New Agents in Management of
Indolent B-Cell NHLs
F B Hagemeister MD
Department of Lymphoma/Myeloma
M D Anderson Cancer Center
Las Vegas, Nevada
February 27, 2014
New Agents in Management of
Indolent B-Cell NHLs
•
•
•
Monoclonal Antibodies
•
Rituximab
•
Ofatumumab
•
Obinutuzumab
Protein Inhibitors
•
BTK Inhibitors
•
PI3K Inhibitors
•
Others
Immunomodulatory Agents
Phase III MR, 2 Schedules, for Untreated FL
Following SA Rituximab x 4: SAKK 35/03
• Med PFS: (MR = 4 doses, vs 5 years, both q 2 mo):
– For all 165 enrolled: A-3.4 yr vs B-5.3 (p=0.14)
– Thought due to higher relapse rate before MR
begun for those in Gp A for “unexplained reasons”
– For only those in remission at 8 mo: A-7.1 yr vs B2.9 (p=0.004)
• Gr 3-4 infections (Pt): A-1 vs B-5
• No differences in OS or ORR
• Conclusion: If in remission after SA Rituximab, MR
prevents relapse if given longer vs shorter interval
Taverna et al, ASH 2013, # 508
But best duration of MR is still unclear.
The PRIMA Trial: A 6 Year Update
• Med f/u 73 months (from randomization)
• 6 year PFS results:
– 60% with R vs 42% without R (p<0.0001)
• Favorable features affecting PFS by MVA:
Feature
HR
P Value
Maintenance R
0.47
<0.0001
FLIPI 0-2
0.67
<0.0001
Female
0.72
0.0003
Age over 60
0.79
0.015
• OS rates, transformation rates not different
• Still No result on differences related to type of
chemotherapy administered
Salles et al. ASH 2013, # 509.
MR vs Obs after R-Chemo for FL:
PFS in the PRIMA Trial
Progression-Free Survival
24
72
Months
Salles et al. ASH 2013 # 509
Early Relapse Of R-CHOP for FL: Effect
of Early Relapse on OS Result
Early Relapse in Lymphocare Study: <2 yrs from
diagnosis (21% of 588 pts) By MVA: ER Associated with
High LDH, PS > 1, Marrow DZ, and B Sx.
Casulo et al. ASH 2013 # 510
90Y-Ibritumomab for Advanced Stage FL
in First Remission: The FIT trial
Med PFS Results (Mo)
Control
90Y I
P
HR
Patients in CR (%)
53.3
87.4
NR
NR
All Pts
13.5
37
<0.0001
0.46
Initial PR
6.3
29.7
<0.0001
0.30
Initial CR
29.9
54.6
.01
0.61
24.1
NR
0.05
0.6
2
11.3
53.9
<0.1
0.23
3-5
6.5
23.8
0.08
0.59
FLIPI, 0-1
*Note:
All patients
Only 10-15% had received induction rituximab.
A second randomized trial was planned with induction R-CHOP .
High-risk pts receive RIT vs SCT, low risk receive RIT vs Obs.
All would receive maintenance rituximab. But trial abandoned
Hagenbeek et. al. ASH 2007, Abstract # 693
90YIbritumomab
Consolidation vs MR
for Untreated FL in CR/PR After R-CHOP
Conclusion: MR is better than 90YIbritumomab after R-CHOP
Lopez-Guillermo, et al. ASH 2013 # 369
New Agents in Management of
Indolent B-Cell NHLs
•
•
•
Monoclonal Antibodies
•
Rituximab
•
Ofatumumab
•
Obinutuzumab
Protein Inhibitors
•
BTK Inhibitors
•
PI3K Inhibitors
•
Others
Immunomodulatory Agents
Novel Anti-CD20 MoAbs for
Relapsed/Refractory Indolent Lymphomas
MoAb
Phase
Efficacy
I/II
Dose (ORR): 300 mg (63%); 500 mg (33%);
700 mg (20%); 1000 mg (50%)
II
ORR: 11%, 6-mo PFS in 116 pts with
rituximab-refractory FL
Ofatumumab
IV administration: ORR: 44%, CR: 27%
DOR in pts with FL: 19.7 mos
Veltuzumab
I/II
Ocrelizumab
I/II
ORR: 38%; PFS: 11.4 mos in pts with FL
I/II/III
ORR: 69%, CR: 38% in 13 pts with FL
GA101
Subcutaneous administration: ORR: 53%
CR: 20% in pts with indolent NHL
Morschhauser. Ann Oncol. 2010; Morschhauser. JCO. 2009;27: 3346;
Negrea. ASH. 2009 (abstr 3757); Hagenbeek. ASH. 2009 (abstr 935);
Hagenbeek. Blood. 2008;111:5486; Salles. ASH. 2009 (abstr 1704).
