Aktuelle Behandlungsstrategien Studien des European MCL net Prof. Dr. Martin Dreyling Medizinische Klinik III LMU München

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1 Medizinische Klinik und Poliklinik III Direktor: Prof. Dr. W. Hiddemann Aktuelle Behandlungsstrategien Studien des European MCL net Prof. Dr. Martin Dreyling Medizinische Klinik III LMU München

2 Disclosures Research Support (institution) Celgene, Janssen, Mundipharma, Pfizer, Roche Employee - Major Stockholder - Speakers Bureau - Speakers Honoraria Scientific Advisory Board Celgene, Janssen, Gilead, Mundipharma, Pfizer, Roche Bayer, Celgene, Janssen

3 MCL: a spectrum of disease indolent MCL (15%) classical MCL (80%) transformed (5%) Dreyling, ASCO Educational 2014

4 Dreyling, ESMO CR MCL 2014

5 MRD at end of induction Effect of ASCT 100 R-CHOP * * p = 0.08 p = ns R-DHAP * p = 0.03 % MRD negative % * 70% 37% * 60% 83% 79% 70% 85% Hermine (in submission) 0 PB BM PB BM

6 MCL younger Time to treatment failure Hermine (in submission)

7 Dreyling, ESMO CR MCL 2014

8 Immuno-chemotherapy in MCL Progression-free survival Rummel, Lancet 2013

9 MCL elderly Remission duration (R-CHOP) Kluin-Nelemans, NEJM 2012

10 MCL elderly Overall survival (R-CHOP) Kluin-Nelemans, NEJM 2012

11 DGHO: MCL Guidelines 2015

12 Targeted therapy in relapsed MCL ASCO Educational 2014

13 New Bortezomib Ibrutinib Temsirolimus Lenalidomide copyright G. Hess

14 MCL studies 2015 Proteasome inhibition mtor inhibition Immune modulation R-CHOP+/-Bortezomib NLG-MCL4 BR-Lenalidomide R-HAD +/-Bortezomib BeRT BR-Temsirolimus T3 protocol chemotherapy+ Temsirolimus LENA-BERIT BR-Lenalidomide MCL 3001 Ibrutinib vs Temsirolimus SPRINT Lenalidomide vs investigator s choice

15 VR-CAP vs R-CHOP: Progression-free survival Patients alive and progression-free, % R-CHOP VR-CAP R-CHOP VR-CAP Events, n Median PFS, months (95% CI) (12.0, 16.9) (19.8, 31.8) HR (95% CI) 0.63 (0.50, 0.79) P-value < Months from randomization Number of patients at risk: R-CHOP VR-CAP Median follow-up 40 months; 298 (61%) PFS events 59% improvement with VR-CAP vs R-CHOP (hypothesized: 40% improvement) Median PFS by investigator was 16.1 vs 30.7 months with R-CHOP vs VR-CAP; 307 (63%) events; HR 0.51, p<0.001; 96% improvement with VR-CAP Presented by: Franco Cavalli, MD

16 Hematologic AEs and Clinical Significance R-CHOP N=242 VR-CAP N=240 Any-grade thrombocytopenia, % Grade 3 thrombocytopenia, % 6 57 Any-grade bleeding AEs, % 5 6 Grade 3 bleeding AEs, % Platelet transfusions, % 3 23 Cycle delays due to thrombocytopenia, % 2 5 R-CHOP N=242 VR-CAP N=240 Any-grade neutropenia, % Grade 3 neutropenia, % Any-grade infection AEs, % Grade 3 infection AEs, % Systemic antibacterial use, % Colony stimulating factor use, % Cavalli, ASCO 2014

17 Study design Ara-C dose: 1gr/m 2 In patients > 65 years Or previous ASCT

18 MCL studies 2015 Proteasome inhibition mtor inhibition Immune modulation R-CHOP+/-Bortezomib NLG-MCL4 BR-Lenalidomide R-HAD +/-Bortezomib BeRT BR-Temsirolimus T3 protocol chemotherapy+ Temsirolimus LENA-BERIT BR-Lenalidomide MCL 3001 Ibrutinib vs Temsirolimus SPRINT Lenalidomide vs investigator s choice

