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Lymphoma and Myeloma 2014 International Congress on Hematologic Malignancies New York Brentuximab Vedotin. How and When Should it be Used in B and T cell.

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Presentation on theme: "Lymphoma and Myeloma 2014 International Congress on Hematologic Malignancies New York Brentuximab Vedotin. How and When Should it be Used in B and T cell."— Presentation transcript:

1 Lymphoma and Myeloma 2014 International Congress on Hematologic Malignancies New York 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

2 Disclosures Seattle Genetics: Research Funding

3 Brentuximab Vedotin Brentuximab vedotin antibody-drug conjugate (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 CD-30 MMAE is released G2/M cell cycle arrest MMAE disrupts microtubule network Apoptosis

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

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

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10 Median Number of Cycles Received
Phase 2 Relapsed or Refractory HL Pivotal Trial PFS in Patients with CR by Subsequent Transplant Patients Who Achieved a CR N Events Median PFS (95% CI) Median Number of Cycles Received Allogeneic transplant 5 1 21.1 (,) 14 No transplant 30 13 21.7 (9.7, ) 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
72% ALK neg, 62% refractory to front line rx, 22 % prim refr, 26 % prior SCT 97% of patients achieved tumor reduction ORR 86% (57% CR) Pro B, et al. JCO 2012 11

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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
N = 21 (HL), 8 (ALCL), 48% grade 3 neuropathy manageable with dose delay/reduction ORR 68%, CR: 39% Bartlett, et al. J Hematol Oncol 2014.

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

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
N=20, median 3 prior regimens, 45% prior RT 3/6 responders subsequent transplant Forero-Torres The Oncologist 2012

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

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
2y 71 % vs 56.5% 2y 59.3 % vs 26% 2y 56.5% vs 23.8% 1y 9.5 % vs 17.4% Chen, et al. Biol Blood Marrow Transplant. 2014

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
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=1 100 50 100% of patients achieved tumor reduction Tumor Size (Best % Change From Baseline) -50 CR CR CR CR CR CR CR CR CR CR -100 CR CR * Individual Patients (n = 19) Yasenchak A, et al. ASH Abstract 4389.

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 Overall survival in DLBCL patients failing second-line therapy
B-Cell Lymphomas Variable CD30 expression observed in B-cell lymphomas ~14–25% of DLBCL express CD30a,b Potentially favorable prognostic factor and unique gene expression profile in newly diagnosed DLBCLa Relapsed or refractory DLBCL patients have a poor outcomec 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 Median OS ≈ 4 months Reprinted from Clin Lymph Myel Leuk, 10; 192, RL Elstrom, et al, (2010) with permission from Elsevier. 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

29 A Phase 2 Study of Brentuximab Vedotin in Patients with Relapsed or Refractory CD30-Positive B NHL
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 Eligibility Criteria Pretreatment Study Treatment Follow-up Screening/ Enrollment 28 Days 21-Day Cycles Brentuximab vedotin 1.8 mg/kg IV End of Treatment Every 3 months for first 2 years Restage Dosing on Day 1 (q3wk until disease progression or unacceptable toxicity) After Cycles 2, 4, every 3 cycles thereafter, and at EOT

30 Pathological Diagnoses: N=68
Total N (%) DLBCL 50 (74) DLBCL-NOS 43 (63) EBV+ DLBCL of the elderly 5 (7) Plasmablastic lymphoma 1 (1) T-cell-rich B-cell lymphoma Other B-cell lymphomas 18 (26) Grey zone lymphoma 6 (9) Primary mediastinal B-cell lymphoma (PMBL) Follicular lymphoma 3 (4) Post-transplant lymphoproliferative disorder (PTLD) Bartlett NL, et al. ASH 2013, Abstract 848

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33 Due to rounding, some columns do not add to 100% exactly.
One DLBCL patient with % CD30 expression is missing response assessment, so n’s don’t add 30 and percentages do not add to 100% in that column. (Pt )

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 Frontline Therapy with Brentuximab Vedotin Combined with ABVD or AVD in Pts with Newly Diagnosed Advanced Stage HL 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 Cycle 1 Cycle 2 Cycle 3 BV: 1.2 mg/kg IV q 2 weeks Brentuximab Vedotin A(B)VD 6 Cycles +/- XRT 2 4 6 8 10 12 Weeks Younes, et al. Lancet Oncology

39 Pulmonary Toxicity Events generally occurred during Cycles 34
Preferred term, n (%) ABVD with brentuximab vedotin N=25 AVD with brentuximab vedotin N=26 Any event 11 (44) Pulmonary toxicity 9 (36) Interstitial lung disease 1 (4) Pneumonitis 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

40 Outcomes Younes, et al. Lancet Oncology

41 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 Fanale M A et al. JCO 2014

42 Demographics and Baseline Characteristics
Parameter Total N=26 Age* , years 56 (21–82) Gender, n 11 M / 15 F IPI score 2, n (%) 17 (65) Stage III/IV disease, n (%) 18 (69) Diagnosis sALCL, n (%) 19 (73) ALK – / +, n 16 / 3 Other CD30+ T- and NK-cell neoplasms, n (%) 7 (27) Peripheral T-cell lymphoma NOS, n 2 Angioimmunoblastic T-cell lymphoma, n Adult T-cell leukemia/lymphoma, n Enteropathy-associated T-cell lymphoma, n 1 * 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 Sequential Treatment Combination Treatment
Fanale M A et al. JCO 2014

45 7 years 5 years Adapted from Senter and Sievers: Nature Biotechnology 2012

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

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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