New Agents in Management of
Indolent B-Cell NHLs
•
•
•
Monoclonal Antibodies
•
Rituximab
•
Ofatumumab
•
Obinutuzumab
Protein Inhibitors
•
BTK Inhibitors
•
PI3K Inhibitors
•
Others
Immunomodulatory Agents
Obinutuzumab vs Rituximab
for Rel iNHL: The GAUSS Study
• 175 pt with rel CD20 pos iNHL, 149 had FL
• Eligibility: CR or PR to rituximab-based therapy with
response lasting > 6 months
• Features: Median 2 prior Txs, others balanced
• Therapy: G 1000 mg q wk X 4 or R X4. 4-6 wks later,
pt with CR,PR,SD could receive drug q 2 mo X 2 yrs
• Infusion-related RXNs more common with GA-101
(72% vs 49%, any Gr)
• By IR panel, OR for all: G-42% vs R-24%;
for FL: G-43% vs R-28%
Sehn et al. ASH 2011, abst 269.
Obinutuzumab plus FC or CHOP for
Rel/Ref FL: Phase I GAUDI Study
• Obinutuzumab (GA-101): glycosylated, Type II
moab against CD20
• 56 pt, stratified by prior therapy
• Two Ob regimens chosen based on phase I trial:
1600 mg d 1+8, cycle 1, then 800 mg d 1+8 vs
400/400 for max 8 (CHOP) or 6 (FC) cycles
• Toxicity: Not increased with higher doses of Ob
• Results: OR=96% (G-CHOP), 93% (G-FC)
CR=39%(G-CHOP), 50% (G-FC)
• Basis for new G-CHOP study vs R-CHOP for
untreated FL
Radford et al: ASH 2011, abst 270.
Novel Therapeutics for Cancer
Cancer Hallmark
Therapeutic Target
Treatment
Proliferation
Syk, Btk, PKCB,
MToR, PI3K
FosD, PCI-32765, Enzastaurin,
Temsirolimus, Idelalisib
Insensitive to
Growth Inhibition
HDAC, DNMT
Vorinostat, Romidepsin, Belinostat,
Panabinostat, Vidaza
Evading apoptosis
BCL2/BCLX, MCL-1,
Survivin
ABT-263, Obatoclax, YM155
Limitless Replication CDK, PARP
AT7519, AZD7762, AT9283
Neoangiogenesis
VEGFR, FGFR
Sorafenib, Imatinib, Sunitinib
Invasion/Metastasis
Src, Fak, TGF
Dasatinib, LY2109761, XL228
Immune Evasion
NK/T cells
Lenalidomide, Pomalidomide
Stress Response
Proteasome
Bortezomib, Carfilzomib
Stromal Subversion
SHh, Wnt, Notch
GDC-0449, XL139, XAV939,
MK-0752
Cytokine Response
CXCR4, IL-21R
AMD3100, BKT140, IL-21
Mahadavan and Fisher. JCO 29: 1876, 1884, 2011.
