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Targeted Therapies for Relapsed or Refractory

Classical Hodgkin Lymphoma

Weiyun Z. Ai, MD, PhDUCSF Helen Diller Family

Comprehensive Cancer Center

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Learning Objectives

• To understand the outcome and therapeutic options for relapsed or refractory Hodgkin’s lymphoma

• To understand the landscape of development of targeted agents for relapsed and refractory Hodgkin’s lymphoma

• To understand ongoing trials using PD-1 blockades

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Study Case

A 24 yo woman was diagnosed with a stage IIB unfavorable nodular sclerosing Hodgkin’s lymphoma (HL) with a bulky mediastinal mass. She was treated with 6 cycles of ABVD, yielding a CR. Six months later, she presented with progressive abdominal pain. Workup led to small bowl resection. Pathology review of the surgical specimens revealed relapsed HL. A bone marrow biopsy at relapse was negative for HL involvement. She was treated with ICE x 2. Afterwards, a restaging PET/CT was obtained and revealed a new 3 cm mesenteric node in the abdomen.

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ARS Question

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Autologous Transplant Improves FFS in Chemosensitive R/R HL

Schmitz N, et al., for the GHSG and the EBMT, Lancet 2002

N = 88

N = 73

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Druggable Targets in HL

PD-1

Brentuximab vedotin NivolumabCytotoxic T-cell

Bortezomib

HDACiPanobinostat

CART-CD30

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Brentuximab Vedotin

Indication #1: Patients who have failed autologous transplant or have failed two lines of multi-agent regimens

Indication #2: Maintenance therapy after autologous transplant in high risk patients

High Impact trials:First line therapy: Phase III BV+AVD vs ABVDSalvage therapy: BV + bendamustineFor elderly patients: BV single agent or in combination

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Brentuximab Vedotin: An Antibody-Drug Conjugate (ADC)

Brentuximab

Brentuximabtaken into cell

MMAEreleased

MMAE blocks cell division Cell death

(Anti-CD30 antibody)

MMAE (Monomethyl auristatin E)

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PHASE II PIVOTAL STUDY OF BRENTUXIMAB VEDOTIN FOR PATIENTS WITH RELAPSED OR REFRACTORY HODGKIN’S LYMPHOMA

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Key Patient Characteristics

• N= 102• Age: median 31, range 15-77• Functional Status: 41% ECOG 0, 59% ECOG 1• Primary refractory disease: 71%• All relapsed after auto-SCT• Time from auto-SCT to 1st post-SCT relapse: 6.7 months

(10-131)• 89% patients had 1 auto-SCT, 11% had 2

Younes et al., J Clin Oncol 2012;30:2183-2189

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Results: Tumor Burden Reduction

Younes et al., J Clin Oncol 2012;30:2183-2189

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Key Response Results

Younes et al., J Clin Oncol 2012;30:2183-2189

CRPR

PFS

OS

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Grade 3 or 4 Toxicities

Grade 3:• Peripheral sensory neuropathy: 8%• Peripheral motor neuropathy: 1% • Fatigue: 2%• Neutropenia: 14%• Diarrhea 1%• Pyrexia: 2%

Grade 4• Neutropenia: 6%

Younes et al., J Clin Oncol 2012;30:2183-2189

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Durability of Response to BV: PFS

9.3 months NR

6.9 mo5.8 mo

Gopal et al., Blood 2015;125:1236-1243

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Durability of Response to BV: OS

Gopal et al., Blood 2015;125:1236-1243

39.4 mo

NR

18.3 mo

40.5 mo

N = 6 CR pts had consolidative allo-transplant: 3-yr OS 80%N = 28 CR pts did not go to allo-transplant: 3-yr OS 71%

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BRENTUXIMAB VEDOTIN AS MAINTENANCE THERAPY AFTER AUTOLOGOUS TRANSPLANT FOR HIGH-RISK HODGKIN’S LYMPHOMA PATIENTS

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AETHERA Trial

R/R HLSalvage

Chemo

CRPRSD

Autologous Transplant

Randomization

BV Maintenance

Placebo

High Risk:• Primary refractory• Initial remission duration < 12 months• Extra nodal disease at relapse

Stratification:• Primary refractory vs not• Relapse <12 months vs > 12months • Response to salvage treatment

