Immunotherapy with Blinatumomab What are the possibilities? Peter Bader

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1 Immunotherapy with Blinatumomab What are the possibilities? Peter Bader SBTMO 2018 ALL Satellite Symposium Role of MRD and Immunotherapy in Optimizing ALL Treatment Outcomes Rio de Janeiro, August 2 nd, 2018

2 Objectives Refractory ALL Blinatumomab, Product, clinical development Blinatumomab in Children and Adults TOWER Study; BLAST Study, AND RIALTO Study Own data in 18 children Present data from TOWER (AllHSCT in adults with R/R ALL from Phase 3 2

3 Poor Outcome for Patients with r/r pb-all Pediatric patients Adult patients Standard pb-all CR with frontline chemo 98-99% 85-90% relapse 15-20% 30-50% Long-term survival after early relapses late relapses 25% 50-60% r/r pb-all 8% 24% Median OS with chemo only months 5y-median OS with chemo only % Median OS after chemo only - 10 months Median OS after HSCT 7.4 months 5.8 months New agents with reduced toicity are needed to improve outcomes for patients with r/r pb-all 3

4 Bispecific T-Cell Engager: Blinatumomab Activation signals promote CTC proliferation Klinger M. et al. Blood 2012 Serial lysis of CD19+ B cells Hoffmann P. et al. Int J Cancer 2005 Nagorsen et al. Leuk & Lymph 2009 Baeuerle P.A. et al. Cancer Res Bargou R. et al. Science 2008 Topp M.S. et al. Lancet Oncol

5 Blinatumomab Mode of Action Nagorsen et al

6 Blinatumomab Clinical Develpoment Nagorsen et al

7 A Phase 3, Randomized, Open Label Study Investigating the Efficacy of the BiTE Antibody Blinatumomab Versus Standard of Care Chemotherapy in Adult Subjects With Relapsed/Refractory B-precursor Acute Lymphoblastic Leukemia (ALL) Study (TOWER) NCT Amgen Inc. All Rights Reserved.

8 Screening/Pre-phase Randomization Safety follow-up TOWER Study in Adult r/r pb-all Blinatumomab civ infusion 4 weeks on 2 weeks off 2 cycles SOC chemotherapy 2 cycles Consolidation 3 cycles Maintenance 12 months 8

9 BLAST: A Confirmatory, Single-Arm, Phase 2 Study of Blinatumomab, a Bispecific T-Cell Engager (BiTE) Antibody Construct, in Patients with Minimal Residual Disease B- Precursor Acute Lymphoblastic Leukemia (ALL) Study (BLAST) NCT Amgen Inc. All Rights Reserved.

10 Screening/Pre-phase Safety follow-up Long-term follow-up BLAST Study in Adult r/r pb-all, MRD-based Blinatumomab 15 μg/m 2 civ infusion i.th. prophylais 4 weeks on 2 weeks off Up to 4 cycles HSCT offered to patiens in CR 10

11 Open-label, multicentre, epanded access study of blinatumomab* in paediatric and adolescent patients with relapsed/refractory B-precursor ALL Study 320 (RIALTO) NCT *Blinatumomab is not licensed for use in paediatric patients in the EU SC-EU-AMG SC-DE-AMG Amgen Inc. All Rights Reserved.

12 Screening/Pre-phase Safety follow-up Long-term follow-up RIALTO Study in r/r pb-all Blinatumomab civ infusion 4 weeks on 2 weeks off Up to 5 cycles HSCT offered to patiens in CR 12

13 Key Eligibility Criteria TOWER Study BLAST Study RIALTO Study Age 18 y 18 y >28 d and <18 y CD19+ pb-all with 5% blasts in BM CD19+ pb-all with <5% blasts in BM MRD 10E-4 (- 10E-3) Ph negative 2nd or later relapse, any rlps. after HSCT, refractory disease 1st relapse w remisson duration <12 months Adequate liver function ECOG status 2 0 or 1 () No prior HSCT 13

14 Key Eclusion Criteria Clinical relevant CNS pathology Isolated etramedullary disease Chemotherapy within 2 wk, Radiotherapy within 2-4 wk Immunotherapy TOWER Study BLAST Study RIALTO Study Immunosuppression within 2 weeks Auto HSCT within 6 wk Allo HSCT within 12 wk Grade 2-4 agvhd, Active cgvhd Abnormal liver or renal function 14

15 Study Endpoints TOWER Study BLAST Study RIALTO Study Primary endpoint: Efficacy OS Primary endpoint: Efficacy MRD response after 1 cycle (MRD neg with sensitivity of at least 10E-4 by PCR in reference lab) Primary endpoint: Safety Treatment-emergent/related AEs Secondary endpoint: Efficacy EFS Remission rate Safety Incidence and severity of AEs Secondary endpoint: Efficacy (w/wo HSCT) RFS OS Duration of MRD response Safety Incidence and severity of AEs Secondary endpoint: Efficacy CR within first 2 cycles MRD neg. within first 2 cycles RFS OS Rate of allo-hsct after CR 15