Novel Therapeutics for NHLs
Cancer Hallmark
Therapeutic Target
Treatment
Proliferation
Syk, Btk, PKCB,
MToR, PI3K
FosD, Ibrutinib, Enzastaurin,
Temsirolimus, Idelalisib
Insensitive to
Growth Inhibition
HDAC, DNMT
Vorinostat, Romidepsin, Belinostat,
Panabinostat, Vidaza
Evading apoptosis
BCL2/BCLX, MCL-1,
Survivin
ABT-263, Obatoclax, YM155
Limitless Replication CDK, PARP
AT7519, AZD7762, AT9283
Neoangiogenesis
VEGFR, FGFR
Sorafenib, Imatinib, Sunitinib
Invasion/Metastasis
Src, Fak, TGF
Dasatinib, LY2109761, XL228
Immune Evasion
NK/T cells
Lenalidomide, Pomalidomide
Stress Response
Proteasome
Bortezomib, Carfilzomib
Stromal Subversion
SHh, Wnt, Notch
GDC-0449, XL139, XAV939,
MK-0752
Cytokine Response
CXCR4, IL-21R
AMD3100, BKT140, IL-21
Mahadavan and Fisher. JCO 29: 1876, 1884, 2011.
New Agents in Management of
Indolent B-Cell NHLs
•
•
•
Monoclonal Antibodies
•
Rituximab
•
Ofatumumab
•
Obinutuzumab
Protein Inhibitors
•
BTK Inhibitors
•
PI3K Inhibitors
•
Others
Immunomodulatory Agents
The B-Cell Receptor Pathway: A Useful
Target in Therapy of B-Cell NHL
• A transmembrane receptor
protein on B cells
• An antibody which binds
antigen, inducing
proliferation of plasma and
memory B cells
• Composed of two parts:
– Ligand-binding moiety
(IgM or IgD)
– Signal transduction
moiety (CD79) with an
ITAM
Results of Activation of the B-Cell
Receptor and Targets for Manipulation
Idelalisib
fostamatinib
Ibrutinib
?
enzastaurin
?
bortezomib
carfilzomib
temsirolimus
everolimus
deferolimus
Phase I Ibrutinib for
Relapsed NHL/CLL: Response Rates
Histology
N
CR
PR
SD
ORR%
(ITT, n=56)
ORR%
(Eval, n=50)
CLL/SLL
16
1
10
3*
69
79
MCL
9
3
4
1
78
78
WM
4
3**
1
75
75
FL
16
3
3
38
46
MZL/MALT
4
1
1
25
33
DLBCL
7
2
1
29
29
TOTAL
56
24
9
55
62
3
7
• * 1 CLL pt had nodal response, but increased lymphocytosis
• ** On the basis of decreased IgM
Advani R, Fowler N et al. ICML 2011.
Phase I/II Trial of Ibrutinib for Ref/Ref
MCL: Best Response by Patient Features
Wang et al. NEJM 2013.
Breakthrough approval for MCL and CLL
granted by FDA 2013.
Ongoing studies:
Placebo Controlled I + BR for Untreated MCL;
I + R for Rituximab-Refractory FL
New Agents in Management of
Indolent B-Cell NHLs
•
•
•
Monoclonal Antibodies
•
Rituximab
•
Ofatumumab
•
Obinutuzumab
Protein Inhibitors
•
BTK Inhibitors
•
PI3K Inhibitors
•
Others
Immunomodulatory Agents
PI3Kδ Inhibition Impacts Multiple
Critical Pathways in iNHL
Idelalisib: Inhibitor of PI3K Delta
Select Phase I Results in NHL (ASCO 2013)
Agents
Path
N
ORR
PFS (mo)
invest
Idelalisib
iNHL
64
48%
7.8
Benson
Idelalisib + Rituximab
iNHL
32
72%
2 yr 60%
Leonard
Idelalisib + Benda
iNHL
33
85%
2 yr 62%
Leonard
Idelalisib
MCL
40
40%
3.7
Spurgeon
Idelalisib + R + Benda
MCL
4
100%
NR
Wagner
Idelalisib + Everolimus
MCL
18
39%
4.3
Wagner
Idelalisib + Bortezomib
MCL
11
46%
5.2
Wagner
Fowler, N. ASH 2013 Education Session
Phase I Idelalisib for iNHL and MCL:
Response Rates
PFS Longer with Doses of 150 mg BID
Kahl, B et al. ICML 2011.
Idelalisib Doses of 150 mg BID Were
Associated With Longer PFS Results
PFS -- By CAL-101 Dosing Regimen
100
% Progression-Free
75
50
25
0
0
2
4
6
8
10
12
14
16
18
20
Cycles (28 days)
Group: Median PFS (N)
150-350 mg BID (includes 300 mg QD): 18 cycles (39)
50-100 mg BID: 5 cycles (16)
Kahl, B et al. ICML 2011.
