Hodgkin Lymphom Aktuelle Strategien und Studien Andreas Engert, MD Chairman, German Hodgkin Study Group University Hospital of Cologne

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1 German Hodgkin Study Group Deutsche Hodgkin Studiengruppe Hodgkin Lymphom Aktuelle Strategien und Studien Andreas Engert, MD Chairman, German Hodgkin Study Group University Hospital of Cologne

2 Hodgkin Lymphom Aktuelle Strategien und Studien First-line Rezidive Anti-PD1 Zusammenfassung

3 Hodgkin Lymphoma Cumulative relative Survival (Sweden) Sjöberg et al, Blood 2012

4 Hodgkin Lymphoma Late side effects after treatment 2nd NPL Organ damage Others AML NHL Solid tumours Lung Heart Thyroid Fatigue Fertility Psychosocial NPL, neoplasias; AML, acute myeloid leukemia; NHL, non-hodgkin lymphoma; OPSI, overwhelming post-splenectomy infection

5 GHSG Risk Allocation for HL Stage (Ann Arbor) Risk factors IA, IB, IIA IIB IIIA, IIIB IVA, IVB None 3 LK- Areas Elevated ESR Large Med Mass Extranodal disease Early favorable Early unfavorable Advanced

6 Hodgkin Lymphoma Evolution of Radiotherapy Mantle field Involved Field Involved Node Courtesy R v.d. Maazen

7 GHSG HD10 Study Weakest vs strongest arm (FFTF) HD10, arms A vs. D (ITT) Freedom from Treatment Failure Freedom from Treatment Failure A At 5 years: 4xABVD + 30Gy IFRT: 92.8% 2xABVD + 20Gy IFRT: 91.2% Difference -1,6%; 95% CI [-6,3%; 3,1%] D Time [months] Pts. at Risk Time (months) A D Engert A et al, NEJM 2010

8 GHSG HD13 trial Progression-free survival PFS year estimate: 2xABVD+IF: 93.3% 2xABV+IF: 82.0% 2xAVD+IF: 89.0% 2xAV+IF: 80.6% ABVD ABV AVD AV Pts. at Risk Time [months] ABVD ABV AVD AV Behringer K et al, Lancet 2015

9 HD13: Overall survival All patients (ITT) OS year estimate [95%-CI] median obs. time 2xABVD+IF: 97.4% [95.9% to 98.9%] 53 months 2xABV+IF: 94.4% [91.2% to 97.6%] 83 months 2xAVD+IF: 97.3% [95.9% to 98.8%] 55 months 2xAV+IF: 98.3% [96.4% to 100.0%] 82 months ABVD ABV AVD AV Pts. at Risk Time [months] ABVD ABV AVD AV

10 UK NCRI RAPID trial Early stage HL Radford J et al, NEJM (2015) 372;17:

11 Ongoing GHSG trial (HD16) Early favorable HL CS I/II without RF* StandardArm Experimental Arms 2 x ABVD PET (+/-) 2 x ABVD PET- 2 x ABVD PET+ 20 Gy IF Follow-up 20 Gy IF *a) large mediastinal mass; b) extranodal disease; c) high ERS; d) 3 or more areas

12 HD14 study for early unfavorable HL (PFS) Probability ABVD Besc+ABVD Progression-free Survival v Tresckow et al JCO 2012

13 PET+ after 2xABVD: B.esc vs. ABVD Progression-free survival (PFS) BEACOPPesc+INRT ABVD+INRT HR (95% CI) = 0.42 (0.23, 0.74); p=0.002 * 5-yr PFS: 91% vs. 77% *: Alpha=0.037 is the significance level to be used at the final analysis as alpha=0.018 has already been spent at the IA Raemaekers et at; ICML 2015

14 GHSG Risk Allocation for HL Stage (Ann Arbor) Risk factors IA, IB, IIA IIB IIIA, IIIB IVA, IVB None 3 LK- Areas Elevated ESR Large Med Mass Extranodal disease Early favorable Early unfavorable Advanced

