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Brentuximab Vedotin. How and When Should it be Used in B and T cell Lymphomas

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. Disclosures.

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Brentuximab Vedotin. How and When Should it be Used in B and T cell Lymphomas

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  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 RanjanaAdvani MD Professor of Medicine Saul Rosenberg Professor of Lymphoma Stanford University

  2. Disclosures • Seattle Genetics: Research Funding

  3. BrentuximabVedotin Brentuximabvedotin antibody-drug conjugate (ADC) Monomethylauristatin E (MMAE), microtubule-disrupting agent Protease-cleavable linker Anti-CD30 monoclonal antibody ADC binds to CD30 CD-30 ADC-CD30 complex is internalized and traffics to lysosome MMAE is released G2/M cell cycle arrest MMAE disruptsmicrotubule 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 • 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. PastKey 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

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

  9. Phase 2 Relapsed or Refractory HL Pivotal Trial PFS in Patients with CR by Subsequent Transplant • Subsequent transplant did not appear to meaningfully impact PFS in this small dataset Younes et al JCO 2012

  10. 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. JCO2012

  11. Outcomes according to response and ALK status Pro B, et al. JCO2012

  12. 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

  13. 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 allogenictransplant • Experience in elderly pts • Experience in other CD 30 + PTCL • Experience in CD 30+ DLBCL

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

  15. Retreatment with BrentuximabVedotinMedian DOR 9.5 months Progression Free Survival Overall Survival CR patients: 45% > 1yr duration • Bartlett, et al. J HematolOncol2014.

  16. BrentuximabVedotin Retreatment Humala and Younes, Hematologica 2012

  17. Response in Transplant Naïve pts with R/R HLAnalysis of 2 Phase 1 studies N=20, median 3 prior regimens, 45% prior RT 3/6 responders subsequent transplant Forero-Torres The Oncologist 2012

  18. Consolidative Allogeneic Transplant Following BrentuximabVedotin 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 LeukLymphoma 2014

  19. Brentuximabvedotin for HL recurring after allogeneic stem cell transplantation . Gopal A K et al. Blood 2012

  20. Reduced Intensity Allogeneic Transplantation for HLPre 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

  21. Experience of BrentuximabVedotin in pts > 60 • Gopal, et al. Leukemia & Lymphoma 2014

  22. Single Agent BrentuximabVedotin 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=1 100 50 100% of patients achieved tumor reduction Tumor Size(Best % Change From Baseline) 0 -50 CR CR CR CR CR CR CR CR CR CR CR CR -100 * Individual Patients (n = 19) Yasenchak A, et al. ASH 2013. Abstract 4389.

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

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

  25. B-Cell Lymphomas Overall survival in DLBCL patients failing second-line therapy • 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 Median OS ≈ 4 months Reprinted from Clin Lymph MyelLeuk, 10; 192, RL Elstrom, et al, (2010) with permission from Elsevier. a Hu et al, Blood 121:2715-2724; 2013 b Slack et al, ASH Annual Meeting Abstracts 120:1558; 2012 c Gisselbrecht et al, J ClinOncol28:4184-4190; 2010

  26. A Phase 2 Study of BrentuximabVedotin 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 Study Treatment Pretreatment Follow-up 21-Day CyclesBrentuximab vedotin 1.8 mg/kg IV Screening/Enrollment28 Days End of Treatment Every 3 months for first 2 years Restage Dosing on Day 1 (q3wk until disease progressionor unacceptable toxicity) After Cycles 2, 4, every 3 cycles thereafter, and at EOT

  27. Pathological Diagnoses: N=68 • Bartlett NL, et al. ASH 2013,Abstract 848

  28. 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

  29. BrentuximabVedotin in Malignant Lymphoma Kumar et al Current Treatment Options in Oncology (2014)

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

  31. SGN-35 + chemotherapyPreclinical models Oflazoglu et al BJH 2010

  32. 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 Frontline Therapy with BrentuximabVedotin Combined with ABVD or AVD in Pts with Newly Diagnosed Advanced Stage HL Cycle 3 Cycle 1 Cycle 2 BV: 1.2 mg/kg IV q 2 weeks Brentuximab Vedotin A(B)VD 6 Cycles +/- XRT 0 2 4 6 8 10 12 Weeks • Younes, et al. Lancet Oncology 2013.

  33. 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 brentuximabvedotin • Younes, et al. Lancet Oncology 2013.

  34. Outcomes • Younes, et al. Lancet Oncology 2013.

  35. BrentuximabVedotin 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

  36. Demographics and Baseline Characteristics * Median (range) Fanale M A et al. JCO 2014

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

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

  39. 7 years 5 years Adapted from Senterand Sievers: Nature Biotechnology 2012

  40. Major Progress2011-2014 (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

  41. BrentuximabVedotinOngoing trials in relapsed HL • First line salvage (pre ASCT) • BrentuximabVedotin x 2 +/- ICE using a PET adapted strategy • Bendamustine + BrentuximabVedotin

  42. 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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