Targeted therapy for Hodgkin’s Lymphoma

1. Targeted therapy for Hodgkin’s Lymphoma Larry W. Kwak, M.D., Ph.D. Chairman, Department of Lymphoma/Myeloma Justin Distinguished Chair in Leukemia Research Co-Director, Center for Cancer Immunology Research MD Anderson Cancer Center

2. Goals of Ongoing Research • Improve remission rates and decrease risk of death • Minimize side effects and maintain or prolong remissions • Develop additional therapeutic options for relapsed/refractory disease (e.g. post-SCT)

3. Development of (Deacetylase inhibitors) DACi in Hodgkin lymphoma • Dual antiproliferative activity: • Induction of cell cycle arrest and apoptosis (direct) • Downregulation of TARC/CCL17 and alteration of the microenvironment (indirect) TH DC OX40L C Ligation of OX40 receptor (on T cells) inhibits the induction of Treg cells Vorinostat/SAHA MGCD0103 B Treg A SOCS IL13 STAT6 JAK1/3 TARC Chemotaxix of TH2 cells TH2 Bcl-xL TH2 TH2 Hodgkin’s Reed-Sternberg cell Buglio et al, BLOOD 2008 Survival

4. Oral HDAC Inhibitor Mocetinostat (MGCD0103) Clinical Activity in Hodgkin Lymphoma Baseline 2 months 31 year old female Extensive Prior Therapy Regimen Best Response ABVD PR XRT Not Eval DHAP PR Auto Transplant Not Eval IGEV Progression DHAP Progression Fludarabine/ Melphalan Progression Allo Transplant Progression Donor lymphocyte Progression MOPP Not Eval ESHAP Progression IEV Progression PET Single-arm Phase II study (n=51) R21 “quick trials” grant Younes et al, Lancet Oncology 2011

5. DACi in Hodgkin lymphomaEarly decline in plasma TARC Levels correlates with clinical response R2=0.40 2 1.8 1.6 1.4 1.2 Ratio of tumor change 1 0.8 0.6 0.4 0.2 0 0.00 0.20 0.40 0.60 0.80 1.00 1.20 1.40 1.60 1.80 Ratio of TARC change Younes et al, Lancet Oncology 2011

6. International oral Panobinostat (pan-HDACi) Phase II Study in HL 71% of patients with tumor reduction Younes A, et al. JCO 2012

7. Efficacy of Unconjugated Anti-CD30 Antibodies in CD30 Positive Lymphomas

8. Brentuximab Vedotin: Mechanism of Action Brentuximab vedotin (SGN-35) ADC monomethyl auristatin E (MMAE), microtubule disrupting agent protease-cleavable linker anti-CD30 monoclonal antibody ADC binds to CD30 ADC-CD30 complex is internalized and traffics to lysosome MMAE is released G2/M cellcycle arrest MMAE disruptsmicrotubule network Apoptosis

9. Brentuximab Vedotin: Phase I Results • Every 3 wk treatment 45 pts (42 HL, 2 ALCL, 1 AITCL) 73% prior ASCT Doses 0.1 to 3.6 mg/kg every 3 wks MTD 1.8 mg/kg 86% tumor regression, 38% ORR, 24% CR Peripheral sensory neuropathy: ≥ grade 1 in 36% • Weekly treatment 44 pts (38 HL, 5 ALCL, 1 PTCL-NOS) 68% prior ASCT Doses of 0.4 to 1.4 mg/kg on D1, 8, 15 of 28-day cycle MTD 1.2 mg/kg 85% tumor regression, 58% ORR, 34% CR Peripheral sensory neuropathy: ≥ grade 1 in 66% Younes A et al, NEJM, 2010; Fanale, M et al, CCR, 2011

10. Maximum Reduction in Target Lesions 81% of patients achieved tumor reductions Bartlett et al. JCO 27: 434s, 2009 (abst 8500).

