Treatment of relapsed/refractory

Hodgkin lymphoma

ESMO preceptorship in lymphoma

Lugano, November 2018

Martin Hutchings

Rigshospitalet, Copenhagen, Denmark

2nd line salvage therapy

Salvage Chemotherapy Regimens in relapsed and refractory HL

54

33

5968

52 51

38

27

49

26

21

17 19

76

45

0

20

40

60

80

100

Re

sp

on

se

(%

)

Complete response Partial response

Treatment(data pooled from multiple studies)

*Partial response data not reported.

BEAM - carmustine, etoposide, cytarabine, melphalan; DEXA - dexamethasone; DHAP - dexamethasone, ara-C, cisplatin; GDP - gemcitabine, dexamethasone, cisplatin; GVD, gemcitabine, vinorelbine,

doxil (liposomal doxorubicin); ICE - ifosfamide, carboplatin, etoposide; IEV - ifosfamide, etoposide, vinorelbine; IV - fosfamide, vinorelbine.

Kuruvilla J et al, Blood 2011;117:4208–17

Second line therapy

For patients eligible for HD chemotherapy, HD+ASCT represents the most effective strategy

Cures app. 50% of all relapsing/refractory patients with chemosensitive disease

Linch DC, et al. Lancet 1993; 341: 1051-54.

Schmitz N, et al. Lancet 2002; 359: 2065–71.

Years after randomisation

Risk factors for relapse after HD+ASCT

• In Part 1 of the study, 23

potential risk factors were

evaluated in 656 patients (A)

• Validation in an independent

sample of 389 patients

• New prognostic score

additively composed of 5 RF

at relapse:

– Stage IV

– Time to relapse ≤3

months

– ECOG ≥1

– Bulk ≥5 cm

– Response to salvage <PR

Brockelmann PJ, et al. Ann Oncol. 2017 Jun 1;28(6):1352-1358.

Risk factors for relapse post ASCT

Sirohi B et al. Ann Oncol 2008;19:1312–1319.

Depth of response with salvage therapy predicts survival

Time since transplant (years)

0

2

0

4

0

6

0

8

0

10

0

20151050

Pro

bab

ilit

y o

f O

S (

%)

Response Pre

ASCT

OS

5 years

CR 79%

PR 59%

EE/EP 17%P<0.0001

Risk factors for relapse: CT response

Risk factors for relapse: PET response

PFS/EFS for relapsed HL patients according to pre-transplant PET/CT

76 patients, 2-y PFS 73% vs. 36%1 46 patients, 3-y EFS 82% vs. 41%2

1. Mocikova H, et al. Leuk Lymphoma 2011;52:1668–74.

2. Smeltzer JP, et al. Biol Blood Marrow Transplant 2011;17:1646–52.

PET-response adapted 2nd line therapy

PET/CT may help tailor salvage treatment for relapsed

HL

1. Moskowitz CH, et al. Blood 2012; 119:1665-1670.©2012 by American Society of Hematology

Relapse after 2nd line therapy

For patients in 2nd relapse, outcomes used to be poor

1. Arai S, et al. Leukemia & Lymphoma 2013;11:2531–3.

In post- or non-ASCT setting, chemotherapy regimens have CR rates of 0% to

17%1–3

Drugs used in the R/R HL post- or non-ASCT setting

1. Venkatesh H et al. Clin Lymphoma 2004;5:110–5;

2. Bartlett N et al. Ann Oncol 2007;18:1071–9;

3. Little R et al. J Clin Oncol 1998;16:584–8.

*Observed in ≥20% of patients.

Agent n ORR (%) CR (%) Most common Grade 3/4 AEs (% of patients)*

Gemcitabine1

Patients with prior

transplant

Patients without

prior transplant

16

11

31

9

0

0

Thrombocytopenia (33), neutropenia (30)

GVD2 36 70 17 Thrombocytopenia (43), neutropenia (51)

Vinblastine3 17 59 12 NR

Chemotherapy regimens in R/R HL

Combination chemotherapy for r/r HL

GVD: Gemcitabine, vinorelbine and liposomal doxorubicin

4-year EFS 52% in patients who went on to HD+ASCT

4-year EFS 10% in patients who were previously transplanted

ORR = 70%

Bartlett NL, et al. Ann Oncol 2007, 18: 1071-79.

