SlideShare a Scribd company logo
1 of 31
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’s
Reed-Sternberg cell
IL13
TH2
Vorinostat/SAHA
MGCD0103
Bcl-xL
Survival
DC
OX40L
TH
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
Baseline
31 year old female
Extensive Prior Therapy
Regimen Best Response
ABVD PR
XRT Not Eval
DHAP PR
Auto Transplant Not Eval
IGEV Progression
DHAP Progression
Fludarabine/
Melphalan Progression
Allo Transplant Progression
Donor lymphocyte Progression
MOPP Not Eval
ESHAP Progression
IEV 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
Ratiooftumorchange
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
Best%ChangeinSPDFromBaseline
(indexlesionsonly)
Active
Discontinued
PR
PD
4 patients - SD (0%)
6 patients - off AE prior to Eval 1
1 patient - withdrew consent prior to Eval 1
1 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) ADC
monomethyl auristatin E (MMAE), microtubule disrupting agent
protease-cleavable linker
anti-CD30 monoclonal antibody
ADC binds to CD30
MMAE disrupts
microtubule network
ADC-CD30 complex
is internalized and
traffics to lysosome
MMAE is released
Apoptosis
G2/M cell
cycle 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 treatment
44 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 (15 77)
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 (1 13)
Relapse ≤1 year post ASCT 72 (71%)
Time from ASCT to first post transplant relapse* 6.7 mo (0 131)
* 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 neuropathy
largely 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
Weeks
0 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
Demographics and Baseline Characteristics
Parameter
a Median (range)
Summary of Adverse Events ≥Grade 3
Preferred term*
* Grade 3 or higher adverse events (AEs) occurring in more than 1 patient overall, regardless of relationship
Pulmonary Toxicity
Preferred term
• Events generally occurred during Cycles 3 4
• 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*
* 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 Cycle
1 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
a Assessed using Cheson 2007
b 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. Fowler
F. Samaniego
S. Neelapu
L. Fayad
L. Kwak
T cell
lymphoma
Multiple
myeloma
D. Weber
J. Shah
S. Thomas
M. Wang
R. Alexanian
Q. Yi
Michael Wang, M.D.
Nathan Fowler, M.D.
Co-Directors
Lymphoma Clinical Research
Robert Orlowski, M.D., Ph.D.
Director
Myeloma Clinical Research
Burkitt
HIV
Brain
Testicular
M. Fanale N. Fowler
M. Fanale
N. Fowler
J. Shah
J. Westin
Larry W. Kwak, M.D., Ph.D.
Chairman, Lymphoma/Myeloma
Low Grade
lymphoma
Large Cell
lymphoma
Mantle cell
lymphoma
Hodgkins
L. Fayad
A. Rodriguez
F. Hagemeister
J. Westin
M. Wang
J. Romaguera M. Fanale
F. Hage-
meister
Phase
I
Y. Oki
M. Fanale
Rituximab plus ABVD
Rituximab weekly x 6 plus ABVD x 6
70 patients with stage II to IV disease
Median age 28 yo
IPS ≥ 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 negative
5-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% relapse
R-ABVD appears to give better results for high risk
patients with HL
In 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.
Wedgwood et al. Submitted to ASH 2007.
FDG-PET positive
16 Patients, prog=11
2-year PFS 0%
1.0
.08
.06
.04
.02
0.0
PercentProgression-Free
PET neg
61 Pts, 3 prog
2 yr PFS 96%
3210
PET after 2 cycles
P < .001
Years
1.0
.08
.06
.04
.02
0.0PercentProgression-Free
CR, PR
2 Pts, 0 prog
2 yr PFS 100%
3210
CT after 2 cycles
< PR
62 Pts, 11 prog
2 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 ps
14 Pts, 11 prog
2 yr PFS 0%
PercentEvent-Free
100
75
50
25
0
4836240 6012
Months
EFS for R-ABVD
Score 0-1
Score 0-2
Score 2
Score >2
Score >3
Score >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 84
0
20
40
60
80
100
Score, 0
Score, 1
Score, 2
Score, 3
Score, 4
Score, ≥5
EFS for IPS
Months
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

