ASH REVIEW- Lymphoma January 31 , 2014

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ASH REVIEWLymphoma
January 31st, 2014
Kami Maddocks, MD
Overview
 Indolent Non-Hodgkin’s Lymphoma
 Targeting B-cell Receptor Signaling
 Mantle Cell Lymphoma
 Is there a role for a non-chemotherapeutic approach?
 Aggressive Non-Hodgkin’s Lymphoma
 Can we improve R-CHOP?
 OSU Lymphoma Trials
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
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B-cell receptor signalling
Stevenson F K et al. Blood 2011;118:4313-4320
Research Institute
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Kinase inhibitors
Woyach J A et al. Blood 2012;120:1175-1184
Research Institute
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Rationale for Targeting PI3K-δ
• PI3K-δ expressed
primarily in
hematopoietic cells
• PI3K-δ inhibition cells
promotes
↑ Apoptosis
↓ Proliferation
↓ Microenvironment
response
Herman S et al: Blood 2010
Lanutti B, et al: Blood 2011
Research Institute
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Idelalisib/CAL-101/GS-1101
 Selective orally available PI3K-δ
inhibitor
 Phase 1 Study 61% ORR in
indolent NHL and MCL
 150 mg BID
Herman S et al: Blood 2010
Kahl et al: ICML 2011
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Mature Response Data from a Phase 2 Study of PI3KDelta Inhibitor Idelalisib in Patients with Double (Rituximab
and Alkylating Agent)-Refractory Indolent B-cell NonHodgkin Lymphoma
Baseline Characteristics in Patients N = 125
Median Age
64 (33-86)
Median Prior Therapies
4 (2-12)
Histology
Follicular
72 (58%)
Small Lymphocytic
28 (22%)
Marginal Zone
15 (12%)
Lymphoplasmacytic/Waldenstrom’s
10 (8%)
Refractory to Last Regimen
112 (90%)
Gopal A et al. ASH 2013 Abstract 85
Research Institute
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Median Follow up
9.4 months
ORR
57% (71 )
CR
6% (7)
PR
50% (63)
Minor Response
1 WM
Stable Disease
33% (42)
ORR by Histology
FL
54%
SLL
61%
MZL
47%
LPL/WM
80%
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Median Time to Response
1.9 months
Median Time to CR
3.7 months
Median Duration of Response
12.5 months
Median PFS
11.0 months
Median OS
20.4 months
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Adverse Events
Total % / ≥ grade 3%
Diarrhea
43/13
Fatigue
30/2
Nausea
30/2
Cough
29/0
Pyrexia
28/2
Dyspnea
18/3
Rash
13/2
Pneumonia
11/7
ALT/AST
13% (16 pts), 11/14 retreated no issue
Neutropenia
27%
Thrombocytopenia
6%
Anemia
2%
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 Well tolerated, acceptable safety profile
 Highly effective in this population of refractory
patients
 Response rate consistent across all histologies
 Responses durable beyond one year
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Bruton’s Tyrosine Kinase (BTK)
A critical kinase for lymphoma cell survival and proliferation
• Bruton’s tyrosine kinase (BTK) is an essential element of the BCR
signaling pathway
• Inhibitors of BTK block BCR signaling and induce apoptosis
 Targeted inhibition of BTK is a novel approach for the treatment
of B-cell malignancies