22
24
Phase 2 Idelalisib for 125 Alkylator-Rituximab
Ref iNHL: Nodal Response and PFS Results
Maximum Nodal Response
Median PFS = 11.4 months
100
% Progression-Free
SPD of Measured Lymph Nodes,
Best % Change from Baseline
+50
+25
0
-25
-50a
-75
Historical Control:
Bendamustine: DOR 10mo
75
50
25
53% ORR
0
-100
Individual Patients (N=125)
0
(125)
3
(100)
6
(34)
9
(19)
12
(13)
15
(6)
Time from Start of Idelalisib, Months
(N, Patients at Risk)
•90% had improvement in lymphadenopathy
•57% had ≥50% decrease from baseline
Gopal et al. ASH 2013 #85
18
(0)
Phase 1 Idelalisib for 40 Rel/Ref MCL:
Dose 50-350 mg po BID Continuously
Features
Median age (range), years
Age >60
PS ≥ 2
(N = 40)
69 (52-83)
35 (88)
4 (10)
LDH > ULN
19 (48)
Bulky Disease (>5cm)
24 (60)
MIPI-High (>6.2)
14 (35)
Med No Prior TX (Range)
4 (1-14)
Refractory to Last TX (< 6 mo)
17 (43)
ORR: 16 (40%), CR 3 (7.5%)
ORR at < 150 = 29% (8/28), ORR with > 150 = 67% (8/12)
Spurgeon et al. Lugano 2013.
Tumor Shrinkage in MCL
Following Therapy with Idelalisib
Best On-Treatment Change in Tumor Size
(ITT Analysis)
+100
% Change in Lymph Node Area
+75
+50
MCL
(N=38a)
+25
0
-25
-50*
-75
-100
Inevaluable (patients without a follow-up tumor assessment)
* Criterion for response [Cheson 2007]
a
Tumor assessments for 2 patients have not been recorded
Kahl, B et al. ICML 2011.
Idelalisib + Bendamustine:
Response Rates
De Vose S, et al. ASH 2011 Abstract 2699.
Other PI3k Inhibitors for Rel/Ref FL:
The ARD12130 Study and BAY 80-6046
• Phase II SAR245409: Inhibits Isos α, β, γ and δ, mTORC1, TORC2.
– Study enrolls FL, CLL/SLL, MCL, and DLBCL.
– Phase 2, Stage 1 results for FL (Gr 1, 2, 3A) reported.
– Doses: 50 mg PO BID; Resp: ORR= 12/24 (50%), CR=2/24 (8%)
– AEs: Diarrhea, Pneumonias, cataracts
• BAY 80–6946, Inhibits Isoforms δ and α. May overcome
resistance to PI3K-δ.
• Phase II Study: 27 iNHL and 34 aggNHLs
• Med Prior TXs: 3. Prior ASCT: 20%
Brown et al. ASH 2013 # 86, Dreyling et al. ASH 2013 # 87.
New Agents in Management of
Indolent B-Cell NHLs
•
•
•
Monoclonal Antibodies
•
Rituximab
•
Ofatumumab
•
Obinutuzumab
Protein Inhibitors
•
BTK Inhibitors
•
PI3K Inhibitors
•
Others
Immunomodulatory Agents
Aurora Kinase A and B:
Effects on the Cell Cycle
Meraldi et al. Curr Op Genet Dev 2004.
Alisertib for Rel/Ref Aggressive NHLs:
Response and Survival Rates
• Response: ORR – 13/48 (27%), CR – 10%
• Path: DLBCL-3/21, MCL-3/13, BL-1/1, Tr FL-2/5, TCL-4/8
Waterfall Plot
Progression-Free Survival
• Gr 3-4 Toxicities: Heme - ANC-63%, HGB-35%, PLT-33%
Non-Heme – Stomatitis-15%
Friedberg et al. JCO 32: 2014.