More Related Content

What's hot

Lymphoma overview
Lymphoma overviewLymphoma overview
Lymphoma overview
derosaMSKCC
 

What's hot (20)

Hodgkin's Lymphoma: Treatment Update
Hodgkin's Lymphoma: Treatment UpdateHodgkin's Lymphoma: Treatment Update
Hodgkin's Lymphoma: Treatment Update
 
Lymphoma overview
Lymphoma overviewLymphoma overview
Lymphoma overview
 
DLBCL
DLBCLDLBCL
DLBCL
 
Treatment of Large Cell Lymphoma
Treatment of Large Cell Lymphoma Treatment of Large Cell Lymphoma
Treatment of Large Cell Lymphoma
 
New Directions in the Management of Relapsed/Refractory Follicular Lymphoma
New Directions in the Management of Relapsed/Refractory Follicular LymphomaNew Directions in the Management of Relapsed/Refractory Follicular Lymphoma
New Directions in the Management of Relapsed/Refractory Follicular Lymphoma
 
Molecular testing of breast ca
Molecular testing of breast caMolecular testing of breast ca
Molecular testing of breast ca
 
Molecular profiling of breast cancer
Molecular profiling of breast cancerMolecular profiling of breast cancer
Molecular profiling of breast cancer
 
Osteosarcoma ppt
Osteosarcoma pptOsteosarcoma ppt
Osteosarcoma ppt
 
Basics of immunotherapy in colorectal cancer
Basics of immunotherapy in colorectal cancerBasics of immunotherapy in colorectal cancer
Basics of immunotherapy in colorectal cancer
 
Putting a Personalized Colorectal Cancer Treatment Algorithm Into Practice: N...
Putting a Personalized Colorectal Cancer Treatment Algorithm Into Practice: N...Putting a Personalized Colorectal Cancer Treatment Algorithm Into Practice: N...
Putting a Personalized Colorectal Cancer Treatment Algorithm Into Practice: N...
 
Molecular Biology of Esophageal and Gastric Cancer
Molecular Biology of Esophageal and Gastric CancerMolecular Biology of Esophageal and Gastric Cancer
Molecular Biology of Esophageal and Gastric Cancer
 
Hodgkin lymphoma db.pptx
Hodgkin lymphoma db.pptxHodgkin lymphoma db.pptx
Hodgkin lymphoma db.pptx
 
lung cancer biomarkers
lung cancer biomarkerslung cancer biomarkers
lung cancer biomarkers
 
Melanoma Immunotherapy - Dr. Patrick Hwu
Melanoma Immunotherapy - Dr. Patrick HwuMelanoma Immunotherapy - Dr. Patrick Hwu
Melanoma Immunotherapy - Dr. Patrick Hwu
 
immunotherapy and PDL1 IHC
immunotherapy and PDL1 IHCimmunotherapy and PDL1 IHC
immunotherapy and PDL1 IHC
 
ALK INHIBITORS NSCLC.pptx
ALK INHIBITORS NSCLC.pptxALK INHIBITORS NSCLC.pptx
ALK INHIBITORS NSCLC.pptx
 
Presentation1 fgfr
Presentation1 fgfrPresentation1 fgfr
Presentation1 fgfr
 
Cancer Biomarkers
Cancer BiomarkersCancer Biomarkers
Cancer Biomarkers
 
Hodgkins lymphoma pathogenesis and targets for therapy
Hodgkins lymphoma pathogenesis and targets for therapyHodgkins lymphoma pathogenesis and targets for therapy
Hodgkins lymphoma pathogenesis and targets for therapy
 
metastatic colorectal cancer; a new chapter in the story
metastatic colorectal cancer; a new chapter in the storymetastatic colorectal cancer; a new chapter in the story
metastatic colorectal cancer; a new chapter in the story
 

Similar to Targeted therapy for Hodgkin’s Lymphoma

8 jason westin
8 jason westin8 jason westin
8 jason westin
spa718
 
Pembrolizumab - “Treatment of melanoma has never been this promising”
Pembrolizumab - “Treatment of melanoma has never been this promising”Pembrolizumab - “Treatment of melanoma has never been this promising”
Pembrolizumab - “Treatment of melanoma has never been this promising”
Patwant Dhillon
 