11. Demographics and Baseline Characteristics in Pivotal HL Trial Younes , A et al, ICML, 2011

12. Conclusions from Pivotal HL Trial • Multiple durable CRs obtained with brentuximab vedotinin highly treatment-refractory patients with HL • Similar duration of remissions with or without allogeneic transplant • Manageable adverse events; peripheral neuropathylargely reversible • 55% of patients had at least 1 event of peripheral neuropathy • No grade 4 events of peripheral neuropathy • Resolution or some improvement of PN : 80% at 13.2 weeks Younes, A et al, ICML, 2011

13. Introduction of Targeted Therapies into Front-line

14. Rationale • Treatment-naïve patients with Hodgkin lymphoma (HL) are commonly treated with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD)1 • Frontline therapy with ABVD generally yields a 70% to 80% CR rate2,3 • Bleomycin-induced pulmonary toxicity occurs in 10% to 25% of patients receiving this regimen4 • Single-agent brentuximab vedotin (ADCETRIS®) in relapsed or refractory HL patients has shown an objective response rate of 75% (CR, 33%) with manageable toxicity5 • Connors et al, 2005 • Gordon et al, presented at ASH 2010 • Gallamini et al, 2007 4 Horning et al, 1994 5 Smith et al, presented at EHA 2012

15. Study Design • Phase 1, multicenter, dose-escalation study • Major eligibility criteria • Treatment-naïve HL patients • Age ≥18 to ≤60 years • Stage IIA bulky disease or Stage IIB-IV disease • Treatment design • 28-day cycles (up to 6 cycles) with dosing on Days 1 and 15 Cycle 3 Cycle 1 Cycle 2 Brentuximab Vedotin A(B)VD 6 Cycles +/- XRT 0 2 4 6 8 10 12 Weeks Ansell S. et al. ASH 2012

16. Key Study Objectives • To assess the safety profile of brentuximab vedotin in combination with ABVD and in combination with AVD • To determine the maximum tolerated dose (MTD), if reached, of brentuximab vedotin in combination with ABVD and in combination with AVD • To assess the antitumor activity of brentuximab vedotin in combination with ABVD and in combination with AVD

17. Description of Dose Cohorts

18. Demographics and Baseline Characteristics a Median (range)

19. Summary of Adverse Events ≥Grade 3 * Grade 3 or higher adverse events (AEs) occurring in more than 1 patient overall, regardless of relationship

20. Pulmonary Toxicity • Events generally occurred during Cycles 34 • Two patient deaths were associated with pulmonary toxicity • Events resolved in 9 of 11 patients (82%) • Median time to resolution was 2.6 weeks (range, 1.6 to 5 weeks) • 8 of 11 patients with events discontinued bleomycin and were able to complete treatment with AVD combined with brentuximab vedotin

21. Peripheral Neuropathy * Summary of events using a standard MedDRA query (SMQ), regardless of relationship or severity • Events were managed with dose modifications • Most events were Grade 1 or 2 and no events were Grade 4 or 5 • One patient experienced Grade 3 events of peripheral sensory neuropathy (fingers and toes) and peripheral motor neuropathy (hands and feet) • Overall, 6 of 51 patients discontinued brentuximab vedotin due to peripheral neuropathy; these discontinuations occurred in Cycles 5 or 6

22. Maximum Dose and Dose-Limiting Toxicities • Dose-limiting toxicities (DLTs) were defined as any Cycle1 toxicity requiring a dose delay ≥7 days in standard ABVD or AVD therapy • No protocol-defined DLTs observed with either ABVD or AVD in combination with up to 1.2 mg/kg brentuximab vedotin (the maximum planned dose) • A 1.2 mg/kg dose of brentuximab vedotin administered every 2 weeks is expected to achieve the same exposure (AUC) as the approved single-agent dose of 1.8 mg/kg every 3 weeks

23. Response Results at End of Frontline Therapy a Assessed using Cheson 2007 b Patient had a Grade 5 event of pulmonary toxicity prior to the end of frontline therapy • Response results at end of frontline therapy: • ABVD cohorts: 21 of 22 CR (95%) • AVD cohorts: 24 of 25 CR (96%) • In addition, 1 patient withdrew consent and 3 patients were lost to follow-up prior to completion of frontline therapy and were not evaluable for response

24. Conclusions • Concomitant administration of brentuximab vedotin and bleomycin is contraindicated due to pulmonary toxicity • Recommended regimen is 1.2 mg/kg brentuximab vedotin every 2 weeks combined with AVD • AVD combined with brentuximab vedotin appears to be well tolerated with manageable AEs • CR rate of 96% observed at the end of frontline therapy with brentuximab vedotin combined with AVD • Phase 3 study ongoing to assess treatment with brentuximab vedotin in combination with AVD as compared to ABVD alone in treatment-naive patients