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Rationale for Targeting BTK in CLL
• Inhibition of BTK inhibits
PI3K, MAPK, and NF-kB
• BTK inhibition promotes
↑ Apoptosis
↓ Proliferation
↓ Chemokines
↓ Microenvironment response
Herman S, et al: Blood 2011
Ponader S, et al: Blood 2012
de Rooij MF, et al: Blood 2002
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Ibrutinib (PCI-32765, Imbruvica)
O
NH2
N
N
N

Potent irreversible Btk inhibition

Inhibits BCR signaling

Orally available

Once daily dosing results in 24-hr
sustained target inhibition
N
N
O
Honigberg LA et al: Proc Natl Acad Sci U S A.107:13075-80, 2010
Research Institute
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A Prospective Multicenter Study of the Bruton’s Tyrosine
Kinase Inhibitor Ibrutinib in Patients with Relapsed or
Refractory Waldenstrom’s Macroglobulinemia
 Whole genome sequencing somatic mutations in
WM
 MYD88 L265P
 > 90% pts
 Supports malignant growth via signaling involving BTK
 Ibrutinib induces apoptosis of WM cells with MYD88
 WHIM-like mutations in CXCR4
 1/3 pts
 Expression induces BTK activity, confers decreased
sensitivity to ibrutinib mediated growth suppression in
WM cells
Treon et al. ASH 2013 Abstract 251
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 Symptomatic WM with > 1 prior therapy
 420 mg oral daily for 2 years or until progression
 Sanger sequencing to determine MYD88 and
CXCR4 mutations in BM LPC
 93% MYD88 L265P mutations
 25% WHIM-like CXCR4
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Baseline Characteristics N = 63
Median age
63 (range 44-86)
Prior therapies
2 (1-6)
Hemoglobin
10.5 g/dL (8.2-13.8)
Serum IgM
3,610 mg/dL (735-8390 mg/dL)
Serum M-protein
2.14 g/dL (0.5-5.4)
Bone Marrow involvement
65% (3.2-95%)
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Median Follow Up
6 cycles (2-15)
ORR
81% (51 pts)
Major response
57.1%
Minor response
23.8%
Stable Disease
17.4%
Non-responder
1 patient
Hemoglobin*
12.6 g/dL (2 g/dL)
Serum IgM*
1340 mg/dL
Serum M-protein*
.84 g/dL
Bone Marrow involvement*
75% to 40%
*At best response
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Adverse Events Grade > 2
N, %
Thrombocytopenia
9, 14.3%
Neutropenia
12, 19.1%
Stomatitis
1, 1.6%
Atrial fibrillation
1, 1.6%
Diarrhea
1, 1.6%
Herpes Zoster
1, 1.6%
Hematoma
1, 1.6%
Hypertension
1, 1.6%
Epistaxis
1, 1.6%
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 1 non-responder wild type MYD88 L265P
 MR impacted by mutations in CXCR4, not MYD88
 77% MR in wild-type CXCR4 vs 30% in WHIM-like
CXCR4 mutations
 Improvement in disease parameters associated with
wild-type CXCR-4
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 Highly active and well-tolerated in R/R WM
 Rapid reductions in serum IgM and improved Hgb
 WHIM-like CXCR4 mutations impact response
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IPI-145
 Phase I
 31 patients R/R NHL
 MTD 75 mg oral BID
 DLT rash and
transaminitis
 ORR 52%
Kahl et al, B Lugano 2013
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Upfront Follicular Lymphoma
Lenalidomide
20 mg orally
daily
Rituximab
375 mg/m2
• Days 1-21
of 28