Nivolumab vs Docetaxel in Lung SCC
Nivolumab vs Docetaxel in Lung SCCNivolumab vs Docetaxel in Lung SCC
Nivolumab vs Docetaxel in Lung SCC
Abdelrahman Labban
 
6 frederick
6 frederick6 frederick
6 frederick
spa718
 
MAINTENANCE THERAPY IN MULTIPLE MYELOMA
MAINTENANCE THERAPY IN MULTIPLE MYELOMAMAINTENANCE THERAPY IN MULTIPLE MYELOMA
MAINTENANCE THERAPY IN MULTIPLE MYELOMA
spa718
 
Slide deck updates on cml (1)
Slide deck updates on cml (1)Slide deck updates on cml (1)
Slide deck updates on cml (1)
madurai
 
TREATMENT_OF_MYELOID_LEUKEMIA Final.pptx
TREATMENT_OF_MYELOID_LEUKEMIA Final.pptxTREATMENT_OF_MYELOID_LEUKEMIA Final.pptx
TREATMENT_OF_MYELOID_LEUKEMIA Final.pptx
Pavan Sagar
 
02 ptcl ylk
02 ptcl  ylk02 ptcl  ylk
02 ptcl ylk
spa718
 

Similar to Targeted therapy for Hodgkin’s Lymphoma (20)

8 jason westin
8 jason westin8 jason westin
8 jason westin
 
Pembrolizumab - “Treatment of melanoma has never been this promising”
Pembrolizumab - “Treatment of melanoma has never been this promising”Pembrolizumab - “Treatment of melanoma has never been this promising”
Pembrolizumab - “Treatment of melanoma has never been this promising”
 
brenutuximab-journal club.pptx
brenutuximab-journal club.pptxbrenutuximab-journal club.pptx
brenutuximab-journal club.pptx
 
Nivolumab vs Docetaxel in Lung SCC
Nivolumab vs Docetaxel in Lung SCCNivolumab vs Docetaxel in Lung SCC
Nivolumab vs Docetaxel in Lung SCC
 
S.c.l.c dr.hatem
S.c.l.c dr.hatemS.c.l.c dr.hatem
S.c.l.c dr.hatem
 
6 frederick
6 frederick6 frederick
6 frederick
 
Renal cell cancer
Renal cell cancerRenal cell cancer
Renal cell cancer
 
MAINTENANCE THERAPY IN MULTIPLE MYELOMA
MAINTENANCE THERAPY IN MULTIPLE MYELOMAMAINTENANCE THERAPY IN MULTIPLE MYELOMA
MAINTENANCE THERAPY IN MULTIPLE MYELOMA
 
Unmet need in multiple myeloma
Unmet need in multiple myelomaUnmet need in multiple myeloma
Unmet need in multiple myeloma
 
Slide deck updates on cml (1)
Slide deck updates on cml (1)Slide deck updates on cml (1)
Slide deck updates on cml (1)
 
Small cell carcinoma
Small cell carcinomaSmall cell carcinoma
Small cell carcinoma
 
TREATMENT_OF_MYELOID_LEUKEMIA Final.pptx
TREATMENT_OF_MYELOID_LEUKEMIA Final.pptxTREATMENT_OF_MYELOID_LEUKEMIA Final.pptx
TREATMENT_OF_MYELOID_LEUKEMIA Final.pptx
 
02 ptcl ylk
02 ptcl  ylk02 ptcl  ylk
02 ptcl ylk
 
Improving Patient Outcomes With Cancer Immunotherapies Throughout the Lung Ca...
Improving Patient Outcomes With Cancer Immunotherapies Throughout the Lung Ca...Improving Patient Outcomes With Cancer Immunotherapies Throughout the Lung Ca...
Improving Patient Outcomes With Cancer Immunotherapies Throughout the Lung Ca...
 
