Fowler et al. ASH 2012, Abstract 901 Phase II Study of L+R

Report
What’s New in Indolent NHL, MCL and PTCL?
ASH 2012 Review
March 14, 2013
Myron S. Czuczman, MD
Professor of Medicine and Oncology
Chief, Lymphoma/Myeloma Section
Head, Lymphoma Translational Research Laboratory
Roswell Park Cancer Institute, Buffalo, NY
Disclosure of Conflicts of Interest
Myron S. Czuczman, MD
Reported a financial interest/relationship or affiliation in
the form of participating in Advisory Boards:
Celgene Corporation, Genentech BioOncology, Spectrum,
Millennium, Onyx Pharmaceuticals
Today’s presentation will discuss off-label use of novel
agents, many of which are in early clinical development
Agenda
• Frontline Therapy for Follicular Lymphomas
• Novel Therapies for Advanced Follicular Lymphoma
• The Role of PI3K and BTK Inhibitors
• Novel Therapies for MCL
• Advances in T-cell Lymphoma Therapy
Subanalysis of the StiL NHL-1 Study: Achievement of
CR Results in Superior Survival c/w PR
Subanalysis of
responders in
NHL1 (StiL) phase
III study in
indolent
lymphoma and
MCL
Frontline BR vs CHOP-R
(max 6 cycles)
Subanalysis of the
impact of response
quality on outcome
Rummel et al. ASH 2012, Abstract 2724
Responder Subanalysis of BR vs CHOP-R in Indolent and
MCL (StiL): Subgroup Analysis/Conclusions
CR
PR
P
All Patients
57.5
43.5
0.0037*
BR Arm
NR
57
0.1912
R-CHOP Arm
54
31
0.0215*
All Patients
90%
78%
0.0008*
BR Arm
91%
80%
0.0044*
R-CHOP Arm
90%
75%
0.0737
Male vs Female
Male (n=272)
Female (n=242)
CR rates
29%
42%
0.0016*
Median PFS, mo
38.6
51.4
0.0866
Median PFS, mo
OS at 5 y

Pts in CR c/w PR following 1st-line Rx: significantly longer PFS and OS

Results suggest: association between quality of response vs outcome
*Denotes statistically significant differences
Rummel et al. ASH 2012, Abstract 2724
Frontline BR vs R-CHOP/R-CVP in Advanced Indolent
NHL (The BRIGHT Study): Study Design
Bendamustine 90 mg/m2 Day 1 and 2
Rituximab 375 mg/m2 on D1 q28d
Frontline
advanced
indolent NHL
(Preassignment
of chemo arms
by investigator)
(6-8 cycles); n=224
R-CHOP and R-CVP: std dosing q21d
Primary: Noninferiority
of CR for BR vs standard
treatment (IWG criteria);
independent and
investigator review)
(6-8 cycles); n=223
• 447 randomized; 436 received treatment; 419 evaluable for efficacy
• Most patients completed 6 cycles of treatment
• Dose delays more common for BR-treated patients (35% vs 19%);
dose reductions less common (22% vs 29%)
Flinn et al. ASH 2012, Abstract 902
Frontline BR vs R-CVP or R-CHOP in Advanced Indolent
NHL (The BRIGHT Study): Efficacy/Conclusions
CR Rates
BR, %
R-CVP/
R-CHOP, % Ratio (95% CI)
P value
Evaluable, IRC
31
25
1.25 (0.93-1.73)
0.0225a
Randomized, IRC
31
23
1.34 (0.98-1.83)
0.0084a
In NHL
27
23
1.16 (0.81-1.65)
0.1289a
In MCL
51
24
1.95 (1.01-3.77)
0.0180b
31
18
1.60 (1.14-2.25)
0.0013b
Randomized,
Investigator
IRC, independent review committee. aTest for noninferiority; bTest for superiority
• High ORRs were attained in both groups (94% BR vs 84% R-CVP/R-CHOP)
• BR shows CR rate that is non-inferior to that of R-CHOP/R-CVP
– MCL: BR produced significantly higher CR rate
• AE profile of BR was distinct from R-CHOP/R-CVP
Flinn et al. ASH 2012, Abstract 902
Phase II Study of Lenalidomide and Rituximab (L+R) in
Untreated iNHL: Final Results
Study Design/Patient Characteristics
Phase II
