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SCHH. Barcelona, 22 de juny de 2016
Immunoteràpia en el Limfoma de HodgkinA. Sureda
Servei d’HematologiaInstitut Català d’Oncologia - Hospitalet
The European Group for Blood and Marrow TransplantationThe European Group for Blood and Marrow TransplantationThe European Group for Blood and Marrow Transplantation
Median follow-up of survivors 50 months (75% of cases > 34 months)
OS from relapse after an ASCT. The experience of the LWP EBMT/GITMO
39.5% (95% CI: 35-44) at 3 years
0.00
0.20
0.40
0.60
0.80
1.00
0 12 24 36 48 60 72 84 96
Months from relapse
OS
29.7% (95% CI: 25-34) at 5 years
Martínez et al, Ann Oncol 2013
Chen R, et al. ASH 2015, Poster presentation from Abstract #2736
Progression free survivalOverall median PFS = 9.3 mo (95% CI: 7.1, 12.2)
PFS, progression-free survival; mo, months; ITT intention to treat; PD, progressive disease
Ongoing Phase II Study of Brentuximab VedotinPFS Per Investigator – 5 Year Follow-up
Introduction• Classical Hodgkin lymphoma (cHL) is characterized by
expression of PD-L1 and PD-L2 on malignant Reed–Sternberg cells and on inflammatory cells in the tumor microenvironment
• PD-L1 expression in cHL frequently occurs in the setting of genetic amplification of the 9p24.1 locus
• Prognosis for patients with relapsed cHL is poor
4
PD-L1 expression in cHL
Chen BJ, et al. Clin Cancer Res. 2013;19:3462–3473.Ansell SM, et al. N Engl J Med. 2015;372:311–319.
PD-L1/L2 copy gains and amplification visible by FISHCopy Gain Amplification
Inst itut Català d'OncologiaInstitut Català d’Oncologia
Inst itut Català d'OncologiaInstitut Català d’Oncologia
MHC
PD-L1
PD-1 PD-1
PD-1 PD-1
PD1 Receptor Blocking Ab
Recognition of tumour by T cell through MHC/antigen interaction mediates IFNγ release
and PD-L1/2 upregulation on tumour
T-cellreceptorT cell
receptor
PD-L1PD-L2
PD-L2
MHC
CD28 B7
T cell
NFκBOther
PI3KDendritic
cellTumour cell
IFNγIFNγR
Shp-2
Shp-2
PD-1/PD-L1 Blockade
WCLC 2013
• Nivolumab is a fully human immunoglobulin G4 monoclonal antibody targeting the programmed death-1 (PD-1) immune checkpoint pathway
June 2014
Relapsed or Refractory HL
(N = 105)
• No autoimmune disease
• No prior organ or stem cell allografting
• No prior checkpoint blockade
Endpoints
Primary• Safety and tolerability
Secondary• Best overall response
• Investigator assessed
• Objective response• Duration of response• Progression-free
survival (PFS)• Biomarker studies
Dose Expansion (3 mg/kg)
Hodgkin Lymphoma (n=23)
Non-Hodgkin lymphoma (n = 69)
Dose Escalation
Nivolumab 1 mg/kg → 3 mg/kg
Weeks 1 and 4, then every 2 weeks
Non-Hodgkin lymphoma (n = 13)
August 2012 April 2015Median Follow-up
40 weeks 76 weeksAugust 2015
Hodgkin lymphoma (n = 23)
101 weeks
7
Phase 1 Study (CA209-039) Clinical Outcomes From Extended Follow-up
Study design
Baseline Characteristics
Characteristic cHL (n = 23)
Age, median (range) 35 (20–54)
Histology, n
Nodular sclerosing 22
Mixed cellularity 1
Prior autotransplant, n (%) 18 (78)
Prior brentuximab vedotin, n (%) 18 (78)
Number of prior therapies, median (range) 5 (2–15)
8
Select Treatment-Related Adverse Events
9
Adverse Event cHL (n = 23)Any Grade,
n (%)Resolved, %
Gastrointestinal 4 (17)Diarrhea 3 (13) 100Colitis 1 (4) 100
Hepatic 2 (9)ALT increased 1 (4) 100AST increased 1 (4) 100Blood alkaline phosphatase increased 1 (4) 0
Pulmonary 1 (4)Pneumonitis 1 (4) 100
Skin 5 (22)Rash 4 (17) 100Pruritus 3 (13) 100Pruritic rash 1 (4) 100Skin hypopigmentation 1 (4) 0
Endocrine disordersHyperthyroidism 4 (17) 75
Hypersensitivity/infusion reaction 2 (9)Bronchospasm 1 (4) 100Infusion-related reaction 1 (4) 100
