CE-1

Lenalidomide Efficacy

Alan List, MD

Professor of Medicine and OncologyChief, Division of Malignant Hematology

H. Lee Moffitt Cancer Center and Research Institute

University of South Florida College of Medicine

CE-2

Lenalidomide Del 5q MDS Studies

MDS-001 (N = 43 MDS)

– Single-center, phase 2 pilot study

– All FAB/IPSS-Risk MDS (del 5q, n = 12)

– Established 10 mg starting dose

MDS-003 (N = 148)

– Multicenter, confirmatory, phase 2 study

– Del 5q chromosomal abnormality

– Low/Int-1 IPSS-Risk

– RBC transfusion dependent

CE-3

Pilot Study of Lenalidomide in MDSStudy MDS-001

EligibilityAll FAB/IPSSHgb < 10 g/dLANC > 500/µL

Platelets > 10,000/µL

Activation: 3-1-02Cohorts

25 mg po qd10 mg po qd

10 mg × 21/28 days

0 161284Wk:

Primary endpoint: erythroid response (IWG criteria)Secondary endpoints: cytogenetic response, biologic correlates

List A, et al. N Engl J Med. 2005;352:549-557.

RREESSPPOONNSSEE

RREEGG IISSTTEERR No→Off study

Yes→Continue

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Key OutcomesStudy MDS-001

43 MDS patients: Low/Int-1: 38/43

Del 5q (n = 12)

– 75% major erythroid response (MER)

– All MER achieved complete cytogenetic response

Non del 5q (n = 31)

– 33% MER

– 12% cytogenetic response

Sustained anemia relief to > 2 yr

Established phase 2 starting dose: 10 mg

DV

CE-5

Phase 2 Study of Lenalidomide MDS Del 5q (MDS-003)

RREESSPPOONNSSEE

RREEGG IISSTTEERR

Wk: 0 4 8 12 16 20 24

Activation date: 7-15-03 Cohorts

10 mg × 21 days10 mg po qd

Treatment until progression/relapse

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Eligibility Criteria Del 5q (MDS-003)

Del 5q cytogenetic abnormality

Low/Int-1 MDS

Transfusion-dependent anemia

≥ 2 units within 8 wk (56 days) of lenalidomide treatment

Age ≥ 18 yr

ECOG PS 0 - 2

Negative pregnancy test for WCBP

CE-7

Key Exclusion CriteriaDel 5q (MDS-003)

ANC < 500/µL

Platelet count < 50,000/µL

Pregnant/lactating females

Proliferative CMML (WBC > 12,000/µL)

Anemia due to other factors

Secondary MDS

Medications for MDS

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Endpoints Del 5q (MDS-003)

Primary efficacy– RBC transfusion independence

Secondary efficacy– Duration of response– Change in Hgb level– Minor erythroid response– Cytogenetic response– Pathologic response (bone marrow) – Neutrophil/platelet responses

Safety

CE-9

Study ConductDel 5q (MDS-003)

Initially, CBC q2 wk × 8 wk, then q1 mo

– Amended to include weekly CBC, wk 1-8Concomitant medications

– rhu-EPO excluded

– Myeloid growth factors permitted RBC transfusion guidelines

– Hgb ≤ 8.0/Hct 25 or

– Pre-study threshold

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Characteristic

Patients, N 148

Median age, yr range 71 (37 - 95)

Male: Female 51 (35%): 97 (65%)

Del 5q abnormality 148 (100%)

Median duration of MDS, yr (range) 2.5 (0.1 - 20.7)

Median RBCs/8 wks, units (range) 6 (0 - 18)

≥ 2 units RBCs/4 wks 105 (71%)

Baseline ANC < 1500 43 (29%)

Baseline PLT < 100,000 25 (17%)

Patient Baseline Characteristics Del 5q (MDS-003)

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IPSS/FAB by Central ReviewDel 5q (MDS-003)

IPSS FAB

Low37% RA

52%Int-144%

Unclass14%

Int-2/High5%

RARS12%

RAEB20%

Unclass11%

AML 0.7%Atypical CML 2%

CMML 2%

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Prior Therapy for MDSDel 5q (MDS-003)

Prior medicationPatients, n (%)

N = 148

Erythropoietin

US population

Germany

108 (73)

98/111 (88)

10/35 (29)

Chemotherapy agents 58 (39)

Iron chelating therapy 55 (37)

No previous therapy 18 (12)

Unknown 1 (0.7)

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Analysis Populations and Data SetsDel 5q (MDS-003)

Intent to treat (ITT)– All patients registered to the trial

Modified ITT (MITT) – Prospectively defined based on FDA advice – 16-wk pre-study documentation of transfusions– Centrally confirmed Low/Int-1 MDS with del 5q

Data sets– NDA submission (9-15-04)– Efficacy update (3-31-05)

