Targeted therapy for Hodgkin’s Lymphoma
Transcript of Targeted therapy for Hodgkin’s Lymphoma
Targeted therapy for Hodgkin’s Lymphoma
Larry W. Kwak, M.D., Ph.D.
Chairman, Department of Lymphoma/Myeloma
Justin Distinguished Chair in Leukemia Research
Co-Director, Center for Cancer Immunology Research
MD Anderson Cancer Center
Goals of Ongoing Research
• Improve remission rates and decrease risk of death
• Minimize side effects and maintain or prolong remissions
• Develop additional therapeutic options for relapsed/refractory disease (e.g. post-SCT)
STAT6 TARCJAK1/3
SOCS
Treg
Hodgkin’sReed-Sternberg cell
IL13
TH2
Vorinostat/SAHAMGCD0103
Bcl-xL
Survival
DCOX40L
TH
Che
mot
axix
of T
H2 c
ells
TH2
TH2
A
B
Development of (Deacetylase inhibitors) DACi in Hodgkin lymphoma
Dual antiproliferative activity: 1) Induction of cell cycle arrest and apoptosis (direct)2) Downregulation of TARC/CCL17 and alteration of the microenvironment (indirect)
Buglio et al, BLOOD 2008
Ligation of OX40 receptor (on T cells) inhibits the induction of Treg cells
C
Baseline31 year old femaleExtensive Prior TherapyRegimen Best ResponseABVD PRXRT Not EvalDHAP PRAuto Transplant Not EvalIGEV ProgressionDHAP ProgressionFludarabine/ Melphalan ProgressionAllo Transplant ProgressionDonor lymphocyte ProgressionMOPP Not EvalESHAP ProgressionIEV Progression
2 months
Oral HDAC Inhibitor Mocetinostat (MGCD0103) Clinical Activity in Hodgkin Lymphoma
PET
Younes et al, Lancet Oncology 2011
Single-arm Phase II study (n=51)
R21 “quick trials” grant
R2=0.40
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
1.8
2
0.00 0.20 0.40 0.60 0.80 1.00 1.20 1.40 1.60 1.80
Ratio of TARC change
Rat
io o
f tu
mo
r ch
ang
e DACi in Hodgkin lymphoma
Early decline in plasma TARC Levels correlates with clinical response
Younes et al, Lancet Oncology 2011
International oral Panobinostat (pan-HDACi) Phase II Study in HL
-100
-75
-50
-25
0
25
50
75
100
Be
st %
Ch
an
ge
in S
PD
F
rom
Ba
selin
e(i
nd
ex
lesi
on
s o
nly
)
Active
Discontinued
PR
PD
4 patients - SD (0%)
6 patients - off AE prior to Eval 11 patient - withdrew consent prior to Eval 11 patient - pending Eval 1 measurements
5 patients with SPD < 50% had new lesions at Eval 1
71% of patients with tumor reduction
Younes A, et al. JCO 2012
Efficacy of Unconjugated Anti-CD30 Antibodies in CD30 Positive Lymphomas
Drug Patients Dose Outcomes Authors
SGN-30 Chimeric Ab
24 pt (21 HL, 3 ALCL) Phase I
2 - 12 mg/kg weekly x 6
1 CR in cALCL, 6 SD (4 in HL)
Bartlett Blood 111: 2008
SGN-30 79 pt (38 HL, 41 sALCL) Phase II
6 - 12 mg/kg weekly x 6
HL No Resp, sALCL 17% Resp, 2 CR, 5 PR, All were ALK neg
Forero-Torres Br J Haematol, 2009
MDX-060 Fully Human Ab
72 pt (63 HL, 4 ALCL) Phase I/II
1 - 15 mg/kg weekly x 4
RR 8% (CRs in 2 HL, 2 ALCL)
Ansell JCO 25: 19, 2007
Brentuximab vedotin (SGN-35) ADCmonomethyl auristatin E (MMAE), microtubule disrupting agent
protease-cleavable linker
anti-CD30 monoclonal antibody
ADC binds to CD30
MMAE disruptsmicrotubule network
ADC-CD30 complex is internalized and traffics to lysosome
MMAE is released
Apoptosis
G2/M cellcycle arrest
Brentuximab Vedotin: Mechanism of Action
Brentuximab Vedotin: Phase I Results• Every 3 wk treatment
45 pts (42 HL, 2 ALCL, 1 AITCL)
73% prior ASCT
Doses 0.1 to 3.6 mg/kg every 3 wks
MTD 1.8 mg/kg
86% tumor regression, 38% ORR, 24% CR
Peripheral sensory neuropathy: ≥ grade 1 in 36%
• Weekly treatment44 pts (38 HL, 5 ALCL, 1 PTCL-NOS)
68% prior ASCT
Doses of 0.4 to 1.4 mg/kg on D1, 8, 15 of 28-day cycle
MTD 1.2 mg/kg
85% tumor regression, 58% ORR, 34% CR
Peripheral sensory neuropathy: ≥ grade 1 in 66%
Younes A et al, NEJM, 2010; Fanale, M et al, CCR, 2011
Maximum Reduction in Target Lesions
81% of patients achieved tumor reductions
Bartlett et al. JCO 27: 434s, 2009 (abst 8500).
