Hodgkin Lymphoma HL by the Numbers Optimal Upfront Treatment 8700 pts Favorable ES Unfavorable ES Unfavorable ES with Bulk Favorable AS Unfavorable AS 1000 2500 1000 2500 1000 100 Fail ID: 774948
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Slide1
Meet The Professors Hodgkin Lymphoma 2018
Slide2Hodgkin Lymphoma (HL) by the Numbers
Optimal Upfront Treatment 8700 pts
Favorable ES
Unfavorable ES
Unfavorable ES with Bulk
Favorable AS
Unfavorable AS
1000
2500
1000
2500
1000
100 Fail
300 Fail
200 Fail
500 Fail
300 Fail
700 Pts ≥70 years
No standard TX
TREATMENT FAILS IN 1400 PATIENTS
ES = early stage, AS = advanced stage
Courtesy of
Dr
Craig Moskowitz
Slide3Relapsed/Refractory HL: 1400 pts/year
Salvage therapy (1-2)
PET neg.
PET pos. PR
No Response
63%
20%
17%
705 Pts Cured with ASCT
280 pts
238 pts
130 pts Cured with ASCT
150 pts Treatment Failure
565 pts Allo vs CPI
177 pts
Treatment Failure
882 pts
Courtesy of
Dr
Craig Moskowitz
Slide4ECHELON-1: Open-label, global, randomized, phase 3 study of A+AVD versus ABVD in patients with newly diagnosed advanced cHL
Connors JM et al. Proc ASH 2017;Abstract 6.
ECHELON-1: Open-label, global, randomized, phase 3 study of A+AVD versus ABVD in patients with newly diagnosed advanced cHL
ScreeningCT/PET scan
1:1 randomization(N = 1,334)
ABVD x 6 cycles (n = 670)
A+AVD x 6 cycles (n = 664)Brentuximab vedotin: 1.2 mg/kg IV infusionDays 1 & 15
End-of-cycle-2 PET scanDeauville 5; could receive alternate therapy per physician’s choice (not a modified PFS event)
EOTCT/PET scan
Follow-upEvery 3 months for 36 months, then every 6 months until study closure
Inclusion criteriacHL stage III or IVECOG PS 0, 1 or 2Age ≥18 yearsMeasurable diseaseAdequate liver and renal function
2018 study sites in 21 countries worldwide
cHL
, classic Hodgkin lymphoma; ECOG PS, Eastern Cooperative Oncology Group performance status; EOT, end-of-treatment; PFS, progression-free survival
Slide5ECHELON-1: Primary endpoint definition
Connors JM et al. Proc ASH 2017;Abstract 6.
Primary endpoint: modified PFS per IRFA modified PFS event was defined as the first ofProgressionDeath from any cause
Dx
Tx
Follow-up
PET6 = D1, 2
Dx
Tx
Follow-up
PET6 = D3, 4, 5
Dx
Tx
Follow-up
PET6 = D3, 4, 5
No event
No event
Dx
Tx
Follow-up
PET6 = D1, 2
Tx
No event
Event
PET6 = D3, 4, 5 after completion of front-line therapy followed by subsequent anticancer therapy
D, Deauville score;
Dx, diagnosis; IRF, independent review facility; PD, progressive disease; PET6, end-of-cycle-6 PET; Tx, treatment
Per IRF
Event
Dx
Tx
Follow-up
PD/death at any time
ECHELON-1: Primary endpoint definition
Tx
w/o “Cheson” progression
PET6 = D1-5
Slide6Disease characteristics comparable between A+AVD and ABVD
Connors JM et al.
Proc ASH
2017;Abstract 6.
* Percentages do not total 100% due to rounding; † Unknown/missing data for 5% and 4% in the A+AVD and ABVD groups, respectively; IPS, International Prognostic Score
Baseline disease characteristicsA+AVDN = 664ABVDN = 670Ann Arbor stage, % III IV36643763IPS risk factors, %* 0-1 2-3 4-7215325215227ECOG PS, % 0 1 25739457394B symptoms, %6057Bone marrow involvement, %2223Sites of extranodal involvement, %† None 1 >1333329343329
Baseline patient characteristicsA+AVDN = 664ABVDN = 670Male, %5759Not Hispanic or Latino, %8686White, %8483Median age, years (range)35 (18-82)37 (18-83)Age, years, % <45 45-59 60-64 ≥65681949632269Median time since initial diagnosis, months0.920.89Region, % Americas Europe Asia 395011395011
Disease characteristics comparable between A+AVD and ABVD
Slide7Modified PFS per independent review
Connors JM et al. Proc ASH 2017;Abstract 6.
