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Brentuximab Vedotin. How and When Should it be Used in B and T cell Lymphomas Ranjana Advani MD Professor of Medicine Saul Rosenberg Professor of Lymphoma.

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Presentation on theme: "Brentuximab Vedotin. How and When Should it be Used in B and T cell Lymphomas Ranjana Advani MD Professor of Medicine Saul Rosenberg Professor of Lymphoma."— Presentation transcript:

1 Brentuximab Vedotin. How and When Should it be Used in B and T cell Lymphomas Ranjana Advani MD Professor of Medicine Saul Rosenberg Professor of Lymphoma Stanford University Lymphoma and Myeloma 2014 International Congress on Hematologic Malignancies New York

2 Disclosures Seattle Genetics: Research Funding

3 Brentuximab vedotin antibody-drug conjugate (ADC) Monomethyl auristatin E (MMAE), microtubule-disrupting agent Protease-cleavable linker Anti-CD30 monoclonal antibody ADC binds to CD30 MMAE disrupts microtubule network ADC-CD30 complex is internalized and traffics to lysosome MMAE is released Apoptosis G2/M cell cycle arrest Brentuximab Vedotin CD-30

4 Brentuximab Vedotin Approved Indications Treatment of patients with Hodgkin Lymphoma (HL) after failure of autologous stem cell transplant (ASCT) or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not ASCT candidates Treatment of patients with systemic Anaplastic Large Cell Lymphoma (ALCL) after failure of at least one prior multi-agent chemotherapy regimen

5 Outline Past – Key data of two pivotal trials which led to approval Present – Emerging data of subset experiences from phase 1 and pivotal trials – Phase 2 trials in other CD 30 + PTCL and DLBCL setting Future – Combination with standard chemotherapy to improve cure in front line in HL and CD30 pos PTCL B cell Lymphoma: Hodgkin Lymphoma and other B NHL T cell lymphoma: PTCL

6 Past Key data of two pivotal trials which led to approval

7 Phase II Pivotal trial in relapsed HL All ASCT failures Toxicity > Gr 3: ANC 20%, sensory neuropathy 8% thrombocytopenia 6% Individual Patients (n=98)* Tumor Size (% Change from Baseline) 94% (96 of 102) of patients achieved tumor reduction Younes et al JCO 2012 Med age 31 y, 71% refractory to front line, 66% prior RT ORR 75% (32% CR)

8 Phase 2 Relapsed or Refractory HL Pivotal Trial Outcomes According to Best Response Younes et al JCO 2012 Progression Free SurvivalOverall Survival

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10 Phase 2 Relapsed or Refractory HL Pivotal Trial PFS in Patients with CR by Subsequent Transplant Patients Who Achieved a CRNEvents Median PFS (95% CI) Median Number of Cycles Received Allogeneic transplant ( ,  ) 14 No transplant (9.7,  ) 13 Subsequent transplant did not appear to meaningfully impact PFS in this small dataset Younes et al JCO 2012

11 Relapsed or Refractory Systemic ALCL Trial Maximum Tumor Reduction Pro B, et al. JCO % of patients achieved tumor reduction ORR 86% (57% CR) 72% ALK neg, 62% refractory to front line rx, 22 % prim refr, 26 % prior SCT

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13 Outcomes according to response and ALK status Pro B, et al. JCO 2012

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15 Summary of “Past” High response rate in HL relapsed after ASCT High response rate in R/R ALCL More CRs in ALCL In pts with a CR durable responses Neuropathy

16 Present Retreatment strategy Response in chemo refractory transplant naive pts Can pts get an allogenic consolidation after responding to brentuximab Response in pts relapsing after an allogenic transplant Experience in elderly pts Experience in other CD 30 + PTCL Experience in CD 30+ DLBCL

17 Retreatment with Brentuximab Vedotin Bartlett, et al. J Hematol Oncol N = 21 (HL), 8 (ALCL), 48% grade 3 neuropathy manageable with dose delay/reduction ORR 68%, CR: 39%