15 HD15 in advanced HL Freedom from Treatment Failure (FFTF) 1.0 Freedom from Treatment Failure p-value 60 months difference A vs. B: % 97.5%-CI: [ 0.5%, 9.3%] A vs. C: % 97.5% CI: [-3.7%, 5.8%] C vs. B: 0.04 (n.s.) 3.9% 97.5% CI: [-0.5%, 8.2%] A: 84.4% B: 89.3% C: 85.4% Time [months] Engert A et al, Lancet 2012

16 ECHELON-1: Phase III Trial BV + AVD vs. ABVD in Frontline Advanced chl R A N D O M I Z E Brentuximab Vedotin 1,2 mg/kg q2w + AVD 28-day cycles ABVD 28-day cycles * Assessment based on Revised Response Criteria for Malignant Lymphoma E V A L U A T I O N Younes A et al, ASCO 2013 ATPS8612

17 HD21: GHSG Perspective BV in advanced stage HL 2 x BEACOPP esc 2 x BrECADD Centrally reviewed PET 4x BEACOPP esc 4x BrECADD End of therapy and residual nodes > 2.5 cm: PET positive: Rx PET negative: Follow up HL, Hodgkin Lymphoma; GHSG, German Hodgkin Study Group; BV, brentuximab vedotin; BEACOPPesc, bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone; BrECADD, brentuximab vedotin, etoposide, cyclophosphamide, doxorubicin, dacarbazine, dexamethasone; PET, positron emission tomography; RX, radiotherapy

18 Hodgkin Lymphom Aktuelle Strategien und Studien First-line Rezidive Anti-PD1 Zusammenfassung

19 HDR2 Study for Relapsed HL PFS by treatment arm (final analysis) Probability P = Standard (at 3y: 72%) Intensified (at 3y: 67%) Time, months HL, Hodgkin lymphoma; PFS, progression free survival Josting A et al, J Clin Oncol. 2010:28:

20 Relapse After Auto-TX OS by time to relapse after TX (n=756) TTR n OS (y) >12 m m m m p < Years auto-tx, autologous stem cell transplant; OS, overall survival; TTR, time to relapse Arai et al, Leuk & Lymphoma 2013:54:

21 Brentuximab Vedotin (SGN-35) Mechanism of action Brentuximab vedotin (SGN-35) ADC monomethyl auristatin E (MMAE), potent antitubulin agent protease-cleavable linker anti-cd30 monoclonal antibody ADC binds to CD30 ADC-CD30 complex traffics to lysosome MMAE is released MMAE disrupts Microtubule network G2/M cell cycle arrest Apoptosis

22 Phase II Pivotal Study of BV Progression-Free Survival Chen, et al ASH 2015

23 Random. Phase III (AETHERA) BV in HL pts after auto-tx N = 329 HL post ASCT high risk (no CR, R/R <12 mo, ex-nodal) Placebo q3wk Brentuximab Vedotin 1.8 mg/kg q3wk SCREENING 28 days - 49 TREATMENT PHASE 16 three-wk cycles FOLLOW-UP Every 12 wk Assessments: 3, 6, 9, 12, 18, 24 mo, then every 6 mo Follow-up: every 12 wk until death BV, brentuximab vedotin; HL, Hodgkin lymphoma; pts, patients; ASCT, autologous stem cell transplantation; q3wk, every three weeks; CR, complete response; R/R, relapsed/refractory; mo, months, wk, weeks; auto-tx, autologous stem cell transplantation Takeda, data on file