Demographics and Baseline Characteristics in Pivotal HL Trial
N=102
Age* (years) 31 (1577)
Gender (M / F) 48 / 54
ECOG status (0 / 1) 42 / 60
Refractory to frontline therapy 72 (71%)
Refractory to most recent treatment 43 (42%)
Prior chemotherapy regimens* 3.5 (113)
Relapse ≤1 year post ASCT 72 (71%)
Time from ASCT to first post transplant relapse* 6.7 mo (0131)
* Median (range)
Younes , A et al, ICML, 2011
Conclusions from Pivotal HL Trial• Multiple durable CRs obtained with brentuximab vedotin
in highly treatment-refractory patients with HL
• Similar duration of remissions with or without allogeneic transplant
• Manageable adverse events; peripheral neuropathylargely reversible◦ 55% of patients had at least 1 event of peripheral neuropathy
◦ No grade 4 events of peripheral neuropathy
◦ Resolution or some improvement of PN : 80% at 13.2 weeks
CR ORR
Rate 34% 75%
Median Duration 20.5 mo 6.7 mo
Younes, A et al, ICML, 2011
Introduction of Targeted Therapies into Front-line
Rationale
• Treatment-naïve patients with Hodgkin lymphoma (HL) are commonly treated with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD)1
• Frontline therapy with ABVD generally yields a 70% to 80% CR rate2,3
• Bleomycin-induced pulmonary toxicity occurs in 10% to 25% of patients receiving this regimen4
• Single-agent brentuximab vedotin (ADCETRIS®) in relapsed or refractory HL patients has shown an objective response rate of 75% (CR, 33%) with manageable toxicity5
1 Connors et al, 2005
2 Gordon et al, presented at ASH 2010
3 Gallamini et al, 2007
4 Horning et al, 1994
5 Smith et al, presented at EHA 2012
Study Design
• Phase 1, multicenter, dose-escalation study • Major eligibility criteria
◦ Treatment-naïve HL patients
◦ Age ≥18 to ≤60 years
◦ Stage IIA bulky disease or Stage IIB-IV disease
• Treatment design◦ 28-day cycles (up to 6 cycles) with dosing on Days 1 and 15
A(B)VD
Brentuximab Vedotin
Cycle 1 Cycle 2 Cycle 3
6 Cycles +/- XRT
Weeks0 2 4 6 8 10 12
Ansell S. et al. ASH 2012
Key Study Objectives
• To assess the safety profile of brentuximab vedotin in combination with ABVD and in combination with AVD
• To determine the maximum tolerated dose (MTD), if reached, of brentuximab vedotin in combination with ABVD and in combination with AVD
• To assess the antitumor activity of brentuximab vedotin in combination with ABVD and in combination with AVD
Description of Dose Cohorts
ABVD with brentuximab vedotin
N=25
AVD with brentuximab vedotin
N=26
Cohort 1 Cohort 2 Cohort 3 Cohort 4 Expansion
Brentuximab vedotin dose, mg/kg
0.6 0.9 1.2 1.2 1.2
Patients treated, N 6 13 6 6 20
Demographics and Baseline Characteristics
Parameter
ABVD withbrentuximab vedotin
N=25
AVD with brentuximab vedotin
N=26TotalN=51
Age, yearsa 35 (1959) 33 (1858) 33 (1859)
Gender 20 M / 5 F 17 M / 9 F 37 M / 14 F
IPS ≥4, n (%) 7 (28) 6 (23) 13 (25)
Bulky disease, n (%) 5 (20) 12 (46) 17 (33)
Stage, n (%)
IIA bulky 0 3 (12) 3 (6)
IIB 4 (16) 4 (15) 8 (16)
IIIA 5 (20) 3 (12) 8 (16)
IIIB 4 (16) 5 (19) 9 (18)
IV 12 (48) 11 (42) 23 (45)
a Median (range)
Summary of Adverse Events ≥Grade 3
Preferred term*
ABVD with brentuximab vedotin
N=25
AVD with brentuximab vedotin
N=26
Neutropenia 20 (80) 20 (77)
Anemia 5 (20) 3 (12)
Febrile neutropenia 5 (20) 2 (8)
Pulmonary toxicity 6 (24) 0
Syncope 3 (12) 2 (8)
Dyspnea 3 (12) 1 (4)
Pulmonary embolism 3 (12) 0
Fatigue 1 (4) 1 (4)