Hodgkin chemo final
Hodgkin chemo finalHodgkin chemo final
Hodgkin chemo final
 
MANAGEMENT OF GLIOMAS
MANAGEMENT OF GLIOMASMANAGEMENT OF GLIOMAS
MANAGEMENT OF GLIOMAS
 
Membranous Nephropathy
Membranous NephropathyMembranous Nephropathy
Membranous Nephropathy
 
Carfilzomib: new standard of care for myeloma
Carfilzomib: new standard of care for myelomaCarfilzomib: new standard of care for myeloma
Carfilzomib: new standard of care for myeloma
 
V_Hematology_Forum_Dr_Moskowitz
V_Hematology_Forum_Dr_MoskowitzV_Hematology_Forum_Dr_Moskowitz
V_Hematology_Forum_Dr_Moskowitz
 
( )Anal scc
( )Anal scc( )Anal scc
( )Anal scc
 

More from spa718

1600 1620 siwanon jirawatnotai
1600 1620 siwanon jirawatnotai1600 1620 siwanon jirawatnotai
1600 1620 siwanon jirawatnotai
spa718
 

More from spa718 (20)

1600 1620 siwanon jirawatnotai
1600 1620 siwanon jirawatnotai1600 1620 siwanon jirawatnotai
1600 1620 siwanon jirawatnotai
 
Controversies in hepato-biliary surgery
Controversies in hepato-biliary surgery Controversies in hepato-biliary surgery
Controversies in hepato-biliary surgery
 
Controversies in Colorectal Cancer
Controversies in Colorectal CancerControversies in Colorectal Cancer
Controversies in Colorectal Cancer
 
Pancreatic Cancer
Pancreatic CancerPancreatic Cancer
Pancreatic Cancer
 
Chemoradiation vs Surgery for rectal cancer
Chemoradiation vs Surgery for rectal cancerChemoradiation vs Surgery for rectal cancer
Chemoradiation vs Surgery for rectal cancer
 
Cholangiocarcinoma
CholangiocarcinomaCholangiocarcinoma
Cholangiocarcinoma
 
Immunotherapy for Colorectal Cancer
Immunotherapy for Colorectal CancerImmunotherapy for Colorectal Cancer
Immunotherapy for Colorectal Cancer
 
Surgical Approach to Non Small Cell Lung Cancer
Surgical Approach to Non Small Cell Lung CancerSurgical Approach to Non Small Cell Lung Cancer
Surgical Approach to Non Small Cell Lung Cancer
 
Role of Radiation Therapy for Lung Cancer
Role of Radiation Therapy for Lung CancerRole of Radiation Therapy for Lung Cancer
Role of Radiation Therapy for Lung Cancer
 
Update on Management of Triple Negative Breast Cancer
Update on Management of Triple Negative Breast CancerUpdate on Management of Triple Negative Breast Cancer
Update on Management of Triple Negative Breast Cancer
 
Technical Advances in radiotherapy for Lung (and liver) Cancer
Technical Advances in radiotherapy for Lung (and liver) CancerTechnical Advances in radiotherapy for Lung (and liver) Cancer
Technical Advances in radiotherapy for Lung (and liver) Cancer
 
Controversies in Surgical Approach to Breast Cancer
Controversies in Surgical Approach to Breast CancerControversies in Surgical Approach to Breast Cancer
Controversies in Surgical Approach to Breast Cancer
 
ImmunoOncology in Lung Cancer
ImmunoOncology in Lung CancerImmunoOncology in Lung Cancer
ImmunoOncology in Lung Cancer
 
Breast Cancer Highlights: ASCO 2015
Breast Cancer Highlights: ASCO 2015Breast Cancer Highlights: ASCO 2015
Breast Cancer Highlights: ASCO 2015
 
Updates in Radiotherapy for Breast Cancer
Updates in Radiotherapy for Breast CancerUpdates in Radiotherapy for Breast Cancer
Updates in Radiotherapy for Breast Cancer
 
Regulatory T Cells and GVHD
Regulatory T Cells and GVHDRegulatory T Cells and GVHD
Regulatory T Cells and GVHD
 
Immunotherapy for Multiple Myeloma
Immunotherapy for Multiple MyelomaImmunotherapy for Multiple Myeloma
Immunotherapy for Multiple Myeloma
 
NHL immunotherapy
NHL immunotherapyNHL immunotherapy
NHL immunotherapy
 
AML and Cell Therapy
AML and Cell TherapyAML and Cell Therapy
AML and Cell Therapy
 