• 12 cycles
• Weekly x
4
• Day 1
cycles
4,6,8,10
Martin P et al, Lugano Abstract 2013
N = 53 evaluable patients
ORR
CR
PFS
92.6
72.2
More
follow up
needed
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Combination Biologic Therapy without Chemotherapy as
Initial Treatment for Mantle Cell Lymphoma: Multi-Center
Phase II Study of Lenalidomide Plus Rituximab
Treatment Phase
Lenalidomide
Rituximab
Induction
20 mg days 1-21 of 28 x
12 cycles
375 mg/m2 weekly x4
cycle 1 and then every
other cycle
Maintenance
15 mg days 1-21 of 28
375 mg/m2 every other
until disease progression cycle until disease
progression
Ruan J et al. ASH 2013 Abstract 247
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Phase II Study of Lenaldomide Plus Rituximab
Baseline Characteristics N = 31
Median Age
65 (42-86)
Stage III-IV
31
Bone marrow involvement
27 (87%)
MIPI
Low
36%
Intermediate
32%
High
36%
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Grade 3-4 Adverse Events
Hematologic
Neutropenia
39%
Thrombocytopenia
13%
Anemia
7%
Non-hematologic
Rash
23%
Tumor flare
7%
Serum Sickness
7%
Grade 1-2 infections: URI (29%), UTI (10%), pneumonia (10%), sinusitis (7%)
1 each of DVT and PE resolved with treatment
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Median Follow Up
12 months (5-23)
ORR
77%
CR
40%
PR
37%
SD
13%
Median time to response
2.8 months
Median time to confirmed CR
6-12 months
Median PFS and DOR
Not Reached
Reasons for discontinuation
Withdraw of consent
Progression of disease
Toxicity (tumor flare)
1
2
1
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 Chemotherapy-free, combination biologic approach
is feasible as initial therapy for MCL
 Combination safe in frontline therapy for MCL
 Further assessment of response rate and durability
with additional follow-up
 Combination alone and with addition of novel agents
warrants further study in frontline and relapsed
setting
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The Single-Agent BCL-2 inhibitor ABT-199 (GDC-0199) in
Patients with Relapsed/Refractory Non-Hodgkin
Lymphoma: Responses Observed in all Mantle Cell
Lymphoma Patients
 Dysregulation of anti-apoptotic protein Bcl-2 in NHL
 ABT-199
 Selective, potent, orally bioavailable small molecule
bcl-2 inhibitor
 Phase I Dose-Escalation
 200, 300, 400, 600 and 900 mg
 32 patients enrolled
 Median age 68
 Median prior therapies 3.5 (1-7)
Davids MS et al. ASH 2013 Abstract 1789
Research Institute
Lymphoma Patients
 Most Common Adverse Events ≥ 20%
 Nausea
 Diarrhea
 Vomiting
 Fatigue
 URI
 Grade 3/4 Adverse Events
 Hematologic
 Tumor Lysis (1 MCL, 1 DLBCL)
 DLT
 Grade 3 febrile neutropenia
 Grade 4 neutropenia
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Histology
Overall
Response
(CR + PR)
Complete Partial
Response Response
n (%)
n (%)
Stable
Disease
n (%)
Progressive
Disease
n (%)
Total
(n=32)
53%
2/32 (6)
15/32 (47)
9/32 (28)
6**/32 (19)
DLBCL* 8
38%
1/8 (13)
2/8 (25)
1/8 (13)
4/8 (50)
FL* 11
27%
3/11 (27)
8/11 (73)
MCL 8
100%
8/8 (100)
MM 1
1/1 (100)
MZL 1
1/1 (100)
WM 3
100%
1/3 (33)
2/3 (67)
*In DLBCL and FL pts, all responses occurred at doses ≥600 mg.