16 TOWER Study Blinatumomab vs. Chemo in Adult-ALL Prospective 2:1 randomized trial: n=405 Blina: 271 Chemo: 134 Median OS Blina: 7.7 mo Chemo: 4.0 mo CR/Cri (12 weeks): Blina: 36/44% Chemo: 16/25% 6 months EFS: Blina: 31% Chemo: 12% Longer remission duration Blina: 7.3 mo Chemo: 4.6 mo AES grade 3 Blina: 87% Chemo: 92% Treatment with blina resulted in longer OS Hagop Kantarjiann et al. NEJM

17 BLAST Study Blinatumomab in MRD Positive Adult-ALL n=36 Zugmaier et al. Blood

18 BLAST Study Blinatumomab in MRD Positive Adult-ALL 28% achieved an OS of 30 mo Survival may be associated with MRD response n=36 Zugmaier et al. Blood

19 BLAST Study (Follow-up) Blinatumomab in MRD Positive Adult-ALL Results Evaluable 113 Median age 45 (18-76) yrs In 2 nd /later CR: 36% MolCR: 78% Median OS: 36.5 mo - Mol CR y/n: 38.9 vs 12.5 mo Median RFS: 18.9 mo - Mol CR y/n: 23.6 vs 5.7 mo - 1 st / later CR: 24.6 vs 11 mo MRD response resulted in improved OS and RFS Gökbuget et al. Blood

20 RIALTO Study: Patient Demographics and Baseline Characteristics Characteristic All patients (N=40) Male, n (%) 19 (48) Median (range) age, years 9 (1 17) Age group, n (%) 1 month to <2 years 2 to <12 years 12 to <17 years Prior relapses, n (%) 0 (primary refractory) (13) 20 (50) 15 (38) 5 (13) 11 (28) 24 (60) Prior allogeneic HSCT, n (%) 21 (53) Bone marrow blasts (local), n (%) <50% 50% 22 (55) 18 (45) Locatelli F, et al. ASCO 2017; Abstract and poster presentation. 20

21 RIALTO Study: Response Within first 2 Cycles CR during the first two cycles <50% blasts 50% blasts t(17;19) MRD response during the first two cycles <50% blasts 50% blasts t(17;19) HSCT realisation Allogeneic HSCT after CR Allogeneic HSCT without CR All patients (N=40) n/n1* % 95% CI 25/40 15/22 10/18 2/2 19/25 12/15 7/10 2/2 10/25 3/ NA NA Median number of cycles started and completed: 2 (range, 1 5) Locatelli F, et al. ASCO 2017; Abstract and poster presentation. 21

22 Survival probability RIALTO Study: Overall Survival Censored at time of allogeneic HSCT N Median OS, months 95% CI, months Not censored NE Censored Median follow-up: 11.8 months Not censored Censored Number of subjects at risk: Time (months) Locatelli F, et al. ASCO 2017; Abstract and poster presentation. 22

23 Frankfurt Patients (N=18) N (%) N (%) Se Male Female 14 4 (78) (22) Age median [range] 13 years [2-20] Diagnosis ALL B-NHL 17 1 (94) (6) Number of SCTs before treatment (39) (56) (6) Number of relapses before treatment (50) (33) (11) (6) Number of Blinatumomab cycles (61) (39) Duration of Blinatumomab cycle median [range] 28 days [2-36]

24 Course after Blinatumomab median post treatment observation period: 1.6 years [25 days 5.5 years] Response to Blinatumomab SCT after treatment Total Yes (%) No (%) CR (MRD +/- ) NR Total 8 6 (75) 2 (25) 10 7 (70) 3 (30) (72) 5 (28)

25 Outcome in Patients with SCTs after Blinatumomab median post SCT observation period: 2.5 years [83 days 5.4 years] Response to Blinatumomab Outcome Total CR (%) Relapse (%) TRM (%) CR (MRD +/- ) NR Total 6 2 (33) 2 (33) 2 (33) 7 3 (43) 3 (43) 1 (14) 13 5 (39) 5 (39) 3 (23)

26 Outcome of patients without SCT (n=5) Response to Blinatumomab Outcome Total CR (%) Lost to follow-up (%) Death (%) CR (MRD +/- ) NR Total 2 2 (100) 0 (0) 0 (0) 3 0 (0) 2 (66) 1 (33) 5 2 (40) 2 (40) 1 (20)

27 Outcome of all patients (n=18) median post treatment observation period: 1.6 years [25 days 5.5 years] Response to Blinatumomab Outcome Total CR (%) Relapse (%) NRM (%) Lost to FU (%) CR NR Total 8 4 (50) 2 (25) 2 (25) 0 (0) 10 3 (30) 4 (40) 1 (10) 2 (20) 18 7 (39) 6 (33) 3 (17) 2 (11)

28 Overall survival of patients since begin of treatment with Blinatumomab Overall survival (%) y-p= 54.6%, 95%-CI: 32.4% % Time since begin of treatment (years)