Acute Lymphoblastic Lymphoma: Treatment Update
Acute Lymphoblastic Lymphoma: Treatment UpdateAcute Lymphoblastic Lymphoma: Treatment Update
Acute Lymphoblastic Lymphoma: Treatment Update
 

Recently uploaded

Spellings Wk 3 English CAPS CARES Please Practise
Spellings Wk 3 English CAPS CARES Please PractiseSpellings Wk 3 English CAPS CARES Please Practise
Spellings Wk 3 English CAPS CARES Please Practise
AnaAcapella
 
Salient Features of India constitution especially power and functions
Salient Features of India constitution especially power and functionsSalient Features of India constitution especially power and functions
Salient Features of India constitution especially power and functions
KarakKing
 
Jual Obat Aborsi Hongkong ( Asli No.1 ) 085657271886 Obat Penggugur Kandungan...
Jual Obat Aborsi Hongkong ( Asli No.1 ) 085657271886 Obat Penggugur Kandungan...Jual Obat Aborsi Hongkong ( Asli No.1 ) 085657271886 Obat Penggugur Kandungan...
Jual Obat Aborsi Hongkong ( Asli No.1 ) 085657271886 Obat Penggugur Kandungan...
ZurliaSoop
 

Recently uploaded (20)

Jamworks pilot and AI at Jisc (20/03/2024)
Jamworks pilot and AI at Jisc (20/03/2024)Jamworks pilot and AI at Jisc (20/03/2024)
Jamworks pilot and AI at Jisc (20/03/2024)
 
Spellings Wk 3 English CAPS CARES Please Practise
Spellings Wk 3 English CAPS CARES Please PractiseSpellings Wk 3 English CAPS CARES Please Practise
Spellings Wk 3 English CAPS CARES Please Practise
 
Salient Features of India constitution especially power and functions
Salient Features of India constitution especially power and functionsSalient Features of India constitution especially power and functions
Salient Features of India constitution especially power and functions
 
Key note speaker Neum_Admir Softic_ENG.pdf
Key note speaker Neum_Admir Softic_ENG.pdfKey note speaker Neum_Admir Softic_ENG.pdf
Key note speaker Neum_Admir Softic_ENG.pdf
 
HMCS Max Bernays Pre-Deployment Brief (May 2024).pptx
HMCS Max Bernays Pre-Deployment Brief (May 2024).pptxHMCS Max Bernays Pre-Deployment Brief (May 2024).pptx
HMCS Max Bernays Pre-Deployment Brief (May 2024).pptx
 
Jual Obat Aborsi Hongkong ( Asli No.1 ) 085657271886 Obat Penggugur Kandungan...
Jual Obat Aborsi Hongkong ( Asli No.1 ) 085657271886 Obat Penggugur Kandungan...Jual Obat Aborsi Hongkong ( Asli No.1 ) 085657271886 Obat Penggugur Kandungan...
Jual Obat Aborsi Hongkong ( Asli No.1 ) 085657271886 Obat Penggugur Kandungan...
 
Wellbeing inclusion and digital dystopias.pptx
Wellbeing inclusion and digital dystopias.pptxWellbeing inclusion and digital dystopias.pptx
Wellbeing inclusion and digital dystopias.pptx
 
Basic Civil Engineering first year Notes- Chapter 4 Building.pptx
Basic Civil Engineering first year Notes- Chapter 4 Building.pptxBasic Civil Engineering first year Notes- Chapter 4 Building.pptx
Basic Civil Engineering first year Notes- Chapter 4 Building.pptx
 
Unit 3 Emotional Intelligence and Spiritual Intelligence.pdf
Unit 3 Emotional Intelligence and Spiritual Intelligence.pdfUnit 3 Emotional Intelligence and Spiritual Intelligence.pdf
Unit 3 Emotional Intelligence and Spiritual Intelligence.pdf
 
Spatium Project Simulation student brief
Spatium Project Simulation student briefSpatium Project Simulation student brief
Spatium Project Simulation student brief
 