18 Retreatment with Brentuximab Vedotin Median DOR 9.5 months Bartlett, et al. J Hematol Oncol CR patients: 45% > 1yr duration Overall SurvivalProgression Free Survival

19 Brentuximab Vedotin Retreatment Humala and Younes, Hematologica 2012

20 Response in Transplant Naïve pts with R/R HL Analysis of 2 Phase 1 studies Forero-Torres The Oncologist /6 responders subsequent transplant N=20, median 3 prior regimens, 45% prior RT

21 Consolidative Allogeneic Transplant Following Brentuximab Vedotin in Patients with R/R HL and Systemic ALCL from two pivotal trials Illidge et al Leuk Lymphoma 2014 Progression Free SurvivalOverall Survival 2 yr estimated 66%2 yr estimated 80%

22 Brentuximab vedotin for HL recurring after allogeneic stem cell transplantation. Gopal A K et al. Blood 2012

23 Reduced Intensity Allogeneic Transplantation for HL Pre and post brentuximab era Chen, et al. Biol Blood Marrow Transplant y 59.3 % vs 26% 2y 56.5% vs 23.8% 2y 71 % vs 56.5% 1y 9.5 % vs 17.4%

24 Experience of Brentuximab Vedotin in pts > 60 Gopal, et al. Leukemia & Lymphoma 2014

25 Single Agent Brentuximab Vedotin Frontline Therapy for HL in pts > 60 y N=19 Antitumor activity: 89% efficacy-evaluable patients achieved objective response – CR: 12 patients – PR: 5 patients – 2 patients had maximal response of SD Tumor reduction achieved in 100% of patients Grade 3 neuropathy n=1 Yasenchak A, et al. ASH Abstract % of patients achieved tumor reduction Individual Patients (n = 19) Tumor Size (Best % Change From Baseline) CR *

26 Response in other CD 30 positive PTCL Objective responses in relapsed PTCL with single-agent brentuximab vedotin Horwitz S M et al. Blood 2014

27 Outcome by histology and CD30 expression Horwitz S M et al. Blood 2014

28 B-Cell Lymphomas Variable CD30 expression observed in B-cell lymphomas – ~14–25% of DLBCL express CD30 a,b – Potentially favorable prognostic factor and unique gene expression profile in newly diagnosed DLBCL a Relapsed or refractory DLBCL patients have a poor outcome c Autologous transplant of limited efficacy in rituximab era with 3-year EFS of 21% c No standard of care for transplant- ineligible patients Overall survival in DLBCL patients failing second-line therapy a Hu et al, Blood 121: ; 2013 b Slack et al, ASH Annual Meeting Abstracts 120:1558; 2012 c Gisselbrecht et al, J Clin Oncol 28: ; 2010 Median OS ≈ 4 months Reprinted from Clin Lymph Myel Leuk, 10; 192, RL Elstrom, et al, (2010) with permission from Elsevier.

29 A Phase 2 Study of Brentuximab Vedotin in Patients with Relapsed or Refractory CD30-Positive B NHL Eligibility Criteria Relapsed/refractory disease after ≥1 prior systemic therapy CD30 expression by IHC using the anti-CD30 BerH2 antibody Age ≥12 years ECOG ≤2 or Lansky ≥50 Pretreatment Study Treatment End of Treatment Follow-up 21-Day Cycles Brentuximab vedotin 1.8 mg/kg IV Restage Dosing on Day 1 (q3wk until disease progression or unacceptable toxicity) Screening/ Enrollment 28 Days Every 3 months for first 2 years After Cycles 2, 4, every 3 cycles thereafter, and at EOT

30 Pathological Diagnoses: N=68 Total N (%) DLBCL 50 (74) DLBCL-NOS43 (63) EBV+ DLBCL of the elderly5 (7) Plasmablastic lymphoma1 (1) T-cell-rich B-cell lymphoma1 (1) Other B-cell lymphomas 18 (26) Grey zone lymphoma6 (9) Primary mediastinal B-cell lymphoma (PMBL)6 (9) Follicular lymphoma3 (4) Post-transplant lymphoproliferative disorder (PTLD)3 (4) Bartlett NL, et al. ASH 2013, Abstract 848

