new agents in management of indolent b-cell nhls f b hagemeister md department of lymphoma/myeloma m...

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


• 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 B-

2.9 (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.

• 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:

• OS rates, transformation rates not different

• Still No result on differences related to type of chemotherapy administered

The PRIMA Trial: A 6 Year Update

Salles et al. ASH 2013, # 509.

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

MR vs Obs after R-Chemo for FL: PFS in the PRIMA Trial

Salles et al. ASH 2013 # 509

Progression-Free Survival

24 72

Months

Early Relapse Of R-CHOP for FL: Effect of Early Relapse on OS Result

Casulo et al. ASH 2013 # 510

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.

90Y-Ibritumomab for Advanced Stage FL in First Remission: The FIT trial

Hagenbeek et. al. ASH 2007, Abstract # 693

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

FLIPI, 0-1 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

* All patientsNote: 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

90YIbritumomab Consolidation vs MR for Untreated FL in CR/PR After R-CHOP

Lopez-Guillermo, et al. ASH 2013 # 369

Conclusion: MR is better than 90YIbritumomab after R-CHOP



• Rituximab

• Ofatumumab

• Obinutuzumab


• BTK Inhibitors

• PI3K Inhibitors

• Others


Novel Anti-CD20 MoAbs for Relapsed/Refractory Indolent Lymphomas

MoAb Phase Efficacy

Ofatumumab

I/IIDose (ORR): 300 mg (63%); 500 mg (33%);

700 mg (20%); 1000 mg (50%)

IIORR: 11%, 6-mo PFS in 116 pts with

rituximab-refractory FL

Veltuzumab I/II

IV administration: ORR: 44%, CR: 27%

DOR in pts with FL: 19.7 mos

Subcutaneous administration: ORR: 53%

CR: 20% in pts with indolent NHL

Ocrelizumab I/II ORR: 38%; PFS: 11.4 mos in pts with FL

GA101 I/II/III ORR: 69%, CR: 38% in 13 pts with FL

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).



• Rituximab

• Ofatumumab

• Obinutuzumab


• BTK Inhibitors

• PI3K Inhibitors

• Others


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.



• Rituximab

• Ofatumumab

• Obinutuzumab


• BTK Inhibitors

• PI3K Inhibitors

• Others


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

bortezomib carfilzomib

?

?

fostamatinib

temsirolimus everolimus deferolimus

Idelalisib

enzastaurin

Ibrutinib

Phase I Ibrutinib for Relapsed NHL/CLL: Response Rates

Histology N CR PR SDORR%

(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 3 38 46

MZL/MALT 4 1 1 25 33

DLBCL 7 2 1 29 29

TOTAL 56 7 24 9 55 62

• * 1 CLL pt had nodal response, but increased lymphocytosis

• ** On the basis of decreased IgMAdvani 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



• Rituximab

• Ofatumumab

• Obinutuzumab


• BTK Inhibitors

• PI3K Inhibitors

• Others


PI3Kδ Inhibition Impacts Multiple Critical Pathways in iNHL

Idelalisib: Inhibitor of PI3K DeltaSelect 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.

PFS -- By CAL-101 Dosing Regimen

0 2 4 6 8 10 12 14 16 18 20 22 240

25

50

75

100

50-100 mg BID: 5 cycles (16)

150-350 mg BID (includes 300 mg QD): 18 cycles (39)

Group: Median PFS (N)

Cycles (28 days)

% P

rog

ressio

n-F

ree

Idelalisib Doses of 150 mg BID Were Associated With Longer PFS Results


Phase 2 Idelalisib for 125 Alkylator-Rituximab Ref iNHL: Nodal Response and PFS Results

-100

-75

-25

0

-50a

+25

+50

Individual Patients (N=125)

SP

D o

f M

easu

red

Lym

ph

No

des

,B

est

% C

han

ge

fro

m B

asel

ine

•90% had improvement in lymphadenopathy•57% had ≥50% decrease from baseline

Gopal et al. ASH 2013 #85

Median PFS = 11.4 monthsMaximum Nodal Response

Historical Control:

Bendamustine: DOR 10mo

53% ORR

Phase 1 Idelalisib for 40 Rel/Ref MCL: Dose 50-350 mg po BID Continuously

Spurgeon et al. Lugano 2013.

Features (N = 40)

Median age (range), years 69 (52-83)

Age >60 35 (88)

PS ≥ 2 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)

Best On-Treatment Change in Tumor Size(ITT Analysis)

-50*

+25

+50

+75

+100

-25

0

-100

-75

Inevaluable (patients without a follow-up tumor assessment)* Criterion for response [Cheson 2007]a Tumor assessments for 2 patients have not been recorded

MCL(N=38a)

% C

han

ge in

Lym

ph

No

de A

rea

Tumor Shrinkage in MCL Following Therapy with Idelalisib


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

Brown et al. ASH 2013 # 86, Dreyling et al. ASH 2013 # 87.