• All AEs were Grade 1/2 except colitis and pneumonitis which were Grade 3• There were no Grade 4 or Grade 5 AEs and no treatment-related deaths
Select Treatment-Related Adverse Events
10
Adverse Event cHL (n = 23)Any Grade,
n (%)Resolved, %
Gastrointestinal 4 (17)Diarrhea 3 (13) 100Colitis 1 (4) 100
Hepatic 2 (9)ALT increased 1 (4) 100AST increased 1 (4) 100Blood alkaline phosphatase increased 1 (4) 0
Pulmonary 1 (4)Pneumonitis 1 (4) 100
Skin 5 (22)Rash 4 (17) 100Pruritus 3 (13) 100Pruritic rash 1 (4) 100Skin hypopigmentation 1 (4) 0
Endocrine disordersHyperthyroidism 4 (17) 75
Hypersensitivity/infusion reaction 2 (9)Bronchospasm 1 (4) 100Infusion-related reaction 1 (4) 100
• All AEs were Grade 1/2 except colitis and pneumonitis which were Grade 3• There were no Grade 4 or Grade 5 AEs and no treatment-related deaths
Response Rates
Best Objective Response cHL(n = 23)
n (%) 95% CI
Objective response rate 20 (87) 66.4–97.2
CR 5 (22) 7.5–43.7
PR 15 (65) 42.7–83.6
SD 3 (13)
11
Patients (n = 23)
Perc
ent C
hang
e in
Tum
or B
urde
n
CR (22%)PR (65%)SD (13%)25
0
–25
–50
–75
–100
On treatment, ongoing responseOff treatment without disease progressiona
Progressive disease, following response or stable disease
Best Response
aMaximum clinical benefit, transplant, or toxicity 12
Durability of Response
–100
–50
0
50
100
Time Since First Treatment Date, Weeks
Perc
ent C
hang
e Fr
om B
asel
ine
in T
arge
t Les
ions
/Tum
or B
urde
n
0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102 108 114
On treatment, ongoing response
Off treatment without progression
Progressive disease, following response or stable disease
First occurrence of new lesion13
Duration of Response
14
Median DOR (95% CI): NA (15.5–NA)
Time, Months
Prob
abili
ty o
f Pat
ient
s in
Resp
onse
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 3 6 9 12 15 21 2418
18 15 12 10 9 7 2 04
No. Patients at Risk
• Median follow-up: 101 wks• Median DOR not reached
Responding Patients
15
0 8 16 24 32 40 48 56 64 72 80 88 96 104 112
17
15
201918
16
14131211
9
7654321
10
8
Patie
nts
PFS Responders Time, Weeks
• On treatment, ongoing responses
First CRFirst PRDeathOngoing response
Responding Patients
16
0 8 16 24 32 40 48 56 64 72 80 88 96 104 112
17
15
201918
16
14131211
9
7654321
10
8
Patie
nts
PFS Responders Time, Weeks
• On treatment, ongoing responses
• 13 patients off treatment without disease progression
• 6 with maximum clinical benefit
• 5 proceeded to transplant
• 2 discontinued for toxicity
First CRFirst PRDeathOngoing response
Responding Patients
17
0 8 16 24 32 40 48 56 64 72 80 88 96 104 112
17
15
201918
16
14131211
9
7654321
10
8
Patie
nts
First CRFirst PRDeathOngoing response
• On treatment, ongoing responses
• 13 patients off treatment without disease progression
• 6 with maximum clinical benefit
• 5 proceeded to transplant
• 2 discontinued for toxicity
• Disease progression following initial response
PFS Responders Time, Weeks
Progression-Free Survival
18
Median PFS (95% CI): NA (18.6–NA)
Time, Months
Prop
ortio
n of
Pat
ient
s With
out P
rogr
essi
on
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 3 6 9 12 15 21 2718No. Patients at Risk
24
23 20 13 12 11 8 1 0511
• Median follow-up: 101 wks• Median PFS not reached
Overall Survival
19
Time Since First Dose, Months
Prop
ortio
n of
Pat
ient
s Aliv
e
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 3 6 9 12 15 21 3018 24
No. Patients at Risk
23 23 23 22 21 18 2 0721 17
27
OS (N=23)
1 Year
OS rate, % (95% CI) 91 (69.5–97.8)
1.5 Years
OS rate, % (95% CI) 83 (60.1–93.1)
CheckMate 205: Overall Study Design
Cohort BCohort A Cohort C Cohort D
Brentuximab-vedotin naïve
Stop treatment if persistent CR for 1 year, if relapse, reinitiate nivo
Now enrolling
The same inclusion
criteria as cohort B.
