2012 ASCO Highlights:Hematologic Malignancies

Wei Ai, M.D., Ph.D.June 2012

A Year of New Agents!

I. Lymphoma: bendamustineII. CLL/SLL: Btk inhibitorIII. Pre-B ALL: Bite biphasic antibodyIV. Multiple Myeloma: Carfilzomib

Lymphomas and CLL/SLL

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The Best First-line Therapy is Undefined for FL and MCL

National LymphoCare Study 2004 -2007 N = 2728

Friedberg, et al., JCO 2009

R + chemotherapy:

Regimen Users (%)

RCHOP 55.0%

RCVP 23.1%

R-fludarabine 15.5%

Other 6.4%

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Newly diagnosed indolent lymphoma or mantle cell lymphoma:- Follicular lymphoma (grade 1-3a), small lymphocytic lymphoma, marginal zone lymphoma, wadenstroms, mantle cell lymphoma (elderly)

Stage III and IV Meet criteria for initiating treatment

Major Inclusion Criteria

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A Phase Ib/II study evaluating activity and tolerability of BTK

inhibitor PIC-32765 and ofatumumab in patients with CLL/SLL and related disease

Samantha Mary Jaglowski, et al.The Ohio State University

BTK inhibitor, an oral agent, showed promising activity as a single agent in untreated elderly pts (>65 yo) with CLL/SLL (John Byrd 2012 ASCO)- N = 26 - ORR 81%, CR 12% with medium f/u 14 mos

Ofatumumab is active in fludarabine- or alemtumumab-refractory CLL/SLL pts: ORR approximately 50%

Background

Wierda, et al., JCO 2010

Ibrutinib 420 mg po qd Oftumumab

- 300 mg C2, day1- 2000 mg C2,days 8, 15, 22- 2000 mg C3, days 1, 8, 15, 22- 2000 mg C4-8, day 1 only

Schema

To determine the toxicity of the combination regimen- Tolerability is defined as no more than 1 DLT in the first 6 pts treated for 2 cycles

To evaluate ORR at one year: N = 27, including the initial 6

Objectives

CLL/SLL or Richter’s transformation Two or more prior therapy, including a

purine analog- containing regimen More than 10% CD20 expression on CLL

cells by flow cytometry Adequate organ functions

Major Eligibility

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Ibrutinib combined with ofatumumab is a well tolerated and highly active regimen in patients with relapsed and refractory CLL/SLL

Conclusions

Acute Leukemia

Effect of anti-CD19 BiTE blinatumomab on complete remission rate and overall survival in adult patients

with relapsed/refractory pre-B ALL

Max Topp et al.

Mechanism of BITE Monoclonal Antibody

Background:Blinatumomab has high response rate and durable response in MRD-positive preB- ALL

Topp, et al., JCO 2011

80%

15 ug/m2/24 hrs CIV x 4 weeks, 2 weeks off, q 6wk-cycle

Dose-finding Phase:- Cohorts: 1, 2a, 2b

Expansion Phase: Dosing: CIV 4 wks on, 2 wks off, for up to 5

cycles- CR/CRh within the first 2 cycles -> allo

Primary Endpoint: CR/CRh within 2 cycles

Phase II Blinatumumab in R/R ALL: Study Design

R/R ALL, > 5% blasts in BM Ph+ and relapsed after allo were permitted

Key Inclusion Criteria

Selected dose for expansion cohort based on lowest treatment-related AEs (3/5 pts): 5ug/m2/d CIV week 1, then 15ug/m2/d CIV thereafter

Dose-finding Phase

Patient CharacteristicsN = 23

Median Age 31 (21 – 66)

Refractory 1 (4%)

Relapsed 21 (91%)

1st relapse <= 18 mos

9 (43%)

1st relapse > 18 mos 4 (19%)

>= 2nd relapse 8 (38%)

Prior SCT 10 (43%)

Ph + 2 (9%)

T (4,11) 1 (4%)

Blasts in BM

>60% 12 (52%)

10% - 60% 6 (24%)

