Directed Against CD19 (CTL019) in Patients with Relapsed or Refractory CD19+ Lymphomas Stephen J. Schuster 1, Jakub Svoboda 1, Sunita Dwivedy Nasta 1, David L. Porter 1, Elise A. Chong 1, Daniel J. Landsburg 1, Anthony R. Mato 1, Simon F. Lacey 1*, Jan J. Melenhorst 1*, Anne Chew 1*, Jens Hasskarl 2*, Mariusz A. Wasik 1*, Katherine T. Marcucci 1*, Zhaohui Zheng 1*, Bruce L. Levine 1 and Carl H. June 1 1 University of Pennsylvania, Philadelphia, PA 2 Novartis, Basel, CH

Background CD19 CTL019 engineered T cells express a chimeric antigen receptor (CAR) with specificity for CD19 and activation and costimulatory signaling via CD3-zeta and CD137 (4-1BB) domains, respectively Chimeric antigen receptor-modified T cell therapy against CD19 is effective in treating relapsed and refractory ALL 1, 2 and CLL 3 CD3-ζ 1. Maude et al. N Engl J Med 2014; 371:1507-17. 2. Grupp et al. N Engl J Med 2013; 368:1509-18. 3. Porter et al. N Engl J Med 2011; 365:725-33. Chimeric Antigen Receptor (CAR) 23 30 Nov 2015

Study Design: Inclusion and Exclusion Inclusion Criteria: CD19+ B cell lymphoma patients with no available curative treatment options Age >18, expected survival >12 weeks, measurable disease, ECOG PS 0 or 1 Diffuse large B cell lymphoma: relapsed/refractory disease after ASCT or ineligible for ASCT; transformation from CLL/SLL or FL allowed Follicular lymphoma: at least 2 prior immunochemotherapy regimens and progression <2 years after most recent line of therapy Mantle cell lymphoma: relapsed or progressive disease after or during first line rituximabchemotherapy; persistent disease after first line rituximab-chemotherapy and not eligible or appropriate for allogeneic or autologous SCT; relapsed after prior autologous SCT Exclusion Criteria: Pregnancy; uncontrolled active infection; HIV; active hepatitis B/C; concurrent use of steroids; active CNS involvement; patients in complete remission 24 30 Nov 2015

Protocol Schema CD19+ Lymphoma Eligibility determination Enrollment Apheresis Baseline immune assays Restaging and Lymphodepleting chemotherapy CT scans Bone marrow Physician s choice Ends 1 4 days before CTL019 infusion CTL019 Infusion, Monitoring and Response Assessments CTL019 infusion Month +3 response assessment = Clinical evaluation; immune/ctl019 assays Adverse event monitoring Day -1 Day 0 Month +1 Month +2 and +3 evaluations Quarterly f/u x 2 years Long-term f/u x 15 years 25 30 Nov 2015

Patient allocation Patients enrolled (n = 43) DLBCL (n = 26) FL (n = 14) MCL (n = 3) CTL019 not infused (n = 13) Progressive disease (n = 4) Production failure (n = 6) Withdrew consent (n = 3) Received 1.0-5.0E+08 CTL019 (n = 30) DLBCL (n = 15) FL (n = 13) MCL (n = 2) 26 30 Nov 2015

Results: Diffuse Large B Cell Lymphoma DLBCL: Patient Characteristics (n = 26 enrolled) Median age 54.5 years (range 25-77) Sex 18 (69%) men Median prior therapies 3 (range 1-8) Prior stem cell transplant 9 (35%) Stage III IV (enrollment) 19 (73%) Increased LDH (enrollment) 20 (77%) > 1 extranodal site (enrollment) 11 (42%) Median ECOG PS (enrollment) 1 (range 0-1) 27 Lymphodepleting therapy (n = 15) 2 EPOCH (w/o vincristine); 7 hyperfractionated cyclophosphamide (1.8 gm/m2); 2 bendamustine (180 mg/m2); 2 cyclophosphamide (1 gm/m2); 1 XRT (4000 cgy) + cyclophosphamide (750 mg/m2); 1 infusional etoposide + bolus cyclophosphamide ("EPOCH" dosing) 30 Nov 2015

Response Rates: Diffuse Large B Cell Lymphoma DLBCL: ORR at 3 months 47% (N = 15) - CR: 3 - PR: 4 - PD: 8 DLBCL: Best Response Rate 47% (N = 15) - CR: 6 - PR: 1 - PD: 8 3 patients with PRs by CT criteria at 3 months converted to CRs by 6 months 1 patient with PR at 3 months had PD at 6 months 28 30 Nov 2015

Results: Diffuse Large B Cell Lymphoma 13413-01 13413-02 13413-05 DLBCL: PFS (months) ID Total CTL019 Dose Peak %CD3+CAR19+ Peak Day 13413-01 5.00E+08 28.30% +10 13413-02 5.00E+08 29.30% +7 13413-06 13413-09 13413-10 13413-12 13413-16 13413-17 13413-21 13413-22 13413-23 13413-28 13413-05 5.00E+08 5.30% +7 13413-06 5.00E+08 6.90% +7 13413-09 5.00E+08 3.90% +7 13413-10 5.00E+08 43.10% +14 13413-12 5.00E+08 4.10% +2 13413-16 5.00E+08 2.50% +7 13413-17 5.00E+08 12.20% +7 13413-21 5.00E+08 5.70% +7 13413-36 13413-22 5.00E+08 16.50% +10 13413-39 13413-23 5.00E+08 17.80% +10 0,0 5,0 10,0 15,0 20,0 13413-28 1.93E+08 4.10% +10 29 Ongoing clinical responses Days to progressive disease 13413-36 5.00E+08 0.10% +7 30 Nov 2015 13413-39 5.00E+08 1.80% +10