Additionally, brentuximab vedotin prior to ASCT was
allowed.
Post-transplant
brentuximab vedotin
Registrational trial for
regulatory approval
Relapsed/refractory cHL after ASCTNewly diagnosed advanced-stage cHL
Engert A et al. EHA 2016
• Registrational phase 2 study conducted in Europe and North America
CheckMate 205: Study Design, Cohort B
Primary endpoint•ORR assessed by IRRCa
Secondary and other endpoints•IRRC-assessed DOR for complete and partial remission
•Investigator-assessed ORR and DOR
•IRRC-assessed PFS•OS•Safety•QoL•Biomarkers
aPer the 2007 International Working Group (IWG) criteria. IRRC = independent radiologic review committee
Minimum follow-up: 6 months
Single-armNivolumab 3 mg/kg
(every 2 weeks)Treatment until
disease progression or unacceptable toxicity
Prior ASCT
Brentuximab vedotin
Relapsed/refractory cHL
Inclusion criteria
• Patients could elect to discontinue nivolumab and proceed to allogeneic hematopoietic stem cell transplantation
Engert A et al. EHA 2016
Baseline Characteristics
Data shown as n (%) unless indicated otherwiseaExcluding high-dose preparative regimen prior to ASCT
Characteristic Patients(N = 80)
Age, median (range)<65 years
37 (18–72)77 (96)
SexMale 51 (64)
ECOG performance status01
42 (53)38 (48)
Previous lines of therapy,a median (range) ≥5 lines of therapy
4 (3–15)39 (49)
Previous radiation therapy 59 (74)Previous ASCT
12
80 (100)74 (93)6 (8)
Prior brentuximab vedotin therapy after ASCT 80 (100)No response to prior brentuximab vedotin 43 (54)
CheckMate 205B
Engert A et al. EHA 2016
Response Rates
IRRC (N = 80)
Investigator (N = 80)
Objective response rate, n (%)95% CI
53 (66)55–76
58 (73)61–82
Best overall response, n (%)Complete remissionPartial remissionStable diseaseProgressive diseaseUnable to determine
7 (9)46 (58)18 (23)6 (8)3 (4)
22 (28)36 (45)18 (23)3 (4)1 (1)
CheckMate 205B
Patients with no prior response to most recent brentuximab vedotintreatment
IRRC (N = 43)
Investigator (N = 43)
Objective response rate, n (%) 31 (72) 35 (81)
Engert A et al. EHA 2016
Time to and Durability of Response by IRRC
Weeks0 8 16 24 32 40 48 56
Resp
onde
rs: P
R +
CR (n
= 53
)
Censored with ongoing responseFirst partial responseFirst complete response
Median time to response,months (range)
2.1(1.6–5.7)
Median duration of response,months (95% CI)
7.8(6.6–NE)
Patients with ongoing response, n/N (%)
33/53(62%)
Transplant
Engert A et al. EHA 2016
Progression-Free and Overall Survival1.0
0.8
0.6
0.4
0.2
0
Prob
abili
ty o
f eve
nt
0 3 6 9 12
Median follow-up (range) 8.9 months (1.9–11.7)Median PFS (95% CI) 10.0 months (8.41–NA)PFS rate at 6 months (95% CI) 76.9% (65%–85%)Median OS Not reachedOS rate at 6 months (95% CI) 98.7% (91%–100%)
76.9%
PFS (24/80 events)
CheckMate 205
PFS per IRRC assessment
Months
98.7%OS (3/80 events)
Engert A et al. EHA 2016
Adverse Events
• Serious AEs (SAEs) included pyrexia, tumor progression, arrhythmia, infusion reaction, septic meningitis, and pneumonia (≤4% each)
• *One patient experienced a grade 5 SAE of multi-organ failure due to Epstein Barr virus–positive T-cell lymphoma
Total patients with an event (%) Any grade Grade 3–4
Any AE 79 (99) 32 (40)Treatment-related AE 72 (90) 20 (25)Treatment-related AE leading to discontinuation:
Autoimmune hepatitisIncreased ALT and ASTMulti-organ failure*
3 (4)
111
2 (3)
110
Treatment-related serious AE 5 (6) 0Treatment-related death 0 0