Advanced stage,
untreated iNHL;
measurable disease
(>1.5 cm) (N=110)
LEN 20 mg, days 1-21 +
Rituximab 375 mg/m2 day 1,
q28d x 6 cycles
(responders up to 12 cycles)
Responses (1999 IWG)
assessed every
3 cycles
Fowler et al. ASH 2012, Abstract 901
Phase II Study of L+R in Untreated iNHL: Final Results
Conclusions
• The combo of L+R is active and tolerable in pts with untreated iNHL
• All patients: 90% ORR (64% CR)
– FL: 98% ORR (87% CR)
– SLL: 80% ORR (27% CR)
– MZL: 89% ORR (67% CR)
• High CR rates with durable remissions were observed in FL patients
• 2-year PFS = 83% for all patients; 89% for FL
• Randomized studies comparing this regimen with traditional
combination chemotherapy regimens are underway
• Ongoing RELEVANCE study
Fowler et al. ASH 2012, Abstract 901
B-cell Receptor Signaling Pathway
Kersh, Gilbert J(Sep 2007) Lymphocyte Activation Signals: Transduction. In: eLS. John Wiley & Sons Ltd,
Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0001185.pub2]
BCR pathway members as potential
targets in the treatment of NHL
Friedberg J W Clin Cancer Res 2011;17:6112-6117
©2011 by American Association for Cancer Research
Targeted Therapy, Novel Agents
Being Tested in FL
• Btk inhibition in B-cell malignancies
– Ibrutinib shows clinical benefit with single-agent PO
dosing1
– 52% ORR in 48 evaluable pts
• 78% in MCL; 29-33% in FL, DLBCL, MZL, MALT
– Well tolerated, minimal toxicities at <12.5 mg/kg/day
• Idelalisib: Oral PI3K inhibitor
– Clinical benefit in pts with r/r indolent NHL, MCL, and CLL2
– Well tolerated with minimal hematologic toxicity
– Most frequent AE: reversible increase in ALT/AST
– 55% ORR in indolent NHL (n=24); 62% in MCL (N=16)
1Fowler
2Kahl
KH et al. ASH 2010 Abst 964
B et al. ASH 2010 Abst 1777
The BTKi Ibrutinib (PCI-32765) in Relapsed FL
Study Design
Ibrutinib induces apoptosis and inhibits cellular migration and adhesion in
neoplastic B-cells
Phase I
Rel/ref
B-cell lymphoma
(FL); ECOG ≤1,
1-4 prior
therapies,
measurable
disease
Ibrutinib PO dose escalation
Intermittent: 1.25–12.5 mg/kg
Efficacy for doses
≥2.5 mg/kg (ie, full BTK
occupancy)
Continuous: 8.3 mg/kg and
560-mg fixed dose QD
Response measured
every 2 mo (2007 IWG)
Primary objectives: safety and MTD
Dosing
• 1.25, 2.5, 5.0, 9.3, 12.5 mg/kg/d PO
Cycle = 28 days on/7d off: intermittent dosing
• 2 continuous dosing cohorts (cycle = 35 days)
- 8.3 mg/kg /d PO
- 560 mg/d PO (fixed dose)
Fowler et al. ASH 2012, Abstract 156
Ibrutinib in Relapsed FL: Efficacy
•
•
•
•
Efficacy (n=16)
n (%)
ORR
CR/CRu
PR
Median DR, mo
Median time to first
response, mo
(range)
Median time to
first PR, mo
(range)
Median time to
first CR, mo
(range)
Median PFS, mo
Median OS, mo
7 (44)
3 (19)
4 (25)
12.3
1.25 mg/kg/d ≥ 2.5 mg/kg/d ≥ 5.0 mg/kg/d
(n=4 FL)
(n=11 FL)
(n=9 FL)
25%
55%
56%
0
27%
33%
25%
27%
22%
NE
10.3
12.3
4.7 (2-12)
−
−
−
4.6 (2-11)
−
−
−
11.5 (5-12)
−
−
−
13.4
No deaths
NE
−
13.4
−
19.6
−
Median time on treatment = 7 mo (range, 0-29); Well-tolerated
Dose of 5 mg/kg/day or higher recommended for phase II studies
No cumulative toxicity with extended dosing
Response improved with continued treatment in some pts
Fowler et al. ASH 2012, Abstract 156
GS-1101+R vs GS-1101+B vs GS-1101+BR in iNHL:
Results/Conclusions
• Lack of overlapping toxicities allows the oral PI3Kδ inhibitor,
GS-1101, to be delivered at the full single-agent starting dose