29 Overall survival of patients with CR vs. patients with NR after treatment with Blinatumomab Overall survival (%) CR includes CR MRD + 0 CR: 2-y-p= 71.4%, 95%-CI: 44.7% - 100% NR: 2-y-p= 45.7%, 95%-CI: 20.3% - 100% Time since end of treatment (years)

30 Summary Allogeneic SCT remains the gold standard (highest risk, relapsed patients) Children and adolescents with ALL CR1: ultra high risk features, persistent MRD CR2: - late relapses with pers. MRD - early, very early relapse >CR2: all patients Level of MRD prior to transplant is a major predictor for outcome Antibody treatment Remission induction and improvement; reduce toicity and clear MRD post transplant Adult Patients with r/r ALL High risk for relapse and TRM irrespective of treatment Patients with persistent remission after Blinatumomab Efforts are focusing on minimizing the relapse risk by intensifying therapy upfront and by eradicating MRD using the new available immunotherapies e.g. Blinatumomab Combining all these modalities (new therapies, conventional chemotherapy and HCT) is challenging. 30

31 Pediatric Stem Cell Transplantation & Immunology: Peter Bader / Evelyn Ullrich / Thomas Klingebiel Physicians Michael Merker Shahrzad Bakhtiar Eva Rettinger Andre Willasch Andrea Jarisch Jan Sörensen Office Kirsten Schäfer Clinical Trial Office Verena Pfirrmann Bettina Steinmetz Tina Homrighausen Bio Mathematics Emilia Salzmann- Manrique CIK / T Cell Therapy Eva Rettinger Verena Pfirrmann Michael Merker Lisa-Marie Pfeffermann Sarah Oelsner Vida Meyer Graft Manipulation, Cell Therapeutics Sabine Huenecke Melanie Bremm Claudia Cappel Verena Pfirrmann Sibylle Wehner Mesenchymal Stroma Cells Zyrafete Kuçi Selim Kuçi NK cells / Eperimental Sara Tognarelli Juliane Wagner Jochen Früh Katja Thoma Molecular Biology Andre Willasch Christlinde Mauracher Gitta Nozad Fariba Soltani Miriam Stais Hermann Kreyenberg Cooperations Halvard Bönig German Red Cross Blood Donor Service Frankfurt/Main, Germany Winfried S. Wels Georg-Speyer-Haus, Frankfurt/Main, Germany Participating Institutions Düsseldorf, Germany Roland Meisel Florian Babor Friedhelm Schuster Frankfurt/Main, Germany Hubert Serve Gesine Bug Mainz, Germany Matthias Theobald Eva Wagner Hauptrock Beate Heidelberg, Germany Johann Greil

32 Can allogeneic HSCT in ALL be replaced by antibody therapy? 32

33 Principal Considerations Treatment of acute leukemia Multimodal chemotherapy protocols Adults Children and adolescents Considerable improvement Leukemia free survival: 90% in children and adolescents with ALL Indications for SCT CR1 only in high risk patients for ALL Slow response, hypodiploidy, pers. MRD CR2 Only high risk patients in children and adolescents with ALL Early, very early relapses and slow MRD clearance in late relapses CR3 All patients 33

34 Stem-Cell Transplantation in Children With Acute Lymphoblastic Leukemia: A Prospective International Multicenter Trial Comparing Sibling Donors With Matched Unrelated Donors The ALL-SCT-BFM-2003 Trial Christina Peters, Martin Schrappe, Arend von Stackelberg, André Schrauder, Peter Bader, Wolfram Ebell,Peter Lang, Karl-Walter Sykora, Johanna Schrum, Bernhard Kremens, Karoline Ehlert, Michael H. Albert,Roland Meisel, Susanne Matthes-Martin, Tayfun Gungor, Wolfgang Holter, Brigitte Strahm, Bernd Gruhn,Ansgar Schulz, Wilhelm Woessmann, Ulrike Poetschger, Martin Zimmermann, and Thomas Klingebiel MSD: 71% MUD: 69% MSD: 79% MUD: 73% MSD: 24% MUD: 22% MSD: 3% MUD: 10% C. Peters et al. J Clin Oncol

35 Frankfurt Eperience Patient with ALL from n=99 in complete remission at the time of first transplantation Se Male Female Remission CR1 CR2 N % N % Age < 10 years > 10 years Donor MSD MUD Haploidentical Phenotype pb-all T-ALL bi-pheno ALL Immunotherapy (WD of CSA or DLI) Yes No S. Bahktiar, submitted 35

36 pefs Outcome for ALL versus (n=50) = 77% (n=49) = 63% n Events 4-y EFS P ± ± Overall survival (n=50) = 87% (n=49) = 71% n Events 4-y OS P ± ± CIR n Events 4-y CIR P ± ±0.06 TRM n Events 4-y TRM P ± ± months after SCT months after SCT S. Bahktiar, submitted 36

37 CIBMTR Study. Period : Patients n=1458 2y: 50% Segal et.al: Cancer