Holdier Curriculum Vitae (April 2024).pdf
Holdier Curriculum Vitae (April 2024).pdfHoldier Curriculum Vitae (April 2024).pdf
Holdier Curriculum Vitae (April 2024).pdf
 
How to setup Pycharm environment for Odoo 17.pptx
How to setup Pycharm environment for Odoo 17.pptxHow to setup Pycharm environment for Odoo 17.pptx
How to setup Pycharm environment for Odoo 17.pptx
 
SOC 101 Demonstration of Learning Presentation
SOC 101 Demonstration of Learning PresentationSOC 101 Demonstration of Learning Presentation
SOC 101 Demonstration of Learning Presentation
 
Introduction to Nonprofit Accounting: The Basics
Introduction to Nonprofit Accounting: The BasicsIntroduction to Nonprofit Accounting: The Basics
Introduction to Nonprofit Accounting: The Basics
 
Unit-V; Pricing (Pharma Marketing Management).pptx
Unit-V; Pricing (Pharma Marketing Management).pptxUnit-V; Pricing (Pharma Marketing Management).pptx
Unit-V; Pricing (Pharma Marketing Management).pptx
 
REMIFENTANIL: An Ultra short acting opioid.pptx
REMIFENTANIL: An Ultra short acting opioid.pptxREMIFENTANIL: An Ultra short acting opioid.pptx
REMIFENTANIL: An Ultra short acting opioid.pptx
 
Making communications land - Are they received and understood as intended? we...
Making communications land - Are they received and understood as intended? we...Making communications land - Are they received and understood as intended? we...
Making communications land - Are they received and understood as intended? we...
 
Kodo Millet PPT made by Ghanshyam bairwa college of Agriculture kumher bhara...
Kodo Millet  PPT made by Ghanshyam bairwa college of Agriculture kumher bhara...Kodo Millet  PPT made by Ghanshyam bairwa college of Agriculture kumher bhara...
Kodo Millet PPT made by Ghanshyam bairwa college of Agriculture kumher bhara...
 
How to Create and Manage Wizard in Odoo 17
How to Create and Manage Wizard in Odoo 17How to Create and Manage Wizard in Odoo 17
How to Create and Manage Wizard in Odoo 17
 
Sociology 101 Demonstration of Learning Exhibit
Sociology 101 Demonstration of Learning ExhibitSociology 101 Demonstration of Learning Exhibit
Sociology 101 Demonstration of Learning Exhibit
 