TimeA+AVD (95% CI)ABVD(95% CI) 2-year82.1 (78.7-85.0)77.2 (73.7-80.4)
Median follow-up (range): 24.9 months (0.0-49.3)
CategoryA+AVDN = 117ABVDN = 146 Progression90102 Death1822 Modified progression Chemotherapy Radiotherapy97222157
1.0
0.8
0.6
0.4
0.2
0.0
0
2
4
6
8
10
12
14
16
18
20
22
24
26
28
30
32
34
36
38
40
42
44
46
48
50
664
670
640
644
623
626
606
613
544
522
530
496
516
476
496
459
474
439
447
415
350
328
334
308
311
294
200
179
187
168
174
153
99
78
85
68
77
62
27
16
24
13
21
12
6
1
4
1
4
1
0
0
0
0
Time from randomization (months)
Probability of modified PFS
No. of patients at risk:
A+AVD
ABVD
HR 0.77 (95% CI: 0.60-0.98)
Log-rank test
p
-value: 0.035
A+AVD
ABVD
Censored
Censored
0.9
0.7
0.5
0.3
0.1
Modified PFS estimates
Number of events
Modified PFS per independent review
52
Slide8Most clinically important treatment-emergent adverse events
Incidence (any grade) ≥20% + febrile neutropenia
Connors JM et al. Proc ASH 2017;Abstract 6.
Most clinically important treatment-emergent adverse eventsIncidence (any grade) ≥20% + febrile neutropenia
Common adverse events, %*A+AVD (N = 662)ABVD (N = 659)Any gradeGrade ≥3Any gradeGrade ≥3Neutropenia 58544539Constipation 42237<1Vomiting 33 328 1Fatigue 323321Peripheral sensory neuropathy 29 517<1Diarrhea 27318<1Pyrexia 27322 2Peripheral neuropathy26413<1Abdominal pain 21310<1Stomatitis 21216<1Febrile neutropenia191988
* Partial list focusing on the most clinically important adverse events. Adverse events (≥20% any grade in either arm) excluded from the table include nausea, alopecia, weight decreased, and
anemia
Slide9Summary of treatment-emergent febrile
neutropenia
and adverse events by primary prophylaxis with G-CSF
Connors JM et al. Proc ASH 2017;Abstract 6.
G-CSF primary prophylaxis for A+AVD resulted in an overall safety profile comparable to ABVDG-CSF primary prophylaxis is recommended for all A+AVD patients
73%
35%
A+AVD
ABVD
No(n = 579)
Yes(n = 83)
No(n = 616)
Yes(n = 43)
≥Grade 3
Grade 1-2
* Includes preferred terms of ‘neutropenia’ and ‘neutrophil count decreased’;
†
Defined as G-CSF use by Day 5 of study treatment;
TEAEs, treatment-emergent adverse events
100
90
80
70
50
40
30
20
60
57%
21%
G-CSF primary prophylaxis
†
Patients (%)
A+AVD
ABVD
No
(n = 579)
Yes
(n = 83)
No
(n = 616)
Yes
(n = 43)
21%
11%
8%
7%
Patients (%)
87%
57%
67%
47%
A+AVD
ABVD
Yes
(n = 83)
No
(n = 616)
Yes
(n = 43)
No
(n = 579)
10
0
Summary of treatment-emergent febrile neutropenia and adverse events by primary prophylaxis with G-CSF
50
40
30
20
10
0
100
80
40
20
0
60
10
90
70
50
30
Patients (%)
Slide10Peripheral neuropathy and pulmonary events
Connors JM et al. Proc ASH 2017;Abstract 6.
Peripheral neuropathy (PN) and pulmonary events
67%
43%
67% of pts with PN in the A+AVD arm had resolution or improvement by ≥1 grade at last follow-upOf those with ongoing PN at last follow-up:Grade 1 64% Grade 2 29%Grade 3 7%
Interstitial lung disease was more frequent and more severe in ABVD arm
*Includes the preferred terms peripheral sensory neuropathy, PN, hypoesthesia, polyneuropathy, paraesthesia, muscular weakness, peripheral motor neuropathy, peroneal nerve palsy, muscle atrophy, hypotonia, autonomic neuropathy, neuralgia, burning sensation, dysesthesia, gait disturbance, toxic neuropathy, neurotoxicity, and sensory disturbance†Includes the preferred terms lung infiltration, pneumonitis, interstitial lung disease, acute respiratory distress syndrome, organizing pneumonia, pulmonary fibrosis, and pulmonary toxicity
Drug discontinuations due to PN:A+AVD 7%ABVD 2%
80
70
60
50
40
30
20
10
0
A+AVD ABVD
All
A+AVD ABVD
Grade ≥3
Interstitial lung disease
†
Patients (%)
Slide11Experimental arm:BV 1.2 mg/kg every 2 weeksG-CSF mandatory
Fornecker LM et al. Proc ASH 2017;Abstract 736.