19 Progression-free survival (ITT) Hess, JCO 2009

20 BeRT: Benda/Rituximab/Temsirolimus Bendamustin 90 mg/m² Be Be Be Be Rituximab 375 mg/m² R R Temsirolimus 25/50/75 mg T T T G-CSF T d1 Hess, Leukemia 2015 (in press) d8 d15 d22 d29

21 BeRT phase I Responses Hess, Leukemia 2015 (in press)

22 MCL studies 2015 Proteasome inhibition mtor inhibition Immune modulation R-CHOP+/-Bortezomib NLG-MCL4 BR-Lenalidomide R-HAD +/-Bortezomib BeRT BR-Temsirolimus T3 protocol chemotherapy+ Temsirolimus LENA-BERIT BR-Lenalidomide MCL 3001 Ibrutinib vs Temsirolimus SPRINT Lenalidomide vs investigator s choice

23 Study design Rituximab 375 mg/m 2 Lenalidomide 20 mg* Days 1-21 q 28 * Dose escalation to 25 mg allowed Induction (cycles 1-12) Time (months) Rituximab 375 mg/m 2 Lenalidomide 15 mg Days 1-21 q 28 Maintenance (cycle 13 - POD) POD Ruan, ASH 2014

24 Efficacy: Progression-free Survival Probability of progression free survival Progression-Free Survival 24-month PFS OS = 84.6% 92.4% (95% CI = 66.6%, 72.3%, 93.4%) 98.1%) Median follow-up = months (range 5-38) Months from Treatment Number at risk Ruan, ASH 2014

25 European MCL Network MCL R2 elderly 1 st line induction: 8x R-CHOP PR/CR ~80% Rituximab maintenance + Lenalidomide 15 mg daily d1-21, q28 days Treatment: max. 2 years 1 st line induction: 6x R-CHOP/Ara-C Rituximab maintenance sponsor: LYSARC central pathology: W. Klapper MRD diagnostics: M. Ladetto, C. Pott, MH Delfau

26 Mantle cell lymphoma B-cell receptor pathway

27 BTK inhibitor Ibrutinib Adverse events (>15%) Wang, NEJM 2013, ASH 2014

28 BTK inhibitor Ibrutinib Non-hematological grade III/IV toxicities Wang, NEJM 2013, ASH 2014

29 BTK inhibitor Ibrutinib Response rates Wang, NEJM 2013, ASH

30 BTK inhibitor Ibrutinib Duration of response median 26.7-month follow-up Wang, NEJM 2013, ASH 2014

31 Ibrutinib and Rituximab in relapsed MCL Rituximab: Ibrutinib: Cycle 1 4 x weekly 375 mg/m² i.v. 560 mg daily p.o. Cycle 3 8: 375 mg/m² i.v. day 1 Cycle >9 375 mg/m² i.v. every 2nd cycle Wang, ASH 2014 Up to 2 years

32 Best Response % % Wang, ASH % p = % p = % 44% 56% 88% 48% Ki67 50% Ki67 < 50% Total N = 50 40% ORR PR CR

33 Median Follow up 11 months Progression-free survival Overall PFS (n=50) PFS by Ki Probability Probability <50% ( E / N = 2 / 34 ) >=50% ( E / N = 6 / 12 ) P-value < Months Months Wang, ASH 2014

34 A: R-CHOP/ R-DHAP x 3 ASCT Observation A + I: R R-CHOP + I/ R-DHAP x 3 ASCT 2 yrs I-maintenance Observation I: R-CHOP + I/ R-DHAP x 3 2 yrs I-maintenance Observation superiority/non-inferiority: time to treatment failure HR: 0.60; 65% vs. 77% vs. 49% at 5 years

35 European MCL Network Study generation 2015 < 65 years > 60 years > 65 years MCL younger: R-CHOP/DHAP =>ASCT R-CHOP/DHAP+I =>ASCT => I R-CHOP/DHAP + I => I MCL elderly R2: R-CHOP vs R-CHOP/Ara-C => Rituximab M +/-Lenalidomide 1. Relapse MCL elderly I: BR +/- Ibrutinib => Rituximab M +/- Ibrutinib R-HAD +/- Bortezomib 2. Relapse (or not qualifying for R-HAD) Ibrutinib vs BeRT BR-Temsirolimus

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37 Dreyling, ESMO CR MCL 2014