Few treatments in the post-ASCT R/R setting are characterized by favourable

outcomes1

Drugs used in the R/R HL post- or non-ASCT setting

1. Kuruvilla A et al. Blood 2011;117:4208–17; 2. Younes A et al. J Clin Oncol 2012;30:2183-89; 3. Johnston P et al. Am J Hematol 2010;85:320–4; 4. Fehninger T. Blood

2011;19:5119–25; 5. Bociek R et al. ASCO 2008:Abstract 8507; 6. Younes A et al. J Clin Oncol 2012; 30:2197-203; 7. Kirschbaum M et al. Leuk Lymphoma 2012;53:259–62. 8.

Younes A et al. Lancet Oncol 2016:17:1283–94; 9. Chen R, et al. J Clin Oncol 2017;35:2125-32.

Agent n ORR (%) CR (%) Most common Grade 3/4 AEs (% of patients)*

Brentuximab

vedotin2 102 75 34 Neutropenia (20)

Everolimus3 19 47 5 Thrombocytopenia (32), anemia (32)

Lenalidomide4 36 19 3Neutropenia (47), leukopenia (29), anemia (26), lymphopenia

(24)

MGCD01035 38 20–40† 9‡ Thrombocytopenia (20)†

Panobinostat6 129 27 4 Thrombocytopenia (79), anemia (21), neutropenia (21)

Vorinostat7 25 4 0 Anemia (32)

Nivolumab8 80 66 9 Fatigue, immune-related AEs

Pembrolizumab9 210 69 22 Fatigue, immune-related AEs

Emerging therapies in R/R HL post-ASCT2–7

*Observed in ≥20% of patients; †85 mg cohort, ORR=20%; 110 mg cohort, ORR=40%; ‡110 mg cohort. CR not reached in 85 mg cohort.

Brentuximab vedotin in R/R HL

Brentuximab vedotin mode of action

Brentuximab vedotin antibody-drug conjugate (ADC)

Monomethyl auristatin E (MMAE), microtubule-disrupting agent

Protease-cleavable linker

Anti-CD30 monoclonal antibody

Brentuximab vedotin

binds to CD30

MMAE disrupts

microtubule network

Brentuximab vedotin-CD30

complex is internalized and

traffics to lysosome

MMAE is released

Apoptosis

G2/M cell

cycle arrest

Tumour Response per Central Independent Review

SG035-0003: Best response in individual patients

Gopal A, et al. ASH 2013, New Orleans, LA, USA (Abstract 4382).

Efficacy (cont’d): ORR: 72%; CR rate: 33% (per investigator)

Median OS: 40.5 mos

(95% CI: 28.7, 61.9 [1.8–72.9+])

5-yr OS: 41%

(95% CI: 31%, 51%)

Median PFS: 9.3 mos

(95% CI: 7.1, 12.2)

OS PFS

Previous Chen R, et al. Poster presented at ASH 2015:abstract 2736.

SGN35-003: 5-year follow-up from phase 2 study of brentuximab

vedotin in R/R HL post-ASCT

Efficacy (cont’d): Median OS and PFS were not reached in pts with CR

OS by best

response

PFS by best

response

Chen R, et al. Blood 2016;128:1562–6.

SGN35-003: 5-year follow-up from phase 2 study of brentuximab

vedotin in R/R HL post-ASCT1 – Update Blood 2016

Most common adverse events (20%)

0% 10% 20% 30% 40% 50%

Cough

Vomiting

Neutropenia

Pyrexia

Diarrhoea

Upper respiratory tract infection

Nausea

Fatigue

Peripheral sensory neuropathy

% of patients with AE (n=102)

Grades 1/2

Grade 3

Grade 4

21%

47%

46%

42%

37%

36%

29%

22%

22%

Gopal A, et al. ASH 2013, New Orleans, LA, USA (Abstract 4382).