Results: Diffuse Large B Cell Lymphoma DLBCL: Progression-free Survival N = 15 Median PFS 3.0 months 30 Months 30 Nov 2015

Results: Diffuse Large B Cell Lymphoma DLBCL: Response Duration N = 7 Median not reached Median follow-up 14.5 months 31 Months 30 Nov 2015

Results: Follicular Lymphoma FL: Patient Characteristics (n = 14 enrolled) Median age 59 years (range 43-72) Sex 6 (43%) men Median prior therapies 5 (range 2-10) Prior transplant % 4 (29%) Stage III IV (enrollment) 13 (93%) Increased LDH (enrollment) 10 (71%) > 1 extranodal site (enrollment) 4 (29%) Median ECOG PS (enrollment) 0 (range 0 1) 32 Lymphodepleting therapy (n = 13) 6 bendamustine (90 mg/m2) daily x 2 1 cyclophosphamide (200 mg/m2) + fludarabine (20 mg/m2) daily x 3 2 XRT (400 cgy) + cyclophosphamide (1 gm/m2) 1 cyclophosphamide (1 gm/m2) 1 cyclophosphamide (1.2 g/m2) over 4 days 1 carboplatin + gemcitabine 1 modified EPOCH 30 Nov 2015

Response Rates: Follicular Lymphoma FL: ORR at 3 Months 73% (N = 11)* - CR: 4 - PR: 4 - PD: 3 FL: Best Response Rate 73% (N = 11) - CR: 7 - PR: 1 - PD: 3 3 patients with PRs by CT/MR criteria at 3 months converted to CRs by 6 months 1 patient with PR at 3 months who remained in PR at 6 and 9 months had PD at approximately 12 months 33 *11 of 13 patients infused are evaluable at 3 months 30 Nov 2015

Results: Follicular Lymphoma 13413-04 13413-07 13413-11 13413-13 13413-15 13413-19 13413-24 13413-31 13413-32 13413-33 13413-34 13413-37 13413-38 34 FL: PFS (months) 0,0 2,0 4,0 6,0 8,0 10,0 12,0 14,0 16,0 18,0 Ongoing clinical responses Days to progressive disease Total CTL019 Dose Peak %CD3+CAR 19+ Peak Day ID 13413-04 3.76E+08 0.70% +7 13413-07 5.00E+08 3.00% +10 13413-11 5.00E+08 38.20% +7 13413-13 5.00E+08 3.20% +7 13413-15 5.00E+08 40.50% +7 13413-19 1.79E+08 1.00% +7 13413-24 5.00E+08 8.40% +10 13413-31 2.84E+08 3.50% +10 13413-32 1.95E+08 5.10% +10 13413-33 5.00E+08 23.60% +10 13413-34 3.62E+08 40.00% +14 13413-30 Nov 2015 37 5.00E+08 41.90% +7

Results: Follicular Lymphoma FL: Progression-free Survival N = 13 Median not reached Median follow-up 11.9 months 35 Months 30 Nov 2015

Results: Follicular Lymphoma FL: Response Duration N = 8 Median not reached Median follow-up 14.3 months 36 Months 30 Nov 2015

Adverse Events at Least Possibly Related: Grade 3 AE Acute kidney injury Alk. phos. increased G3 G 4 G5 Total G3 AE G3 G 4 G5 Total G3 2 2 Headache 1 1 1 1 Hypoxia 1 1 Atrial fibrillation 1 1 Hypertension 1 1 Agitation 1 Hypotension 1 1 2 Delirium 2 2 Hypocalcemia 1 1 Encephalitis 1 1 Hyponatremia 1 1 CRS 2 2 4 Hypophosphatem ia 3 1 4 Chest pain 1 1 Insomnia 2 2 Dyspnea 1 1 Laryngeal edema 1 1 Edema 1 1 Anemia 5 5 Fatigue 1 1 Lymphopenia 10 8 18 Fever 1 1 Neutropenia 7 7 14 Febrile neutropenia 37 2 2 Thrombocytopeni a 4 2 6 30 Nov 2015 Pneumonia 1 1 Weight loss 1 1

Conclusions Chimeric antigen receptor modified T cells directed against CD19 (CTL019) can achieve durable responses in patients with relapsed or refractory CD19+ diffuse large B cell and follicular lymphomas. - All patients who achieved CR remain in CR. The toxicity of this therapeutic approach appears acceptable. - Cytokine release syndrome was generally grade 2. - There were no deaths from cytokine release syndrome. Single arm, open-label, multi-center, phase II study of efficacy and safety of CTL019 in adult DLBCL patients began in July 2015. - NCT02445248; ( JULIET ) 38 30 Nov 2015

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Vielen Dank Stephen Schuster, University of Pennsylvania Stephen Ansell, Mayo Clinic, Rochester 41

Vielen Dank für die Aufmerksamkeit!