24 AETHERA PFS per Investigator Percent of Subjects Free of PD or Death Median N Events (Months) Stratified Hazard Ratio Placebo+BSC BV+BSC HR = 0.50 [95% CI (0.36, 0.70)] Median BV = NE (, ); Placebo = 15.8m (8.5, ) 24-month PFS rate BV = 65%; Placebo = 45% Time (Months) N at Risk (Events) Pla+BSC 164 (0) 113 (48) 92 (67) 83 (76) 77 (81) 71 (85) 61 (88) 45 (89) 28 (89) 23 (89) 13 (89) 3 (89) 3 (89) 0 (89) BV+BSC 165 (0) 149 (12) 133 (27) 122 (36) 111 (45) 103 (52) 90 (55) 62 (58) 40 (59) 33 (60) 16 (60) 4 (60) 3 (60) 0 (60) PFS, progression free survival; HR, hazard ratio; BV, brentuximab vedotin; NE, non evaluable; BSC, best supportive care; Pla, placebo Moskowitz et al, Lancet 2015;385:

25 Hodgkin Lymphom Aktuelle Strategien und Studien First-line Rezidive Anti-PD1 Zusammenfassung

26 HL and PD-1 Pathway Nivolumab is a fully human immunoglobulin G4 monoclonal antibody targeting the programmed death-1 (PD-1) immune checkpoint pathway Nivolumab binds PD-1 receptors on T cells and disrupts negative signaling triggered by PD-1 ligands, PD-L1/PD-L2, to restore T-cell antitumor function 1,2 IFNγ IFNγR MHC T-cell receptor T-cell receptor MHC Tumor 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 Nivolumab: PD-1 receptor-blocking antibody 1. Brahmer JR et al. J Clin Oncol 2010;28: ; 2. Wang C et al. Cancer Immunol Res 2014;2:846 56

27 PD-L1 and PD-L2 Expression in chl with 9p24.1 Amplification PD-L1 PD-L2 Chen et al, Clin Cancer Res. 2013; 19:3462 Courtesy of S. Rodig

28 Nivovolumab in Lymphoma Pts Duration of Response Phase 1b* Tumor type n ORR (%) Median F-up (w) Median Resp. Duration (w) Multiple Myeloma DLBCL Follicular NHL CTCL/MF PTCL HL *74 weeks median follow-up

29 CheckMate 205B Overall Study Design Relapsed/refractory chl after ASCT Newly diagnosed advanced-stage chl Cohort A Cohort B Cohort C Cohort D BV-naïve Posttransplant BV Same inclusion criteria as cohort B. Now enrolling In addition, BV prior to ASCT allowed Stop treatment if persistent CR for 1 year, if relapse, reinitiate nivo

30 CheckMate 205B Tumor Burden Change From Baseline (n=80) 100 Change from baseline (%) OR 73% (CR 28%) per Investigator CR PR SD, PD, or unable to determine Per IRRC assessment

31 PFS by Best Response Cohort B: Nivolumab After BV Post-ASCT PFS PD Months No. of patients at risk CR PR SD PD CR PR SD Median PFS prolonged by 5 months with extended follow-up Database lock Apr 2016 Median PFS, mo (95% CI) Median PFS in CR, mo (95% CI) Median PFS in PR, mo (95% CI) Median PFS in SD, mo (95% CI) 15 (11, NR) NR (8, NR) 15 (11, NR) 12 (6, NR) 12-month OS, % 95

32 Duration of Response Cohort A: Nivolumab in BV-naïve Patients Proportion of patients in response No. of patients at risk Months CR PR OR CR: 2/14 events PR: 6/29 events OR: 8/43 events Durable responses in both complete and partial responders Median DOR not yet reached Per IRRC assessment, as of June 2016 database lock. Timmerman et al ASH 2016

33 CheckMate 205B Treatment-Related AEs in Patients* Any grade Grade Patients (n) a Within 30 days of last dose

34 KEYNOTE-87 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 CT scans repeated Q12W PET repeated at W12, W24, to confirm CR or PD, and as clinically indicated Progressive Disease Survival Follow-Up Cohort 3 (N = 60) R/R chl who failed ASCT and not treated with BV post transplant Primary end point: ORR (central review) Secondary end points: ORR (investigator review), PFS, OS Prespecified interim analysis, based on investigator-assessed response, performed after 30 patients in all 3 cohorts reached first response assessment Chen R et al. June 12, 2016

