German Hodgkin Study Group Deutsche Hodgkin Studiengruppe

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1 German Hodgkin Study Group Deutsche Hodgkin Studiengruppe Lugano 2013: HL und T-Zell-Lymphome Zusammenfassung und Ausblick Andreas Engert, MD Chairman, German Hodgkin Study Group University Hospital of Cologne

2 Hodgkin Lymphom und T-NHL Post Lugano 2013 HL first-line Relapsed HL T-NHL Zusammenfassung

3 Freedom from Treatment Failure GHSG HD10 Study Chemotherapy (FFTF) y-FFTF difference -1,9%; 95% CI [-5,2%; 1,4%] p=0, xABVD 2xABVD Time [months] Engert et al NEJM 2010

4 GHSG HD13 Trial Design Early-stage favorable HL 2*ABVD 2*ABV 2*AVD 2*AV 30 Gy IF-RT 30 Gy IF-RT 30 Gy IF-RT 30 Gy IF-RT Arm A Arm B Arm C Arm D Randomization stopped in 02/2006 Randomization stopped in 09/2005

5 Freedom from Treatment Failure HD15 in advanced HL Freedom from Treatment Failure (FFTF) 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 et al, Lancet 2012

6 GELA/EORTC trial in advanced HL Progression Free Survival PFS at 5 yrs was 75 % vs. 93 % (HR = 0.3, p=0.008) N. Mournier, Lugano 2013

7 The GHSG perspective BV in advanced stage HL randomization 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 positiv: Rx PET negative: Follow up

8 Hodgkin Lymphom und T-NHL Post Lugano 2013 HL first-line Relapsed HL T-NHL Zusammenfassung

9 HDR2: European Study for Relapsed Hodgkin Lymphoma* D H A P D H A P B E A M R E G I S T R A T I O N D H A P D H A P R A N D O M I Z A T I O N C T X M T X VP 16 B E A M PBSC *GHSG, EORTC, EBMT, GELTAMO Josting et al, JCO 2010

10 Probability HDR2 Study for Relapsed HL PFS by Treatment Arm (Final Analysis) P = Standard (at 3y: 72%) Intensified (at 3y: 67%) Time, months Josting et al, JCO 2010

11 Rezidiv nach auto-tx Dauer der Remission und OS (n=756) TTR n OS (y) >12 m m m m p < Years Arai et al Leukemia&Lymphoma 2013

12 Immunhistologie von HL Zellen CD30 Färbung Courtesy of H. Stein

13 Konsistente CD30 Expression beim Hodgkin Lymphom Treatment- Naïve HL Prior Transplant R/R HL No Prior Transplant Reed-Sternberg cell CD30 + a b c a Courtesy of A. Engert. b Nathwani N, et al. Leuk Lymphoma Apr 18 [Epub ahead of print]. c Courtesy of Hoffbrand 2010 [personal communication].

14 Brentuximab Vedotin (BV) Mechanism of Action 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 1. Bartlett NL, et al. J Clin Oncol. 2010;28(15S):. Abstract Younes A, et al. Blood. 2008;112: Abstract Senter PD. Curr Opin Chem Biol. 2009;13(3): Brentuximab vedotin is not approved by the EMA or in Spain. Brentuximab vedotin no está aprobada por la EMA o en España.

15 Tumour size (% change from baseline) Phase II of BV in r&r HL Maximum reduction in target lesions 100 reduction per IRF 50 Complete remission by PET 94% (96 of 102) of patients achieved tumour reduction Individual patients (n=98*) Younes et al JCO 2012

16 Most frequent Adverse Events >20% of patients (% of pts) All Grades Grade 3 Grade 4 Peripheral neuropathy 47 9 Fatigue 46 2 Nausea 42 3 Respiratory tract infection 37 Diarrhea 36 1 Pyrexia 29 2 Neutropenia Vomiting 22 Cough 21 Other Grade 3/4 events in 5% of patients: thrombocytopenia (6/2%) and anemia (5/1%) There were no Grade 5 (fatal) events

17 Progression-Free Survival in Month Progression-Free Survival in Month PFS With BV Compared to Previous Regimen r/r HL SG ; N = 102 (per investigator) 62% of patients achieved longer PFS with brentuximab vedotin * ** Patients r/r salcl SG ; N = 58 (per investigator) 66% of patients achieved longer PFS with brentuximab vedotin * ** Data cut-off date: 02Apr2012. *, ** exceeded 60 mo. Patients PFS for last therapy received prior to study entry PFS per investigator on brentuximab vedotin Censored Censored

18 Phase II of BV in r&r HL OS (Med follow-up 27 mo) Data cut-off date: 02Apr2012. Median (95% CI) = NR (27.0-NR) 1-y survival 89% (95% CI, 81-94) 2-y survival 65% (95% CI, 54-73) Millenium, data on file