BREACH: Phase II Study Design
R
Arm A
Arm B
PET-CT 0
PET-CT 2
PET-CT 4*
PET-CT
EoT
C1
C2
C3
C4
2W
2W
2W
2W
2W
2W
2W
3 to 4W
Radiotherapy
30Gy
10-12 W
PET-CT 0
PET-CT 2
PET-CT 4*
PET-CT
EoT
C1
C2
C3
C4
2W
2W
2W
2W
2W
2W
2W
3 to 4W
30Gy
10-12 W
Standard arm
Experimental arm
Radiotherapy
AVD +
Brentuximab
vedotin
Refractory
patients:
Premature
withdrawal
Slide12PET
response after 2 cycles, n(%)BV-AVDn = 113ABVDn = 57Negative93 (82.3)43 (75.4)
BREACH: PET-Based Response After 2 Cycles (IRC Assessment)
Fornecker
LM et al.
Proc ASH
2017;Abstract 736.
Slide13BV-AVD
n = 113ABVDn = 55*113 (100)55 (100)Grade 3-4 AE84 (74)31 (56)SAE24 (21)4 (7)Grade 3-4 SAE21 (19)4 (7)Treatment-related SAE19 (17)1 (2)SAE leading to permanent BV treatment discontinuation7 (6)NA
Reasons for permanent BV discontinuation: Weight loss, hyponatremia, febrile neutropenia, epileptic seizure, peripheral neuropathy, hepatitis and cutaneous rash
Select Adverse Events (Cycles 1 and 2)
* 2 patients with no study drug administration due to consent withdrawal
Fornecker
LM et al.
Proc ASH
2017;Abstract 736.
Slide14n (%) of pts
reporting ≥1 eventBV-AVDn = 113ABVDn = 55Neutropenia72 (64)30 (55)Leukopenia35 (31)12 (22)Febrile neutropenia8 (7)1 (2)Gastrointestinal disorders9 (8)0 (0)ALT and/or AST increase5 (4)1 (2)Peripheral neuropathy2 (2)0 (0)Infections and infestations5 (4)1 (2)Skin and subcutaneous tissue disorders1 (1)0 (0)
Common Grade 3-4 AEs (Cycles 1 and 2)
Fornecker
LM et al.
Proc ASH
2017;Abstract 736.
Slide15AETHERA: Phase III Trial Design
Randomization stratified byRisk factors after frontline therapy;Best clinical response to salvage therapy before ASCT.Patients with progressive disease after salvage therapy were not eligible.
Moskowitz CH et al. Lancet 2015;385(9980):1853-62.
Salvage therapy
CR
PR
SD
PD
BV
Placebo
Not eligible
Frontline
therapy
Restagerisk factorsassessed
Refractory to frontline treatment
Relapsed
<12
mo
frontline therapy
Relapsed
<12
mo
with
extranodal
involvement
Restage
ASCT
Eligibility criteria
stratification
Additional
stratification factor
Study treatment start D30-45
post-ASCT
Slide16Risk Factors on AETHERA Only 10% of patients had one unfavorable prognostic factor
Initial remission duration < 1 yearPET positive response to most recent salvage therapy 1 of 5 risk factors≥2 salvage therapiesExtranodal disease at pre-ASCT relapseB symptoms at pre-ASCT relapseI administer maintenance to patients with >1 risk factor
Courtesy of
Dr
Craig Moskowitz
Slide17AETHERA: PFS Per Investigator: ≥2 Risk Factors
Time (months)
Percent
of subjects free of PD or death
NEventsMedian(months)Stratified hazard ratio Placebo + BSC136869.7— BV = BSC14455—0.418
Slide18The issues concerning AETHERA
Neuropathy90% resolution to grade I or less; remember to dose reduce if grade II Overall survivalWith the cross over design and the new era with CPI; only time will tell if there will be a difference but unlikely Indefinite palliative therapy is not funPrevious BV therapyCommon sense approachPre-ASCT PET and outcomeOnly 1 of 5 risk factors in this studyNot prospectively done, read centrally or defined by Deauville criteria
Courtesy of
Dr
Craig Moskowitz
Slide196 studies: Same goal – PET negative CR
Sequential immuno-chemotherapy (published)BV as a single agent and sequential administration of ICE or other salvage therapy only if < CR is achieved (MSKCC, COH studies respectively)Concomitant immuno-chemotherapy (abstract only)BV + bendamustine – in reviewBRAVE: BV + DHAP – presented at ISHLBR-ESHAP – ASH 2016BV + ICE – (Seattle) poster at ASH 2016