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Definition of Transfusion Independence (TI)Del 5q (MDS-003)

Protocol definition

– IWG defined TI

• No RBC transfusions ≥ 2 mo (56 days)

– Additional requirement

• Hgb increase ≥ 1.0 g/dL

Duration of TI response

– From day after last RBC transfusion to day before next RBC transfusion

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Transfusion Independence Response Del 5q (MDS-003)

4.1 (1 - 19)55.9, 71.995 (64%)

4.6 (1 - 49)58.7, 74.499 (67%)

Updated data3-31-05

Median time to response, wk (range)

95% CIOverall, nITT, N = 148

NDA submission9-15-04

5.1 (1 - 49)53.3, 73.560 (64%)

4.7 (1 - 19)50.0, 70.657 (61%)

Median time to response, wk (range)

95% CIOverall, nModified ITT, N = 94

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CE-16Mean Number of RBC Units Transfused per Patient by 56-Day Periods (8 Wk) (ITT)Responders Del 5q (MDS-003) (3-31-05)

4.6 4.7

3.9

0.70.3 0.30.2 0.4

92 95N = 95 95 92 88 59 28

Pretreatment Treatment

0

2

4

6

–16 - –9 –8 - 0 1 - 8 9 - 16 17 - 24 25 - 32 33 - 40 41 - 48

Study wk

pR

BC

, u

nit

s

CE-17Mean Untransfused§ Hgb (g/dL) by Cycle (ITT) Del 5q (MDS-003) (3-31-05)

N = 148

95% confidence intervals are provided when n > 3.§ Hgb values ≤ 30 days following transfusion were excluded, unless the values were on or ≤ 3 days preceding a transfusion date.

0 2 4 6 8 10 12 14 16 186

8

10

12

14

Responders Non-responders

Normalized, per NCCN Guideline

Med

ian

tim

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to r

esp

on

se

Cycle, 28 days

Hg

b, g

/dL

CE-18Hemoglobin Improvement forTI Responders (ITT) Del 5q (MDS-003) (3-31-05)

N = 99

0.0

2.5

5.0

7.5

10.0

12.5

Median = 5.3

Hg

b c

han

ge

fro

m b

asel

ine

CE-19

Durable Transfusion Independence (ITT) Del 5q (MDS-003) (3-31-05)

N = 99

§ Symbols are censored patients who remain transfusion independent at time of data cutoff or at time of study discontinuation.

0 10 20 30 40 50 60 70 800

10

20

30

40

50

60

70

80

90

100

110

57 ongoing responders

83 TI response 24 wk52 TI response 52 wk

Censored§

Median not yet reached

min, max = 8, 75 wk

Wk

Per

cen

t re

spo

nd

ing

CE-20

TI Response by Baseline Cytogenetics Del 5q (MDS-003) (3-31-05)

Patients, n (%)N = 147§

TI patients, n/N (%)

Baseline cytogenetics

Isolated del 5q 110 (74) 75/110 (68)

5q- syndrome 40 (27) 26/40 (65)

Del 5q + 1 25 (17) 13/25 (52)

Complex (≥ 3) 12 (8) 7/12 (58)

§ Excludes 1 patient defined by FISH only.

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Cytogenetic ResponseDel 5q (MDS-003) (NDA)

Patients, N§

Patients, n (%)

CR + PR CR

Eligible patients 72 53 (74) 32 (44)

Baseline cytogenetics

Isolated del 5q 55 41 (75) 24 (44)

5q- syndrome 24 20 (83) 13 (54)

Del 5q + 1 12 8 (67) 5 (42)

Complex (≥ 3) 5 4 (80) 3 (60)

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§ Evaluated patients on 20 or more metaphases at baseline and follow-up based on IWG guidelines.

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Cytogenetic Response Correlates With TIDel 5q (MDS-003) (NDA)

TI response, Patients, n/N (%)

N = 72

CR 31/32 (97)

PR 20/21 (95)

None 5/19 (26)

CE-23

Patients, n (%)Evaluable 84Complete histologic response§ 29 (35)

RAEB 2CMML 2RA 23RARS 2

Excess blasts (RAEB) 16< 5% blasts 9 (56)

Ringed sideroblasts (RARS) 13< 5% RS 6 (46)

Progression 8MDS-FAB 5AML 3

Marrow Histologic ResponseDel 5q (MDS-003) (NDA)

§ 28/29 CRs are major erythroid (TI) responders.

CE-24

Efficacy ConclusionsDel 5q (MDS-003)

Resolution of refractory anemia in 67% patients

– TI and normalization of Hgb (median ↑5.3 g/dL)

– Rapid

– Durable (currently 58% > 1 yr TI)

– Cytogenetic response

• Correlates with TI and resolution of anemia

• Independent of karyotypic complexity

Bone marrow response

– Correlates with TI and resolution of anemia

– Consistent with suppression of del 5q clone