Lenalidomide Efficacy
description
Transcript of Lenalidomide Efficacy
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
CE-4
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
CE-6
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
CE-8
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
CE-10
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)
CE-11
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%
CE-12
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)
CE-13
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)
CE-14
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
CE-15
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
See
BD
for
dat
a
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
e
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.
dv
CE-21
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)
dv
§ Evaluated patients on 20 or more metaphases at baseline and follow-up based on IWG guidelines.
CE-22
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