Alisertib in Aggressive B-Cell and
T-Cell NHL: Response Rates
• ORR: 32% (95% CI: 18-48) in overall population
and responses observed in all histologic disease
subtypes
Response, %
ORR
Pts (N = 41)
32
ORR by Histology,*
%
B-cell
 CR
12
 DLBCL
20
 PR
20
 MCL
23
SD
39
 Transformed FL
40
PD
29
 Burkitt’s lymphoma
100
T-cell
Friedberg J, et al. ASH 2011. Abstract 95.
57
Potential Effects of Anti-PD-1 Antibody
in Therapy of Cancer
Anti-PD-1 Antibodies: Pidilizumab, Nivolumab, Lambrolizumab
McDermott and Atkins. Cancer Medicine 2: 662-673, 2013.
Phase 2 Anti-PD-1 (Pidilizumab) and
Rituximab for Relapsed FL: Results
• Response in 29 Evaluable Pts: OR-19 (66), CR-15 (52%) NO
factor identified a poor response
• Med Time to Response-88 days, with 6 more than 4 mo from
initial infusion
• Med PFS for all pts-18.9 mo
• PFS Affected by FLIPI and FLIPI2 Scores
PFS by FLIPI
PFS by FLIPI2
Months
Months
Westin et al. Lancet Oncol 15: 69-77, 2014.
Phase 2 Anti-PD-1 (Pidilizumab) and
Rituximab for Relapsed FL: Results
Westin et al. Lancet Oncol 15: 69-77,
2014.
New Agents in Management of
Indolent B-Cell NHLs
•
•
•
Monoclonal Antibodies
•
Rituximab
•
Ofatumumab
•
Obinutuzumab
Protein Inhibitors
•
BTK Inhibitors
•
PI3K Inhibitors
•
Others
Immunomodulatory Agents
Cereblon
A Target for Lenalidomide?
• Cereblon: Component of the E3 ubiquitin ligase
complex
• Target protein for thalidomide, lenalidomide and
pomalidomide
– These Inhibit the ubiquitin ligase activity
• May explain many of the known effects of
immunomodulatory agents:
– Teratogenic activity
– Anti-myeloma activity
– T-cell activation
40
Lenalidomide: Targeting the Tumor
Cell and Its Microenvironment
Tumor Cells
IL-6
TNF
IL-1
Tumor
Stroma
ICAM-1
Blood Vessels
NFAT
PKC
IL-2
IL-2
IFN 
VEGF
bFGF
PI3K
Dendritic
Cells
NK Cells
CD28
CD8+
T Cells
Chng. Cancer Control. 2005;12:91; Drach. Expert Rev Cancer. 2005;5:477.
Phase II Lenalidomide/Rituximab for
Relapsed MCL: Response Duration
Results for CR/PR
patients (N = 24)
Goy et al. ASH 2012, abst 905.
Results for Patients
with SD (N = 36)
Rituximab and Lenalidomide for
Untreated iNHL: Study Design
1
2
3
4
5
6
7
8
9
10
11
12
Lenalidomide 20mg Days 1-21 Cycles 1-6*
Lenalidomide 20mg Days 1-21 Cycles 7-12*
Rituximab 375mg/M2 Day 1 of Cycles 1-6
Rituximab 375mg/M2 Day 1 of Cycles 7-12
R =
RESTAGE
R
If clinical benefit,
can proceed to
12 cycles
*For
SLL patients:
Dose escalation of
lenalidomide starting
with cycle 1:
(10mg, 15mg, 20mg)
Fowler N, et al ASH 2012.
R
R
R
•Phase II, single institution
•Planned Enrollment
•50 Follicular Lymphoma (grade I/II)
•30 Small Lymphocytic Lymphoma
•30 Marginal Zone Lymphoma
•Groups analyzed independently for
response and toxicity
Follicular Lymphoma Response by
Tumor Burden and Molecular Features
By GELF Criteria (N=46)
High Tumor Burden (N=22, 48%)
Low Tumor Burden (N=24, 52%)
SD
PR
CR/CRu
ORR
SD
PR
CR/CRu
ORR
0
1 (5%)
21(95%)
100%
1(4%)
4(17%)
19 (79%)
96%
By Bulk of Disease (N=46)
Bulky (N=13, 28%)
Non-Bulky (N=33, 72%)
SD
PR
CR/CRu
ORR
SD
PR
CR/CRu
ORR
0
1(8%)
12(92%)
100%
1(3%)
4 (12%)
28 (85%)
97%
Molecular Response (N=44 Evaluable, Marrow and Blood)
PCR Positive
PCR Negative
PRETREATMENT
17(41%)
26(59%)
POST CYCLE 3
5(11%)
39(89%)
POST CYCLE 6
2(5%)
42(95%)
Fowler et al. ASH 2012, abst 901.
