What’s New in Indolent NHL, MCL and PTCL? ASH 2012 Review

March 14, 2013

Myron S. Czuczman, MDProfessor of Medicine and OncologyChief, Lymphoma/Myeloma SectionHead, Lymphoma Translational Research LaboratoryRoswell Park Cancer Institute, Buffalo, NY

Disclosure of Conflicts of InterestMyron S. Czuczman, MD

Disclosure of Conflicts of InterestMyron 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

Rummel et al. ASH 2012, Abstract 2724

Frontline BR vs CHOP-R (max 6 cycles)

Subanalysis of the impact of response quality on outcome

Subanalysis of responders in

NHL1 (StiL) phase III study in indolent

lymphoma and MCL

Responder Subanalysis of BR vs CHOP-R in Indolent and MCL (StiL): Subgroup Analysis/Conclusions

CR PR PMedian PFS, mo

All Patients 57.5 43.5 0.0037*

BR Arm NR 57 0.1912

R-CHOP Arm 54 31 0.0215*

OS at 5 y

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

*Denotes statistically significant differences Rummel et al. ASH 2012, Abstract 2724

Pts in CR c/w PR following 1st-line Rx: significantly longer PFS and OS

Results suggest: association between quality of response vs outcome

Frontline BR vs R-CHOP/R-CVP in Advanced Indolent NHL (The BRIGHT Study): Study Design

Bendamustine 90 mg/m2 Day 1 and 2Rituximab 375 mg/m2 on D1 q28d

(6-8 cycles); n=224 Primary: Noninferiority of CR for BR vs standard treatment (IWG criteria);

independent and investigator review)

Flinn et al. ASH 2012, Abstract 902

Frontline advanced

indolent NHL

(Preassignment of chemo arms by investigator)

R-CHOP and R-CVP: std dosing q21d

(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%)

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

Randomized, Investigator 31 18 1.60 (1.14-2.25) 0.0013b

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

Responses (1999 IWG) assessed every

3 cycles

Phase IIAdvanced 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)

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 KH et al. ASH 2010 Abst 964 2Kahl B et al. ASH 2010 Abst 1777

The BTKi Ibrutinib (PCI-32765) in Relapsed FL

Study Design

Ibrutinib PO dose escalationIntermittent: 1.25–12.5 mg/kg

Continuous: 8.3 mg/kg and 560-mg fixed dose QD

Efficacy for doses ≥2.5 mg/kg (ie, full BTK

occupancy)

Response measured every 2 mo (2007 IWG)

Phase I

Rel/ref B-cell lymphoma (FL); ECOG ≤1,

1-4 prior therapies,

measurable disease

Fowler et al. ASH 2012, Abstract 156

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)

Primary objectives: safety and MTD

Ibrutinib induces apoptosis and inhibits cellular migration and adhesion in neoplastic B-cells

Ibrutinib in Relapsed FL: Efficacy

Efficacy (n=16) n (%) 1.25 mg/kg/d(n=4 FL)

≥ 2.5 mg/kg/d(n=11 FL)

≥ 5.0 mg/kg/d(n=9 FL)

ORR 7 (44) 25% 55% 56%CR/CRu 3 (19) 0 27% 33%PR 4 (25) 25% 27% 22%

Median DR, mo 12.3 NE 10.3 12.3Median time to first response, mo (range)

4.7 (2-12) − − −

Median time to first PR, mo (range)

4.6 (2-11) − − −

Median time to first CR, mo (range)

11.5 (5-12) − − −

Median PFS, mo 13.4 NE 13.4 19.6Median OS, mo No deaths − − −

• 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 IRel/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)

Davids et al. ASH 2012, Abstract 304

• 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

Phase II Study 0f CT-011 + R in Relapsed FL

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 CT-

011 [total 12])

Primary: ORRCT +/- PET after 2 and

4 infusions CT-011 and q 3 mo for ≤2 y;

BM biopsy needed to confirm CR

Westin et al. ASH 2012, Abstract 793

Phase II

Rituximab-sensitive, grade 1-

2 FL, relapsed after 1-4 prior

therapies, measurable

disease, adequate organ function, ALC ≥0.6x109/L

• 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

Phase II Study 0f CT-011 + R in Relapsed FL:Results/Conclusions

Efficacy (n=29) n (%)ORR 19 (66)

CR 15 (52)

PR 4 (14)

Measurable tumor regression 25 (86)

Median time to response, d 88

Median PFS, moIn responders (n=19)Pts with tumor regression (n=25)

21.1NRNR

• 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

*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.

MCL patients relapsed,

progressed, or refractory

to bortezomib

(N = 134)

Treatment Phase*Lenalidomide 25 mg days 1-21,

q28d; CT every 2 cycles

Follow-UpCT every 90 days

PD or toxicity

Primary endpoints†: ORR and DORSecondary endpoints: CR, PFS, TTP, OS and safety

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

Efficacy

Bort-Naive(n=63)

Bort- Exposed

(n=46)

All Patients(n = 109)

65% 72% 68%

CR/CRu 21% 23% 22%

PR 44% 49% 46%

• 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

Efficacy ASH 2011 (n=51)

ASH 2012 (n=51)

Median time on study treatment, mo

3.8 mo 11.3 mo

ORR 69% 75%

CR 16% 35%

Wang et al. ASH 2012, Abstract 904

Ibrutinib 560 mg/d PO; continuous 28-day cycles until

PD

Primary: ORR (every 2 cycles)

Secondary: DOR, PFS, OS, and safety

Phase II: Rel/ref MCL; phase II study of

bortezomib-naive and bortezomib-exposed patients with MCL

• 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

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 MRSpurgeon et al. ASH 2012, Abstract 3675

Brentuximab Vedotin in Rel/Ref CD30+ Heme MalignanciesRothe (German Hodgkin Study Group) et al

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 causePFS – time from initiation to progression, relapse, or death

Rothe et al. ASH 2012, Abstract 2743

Retrospective analysis of CD30+ refractory or

relapsed HL or relapsed ALCL without

prior high-dose chemotherapy (HDCT) and autologous SCT

(German Hodgkin Study Group)

• 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

Frontline Romidepsin + CHOP in PTCL (Ro-CHOP):

RoCHOPRomidepsin: Starting dose 10 mg/m2 days 1 and 8

+ CHOP: Cyclophosphamide 750 mg/m2 day 1 Doxorubicin 50 mg/m2 day 1Vincristine 1,4 mg/m2 day 1Prednisone 40 mg/m2 days 1 – 5

3 + 3 design; DLT considered in first

2 cycles

Safety, efficacy, tolerability

Dupuis et al. ASH 2012, Abstract 1617

Phase Ib

Previously untreated,

biopsy-proven PTCL (N=18)

• 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

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

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