< 10% 4 (17%)

Cytokine release syndrome- Risks: high tumor burden ans without

cytoreductive phase- Prevention: cytoreduction 5ug/m2 wk 1 and give

Dex for BM>50% CNS Adverse Events:

- 3 seizures and 3 encephalopathy: fully reversible- all 6 pts continued at 5 ug/m2

One pt died of fungal infection

Import Safety Events

CR/CRh: 17/23 pts (74%) All but 2 responders achieved molecular

remission High remission rate in all pt groups,

including Ph+ 13 pts received an allogeneic SCT With a median follow-up of 4.5 months,

median duration of response was 8.9 for all cohorts, not yet reached for the expansion cohort

Results

Well-tolerated at 5 ug/m2/d followed by 15 ug/m2/d CIV, 4 weeks on, 2 weeks off

High hematologic and molecular response rate

Median duration of complete hematologic response was 8.9 months

Median survival was 9 months

Conclusion

Multiple Myeloma

Carfilzomib Coming to the Front-line

Disease status- High risk, intermediate risk vs low risk- special clinical scenarios: plasma leukemia, renal failure

Patient factors- Transplant eligibility- PS and comorbidity

Clinical benefit- response and OS- QOL

Toxicity and convenience Cost

Principles for Front-line Therapy

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Newly approved second-in-class proteasome inhibitor

Well tolerated, no neurotoxicity Overcome bortezomib resistance in vitro Active alone and in combination regimens

for relapsed/refractory MM

Kuhn et al., Blood 2007, O’Connor Clin Cancer Res 2009, Wang, M et al., JCO 2011 Abstract 8052, Vij, et al., Blood, 2012

Carfilzomaib

CMPcarfilzomib, melphalan, prednisone

CYCLONEcarfilzomib, cyclophosphamidethalidomidedexamethasone

CRdcarfilzomib,lenalidomidedexamethasone

Key Criteria Transplant ineligible>65 yo

Transplant eligible Transplant ineligible or eligible

Comparative orParent regimens

VMP CyBorDCTD

RVD,VTD, VTD

Carfilzomib-containing First-line Regimens

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Carfilzomib: 20mg/m2 first week, 27mg/m2 thereafter

Phase II dose

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Stringent complete response (sCR) in patients

with newly diagnosed multiple myeloma(NDMM) treated with carfilzomib (CFZ),

lenalidomide (LEN), and dexamethasone (DEX)AJ Jakubowiak,1 K Griffith,2 D Dytfeld,3 DH Vesole,4 S Jagannath,5 T Anderson,2

B Nordgren,2 K Detweiler-Short,2 D Lebovic,2 K Stockerl-Goldstein,6 T Jobkar,2

S Wear, 7 A Al-Zoubi, 2 A Ahmed, 2 M Mietzel, 2 D Couriel, 2 M Kaminski, 2

M Hussein,8 H Yeganegi,9 R Vij6

1University of Chicago, Chicago, IL; 2University of Michigan Comprehensive Cancer Center,Ann Arbor, MI; 3Poznan University of edical Sciences, Poznan, Poland; 4John Theurer CancerCenter, Hackensack, NJ; 5Mount Sinai Medical Center, New York, NY; 6Washington University

School of Medicine, St. Louis, MO; 7Multiple Myeloma Research Consortium, Norwalk, CT;8 Celgene, Inc, Summit, NJ; 9 Onyx Pharmaceuticals, South San Francisco, CA

ObjectivesPrimary

• Phase 1: MTD of CRd• Phase 1/2: rate of ≥nCR

Secondary• Overall response rate (≥PR)

• TTP, DOR, PFS, and OS• Tolerability and toxicity

• For transplant candidates, evaluate the impact of CRd onstem cell mobilization• Evaluate prognostic factors and markers of response