35 KEYNOTE-87 Tumor Size: Change From Baseline Cohort 1 Cohort 2* Cohort % of patients with reduction in tumor size % of patients with reduction in tumor size % of patients with reduction in tumor size Percent Change From Baseline Percent Change From Baseline Percent Change From Baseline PD SD PR CR *The patient in cohort 2 with a 60% increase in tumor size had thymic hyperplasia, and pathologic CR was confirmed. Data cutoff: April 8, 2016 Chen R et al. June 12, 2016

36 Patient M.M.; 39y Diagnosed 2011 (5 prior therapies) October 2014 February 2015 May 2015

37 HD20 Pilot (NIVAHL) Randomized trial in early unfavorable HL Arm A: Restaging 1 Restaging 2 AVD Cycle 1 AVD Cycle 2 AVD Cycle 3 AVD Cycle 4 AVD D1 PD1 D1 AVD D15 PD1 D15 AVD D1 PD1 D1 AVD D15 PD1 D15 AVD D1 PD1 D1 AVD D15 PD1 D15 AVD D1 PD1 D1 AVD D15 PD1 D15 30Gy IS-RT Screening R PD: biopsy + off-study Restaging 1 AVD Cycle 1 AVD Cycle 2 PD: biopsy + off-study AVD Cycle 3 AVD Cycle 4 Restaging 2 Arm B: PD1 D1 PD1 D15 PD1 D1 PD1 D15 PD: biopsy + off-study AVD D1 PD1 D1 AVD D15 PD1 D15 AVD D1 PD1 D1 AVD D15 PD1 D15 AVD D1 AVD D15 AVD D1 AVD D15 PD: biopsy + off-study 30Gy IS-RT AVD: Adriamycin, Vinblastin, Dacarbazine; PD1: anti-pd1-antibody

38 Hodgkin Lymphom Aktuelle Strategien und Studien First-line Rezidive Anti-PD1 Zusammenfassung

39 Hodgkin Lymphom Zusammenfassung HL ist eine der am besten heilbaren Krebserkrankungen In frühen Stadien 2xABVD+20Gy Mittlere Stadien 2+2 oder 4xABVD+30Gy Sechs Zyklen B.esk in fortgeschrittenen Stadien (5-Jahres FFTF 89.3%, OS 95.3%) Im Rezidiv HDCT und ASCT Brentuximab Vedotin: Konsolidierung bei Risikopatienten nach HDCT; Kombinationen mit Chemo Anti-PD1 MoAk: neuer Wirkmechanismus und Ansprechen unabhängig von gängigen Risikofaktoren Innovative neue Studien in allen Therapielinien

40 German Hodgkin Study Group (GHSG) Chairman: A. Engert Co-Chairman: P. Borchmann Honory Chairman: V. Diehl Pathology: H. Stein Radiotherapy: S. Marnitz, H. Eich Nuclear Medicine: M. Dietlein, C. Kobe Laboratory: E. Pogge v. Strandmann Physicians: K. Behringer, B. Böll, P. Bröckelmann, D. Eichenauer, S. Kreissl, S. Sasse, B. v. Tresckow Trial Coordination Center: Head: M. Fuchs Trial physicians: C. Bürkle, S. Borchmann Data Management: B. Koch, H. Nisters-Backes, H. Ossadnik, A. Rickelt, B. van den Hoonaard Project /Quality Management: S. Domzalski, D. Redweik, D. Siury Database / IT: D. Böhmer, T. Schober, P. Steinhausen, P. Zerhusen Statistics: H. Görgen, H. Haverkamp, H. Müller, A. Plütschow Assistant / Secretary: K. Rust, M. Schumacher, K. Tittmann

41 More Information Thank you for your attention!

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