(150 mg BID) when co-administered with BR in heavily
pretreated indolent NHL patients
• Highly active and generally well tolerated in hard-to-treat
patients, inducing
– Profound reductions in lymphadenopathy ; (ORR 71%-88%;
CR 20%-29%)
– Durable clinical benefit with median DR and PFS not yet reached
• Phase 3 trials should be pursued evaluating these 3 regimens
Fowler et al. ASH 2012, Abstract 3645
Interim Results of Phase I Study of ABT-199
in r/r NHL: Study Design/Results
Phase I
Rel/ref NHL;
median 3 prior
therapies, 35%
bulky
adenopathy
ABT-199, 50 to 200 mg;
Daily dosing targets
200 mg (n=3), 300 mg
(n=3), 400 mg (n=4),
and 600 mg (n=7)
Safety (NCI CTCAE
V4); Responses
(2007 IWG)
• First in human phase I open-label, dose escalation, multicenter study; n=30
• ABT-199: oral, second-generation BH3 mimetic that inhibits BCL-2
• Overall best response rate (CR + PR) = 11/23 patients (48%)
• Laboratory TLS seen in one MCL patient at 200 mg dose
• ABT-199 was active with an acceptable safety profile with daily dosing, particularly in
MCL (7/7 PR)
• Activity also observed in DLBCL (1/4 CR) and WM (2/2 PR)
• No evidence of dose-related thrombocytopenia; consistent with BCL-2 selectivity
• Dose escalation continues to id the optimal dosing regimen and MTD of ABT-199 in NHL
Davids et al. ASH 2012, Abstract 304
Phase II Study 0f CT-011 + R in Relapsed FL
Phase II
Rituximabsensitive, grade 12 FL, relapsed
after 1-4 prior
therapies,
measurable
disease, adequate
organ function,
ALC ≥0.6x109/L
•
•
•
•
CT-011 3 mg/kg IV every 4
wks X 4 + Rituximab 375
mg/m2/wk IV X 4 starting 2
wks after CT-011
(Responders could receive
additional 8 infusions CT011 [total 12])
Primary: ORR
CT +/- PET after 2 and
4 infusions CT-011
and q 3 mo for ≤2 y;
BM biopsy needed to
confirm CR
PD-1: an inhibitory receptor belonging to the B7-receptor family
Presence of PD-1/PDL-1 on tumors: poor prognosis and immune suppression
CT-011 (pidilizumab) is a humanized anti-PD-1 monoclonal antibody
CT-011 blocks the interaction between PD-1 and its ligand, PDL-1
– Leads to enhancing the anti-tumor function of both T-cells and NK cells
Westin et al. ASH 2012, Abstract 793
Phase II Study 0f CT-011 + R in Relapsed FL:
Results/Conclusions
Efficacy (n=29)
ORR
n (%)
19 (66)
CR
15 (52)
PR
4 (14)
Measurable tumor regression
Median time to response, d
Median PFS, mo
In responders (n=19)
Pts with tumor regression (n=25)
25 (86)
88
21.1
NR
NR
• Subgroup analysis for clinical response: No association with FLIPI, FLIPI2, prior
chemo, # of prior rituximab doses, or duration of response to prior therapy
• The ORR of 66% and CR of 52% compare favorably with the previously reported
ORR of 40% and CR rate of 11% with rituximab retreatment in relapsed FL
• These data support further evaluation of PD-1 targeted therapy in FL
Westin et al. ASH 2012, Abstract 793
Lenalidomide Post-Bortezomib in Rel/Ref MCL
(MCL-001); Study Design
Phase II global, multicenter, single-arm, open-label study
MCL patients
relapsed,
progressed,
or refractory
to bortezomib
(N = 134)
Treatment Phase*
Lenalidomide 25 mg days 1-21,
q28d; CT every 2 cycles
PD or
toxicity
Follow-Up
CT every
90 days
Primary endpoints†: ORR and DOR
Secondary endpoints: CR, PFS, TTP, OS and safety
*Aspirin or low molecular weight heparin prophylaxis provided for high-risk patients.
