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

New York

Disclosures

• Seattle Genetics: Research Funding

Brentuximab vedotin antibody-drug conjugate (ADC)Monomethyl auristatin E (MMAE), microtubule-disrupting agentProtease-cleavable linker Anti-CD30 monoclonal antibody

ADC binds to CD30

MMAE disruptsmicrotubule network

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

Toxicity > Gr 3: ANC 20% , sensory neuropathy 8% thrombocytopenia 6%

Individual Patients (n=98)*

Tum

or S

ize (%

Cha

nge

from

Bas

elin

e)

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)

Phase 2 Relapsed or Refractory HL Pivotal Trial Outcomes According to Best Response

Younes et al JCO 2012

Progression Free Survival Overall Survival

Phase 2 Relapsed or Refractory HL Pivotal Trial PFS in Patients with CR by Subsequent Transplant

Patients Who Achieved a CR N EventsMedian PFS

(95% CI)

Median Number of

Cycles Received

Allogeneic transplant 5 1 21.1 (,) 14

No transplant 30 13 21.7 (9.7, ) 13

• Subsequent transplant did not appear to meaningfully impact PFS in this small dataset

Younes et al JCO 2012

Relapsed or Refractory Systemic ALCL Trial Maximum Tumor Reduction

Pro B, et al. JCO 2012

97% of patients achieved tumor reduction

ORR 86% (57% CR)

72% ALK neg, 62% refractory to front line rx, 22 % prim refr, 26 % prior SCT

Outcomes according to response and ALK status

Pro B, et al. JCO 2012

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

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

Retreatment with Brentuximab Vedotin

Bartlett, et al. J Hematol Oncol 2014.

N = 21 (HL), 8 (ALCL), 48% grade 3 neuropathy manageable with dose delay/reduction

ORR 68%, CR: 39%

Retreatment with Brentuximab Vedotin Median DOR 9.5 months

Bartlett, et al. J Hematol Oncol 2014.

CR patients: 45% > 1yr duration

Overall SurvivalProgression Free Survival

Brentuximab Vedotin Retreatment

Brentu

xim

ab V

edotin

Retre

atm

ent B

V

Evero

limus

Panobin

ostat

Moce

tinost

at

Lenal

idom

ide

Vorinost

at

SGN300

20

40

60

80

100

CR PR

Humala and Younes, Hematologica 2012

Response in Transplant Naïve pts with R/R HLAnalysis of 2 Phase 1 studies

Forero-Torres The Oncologist 2012

3/6 responders subsequent transplant

N=20, median 3 prior regimens, 45% prior RT

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 Survival Overall Survival

2 yr estimated 66% 2 yr estimated 80%

Brentuximab vedotin for HL recurring after allogeneic stem cell transplantation

.

Gopal A K et al. Blood 2012

Reduced Intensity Allogeneic Transplantation for HLPre and post brentuximab era

Chen, et al. Biol Blood Marrow Transplant. 2014

2y 59.3 % vs 26%

2y 56.5% vs 23.8%

2y 71 % vs 56.5%

1y 9.5 % vs 17.4%

Experience of Brentuximab Vedotin in pts > 60

Gopal, et al. Leukemia & Lymphoma 2014

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 2013. Abstract 4389.

100% of patients achieved tumor reduction

Individual Patients (n = 19)

100

50

0

-50

-100

Tum

or

Siz

e(B

est

% C

han

ge

Fro

m B

asel

ine)

CR CR CR CR

CR CRCR CR CR

CR CR CR

*

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

Pathological Diagnoses: N=68

TotalN (%)

DLBCL 50 (74)

DLBCL-NOS 43 (63)

EBV+ DLBCL of the elderly 5 (7)

Plasmablastic lymphoma 1 (1)

T-cell-rich B-cell lymphoma 1 (1)

Other B-cell lymphomas 18 (26)

Grey zone lymphoma 6 (9)

Primary mediastinal B-cell lymphoma (PMBL) 6 (9)

Follicular lymphoma 3 (4)

Post-transplant lymphoproliferative disorder (PTLD) 3 (4)

Bartlett NL, et al. ASH 2013, Abstract 848

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

• Phase 3 ALCANZA trial for relapsed CD30-positive cutaneous T-cell lymphoma

• 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

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