Courtesy of
Dr
Craig Moskowitz
Slide20Regimen
Pt #RelPrimaryRefCR-PET neg pre-ASCTCD34ASCT %PFSITTBV-ESHAP66264070%5.7592Too soonBenda-BV54272774%47463% at 2 yearsBV-ICE1651169%1175Too soonBV-DHAP1210290%5.3100Too soonBV Sequential ICE66333373%6.29579% at 3 yrsBV Sequential salvage therapy37132473%5.68972% at 18 moICE/GVD97564176%6.38868% at 8 yrsBenda-GV59273273%8.87363% at 2 yrs
Current State of Salvage Therapy
Courtesy of
Dr
Craig Moskowitz
Slide21Tumor Response on a Phase 1/2 Study of Brentuximab
Vedotin
plus Nivolumab in Patients with Relapsed/Refractory Hodgkin Lymphoma
N = 59
n
(%)Complete response (CR)37 (63) Deauville ≤ 229 (49) Deauville 37 (12) Deauville 5a1 (2)Partial response (PR)13 (22) Deauville 47 (12) Deauville 56 (10)No metabolic response (SD)5 (8) Deauville 55 (8)Progressive disease (PD)3 (5) Deauville 52 (3) Missing1 (2)Clinical progression (CP)1 (2)
At the time of this analysis, 37 patients had proceeded to ASCT
85% objective response rate with 63% complete responses
a 1 pt had uptake in lymph node, but no evidence of disease was found on biopsy
SPD change from baseline
Max SUV change from baseline
Herrera AF et al.
Proc ASH
2016;Abstract 1105.
Slide22Regimen
Pt #RelPrimaryRefCR-PET neg pre-ASCTCD34ASCT %PFSITTBV + Nivo42251763%7.9NAToo soonBV + ChemotherapyBV-ESHAP66264070%5.7592Too soonBenda-BV54272774%47463% at 2 yearsBV-ICE1651169%1175Too soonBV-DHAP1210290%5.3100Too soonBV Sequential ICE66333373%6.29579% at 3 yrsBV Sequential salvage therapy37132473%5.68972% at 18 moChemotherapy ICE/GVD97564176%6.38868% at 8 yrsBenda-GV59273273%8.87363% at 2 yrs
Current State of Salvage Therapy
Slide23I recommend sequential therapy
There is no evidence that a CR to single agent BV is inferior to that of chemotherapy or chemo-immunotherapyNearly 40% of patients can avoid chemotherapy for salvage if BV is used firstChemotherapy alone without BV offers a CR rate of 60-73% with ICE or BeGVBV can be used as salvage number 2Bendamustine-BV seems no better than BeGVPlatinum based salvage regimens combined with BV are “challenging”BV-nivo – need to wait for long term data, but the cost is shocking and the gain is suspect at best
Courtesy of
Dr
Craig Moskowitz
Slide24Analysis of over 100,000 patients with cancer for CD274 (PD-L1) amplification: Implications for treatment with immune checkpoint blockade
Goodman A et al.
Proc ASCO
SITC 2018;Abstract 47.
Slide25Analysis of
CD274 (PD-L1) Gene Amplification in Patients with Cancer
Analysis of CD274 gene copy number amplification (CNA) in >100,000 patient samples from Foundation Medicine database and UC San Diego.CD274 CNAs detected in 0.7% of all tumor samples:
Select tumor typeTotal patients% with CD274 CNASoft tissue sarcoma undifferentiated3133.8Thyroid anaplastic sarcoma1653.0Lung adenocarcinoma≥10,0000.6Breast cancer2,000 – 9,9992.0Colon cancer2,000 – 9,9990.2Prostate cancer2,000 – 9,9990.2
Goodman A et al. Proc ASCO SITC 2018;Abstract 47.
9 patients with
CD274
CNAs received PD-1/PD-L1 blockade at UC San Diego:
Response rate = 6/9 (67%); median PFS = 15.1
mo
Slide26Blood
2017;130(20):2196-203.
Slide27Prognostic Significance of Baseline Metabolic Tumor Volume (
bMTV)
Moskowitz AJ et al. Blood 2017;130(20):2196-203.
Event-free survival for low (<109.5 cm3) or high (>109.5 cm3) bMTV
MTV < 109.5 cm3, n = 48, censored 44
MTV ≥ 109.5 cm3, n = 12, censored 4
p
< 0.001