2nd line salvage therapy - european society for medical …...brockelmann pj, et al. ann oncol. 2017...
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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
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