**2 pts discontinued due to PD prior to first response assessment (1 MZL
and 1 DLBCL)
Ohio State University Comprehensive Cancer Center –
Davids MS et al. ASH 2013 Abstract 1789The
Research Institute
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Lymphoma Patients
 Anti-tumor activity in several NHL subtypes
 ORR 53%
 ORR MCL and WM 100% across all cohort doses
 Response in DLBCL and FL ≥ 600 mg dosing
 Dose escalation continues
Research Institute
A Phase 2 Study of Brentuximab Vedotin in Patients with
Relapsed or Refractory CD30-Positive Non-Hodgkin
Lymphoma
 Anti-CD30
monoclonal antibody
conjuaged to
microtubule-disrupting
agent MMAE
 Variable CD30
expression in several
types of NHL
including DLBCL and
PMBCL
Bartlett N et al. ASH 2013 Abstract 848
Research Institute
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Lymphoma
 Phase 2 single-arm
Baseline characteristics N = 62
 R/R CD30+ NHL by
IHC
Median age
55 (16-85)
Prior Therapies
2 (1-19)
 1.8 mg/kg IV q3
weeks
Histology
Primary Refractory 65%
DLBCL
44
Other
18
Median # Cycles
3 (1-17)
Duration
10.5 wks (2.4-57)
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DLBCL
(N=43)
Other B-cell Neoplasm
(N=18)
CR
7 (16)
2 (11)
PR
10 (23)
2 (11)
ORR (CR + PR), n (%)
17 (40)
4 (22)
36.0
21.7
0.1+, 62.3+
6.1, 37.1
Best clinical response, n (%)
Median duration of OR (weeks)
Min, Max
Median Duration of Response: 21.7 weeks (6.1-37.1)
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Lymphoma
 Most Common Adverse Events ≥ 20%
 Fatigue
 Nausea, vomiting
 Neutropenia
 Fever
 Diarrhea
 Peripheral sensory neuropathy
 Anemia
 Constipation
 Grade 3/4 Adverse Events ≥ 10%
 Neutropenia (29%)
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Lymphoma
 Anti-tumor activity in refractory NHL
 CD30 expression in responders < 1% to 90%
 No correlation between CD30 expression and RR
 40% ORR in DLBCL
 Median duration > 8 months
 Toxicities consistent with known AE’s
Research Institute
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Final Results of Phase II Study of Lenalidomide Plus
Rituximab-CHOP21 in Elderly Untreated DLBCL Focusing
on Cell of Origin: REAL07 Trial of the Fondazione Italiana
Linfomi
R-CHOP21 + 15 mg Lenalidomide Days 1-14
 49 patients enrolled
 Median age 69 years (range 61-80)
 30 (61%) of patients had high-intermediate to high
IPI
 43 (88%) of patients had Stage IV disease
Chiappella A et al. ASH 2013 Abstract 850
Research Institute
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Final Results of Phase II Study of Lenalidomide Plus
Rituximab-CHOP21 in Elderly Untreated DLBCL Focusing
on Cell of Origin: REAL07 Trial of the Fondazione Italiana
Linfomi
ORR
CR
PR
2-year OS
2-year PFS
92%
86%
6%
92%
80%
GCB (16)
88%
81%
71%
non-GCB (16)
88%
88%
81%
Overall (49)
Chiappella A et al. ASH 2013 Abstract 850
Research Institute
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Ph1b: ibrutinib-R-CHOP for DLBCL
A Younes et al. J Clin Oncol 31, 2013 (suppl; abstr 8502)
Research Institute
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i-R-CHOP for DLBCL: Outcomes
A Younes et al, ASH 2013 Abstract 852
Research Institute
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Lack of Clinical Benefit for Routine Surveillance Imaging
For Diffuse Large B-Cell Lymphoma in First Complete
Response
 DLBCL patients





R-CHOP or similar regimen
Tertiary care centers 2001-2011
CR to therapy
1 year + follow up
Followed by routine surveillance imaging vs clinical
surveillance
 Median follow-up 5 years (1-12)
 Baseline characteristics similar
Vose J et al. ASH 2013 Abstract 4303
Research Institute
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391
patients
262
Routine
Imaging
Median # of
images 4
129 Clinical
Surveillance
Median # of
images 0
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Response
 Relapse detected by clinical manifestation
 100% clinical surveillance vs. 43% by routine imaging
(p = 0.01)
 5-year PFS
 76% clinical surveillance vs. 82% in routine imaging
(p = 0.31)
 5-year OS
 87% clinical surveillance vs. 92% in the routine
imaging (p = 0.15)
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5 year Overall Survival
CS Group
RSI Group
p-value
Low IPI (n=174)
94 (84-98)
97 (90-99)
0.53
Low-Int IPI (n=86)
84 (57-95)
88 (74-94)
0.71
High-Int IPI (n=93)
78 (29-93)
90 (68-97)
0.25
High IPI (n=38)
74 (29-93)
78 (53-91)
0.83
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Response
 Majority of relapses in DLBCL in CR1 occur when
signs or symptoms lead to evaluation as opposed to
routine surveillance imaging
 Relapses detected by imaging in this cohort did not
have a PFS or OS benefit in favor of imaging
 Cost, radiation exposure and risk of additional
procedures limits clinical utility of imaging surveillance
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 Abstract 640: Impact of Induction Regimen &
Consolidative Stem Cell Transplantation in Patients
with Double Hit Lymphoma: Large Multicenter
Retrospective Analysis
 R-EPOCH increased CR but not OS, Pts achieving
CR did not benefit from SCT, Primary refractory
disease primary predictor of OS (106 pts, PFS 8.8
mos, OS 12 mos)
 Abstract 1776: Double Hit Lymphoma: M.D.