CheckMate 205B
Engert A et al. EHA 2016
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
6020Engert A et al. EHA 2016
0 20 40 60 80
Skin
Gastrointestinal
Hypersensitivity/infusion reaction
Endocrine
Hepatic
Pulmonary
Renal
Select AEs (immune-related, any cause)
• Drug-related pneumonitis reported in 2 patients (grade 2 and grade 3) between first dose and 35 days after last dose
• Majority of events were manageable, with resolution occurring when immune-modulating medications were administered
Patients (n)
Any gradeResolved Grade 3–4
CheckMate 205B
Engert A et al. EHA 2016
Inst itut Català d'OncologiaInstitut Català d’Oncologia
OPDIVO ®(Nivolumab)
OPDIVO (nivolumab) is indicated for the treatment of patients with cHL that has relapsed or progressed afterASCT and post-transplantation BV. This indication isapproved under accelerated approval based on overallresponse rate. Continued approval for this indication maybe contingent upon verification and description of clinicalbenefit in confirmatory trials.
Inst itut Català d'OncologiaInstitut Català d’Oncologia
The PD-1 and PD-L1/L2 Pathway to Be Continued• PD-1 is an immune checkpoint
receptor1
• Binding of PD-1 by its ligands PD-L1 or PD-L2 leads to downregulation of T-cell function1
• This mechanism is usurped by many tumors1
• PD-1 blockade through mAb therapy can restore effective anti-tumor immunity2,3
• Pembrolizumab is a humanized anti-PD1 mAb with activity in multiple malignancies4,5
30
1. Keir ME et al. Annu Rev Immunol. 2008; 2. Pardoll DM. Nat Rev Cancer. 2012; 3. Topalian et al. N Engl J Med. 2012. 4. Garon et al. N Engl J Med. 2015; 5. Robert et al. Lancet. 2014.
KEYNOTE-087: Study Design
31
Cohort 1 (N = 60)R/R cHL who
progressed after ASCT and subsequent BV
therapy
Progressive Disease
Pembrolizumab 200 mg Q3W
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
Survival Follow-Up
• Primary end point: ORR (central review)• Secondary end points: ORR (investigator review), PFS, OS
• Prespecified interim analysis, based on investigator-assessed response, performed after 30 patients in all 3 cohorts reached first response assessment
CT scans repeated Q12W PET repeated at W12, W24, to confirm CR or PD, and as clinically indicated
Chen R et al. EHA 2016
Baseline Characteristics
32
Characteristic(N = 30 in each cohort)
Cohort 1 Progressed after
ASCT and subsequent BV
therapy%
Cohort 2Failed salvage chemotherapy,
ineligible for ASCT and failed BV therapy
%
Cohort 3 Failed ASCT and not treated with BV post
transplant%
Age, median (range) 36 (19-64) 33 (20-71) 30 (18-67)
Age >65 0 20 3Lines of systemic therapy, median (range)
5 (3-12) 4 (1-10) 3 (2-10)
Primary refractory 23 50 50
Prior radiation therapy 47 27 43
Bulky lymphadenopathy† 7 10 3
Baseline B symptoms 23 20 23
Bone marrow involvement 0 10 3
Prior brentuximab failure 100 100 40‡
†Bulky disease was defined as a mass larger than a third of transthoracic diameter at any level of thoracic vertebrae, or single site of disease in any area that is 10 centimeters or greater in diameter.‡Patients received BV therapy prior to transplant. Data cutoff: April 8, 2016
Chen R et al. EHA 2016
Best Overall Response, Investigator Review
33
†One patient in Cohort 2 had no assessment. The patient had symptomatic deterioration, with subsequent clinical progression.‡For complete remission, a residual mass was permitted for patients who were negative on PET scanning. Data cutoff: April 8, 2016