Study SG035-0003 phase 2 pivotal study of brentuximab vedotin in patients with R/R HL post ASCT

R/R HL patients at high risk of relapse

post-ASCT

SGN35-005 (AETHERA): Phase 3 trial of brentuximab vedotin vs.

placebo in r/r HL pts at high risk of relapse post ASCT

Dose and schedule: Pts were randomized 1:1 to receive 16 21-day cycles of brentuximab vedotin

1.8 mg/kg IV on day 1, or placebo

• Pts who progressed on placebo could receive brentuximab vedotin in another trial

Design: Phase 3 randomized, double-blind, placebo-controlled, multicenter study of

brentuximab vedotin vs. placebo in relapsed or refractory HL pts at risk of progression following

ASCT

Objectives: Primary: PFS per IRF; Secondary: OS, safety/tolerability

Moskowitz CH, et al. 2015 Lancet;385:1853–62; Sweetenham J, et al. ASH 2015, Poster presentation from Abstract #3172

Update ASH 2015

Objectives: Updated efficacy and safety data after ~3 yrs of follow-up since the last pt

was enrolled

Efficacy: Prior publication showed that PFS was significantly improved with

brentuximab vedotin compared with placebo (HR 0.57; p=0.001)1

Sweetenham J, et al. ASH 2015, Poster presentation from Abstract #3172;

1. Previous publication: Moskowitz CH, et al. Lancet 2015;385:185362.*Per investigator

Treatment arm

Median

cycles,

n

PFS rate, % (95% CI)*

Median PFS,

mos HR

24

months

36

months

Brentuximab vedotin (n=165) 15 65 (57, 72) 61 (53, 68)

0.52Placebo (n=164) 15 45 (37, 52) 43 (36, 51) 15.8

SGN35-005 (AETHERA): Phase 3 trial of brentuximab vedotin vs.

placebo in r/r HL pts at high risk of relapse post ASCT

After 3 years since last patient randomized

Sweetenham J, et al. ASH 2015, Poster presentation from Abstract #3172;

1. Previous publication: Moskowitz CH, et al. Lancet 2015;385:185362.

SGN35-005 (AETHERA): Phase 3 trial of brentuximab vedotin vs.

placebo in r/r HL pts at high risk of relapse post ASCT

N Events Hazard ratio (95% CI)

BV 49 22 0.390 (0.221, 0.686)

Placebo 44 34 ─

N Events Hazard ratio (95% CI)

BV 54 21 0.459 (0.272, 0.773)

Placebo 52 35 ─

SGN35-005 (AETHERA): Progression-free survival by response

to 2nd line induction chemotherapy

Stable disease

Partial response

Perc

enta

ge o

f pro

gress

ion-f

ree p

atie

nts

N Events Hazard ratio (95% CI)

BV 62 20 0.931 (0.507, 1.708)

Placebo 68 22 ─

All with complete response

Sweetenham J, et al. ASH 2015, Poster presentation from Abstract #3172;

1. Previous publication: Moskowitz CH, et al. Lancet 2015;385:185362.

PD1 inhibitors in relapsed/refractory HL

HL and PD-1 Pathway

Nivolumab and Pembrolizumab are monoclonal antibodies targeting the

programmed death-1 (PD-1) immune checkpoint pathway

These antibodies bind PD-1 receptors on T cells and disrupt negative signaling

triggered by PD-1 ligands, PD-L1/PD-L2, to restore T-cell antitumor function1,2

MHC

PD-L1

PD-1 PD-1

PD-1 PD-1

T-cellreceptorT-cell

receptor

PD-L1PD-L2

PD-L2

MHC

CD28 B7

T cell

NFκBOther

PI3KDendritic

cellTumor cell

IFNγ

IFNγR

Shp-2Shp-2

Nivolumab: PD-1 receptor-blocking antibody

1. Brahmer JR et al. J Clin Oncol 2010;28:3167–75; 2. Wang C et al. Cancer Immunol Res 2014;2:846–56

CheckMate 205B

KEYNOTE-087: Pembrolizumab in r/r HL

-100

-80

-60

-40

-20

0

20

40

60

80

100

Perc

en

t C

han

ge F

rom

Base

lin

e

-100

-80

-60

-40

-20

0

20

40

60

80

100

Perc

en

t C

han

ge F

rom

Base

lin

e

-100

-80

-60

-40

-20

0

20

40

60

80

100

Perc

en

t C

han

ge F

rom

Base

lin

e

90% of patients with

reduction in tumor size93% of patients with

reduction in tumor size

93% of patients with

reduction in tumor size

PD SD PR CR

Best Overall Response

Chen R, et al. J Clin Oncol ;35(19):2125-2132.