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34 Summary of “Present” Responses seen at re-treatment Responses seen in primary refractory transplant naïve pts Responses seen in pts who have failed allogenic transplant Allows for consolidative allogenic transplant Well tolerated by elderly (> 60 yr) pts Responses seen in AITL Responses seen in DLBCL Response does not correlate with CD30 expression

35 Brentuximab Vedotin in Malignant Lymphoma Kumar et al Current Treatment Options in Oncology (2014)

36 Future Combination with standard chemotherapy to improve cure in front line in HL and CD30 positive PTCL

37 SGN-35 + chemotherapy Preclinical models Oflazoglu et al BJH 2010

38 Major Eligibility – Treatment-naive HL patients – Age ≥18 to  60 years – Stage IIAX or Stage IIb-IV disease Treatment Design – 28-day cycles (6 cycles) with dosing on Days 1 and 15 A(B)VD Brentuximab Vedotin Cycle 1 Cycle 2 Cycle 3 6 Cycles +/- XRT Weeks Frontline Therapy with Brentuximab Vedotin Combined with ABVD or AVD in Pts with Newly Diagnosed Advanced Stage HL BV: 1.2 mg/kg IV q 2 weeks Younes, et al. Lancet Oncology 2013.

39 Preferred term, n (%) ABVD with brentuximab vedotin N=25 AVD with brentuximab vedotin N=26 Any event11 (44)0 Pulmonary toxicity9 (36)0 Interstitial lung disease1 (4)0 Pneumonitis1 (4)0 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 Younes, et al. Lancet Oncology 2013.

40 Outcomes Younes, et al. Lancet Oncology 2013.

41 Fanale M A et al. JCO 2014 Brentuximab Vedotin Administered Concurrently or Sequentially with Multi-Agent Chemotherapy as Frontline Treatment of ALCL and other CD30-Positive Mature T-Cell and NK-Cell Lymphomas

42 Demographics and Baseline Characteristics Parameter Total N=26 Age*, years56 (21–82) Gender, n11 M / 15 F IPI score  2, n (%) 17 (65) Stage III/IV disease, n (%)18 (69) Diagnosis sALCL, n (%)19 (73) ALK – / +, n16 / 3 Other CD30+ T- and NK-cell neoplasms, n (%)7 (27) Peripheral T-cell lymphoma NOS, n2 Angioimmunoblastic T-cell lymphoma, n2 Adult T-cell leukemia/lymphoma, n2 Enteropathy-associated T-cell lymphoma, n1 * Median (range) Fanale M A et al. JCO 2014

43 Response After Sequential or Combination Treatment Fanale M A et al. JCO 2014

44 Outcomes Combination Treatment Sequential Treatment Fanale M A et al. JCO 2014

45 Adapted from Senter and Sievers: Nature Biotechnology years7 years

46 Major Progress (3 yrs) Phase 3 ATHERA trial: Randomized placebo-controlled, post- autologous stem cell transplant maintenance – Press Release 9/26/14 in favor of maintenance arm Phase 3 ECHELON-1 frontline Hodgkin lymphoma in combination with chemotherapy – ABVD vs AVD+BV Phase 3 ECHELON-2 frontline CD30-positive mature T-cell lymphomas in combination with chemotherapy – CHOP vs CHP+BV Phase 3 ALCANZA trial for relapsed CD30-positive cutaneous T-cell lymphoma

47 First line salvage (pre ASCT) – Brentuximab Vedotin x 2 +/- ICE using a PET adapted strategy – Bendamustine + Brentuximab Vedotin Brentuximab Vedotin Ongoing trials in relapsed HL

48 Challenges Need further understanding of mechanism of action – Does activity correlate with target expression – Defining level of target expression which correlates with response Neuropathy is real – Education of physicians and pts imp so that timely dose adjustments can be made With the long PFS for patients achieving CR paradigms of care are being challenged – Role of transplant How is BV best used – Front line Combination with other targeted agents? Combination with chemotherapy? Maintenance for pts with high risk disease? – Relapse disease Single agent vs. combination


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