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Eligibility

Key inclusion criteria• Newly-diagnosed MM requiring first-line therapy1

- Transplant-eligible and -ineligible

• Measurable disease per IMWG Criteria1

• ECOG performance status 0-2

Key exclusion criteria• Grade 3/4 peripheral neuropathy

• ANC <1.0x109/L, Hgb <8.0 g/dL, platelets <75,000/µL• Creatinine clearance <50 mL/min or serum creatinine ≥2 g/dL

• Serious co-morbidities

1. Durie BGM, et al. Leukemia. 2006;20:1467-1473.5

Treatment Schema

Transplant-eligible and-ineligiblepatients

CRdInduction

-CRd Cycles 1-4 CRd Cycles 5-8

Transplant-eligible

≥PR ASCT

Stem cell collection

CRd LenalidomideMaintenance (off protocol)

CRd Cycles 9-24 LEN Cycles 25+

Until disease progression orunacceptable toxicity

• Assessments on D1 and 15 of C1 and D1 thereafter using modified IMWG Criteria with nCR

Cycles 1-8• CFZ 20-27-36 mg/m2 Days

1-2, 8-9, 15-16 1

• LEN 25 mg Days 1-21• DEX 40 mg weekly Cycles 1-

4, 20 mg weekly Cycles 5-8

Cycles 9-24• CFZ on Days 1-2 and 15-

16 only• CFZ, LEN, DEX at last

best tolerated doses

Cycles 25+• LEN at last best

tolerated dose

1. Jakubowiak AJ, et al. Blood. 2011;118: abstract 631. 6

Best ResponseMedian 12 cycles (range 1-25)

≥

PR

10080

60

40

20

0

≥VGPR ≥nCR sCR

98

81

62

42

All patients N=53

There was no difference by disease stage and cytogenetics

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Progression-free Survival

Median follow-up of 13 months (range 4-25)2 patients progressed

All patients with sCR have maintained response for median 9 months(range 1-20)

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Updated Toxicity of CRd InductionThrombocytopenia Grade 3/4

AnemiaNeutropenia Any grade

HyperglycemiaEdema

HypophosphatemiaFatigue

Muscle crampingLFTsRash

DiarrheaInfectionPhlebitis

Peripheral neuropathyDyspnea

DVT/PERenal

ConstipationMood alterations

0 20 40 60 80 100Patients (%)

• Toxicity for cycles 1-8 is similar to previously reported1

• Limited dose modifications1. Jakubowiak AJ, et al. Blood. 2011;118: abstract 631.

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CMPcarfilzomib, melphalan, prednisone

N = 35

CYCLONEcarfilzomib,

cyclophosphamide

thalidomidedexamethasone

N = 24

CRdcarfilzomib,lenalidomidedexamethaso

ne

N = 53

Transplant ineligible>65 yo

Transplant eligible Transplant ineligible or

eligible

Comparative orParent regimens

VMP CyBorDCTD

RVD,VTD, VTD

ORR - CR - sCR - nCR - VGPR - PR

31(89%)1 (3%)

14 (40%)16 (46%)

23 (96%)7 (29%)

11 (46%)5 (21%)

52 (98%)33 (62%) 22 (42%)11 (20%)10 (19%)9 (17%)

Summary (1):Carfilzomib-containing First-line Regimens

Highly active as a first-line treatment for MM

The quality of response seems improved in some studies

Tolerability seems improved with minimum peripheral neuropathy, although comparison with SQ bortezomib remain to be investigated

Summary (2):Carfilzomib-containing First-line Regimens

Lymphoma and CLL/SLL The Stil trial established R-Benda as the

preferred first-line treatment for FL and MCL Ofatumumab + ibrutinib (Btk inhibitor) is

highly active in relapsed/refractory CLL/SLL Acute Leukemia

Blinatumumab (Bite biphasic antibody) is highly active in relapsed/refractory ALL

Multiple MyelomaCarfilzomib is moving to the front line

Summary

Thank you

Hematologic Toxicity

Grade 3/4CHOP-RN =253

BRN = 261

Neutropenia 69% 29%

lymphopenia 43% 74%

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Blinatumomab in MRD Positivepre-B ALL: Durable Response

Topp, et al., JCO 2011