Moskowitz et al., The Lancet 2015;385:1853-1862

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Key Patient Characteristics

Moskowitz et al., The Lancet 2015;385:1853-1862

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AETHERA Trial: PFS

Moskowitz et al., The Lancet 2015;385:1853-1862

2-yr PFS:63% vs 51%

Median PFS:42.9 months vs21.4 months

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AETHERA Trial: OS

Moskowitz et al., The Lancet 2015;385:1853-1862

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Road Map of Treatment of Hodgkin Lymphoma

Initial Treatment

Salvage Treatment

Auto-SCT

Relapse

1BV+AVD 3BV+BendaORR 94%CR 82%

4BV +/- ICE

Maintenance*

RICAllo

BV* 6BVORR 50%CR 38%

2BV for >60 yoORR 92%CR 73%PFS 10.5 months

1Younes A., et al., Lancet Oncol 2013, 2Forero-Torres A., et al., Blood 2015, 3Lacasce A., et al., ASH abstract 2014, 4Moskowitz AJ., et al., Lancet Oncol 2015, 5Chen R., et al., Biol Blood Marrow Transplant 2015, 6Gopal A., et al., Blood 2012, *FDA-approved indication

5BV x4ORR 68%CR 35%

PET-adapted

CR 96%

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BV-associated Progressive Multifocal Leukoencephalopathy (PML)

• A total of 5 cases reported to the FDA• 3 HL, 2 cutaneous T cell lymphoma (1 anaplastic large

cell lymphoma, 1 mycosis fungoides)• 2 CTCL pts had no prior chemo before BV• PML developed after a median of 3 doses (range 2 – 6

doses), and within a median of 7 weeks of BV initiation (range 3 -34 weeks)

• Neuro findings: aphasia, dysarthria, confusion, hemiparesis, gait abnormality

• Diagnosis: 2 CSF by PCR, 2 brain bx, 1 spinal lesion bx• Survival after PML diagnosis: median 8 weeks (range 6-

16 weeks)

Carson K., et al., Cancer 2014;120:2464-2471

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Tumor and its Microenvironment

T cell

Activation

Inhibition

PD-L1PD-L2

PD-1

R-S cell

APC

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Increased PD-L1 Expression in Nodular Sclerosing Hodgkin lymphoma

(NSHL)

Green M, et al., Blood 2010

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PD-1 Blockade with Nivolumab in R/R HL

• Phase I with expansion cohort N =23• Objectives:

- Safety and side effects- Efficacy - PD-1 ligand loci integrity and expression of encoded ligands

• Dosing: 3mg/kg week 1 and 4, then q2 weeks, max 2 years

• DLT not reached

Ansell S., et al, NEJM 2015;372:311-319.

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Key Patient Characteristics

Ansell S., et al, NEJM 2015;372:311-319

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Nivolumab in R/R HL: Toxicity

Common toxicity:• Rash• Decreased platelet count• Decreased lymphocyte count (Grade 3)• Fatigue, pyrexia• Nausea, diarrhea, stomatitis (Grade 3)• Increased lipase level (Grade 3)

Severe Toxicity:• Pancreatitis • MDS• Lymph node pain

Ansell S., et al, NEJM 2015;372:311-319

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Nivolumab in R/R HL: Results

Ansell S., et al, NEJM 2015;372:311-319

• ORR 87%• CR 17%• PR 70%• SD 13%• PD 0%

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PD-1 Blockade with Pembrolizumab

• N =15• All failed brentuximab, 67% failed autologous transplant• Dosing: 10mg/kg, q 2 weeks, max 2 years• Common toxicities: respiratory 20%, thyroid 20%• Grade 3 toxicity: pain and joint swelling, both considered

unrelated to pembrolizumab• Efficacy at 12 weeks: CR 20%, PR 33%, ORR 53%

Moskowitz C, et al., ASH abstract 2014

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Summary

• There are many druggable targets in HL both on the R-S cells and in the tumor microenvironment

• Brentuximab vedotin is highly active in patients with relapsed HL after autologous transplant

• Brentuximab vedotin maintenance in high-risk patients after autologous transplant prolongs PFS

• PML is a very rare but highly fatal complication• PD-1 blockade with nivolumab and pembrolizumab is

highly active in heavily pretreated relapsed and refractory HL

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THANK YOU

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