Lenalidomide Plus Rituximab as Initial
Therapy for iNHL: Response Rates
All Patients
Resp, %
ORR
 CR/CRu
 PR
SD
PD
•
•
SLL, N=30 MZL, N=27 FL, N=46
80
27
53
13
7
89
67
22
11
0
98
87
11
2
0
Eval, N=103 ITT, N=110
90
64
26
8
2
85
60
25
7
2
Responses for FL independent of GELF criteria or disease bulk
Molecular responses for FL increased with treatment duration
Molecular Response, %
Pretreatment
After cycle 3
After cycle 6
*Major
PCR POS
PCR NEG
41
11
5
59
89
95
or minor breakpoints from bone marrow, peripheral blood samples.
Fowler et al. ASH 2012. Abst 901.
Lenalidomide/Rituximab for iNHLs:
PFS by Histology
Marginal Zone
100
100
80
80
Percent survival
Percent survival
Follicular Lymphoma
60
N=46
40
20
36 mo PFS: 81%
0
0
12
24
60
N=27
40
20
36 mo PFS: 89%
0
0
36
12
PFS
PFS (months)
SLL
abst 901.
Percent survival
100
Fowler et al. ASH 2012,
24
80
60
40
N=30
20
36 mo PFS: 66%
0
0
12
24
PFS
36
36
Lenalidomide-R for FcγRIIIa-F iNHLs or
MCLs Refractory To Rituximab
• FCGR3A polymorphisms cause significant impact on
ORR, CR rate, and TTP after SA rituximab (ORR 26%
and 2-Yr PFS of only 14% if F allele present).
• Study: R-Refractory (SA or chemo combo) and F
• Schema: 2 mo Len/Dex (10 mg QD/8 mg QWk, Part
1), then Rituximab q Wk X 4 with Len/Dex (Part 2),
then continue Len/Dex alone.
• Pts: 17/18 tested had F/F alleles, one V/V.
Resp
All
F
MCL , SLL , MZL
Pts
17
12
5
24/53%
25/50%
24/51%
3/5 pt
2/4 pt
1/1 pt
ORR (Part 1/2)
CR (Part 1/2)
Cartron 2002, Weng 2003, Chong et al. ASH 2013, #250.
Lenalidomide-R for FcγRIIIa-F iNHLs or
MCLs Refractory To Rituximab
Med f/u of 52 months, Med PFS is 24.5 months,
2 Yr PFS = 50% compared to 14% for historical controls.
Chong, ASH 2013 # 250
Phase II Lenalidomide-R-CHOP
for Untreated High- Risk (GELF) FL
• Patients: 80 with FL Gr 1, 2, 3a; Med age 57, High
LDH-40%, FLIPI 3-5 in 63%, Mass > 10 cm-25%
• Therapy: Induction of Standard R-CHOP, plus Len 25
mg QD days 1-14, X 6 cycles + 2 R doses
– Maintenance: MR q 8 wks X 2 yrs
– Supportive: Pegfilgrastim day 4, QASA 10 mg QD
• Med F/U 12 mo: ORR – 94%, CR/CRu – 74%
– Gr 4 Toxicity: ANC-64%, PLT-12.5%
– Gr 3 neuropathy: 36%, Gr 1-3 rash (2 Gr 3)
– Thrombosis in 5 (3 catheter related)
Tilly et al. ASH 2013 # 248
Rituximab Plus Lenalidomide 20 mg daily for 21 days, off 7 days
X 6, and if CR, reduce to 10 mg
New Agents in Management of
Indolent B-Cell NHLs
F B Hagemeister MD
Department of Lymphoma/Myeloma
M D Anderson Cancer Center
Las Vegas, Nevada
February 27, 2014