19 Approval of ADCETRIS (SGN-35; Brentuximab Vedotin) FDA approved ADCETRIS TM for two indications: Relapsed HL after HDCT or 2 prior treatments Relapsed ALCL after 1 prior treatment Seattle Genetics, August 19, 2011

20 Phase II Study of BV in HL OS by PET Status at Cycle 4 Adapted from Chen R, et al. ASH 2012, Atlanta, GA, USA (A3689)

21 PFS (months) +/- 95% CI sv +/- 95% CI Named-patient-program BV The GHSG Experience (PFS and OS) Total Total Total Total Median PFS 8 months OS at 12 months 82% Rothe und Sasse et al, Blood 2012

22 Named-patient-program (BV) Patienten ohne HDCT vor SGN-35 Insgesamt 16 pts (14 HL, 2 ALCL) Alter Jahre (4 pt >70) 12/16 primärer refraktär; 4 Comorbidität 2-6 Vortherapien; 13/16 refraktär vor SGN-35 Ansprechen 11/16 (6 CR) HDCT in 6 Patienten (4 auto; 1x auto+allo; 1x allo) Median PFS nach BV 9m; median OS nicht erreicht

23 Brentuximab vedotin (SGN-35) Ongoing clinical trials Agent(s) Trial identifier Phase Condition Status SGN-35 AETHERA III Residual HL following autologous stem-cell transplant SGN-35 SGN35-010* II/III Patients with progression of HL or ALCL SGN-35 SGN II Patients who have previously participated in an SGN-35 study Enrolled Enrolling Enrolling SGN-35 + ABVD SGN I Hodgkin lymphoma Enrolled *SGN-010 is a companion trial to AETHERA **SGN is only open in US and Canada

24 Neu Antikörper und Moleküle Klinische Studien der GHSG beim HL SGN35 (ADCETRIS TM ; anti-cd30) AFM13 (CD16/CD30 bispecific) Lenalidomide (IMID) RAD001 (mtor-inhibitor) Ofatumumab (anti-cd20) Resminostat (H-Dac Inhibitor) 4SC-202 (H-Dac Inhibitor) c-fms inhibitor Others (JAK2 inhibitor, Btk inhibitor)

25 Variety of Antibody Formats Affimed, Germany Ad IgG antibody Generates a Broad Variety Ag of Antibody Formats Fab C H 2 C L C H 1 V L VH Ag scfv Ag V H Diabody Ag V H V H Ag V H V H V H V H Ag Ag TandAb Ag Ag Fc C H 3 Fab V L Ag Ag V H Flexibody Ag C L C H 1 V H V L V L Ag Ag V H Antibody IgG Fab scfv (scfv) 2 Diabody TandAb Flexibody Natural antibodies Recombinant antibodies comprising variable domains Valence mono / bi mono mono bi bi tetra tetra Mol.Weight 159 kda 60 kda 29 kda 58 kda 50 kda 105 kda 115 kda

26 AFM Study Activity of AFM13 expressed as reduction in SPD >50% of patients showed stabilization or reduction in tumor volume

27 Hodgkin Lymphom und T-NHL Post Lugano 2013 HL first-line Relapsed HL T-NHL Zusammenfassung

28 Behandlung des PTCL DSHNHL A

29 Relapsed and refractory PTCL Novel agents Pralatrexat Bendamustin O Connor et al., JCO 2011; 29 (9); Damaj et al. J Clin Oncol 2013; 31: Romidepsin Lenalidomid Lenalidomid Coiffier et al., JCO 2012; 30; Morschauser et al., EJC 2013; 49;

30 PTCL: targets of treatment kinase inhibitor anti-cd52 anti-cd4 anti-cd30 denileukin diftitox HDAC-I Pralatrexat Bendamustin Gemcitabine mtor I Graft v. Lymphoma Bortezomib IMID

31 Tumour size (% change from baseline) Phase II of BV in r&r ALCL Maximum reduction in target lesions 100 reduction per IRF % of patients achieved tumour reduction 88% OR (59% CR) Complete remission by PET 0 97% of patients achieved tumour reduction Individual patients (n=58*) Pro et al JCO 2012

32 Hodgkin Lymphom und T-NHL Post Lugano 2013 HL first-line Relapsed HL T-NHL Zusammenfassung

33 HL und T-NHL Lugano 2013 Zusammenfassung HL eines der best heilbaren malignen Erkrankungen; Spätschäden nach erfolgreicher Therapie In frühen Stadien 2xABVD+20Gy IFRT (HD10); mittlere Stadien 2+2 und IFRT oder 4xABVD+30Gy 6xB.esc Standard für fortgeschrittene Stadien; PET definierte RT Hochdosis und autologe Transplantation im Rezidiv T-NHL: CHOEP und HDCT <60; allo TX in Studien Zahlreiche neue Substanzen BV bei CD30+ Lymphomen effektiv; hohe Effektivität und gute Verträglichkeit; zugelassen für r/r HL und ALCL (Adcetris ) Behandlung innerhalb klinischer Studien!

34 More Information Thank you for your attention!

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