2nd line salvage therapy - european society for medical …...brockelmann pj, et al. ann oncol. 2017...
TRANSCRIPT
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Treatment of relapsed/refractory
Hodgkin lymphoma
ESMO preceptorship in lymphoma
Lugano, November 2018
Martin Hutchings
Rigshospitalet, Copenhagen, Denmark
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2nd line salvage therapy
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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
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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
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Risk factors for relapse after HD+ASCT
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• 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
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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
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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.
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PET-response adapted 2nd line therapy
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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
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Relapse after 2nd line therapy
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For patients in 2nd relapse, outcomes used to be poor
1. Arai S, et al. Leukemia & Lymphoma 2013;11:2531–3.
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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
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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.
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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.
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Brentuximab vedotin in R/R HL
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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
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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).
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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
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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
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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
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R/R HL patients at high risk of relapse
post-ASCT
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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
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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
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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
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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.
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PD1 inhibitors in relapsed/refractory HL
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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
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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
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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
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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
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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
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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
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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
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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.
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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.
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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
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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
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Combinations of BV and anti-PD1
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BV + anti-PD1
Diefenbach CS, et al. ASH annual meeting 2016, abstract 1106.
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Bispecific antibodies and CAR-T
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AFM13: A bispecific anti-CD30/CD16A antibody
construct
Rothe A, et al. Blood. 2015;125(26):4024-4031
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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.
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Summary
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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
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Thank you