Leukopenia 1 (4) 1 (4)
* Grade 3 or higher adverse events (AEs) occurring in more than 1 patient overall, regardless of relationship
Pulmonary Toxicity
Preferred term
ABVD with brentuximab vedotin
N=25
AVD with brentuximab vedotin
N=26
Any event 11 (44) 0
Pulmonary toxicity 9 (36) 0
Interstitial lung disease 1 (4) 0
Pneumonitis 1 (4) 0
• Events generally occurred during Cycles 34• Two patient deaths were associated with pulmonary toxicity• Events resolved in 9 of 11 patients (82%)
◦ Median time to resolution was 2.6 weeks (range, 1.6 to 5 weeks)
• 8 of 11 patients with events discontinued bleomycin and were able to complete treatment with AVD combined with brentuximab vedotin
Peripheral Neuropathy
Preferred term*
ABVD with brentuximab vedotin
N=25
AVD with brentuximab vedotin
N=26
Any event 18 (72) 20 (77)
Peripheral sensory neuropathy 18 (72) 19 (73)
Peripheral motor neuropathy 3 (12) 3 (12)
Muscular weakness 1 (4) 2 (8)
Paraesthesia 1 (4) 0* Summary of events using a standard MedDRA query (SMQ), regardless of relationship or severity
• Events were managed with dose modifications• Most events were Grade 1 or 2 and no events were Grade 4 or 5• One patient experienced Grade 3 events of peripheral sensory
neuropathy (fingers and toes) and peripheral motor neuropathy (hands and feet)
• Overall, 6 of 51 patients discontinued brentuximab vedotin due to peripheral neuropathy; these discontinuations occurred in Cycles 5 or 6
Maximum Dose and Dose-Limiting Toxicities
• Dose-limiting toxicities (DLTs) were defined as any Cycle1 toxicity requiring a dose delay ≥7 days in standard ABVD or AVD therapy
• No protocol-defined DLTs observed with either ABVD or AVD in combination with up to 1.2 mg/kg brentuximab vedotin (the maximum planned dose)
• A 1.2 mg/kg dose of brentuximab vedotin administered every 2 weeks is expected to achieve the same exposure (AUC) as the approved single-agent dose of 1.8 mg/kg every 3 weeks
Response Results at End of Frontline Therapy
Response per Investigatora
ABVD with brentuximab vedotin
N=22
AVD with brentuximab vedotin
N=25
Response at end of frontline therapy, n (%)
Complete remission 21 (95) 24 (96)
Progressive disease 0 1 (4)
Not evaluable due to AEs 1b (5) 0
a Assessed using Cheson 2007b Patient had a Grade 5 event of pulmonary toxicity prior to the end of frontline therapy
• Response results at end of frontline therapy:
◦ ABVD cohorts: 21 of 22 CR (95%)
◦ AVD cohorts: 24 of 25 CR (96%)• In addition, 1 patient withdrew consent and 3 patients were lost to
follow-up prior to completion of frontline therapy and were not evaluable for response
Conclusions
• Concomitant administration of brentuximab vedotin and bleomycin is contraindicated due to pulmonary toxicity
• Recommended regimen is 1.2 mg/kg brentuximab vedotin every 2 weeks combined with AVD
• AVD combined with brentuximab vedotin appears to be well tolerated with manageable AEs
• CR rate of 96% observed at the end of frontline therapy with brentuximab vedotin combined with AVD
• Phase 3 study ongoing to assess treatment with brentuximab vedotin in combination with AVD as compared to ABVD alone in treatment-naive patients
Department of Lymphoma/Myeloma Disease –specific Working Groups
N. FowlerF. SamaniegoS. NeelapuL. FayadL. Kwak
T cell lymphoma
Multiplemyeloma
D. WeberJ. ShahS. ThomasM. WangR. AlexanianQ. Yi
Michael Wang, M.D.Nathan Fowler, M.D.