†Based on independent central review per modified International Working Group criteria. 1-3
1. Cheson et al. J Clin Oncol. 1999;17:1244. 2. Kane et al. Clin Cancer Res. 2007;13:5291-5294.
3. Fisher et al. J Clin Oncol. 2006;24:4867-874. Goy et al. ASH 2012, Abstract 905.
Lenalidomide Post-Bortezomib in Rel/Ref MCL
(MCL-001): Conclusions
• EMERGE trial confirmed lenalidomide efficacy with an
ORR of 28% (CR/CRu 8%); median DR 16.6 months
• Heavily pretreated MCL population
• Subgroup analyses for efficacy (ORR and DR) based on baseline
characteristics/demographics were similar
• Safety profile was manageable and consistent with other studies
of lenalidomide in NHL
• Lenalidomide demonstrated rapid (median TTR, 2 months) and
durable efficacy in MCL patients who failed prior therapies that
included bortezomib
Ibrutinib in Bortezomib-Naive or -Exposed MCL
Phase II: Rel/ref MCL;
phase II study of
bortezomib-naive and
bortezomib-exposed
patients with MCL
Primary: ORR
(every 2 cycles)
Ibrutinib 560 mg/d PO;
continuous 28-day cycles until
PD
Secondary: DOR, PFS,
OS, and safety
• Median DR, PFS, and OS not yet reached
• Median (range) time to PR: 1.9 (1.4 – 8.3) months
• Median (range) time to CR: 3.9 (1.7 – 11.2) months
BortNaive
(n=63)
BortExposed
(n=46)
All
Patients
(n = 109)
Efficacy
Efficacy
Median time on
study treatment, mo
ASH 2011
(n=51)
ASH 2012
(n=51)
3.8 mo
11.3 mo
65%
72%
68%
CR/CRu
21%
23%
22%
ORR
69%
75%
PR
44%
49%
46%
CR
16%
35%
•
Treatment-emergent adverse events were consistent with previous reports (11%
neutropenia, 5% anemia, 5% thrombocytopenia)
•
A pivotal study in R/R MCL previously treated with bortezomib has been initiated
Wang et al. ASH 2012, Abstract 904
Phase I/II Trial of Vorinostat + Cladribine + R (VCR) in
Previously untreated MCL
•
Epigenetic modifications have been identified in MCL
– Cladribine: Cytotoxic plus has hypomethylating properties
– Vorinostat: HDAC inhibitor
•
Phase II dosing
– V (400 mg po D+1 to 14); C (5 mg/m2 IV D+1 to +5); R (wkly x 4, then q month)
– Responders may receive MR
•
n=28 previously untreated MCL
– n=26 evaluable (completed >2 cycles)
– ORR = 100% (69% CR)
• None of the CR pts has relapsed (med F/U = 14.7 m)
• Worse outcomes seen in blastoid MCL
– Toxicities: include marrow suppression, fatigue, anorexia, and dehydration
•
Conclusions:
– “VCR” has significant activity and epigenetic activity in prev untreated MCL
– Initial F/U results are promising in non-blastoid MCL who continue MR
Spurgeon et al. ASH 2012, Abstract 3675
Brentuximab Vedotin in Rel/Ref CD30+ Heme Malignancies
Rothe (German Hodgkin Study Group) et al
Retrospective analysis
of CD30+ refractory or
relapsed HL or
relapsed ALCL without
prior high-dose
chemotherapy (HDCT)
and autologous SCT
(German Hodgkin
Study Group)
•
Brentuximab vedotin 1.8mg/kg