Anderson Experience
 Improvement in 3 yr OS with CR to initial therapy, in
patients achieving CR consolidative transplant had no
statistically significant benefit to OS (56 case, PFS 9
mos, OS 18mos)
Research Institute
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 Abstract 4362: Role of Aggressive
Chemotherapeutic Regimens in Double Hit
Lymphoma- Can Alternate Aggressive Induction
Regimens Overcome the Poor Prognosis of Diffuse
Large B Cell Lymphoma?
 No benefit with aggressive regimens (560 pts, median
OS 12.2 mos – actually less with aggressive but not
statistically significant)
 Abstract 2141: Dose Intensive Induction Followed by
Allogeneic Stem Cell Transplantation more than
Doubles Progression-Free and Overall Survival in
“Double-Hit” Lymphoma
 PFS prolonged with DI regimens as compared to
standard therapy (46 vs 8 mos) with added benefit
with SCT (46 vs 14.8 vs 4.9 PFS, OS not reached vs
11.1 mos)
Research Institute
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OSU Clinical Trials Previously Untreated
 HD: OSU 13016 Phase 3 A+AVD vs. ABVD for Stage III
or IV disease
 HD: CALGB 50801: PET directed therapy for early stage
bulky disease
 FL: A051103 Phase I R + Lenalidomide + Ibrutinib
 FL: CALGB 50901 Phase 2 Ofatumumab
 FL: CALGB 50904 Phase 2 Ofatumumab+Bendamustine
vs Ofatumumab+Bendamustine+Bortezomib
 MCL: ECOG-1411 Phase 2 BR vs BR + Bortez + R vs R+
Lenalidomide Maintenance
 TCL: OSU 13015 Phase 3 CH-P+Brentuximab vs CHOP
Research Institute
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OSU Clinical Trials Relapsed/Refractory
 FL: A051202 Phase 1/2 R + Lenalidomide +
Idelalisib
 FL: OSU 10052 Phase 2 BR + Ibrutinib
 MCL: A051201 Phase 1/2 R + Lenalidomide +
Idelalisib
 NHL: OSU 13022 Ibrutinib + Lenalidomide
 NHL: OSU 11179 Phase I CD37 immunoconjugate
 NHL: OSU 12106 Phase 2 MLN8237
 NHL: OSU 12171 Phase 2 MOROO208 anti-CD19
Ab
Research Institute
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OSU Clinical Trials Relapsed/Refractory
 NHL: OSU 13027 Phase I BKM120 + R
 NHL: OSU 12206 Phase 1 OMP-52M51 (antinotch1)
 HD: OSU 11015 Phase 1/2 Gemcitabine +
Bendamustine
 HD: OSU 10049 Phase 2 Panibinostat +
Lenalidomide
 TCL: OSU 12197: Phase 3 KW-CCR4 vs vorinostat
Research Institute
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TheArthur
OhioG.
State
University
CancerJ.Center
James
CancerComprehensive
Hospital and Richard
Solove–
Arthur
G. James
Cancer Hospital and Richard J. Solove Research Institute
Research
Institute

ASH REVIEW- Lymphoma January 31 , 2014

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