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
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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. - PowerPoint PPT Presentation
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Brentuximab Vedotin.How and When Should it be Used in B and T
cell Lymphomas
Ranjana Advani MDProfessor of Medicine
Saul Rosenberg Professor of LymphomaStanford University
Lymphoma and Myeloma 2014International Congress on Hematologic Malignancies
ADC-CD30 complex is internalized and traffics to lysosome
MMAE is released
Apoptosis
G2/M cell cycle arrest
Brentuximab Vedotin
CD-30
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
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 NHLT cell lymphoma: PTCL
PastKey data of two pivotal trials which led to approval
Phase II Pivotal trial in relapsed HL All ASCT failures
Response in other CD 30 positive PTCLObjective responses in relapsed PTCL with single-agent brentuximab vedotin
Horwitz S M et al. Blood 2014
Outcome by histology and CD30 expression
Horwitz S M et al. Blood 2014
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
a Hu et al, Blood 121:2715-2724; 2013b Slack et al, ASH Annual Meeting Abstracts 120:1558; 2012c Gisselbrecht et al, J Clin Oncol 28:4184-4190; 2010
Median OS ≈ 4 months
Reprinted from Clin Lymph Myel Leuk, 10; 192, RL Elstrom, et al, (2010) with permission from Elsevier.
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
En
d o
f Tre
atm
ent Follow-up
21-Day CyclesBrentuximab vedotin
1.8 mg/kg IVRestage
Dosing on Day 1 (q3wk until disease progressionor unacceptable toxicity)
Screening/Enrollment28 Days
Every 3 months for first 2 years
After Cycles 2, 4, every 3 cycles thereafter, and at EOT
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
Brentuximab Vedotin in Malignant Lymphoma
Kumar et al Current Treatment Options in Oncology (2014)
Future
• Combination with standard chemotherapy to improve cure in front line in HL and CD30 positive PTCL
SGN-35 + chemotherapyPreclinical models
Oflazoglu et al BJH 2010
• 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
Weeks0 2 4 6 8 10 12
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.
Preferred term, n (%)
ABVD with brentuximab vedotin
N=25
AVD with brentuximab vedotin
N=26Any event 11 (44) 0
Pulmonary toxicity 9 (36) 0
Interstitial lung disease 1 (4) 0
Pneumonitis 1 (4) 0
Pulmonary Toxicity
Events generally occurred during Cycles 34 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.
Outcomes
Younes, et al. Lancet Oncology 2013.
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
Demographics and Baseline Characteristics
ParameterTotalN=26
Age* , years 56 (21–82)Gender, n 11 M / 15 FIPI 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 2 Adult T-cell leukemia/lymphoma, n 2 Enteropathy-associated T-cell lymphoma, n 1
* Median (range)
Fanale M A et al. JCO 2014
Response After Sequential or Combination Treatment
Fanale M A et al. JCO 2014
Outcomes
Combination TreatmentSequential Treatment
Fanale M A et al. JCO 2014
Adapted from Senter and Sievers: Nature Biotechnology 2012
5 years7 years
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