• 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%



• Rituximab

• Ofatumumab

• Obinutuzumab


• BTK Inhibitors

• PI3K Inhibitors

• Others


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

• Gr 3-4 Toxicities: Heme - ANC-63%, HGB-35%, PLT-33%

Non-Heme – Stomatitis-15%

Waterfall Plot Progression-Free Survival

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

Friedberg J, et al. ASH 2011. Abstract 95.

Response, % Pts (N = 41)

ORR 32

CR 12

PR 20

SD 39

PD 29

ORR by Histology,* %

B-cell

DLBCL 20

MCL 23

Transformed FL 40

Burkitt’s lymphoma 100

T-cell 57

Potential Effects of Anti-PD-1 Antibody in Therapy of Cancer

McDermott and Atkins. Cancer Medicine 2: 662-673, 2013.

Anti-PD-1 Antibodies: Pidilizumab, Nivolumab, Lambrolizumab

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

Westin et al. Lancet Oncol 15: 69-77, 2014.

PFS by FLIPI PFS by FLIPI2

Months Months

Phase 2 Anti-PD-1 (Pidilizumab) and Rituximab for Relapsed FL: Results

Westin et al. Lancet Oncol 15: 69-77, 2014.



• Rituximab

• Ofatumumab

• Obinutuzumab


• BTK Inhibitors

• PI3K Inhibitors

• Others


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

Chng. Cancer Control. 2005;12:91; Drach. Expert Rev Cancer. 2005;5:477.

Tumor Cells

Tumor Stroma

Dendritic Cells

IL-6TNFIL-1

IL-2

IFN

CD8+ T Cells

Blood Vessels

ICAM-1

VEGF

bFGF

NK Cells

PKCNFAT

PI3K

IL-2

CD28

Phase II Lenalidomide/Rituximab for Relapsed MCL: Response Duration

Results for CR/PR patients (N = 24)

Results for Patients with SD (N = 36)

Goy et al. ASH 2012, abst 905.

Rituximab and Lenalidomide for Untreated iNHL: Study Design

Lenalidomide 20mg Days 1-21 Cycles 1-6*

1 2 3 4 5 6

Rituximab 375mg/M2 Day 1 of Cycles 1-6

If clinical benefit, can proceed to

12 cycles •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

R = RESTAGE

R

Rituximab 375mg/M2 Day 1 of Cycles 7-12

Lenalidomide 20mg Days 1-21 Cycles 7-12*

R RR

7 8 9 10 11 12

*For SLL patients: Dose escalation of lenalidomide starting

with cycle 1: (10mg, 15mg, 20mg)

Fowler N, et al ASH 2012.

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%

Fowler et al. ASH 2012, abst 901.

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%)

Lenalidomide Plus Rituximab as Initial Therapy for iNHL: Response Rates

• Responses for FL independent of GELF criteria or disease bulk• Molecular responses for FL increased with treatment duration

Fowler et al. ASH 2012. Abst 901.

*Major or minor breakpoints from bone marrow, peripheral blood samples.

Resp, % SLL, N=30 MZL, N=27 FL, N=46All Patients

Eval, N=103ITT,

N=110ORR 80 89 98 90 85 CR/CRu 27 67 87 64 60 PR 53 22 11 26 25

SD 13 11 2 8 7PD 7 0 0 2 2

Molecular Response, % PCR POS PCR NEG

Pretreatment 41 59After cycle 3 11 89After cycle 6 5 95

PFS

Per

cen

t su

rviv

al

0 12 24 360

20

40

60

80

100

PFS

Perc

en

t su

rviv

al

0 12 24 360

20

40

60

80

100

PFS (months)

Perc

en

t su

rviv

al

0 12 24 360

20

40

60

80

100

Lenalidomide/Rituximab for iNHLs: PFS by Histology

N=46

36 mo PFS: 81%

Follicular Lymphoma Marginal Zone

SLL

N=27

36 mo PFS: 89%

N=30

36 mo PFS: 66%Fowler et al. ASH 2012,

abst 901.

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.

Cartron 2002, Weng 2003, Chong et al. ASH 2013, #250.

Resp All F MCL , SLL , MZL

Pts 17 12 5

ORR (Part 1/2) 24/53% 25/50% 24/51%

CR (Part 1/2) 3/5 pt 2/4 pt 1/1 pt

Lenalidomide-R for FcγRIIIa-F iNHLs or MCLs Refractory To Rituximab

Chong, ASH 2013 # 250

Med f/u of 52 months, Med PFS is 24.5 months,

2 Yr PFS = 50% compared to 14% for historical controls.

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


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 f b hagemeister md department of lymphoma/myeloma m...

Documents

yr vs b

r pmr vs obs

mo pfs

rit vs sct

rchopnew agents

untreated fl

induction rchop

induction rituximab