Chen R, et al. Oral presentation at EHA annual meeting 2016 (abstract S794)

Cohort 1 (N = 60)

R/R cHL who

progressed after ASCT

and subsequent BV

therapy

Cohort 2 (N = 60)

R/R cHL who failed

salvage chemotherapy,

ineligible for ASCT† and

failed BV therapy

Cohort 3 (N = 60)

R/R cHL who failed

ASCT and not treated

with BV post transplant

Nivolumab long-term FU data 27 March 2018

1. Armand P, et al. JCO 2018, E-pub ahead of print: DOI: https://doi.org/10.1200/JCO.2017.76.0793

CheckMate 205B

Checkmate-205: Objective response

1. Armand P, et al. JCO 2018, E-pub ahead of print: DOI: https://doi.org/10.1200/JCO.2017.76.0793

CheckMate 205B

Checkmate-205: Best response

1. Armand P, et al. JCO 2018, E-pub ahead of print: DOI: https://doi.org/10.1200/JCO.2017.76.0793

CheckMate 205B

Checkmate-205: PFS

1. Armand P, et al. JCO 2018, E-pub ahead of print: DOI: https://doi.org/10.1200/JCO.2017.76.0793

CheckMate 205B

Checkmate-205: OS

1. Armand P, et al. JCO 2018, E-pub ahead of print: DOI: https://doi.org/10.1200/JCO.2017.76.0793

CheckMate 205B

Pruritus

Diarrhea

Nausea

Arthralgia

Pyrexia

Rash

Infusion-related reaction

Fatigue

Treatment-Related AEs in ≥10% of Patientsa

Patients (n)

80400

Any grade

aWithin 30 days of last dose

CheckMate 205B

Grade 3–4

6020

Younes A, et al. Lancet Oncol 2016 Sep; 17(9): 1283–1294.

Engert A, et al. Oral presentation at EHA annual meeting 2016.

0 20 40 60 80

Skin

Gastrointestinal

Hypersensitivity/infusion reaction

Endocrine

Hepatic

Pulmonary

Renal

Select AEs

(immune-related, any cause)

• Majority of events were manageable, with resolution occurring when immune-modulating

medications were administered

Patients (n)

Any grade

Any grade: resolved

Grade 3–4

CheckMate 205B

Younes A, et al. Lancet Oncol 2016 Sep; 17(9): 1283–1294.

Engert A, et al. Oral presentation at EHA annual meeting 2016.

Checkmate-205: GvH after alloSCT

1. Armand P, et al. JCO 2018, E-pub ahead of print: DOI: https://doi.org/10.1200/JCO.2017.76.0793

CheckMate 205B

Checkmate-205: OS and PFS after alloSCT

1. Armand P, et al. JCO 2018, E-pub ahead of print: DOI: https://doi.org/10.1200/JCO.2017.76.0793

CheckMate 205B

Combinations of BV and anti-PD1

BV + anti-PD1

Diefenbach CS, et al. ASH annual meeting 2016, abstract 1106.

Bispecific antibodies and CAR-T

AFM13: A bispecific anti-CD30/CD16A antibody

construct

Rothe A, et al. Blood. 2015;125(26):4024-4031

Chimeric T Cells for Therapy of CD30+ Hodgkin and

Non-Hodgkin Lymphomas

Ongoing study – preliminary data

CARTs were manufactured for 18 patients

Nine patients (7 with HL and 2 ALCL) had received CD30-CARTs at the

time of the analysis

Eight of these had relapsed or progressed after treatment with

brentuximab vedotin

At 6 weeks after treatment, 1 patient had a CR, 1 patient had a very good

PR, and 4 patients had stable disease (persisting for 1½ to 8 months), while

3 patients had disease progression

Preliminary safety data favourable

Ramos CA, et al.ASH 2015, abstract 185.

Summary

Summary – r/r disease

For patients with chemosensitive disease, HD+ASCT is a curative option for HL patients in 1st relapse

A number of clinical risk factors predict failure afterHD+ASCT

PET/CT before HD+ASCT is highly prognostic and PET-response adapted therapy may improve outcomes

Single-agent Brentuximab vedotin is highly active in patients with r/r HL: 75% ORR and 34% CR

Favourable safety profile in heavily pretreated patients

App. 50% of patients who reach CR are alive and progression-freeat 5-year follow-up

PD1-antibody checkpoint inhibitors are a new and effectivetreatment option for patients with relapse or progression with or without prior failure of Brentuximab vedotin

Thank you