What’s New in Indolent NHL, MCL and PTCL? ASH 2012 Review March 14, 2013 Myron S. Czuczman, MD...

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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