body weight; 30-min infusion;
every 3 weeks
Response (revised IWG)
OS – time from initiation of
therapy to death from any
cause
PFS – time from initiation
to progression, relapse, or
death
Retrospective analysis supports previously reported therapeutic efficacy of
brentuximab vedotin in patients with heavily pretreated CD30+ malignancies
•
69% ORR (31% CR); 22% PFS and 68% OS at 12 months
•
Presents the first data indicating therapeutic efficacy of brentuximab vedotin
as reinduction therapy in chemotherapy-refractory HL and ALCL patients
before HDCT and ASCT
•
Broadens spectrum of reinduction treatment that can be used before
HDCT/ASCT in primary refractory HL and ALCL patients who may be ineligible
Rothe et al. ASH 2012, Abstract 2743
Frontline Romidepsin + CHOP in PTCL (Ro-CHOP):
Phase Ib
Previously
untreated,
biopsy-proven
PTCL (N=18)
RoCHOP
Romidepsin: Starting dose 10 mg/m2
days 1 and 8
+ CHOP:
Cyclophosphamide 750 mg/m2 day 1
Doxorubicin 50 mg/m2 day 1
Vincristine 1,4 mg/m2 day 1
Prednisone 40 mg/m2 days 1 – 5
3 + 3 design; DLT
considered in first
2 cycles
Safety, efficacy,
tolerability
• Romidepsin can be combined with CHOP with manageable heme toxicity
• Some cardiovascular events were observed but the relationship with
romidepsin was questionable
• Romidepsin dose of 12 mg/m2 on days 1 and 8 currently under evaluation in
phase II extension of the study (close to accrual)
• Response rates seemed promising (78% ORR; 57% CR), but longer follow-up is
needed
Dupuis et al. ASH 2012, Abstract 1617
Phase II Study of Mogamulizumab in CTCL/PTCL
•
Mogumulizumab (KW-0761): humanized anti-CCR4 mAb (potent ADCC)
•
Phase I in CCR4-positive T-cell malignancies: well-tolerated; encouraging efficacy
•
Phase II in CCR4-positive ATLL: 50% ORR (approved for Rx of ATLL in Japan in 2012)
•
Phase I/IIa prev Rx’d CTCL (US): 37% ORR
•
Current study: Phase II study for relapsed CCR4-positive CTCL and PTCL (Japan)
•
–
Multicenter; primary end-point = ORR; 8 weekly infusions
–
Results: See Table; n=37 assessable; severe AE’s: 14 (in 7 pts); polymyositis, CMV retinitis
Conclusion: Mogamulizumab mono Rx has promising antitumor activity in r/r PTCL/CTCL
Ishida et al. ASH 2012, Abstract 795
New directions in the treatment of NHL in 2013
 The successful use of novel targeted agents in NHL is inducing a
paradigm shift in attitudes toward treatment:
– Therapeutic goals are moving from palliation of indolent NHL to Rx
approaches that result in durable CRs
– Therapeutic principles are changing and novel targeted agents are
being incorporated into upfront and salvage settings and yielding
improved outcomes (esp in poor-risk patients)
–
Continued development and testing of novel targeted agents will
result in higher cure rates of NHL in the foreseeable future
27

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