Targeted therapy for Hodgkin’s Lymphoma

  • 1. 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
  • 2. 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)
  • 3. STAT6 TARCJAK1/3 SOCS Treg Hodgkin’s Reed-Sternberg cell IL13 TH2 Vorinostat/SAHA MGCD0103 Bcl-xL Survival DC OX40L TH 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
  • 4. Baseline 31 year old female Extensive Prior Therapy Regimen Best Response ABVD PR XRT Not Eval DHAP PR Auto Transplant Not Eval IGEV Progression DHAP Progression Fludarabine/ Melphalan Progression Allo Transplant Progression Donor lymphocyte Progression MOPP Not Eval ESHAP Progression IEV 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
  • 5. 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 Ratiooftumorchange DACi in Hodgkin lymphoma Early decline in plasma TARC Levels correlates with clinical response Younes et al, Lancet Oncology 2011
  • 6. International oral Panobinostat (pan-HDACi) Phase II Study in HL -100 -75 -50 -25 0 25 50 75 100 Best%ChangeinSPDFromBaseline (indexlesionsonly) Active Discontinued PR PD 4 patients - SD (0%) 6 patients - off AE prior to Eval 1 1 patient - withdrew consent prior to Eval 1 1 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
  • 7. 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
  • 8. Brentuximab vedotin (SGN-35) ADC monomethyl auristatin E (MMAE), microtubule disrupting agent protease-cleavable linker anti-CD30 monoclonal antibody ADC binds to CD30 MMAE disrupts microtubule network ADC-CD30 complex is internalized and traffics to lysosome MMAE is released Apoptosis G2/M cell cycle arrest Brentuximab Vedotin: Mechanism of Action
  • 9. 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 treatment 44 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
  • 10. Maximum Reduction in Target Lesions 81% of patients achieved tumor reductions Bartlett et al. JCO 27: 434s, 2009 (abst 8500).
  • 11. Demographics and Baseline Characteristics in Pivotal HL Trial N=102 Age* (years) 31 (15 77) 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 (1 13) Relapse ≤1 year post ASCT 72 (71%) Time from ASCT to first post transplant relapse* 6.7 mo (0 131) * Median (range) Younes , A et al, ICML, 2011
  • 12. 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 neuropathy largely 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
  • 13. Introduction of Targeted Therapies into Front-line
  • 14. 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
  • 15. 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 Weeks 0 2 4 6 8 10 12 Ansell S. et al. ASH 2012
  • 16. 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
  • 17. Description of Dose Cohorts ABVD with brentuximab vedotin N=25
  • 18. Demographics and Baseline Characteristics Parameter a Median (range)
  • 19. Summary of Adverse Events ≥Grade 3 Preferred term* * Grade 3 or higher adverse events (AEs) occurring in more than 1 patient overall, regardless of relationship
  • 20. Pulmonary Toxicity Preferred term • Events generally occurred during Cycles 3 4 • 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
  • 21. Peripheral Neuropathy Preferred term* * 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
  • 22. Maximum Dose and Dose-Limiting Toxicities • Dose-limiting toxicities (DLTs) were defined as any Cycle 1 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
  • 23. Response Results at End of Frontline Therapy Response per Investigatora a Assessed using Cheson 2007 b 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
  • 24. 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
  • 25. Department of Lymphoma/Myeloma Disease – specific Working Groups N. Fowler F. Samaniego S. Neelapu L. Fayad L. Kwak T cell lymphoma Multiple myeloma D. Weber J. Shah S. Thomas M. Wang R. Alexanian Q. Yi Michael Wang, M.D. Nathan Fowler, M.D. Co-Directors Lymphoma Clinical Research Robert Orlowski, M.D., Ph.D. Director Myeloma Clinical Research Burkitt HIV Brain Testicular M. Fanale N. Fowler M. Fanale N. Fowler J. Shah J. Westin Larry W. Kwak, M.D., Ph.D. Chairman, Lymphoma/Myeloma Low Grade lymphoma Large Cell lymphoma Mantle cell lymphoma Hodgkins L. Fayad A. Rodriguez F. Hagemeister J. Westin M. Wang J. Romaguera M. Fanale F. Hage- meister Phase I Y. Oki M. Fanale
  • 26.
  • 27. Rituximab plus ABVD Rituximab weekly x 6 plus ABVD x 6 70 patients with stage II to IV disease Median age 28 yo IPS ≥ 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 negative 5-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
  • 28. 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% relapse R-ABVD appears to give better results for high risk patients with HL In 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. Wedgwood et al. Submitted to ASH 2007.
  • 29. FDG-PET positive 16 Patients, prog=11 2-year PFS 0% 1.0 .08 .06 .04 .02 0.0 PercentProgression-Free PET neg 61 Pts, 3 prog 2 yr PFS 96% 3210 PET after 2 cycles P < .001 Years 1.0 .08 .06 .04 .02 0.0PercentProgression-Free CR, PR 2 Pts, 0 prog 2 yr PFS 100% 3210 CT after 2 cycles < PR 62 Pts, 11 prog 2 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 ps 14 Pts, 11 prog 2 yr PFS 0%
  • 30. PercentEvent-Free 100 75 50 25 0 4836240 6012 Months EFS for R-ABVD Score 0-1 Score 0-2 Score 2 Score >2 Score >3 Score >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 84 0 20 40 60 80 100 Score, 0 Score, 1 Score, 2 Score, 3 Score, 4 Score, ≥5 EFS for IPS Months Hasencleaver and Diehl. NEJM 339: 1506-1514,1998.
  • 31. 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

Editor's Notes

  1. 3 current R trials: HD18 2 cycles of Be then if PET-2 positive adds R to Be to complete 8 cycles vs 8 Be and for PET-2 negative 4 vs 8 of Be; randomized R-ABVD vs ABVD, GITL stage I to II A 4 ABVD plus RT vs 4 RABVD