Cohort 1 Progressed after
ASCT and subsequent BV
therapyn (%)
Cohort 2†
Failed salvage chemotherapy,
ineligible for ASCT and failed BV therapy
n (%)
Cohort 3 Failed ASCT and not treated with BV post
transplantn (%)
% (95% CI) % (95% CI) % (95% CI)
Overall response rate 73 (54-88) 83 (65-94) 73 (54-88)
Complete remission‡ 27 (12-46) 30 (15-49) 30 (15-49)
Partial remission 47 (28-66) 53 (34-72) 43 (26-63)
Stable disease 17 (6-35) 7 (1-22) 13 (4-31)
Progressive disease 10 (2-27) 7 (1-22) 13 (4-31)
Chen R et al. EHA 2016
Primary Refractory Disease†
N = 37
% (95% CI)
Overall response rate 78 (62-90)
Complete remission‡ 35 (20-53)
Partial remission 43 (27-61)
Stable disease 11 (3-25)
Progressive disease 8 (2-22)
Best Overall Response, Investigator Review
34
†Defined as failure to achieve complete or partial remission to frontline therapy‡For complete remission, a residual mass was permitted for patients who were negative on PET scanning.Data cutoff: April 8, 2016 Chen R et al. EHA 2016
0 5 10 15 20 25 30 35 40Weeks
®®
®®®®®®®®®
®®®®
®®®
®®®®
®®
®
35Data cutoff: April 8, 2016
Treatment Exposure: Cohort 1Progressed after ASCT and subsequent BV therapy
• Median number of treatment cycles: 9 (range, 4-13)
• 19 patients who responded were still on pembrolizumab treatment
*
Treatment OngoingComplete ResponsePartial ResponseProgressive DiseaseLast Dose
Chen R et al. EHA 2016
36Data cutoff: April 8, 2016
Treatment Exposure: Cohort 2Failed salvage chemotherapy, ineligible for ASCT and failed BV therapy
• Median number of treatment cycles: 9 (range, 1-13)
• 13 patients who responded were still on pembrolizumab treatment
*
Treatment OngoingComplete ResponsePartial ResponseProgressive DiseaseLast Dose
0 5 10 15 20 25 30 35 40Weeks
®
®®®®®®
®®
®®
®®
®®®®
®
Chen R et al. EHA 2016
37Data cutoff: April 8, 2016
Treatment Exposure: Cohort 3Failed ASCT and not treated with BV
• Median number of treatment cycles: 9 (range, 4-14)
• 21 patients who responded were still on pembrolizumab treatment
*
Treatment OngoingComplete ResponsePartial ResponseProgressive DiseaseLast Dose
0 5 10 15 20 25 30 35 40 45Weeks
®®®®®
®
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®®®®®®®®
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Chen R et al. EHA 2016
Treatment-Related Adverse Events
38
≥5% of patientsTotal Population
N = 90%
Any gradePyrexia 13
Diarrhea 10
Neutropenia 8
Fatigue 8
Cough 8
Hypothyroidism 7
Dry skin 6
Nausea 6
AEs of Clinical InterestTotal Population
N = 90%
Rash, all grade 1† 4
Pneumonitis, all grade 2 2
Colitis, grade 3 1
• Four patients (4%) experienced grade 3/4 AEs• No treatment related deaths were observed• Two discontinuations due to treatment-related AEs (pneumonitis and
infusion reaction)
†Includes erythematous rash. Data cutoff: April 8, 2016 Chen R et al. EHA 2016
Inst itut Català d'OncologiaInstitut Català d’Oncologia
• The advent of check point inhibitors (nivolumab, pembrolizumab) will be changing the therapeutic landscape of patients with relapsed / refractory HL
• High response rates / durable remissions• Manageable toxicity profile• The impact on SCT indications / toxicities remains to be seen• All data in relapsed / refractory patients support a quick
clinical development to earlier phases of the disease
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