Co-DirectorsLymphoma Clinical Research
Robert Orlowski, M.D., Ph.D.Director
Myeloma Clinical Research
BurkittHIV
BrainTesticular
M. Fanale N. Fowler
M. FanaleN. FowlerJ. ShahJ. Westin
Larry W. Kwak, M.D., Ph.D.Chairman, Lymphoma/Myeloma
Low Grade lymphoma
Large Cell lymphoma
Mantle cell lymphoma
Hodgkins
L. FayadA. RodriguezF. HagemeisterJ. Westin
M. WangJ. RomagueraM. Fanale
F. Hage- meister
Phase I
Y. OkiM. Fanale
Rituximab plus ABVD
Rituximab weekly x 6 plus ABVD x 670 patients with stage II to IV diseaseMedian age 28 yoIPS ≥ 3 in 55%Protocol modified to include just IPS ≥ 3 based of initial results
Median f/u 32 months: EFS 85% & OS 98%78% of pts PET-2/3 negative5-year EFS for PET-negative vs positive of 93% vs 75%Improvement in EFS with R-ABVD compared to institutional ABVD outcomes
R-ABVD with IPS of 0-2 (89% vs 71%) and IPS ≥ 3 (80% vs 55%)
Copeland, A et al, ASH, 2010
R-ABVD for Advanced HL: Improvement in FFS Related to PET
Newer therapies are needed for HL with Pos PET Early pos PET after 2 ABVD predicts 100% relapseR-ABVD appears to give better results for high risk
patients with HLIn this prospective study, 55 patients with HL had a
PET after 2-3 R-ABVD: Therapy was not changed in these patients based on the PET findings
Results: PET Neg PET Pos p Patients (%) 43 (78) 12 (22) 5 Yr EFS 93% 75% 0.05
R-ABVD may be a better regimen than ABVD because PET positive patients have better results
Hutchings et al. Blood 107:52-59, 2006.Hutchings et al. Blood 107:52-59, 2006.
Wedgwood et al. Submitted to ASH 2007.Wedgwood et al. Submitted to ASH 2007.
FDG-PET positive16 Patients, prog=112-year PFS 0%
1.0
.08
.06
.04
.02
0.0Per
cen
t P
rog
ress
ion
-Fre
e
PET neg61 Pts, 3 prog2 yr PFS 96%
3210
PET after 2 cycles
P < .001
Years
1.0
.08
.06
.04
.02
0.0Per
cen
t P
rog
ress
ion
-Fre
e CR, PR2 Pts, 0 prog2 yr PFS 100%
3210
CT after 2 cycles
< PR62 Pts, 11 prog2 yr PFS 82%
P < .554
Years
PET vs CT for Stage I-IV HL: PFS Results by Radiographic Assessment after 2 CT Cycles
Hutchings et al. Blood 107:52-59, 2006
PET ps14 Pts, 11 prog2 yr PFS 0%
Per
cen
t E
ven
t-F
ree
100
75
50
25
04836240 6012
Months
EFS for R-ABVD
Score 0-1Score 0-2Score 2Score >2Score >3Score >4
R-ABVD for Advanced HD: EFS by IPS Score Compared with IPS Curves
Younes et al. Blood 106:431a, 2005 (abst 1499).
0 12 24 36 48 60 72 840
20
40
60
80
100
Score, 0Score, 1Score, 2Score, 3Score, 4Score, ≥5
EFS for IPSEFS for IPS
MonthsMonths
Hasencleaver and Diehl. NEJM 339: 1506-1514,1998.Hasencleaver and Diehl. NEJM 339: 1506-1514,1998.
GHSG HD18 Trial for Advanced HL: Study Design
2 x BEACOPP escalated
POS PET NEG PET
At End of Therapy:
POS PET: RT to Res Nodes >2.5 cm
NEG PET: NO RT
6xBEACOPPesc6xBEACOPPesc 6xR-BEACOPPesc 2xBEACOPPesc