25. Department of Lymphoma/Myeloma Disease –specific Working Groups Larry W. Kwak, M.D., Ph.D. Chairman, Lymphoma/Myeloma Michael Wang, M.D. Nathan Fowler, M.D. Co-Directors Lymphoma Clinical Research Robert Orlowski, M.D., Ph.D. Director Myeloma Clinical Research Multiple myeloma Low Grade lymphoma T cell lymphoma Large Cell lymphoma Mantle cell lymphoma Hodgkins Phase I D. Weber J. Shah S. Thomas M. Wang R. Alexanian Q. Yi L. Fayad A. Rodriguez F. Hagemeister J. Westin M. Wang J. Romaguera M. Fanale F. Hage- meister N. Fowler F. Samaniego S. Neelapu L. Fayad L. Kwak M. Fanale N. Fowler J. Shah J. Westin Y. Oki M. Fanale Burkitt HIV Brain Testicular M. Fanale N. Fowler

27. Rituximab plus ABVD Rituximab weekly x 6 plus ABVD x 6 70 patients with stage II to IV disease Median age 28 yo IPS ≥ 3 in 55% Protocol modified to include just IPS ≥ 3 based of initial results Median f/u 32 months: EFS 85% & OS 98% 78% of pts PET-2/3 negative 5-year EFS for PET-negative vs positive of 93% vs 75% Improvement in EFS with R-ABVD compared to institutional ABVD outcomes R-ABVD with IPS of 0-2 (89% vs 71%) and IPS ≥ 3 (80% vs 55%) Copeland, A et al, ASH, 2010

28. R-ABVD for Advanced HL: Improvement in FFS Related to PET • Newer therapies are needed for HL with Pos PET • Early pos PET after 2 ABVD predicts 100% relapse • R-ABVD appears to give better results for high risk patients with HL • In this prospective study, 55 patients with HL had a PET after 2-3 R-ABVD: Therapy was not changed in these patients based on the PET findings • Results: PET Neg PET Pos p Patients (%) 43 (78) 12 (22) 5 Yr EFS 93% 75% 0.05 • R-ABVD may be a better regimen than ABVD because PET positive patients have better results Hutchings et al. Blood 107:52-59, 2006. Wedgwood et al. Submitted to ASH 2007.

29. 1.0 1.0 .08 .08 .06 .06 .04 .04 .02 .02 0.0 0.0 0 0 1 1 2 2 3 3 PET vs CT for Stage I-IV HL: PFS Results by Radiographic Assessment after 2 CT Cycles CT after 2 cycles PET after 2 cycles CR, PR 2 Pts, 0 prog 2 yr PFS 100% PET neg 61 Pts, 3 prog 2 yr PFS 96% < PR 62 Pts, 11 prog 2 yr PFS 82% Percent Progression-Free PercentProgression-Free FDG-PET positive 16 Patients, prog=11 2-year PFS 0% PET ps 14 Pts, 11 prog 2 yr PFS 0% P < .554 P < .001 Years Years Hutchings et al. Blood 107:52-59, 2006

30. 100 75 50 25 0 0 12 24 36 48 60 R-ABVD for Advanced HD: EFS by IPS Score Compared with IPS Curves EFS for IPS EFS for R-ABVD 100 80 60 Percent Event-Free Score 0-1 Score 0-2 Score 2 Score >2 Score >3 Score >4 Score, 0 Score, 1 Score, 2 Score, 3 Score, 4 Score, ≥5 40 20 0 0 12 24 36 48 60 72 84 Months Months Hasencleaver and Diehl. NEJM 339: 1506-1514,1998. Younes et al. Blood 106:431a, 2005 (abst 1499).

31. GHSG HD18 Trial for Advanced HL: Study Design 2 x BEACOPP escalated POS PET NEG PET 6xBEACOPPesc 6xR-BEACOPPesc 6xBEACOPPesc 2xBEACOPPesc At End of Therapy: POS PET: RT to Res Nodes >2.5 cm NEG PET: NO RT