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Lenalidomide Efficacy

Lenalidomide Efficacy

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Lenalidomide Efficacy

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  1. Lenalidomide Efficacy Alan List, MD Professor of Medicine and OncologyChief, Division of Malignant Hematology H. Lee Moffitt Cancer Center and Research InstituteUniversity of South Florida College of Medicine

  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

  3. Pilot Study of Lenalidomide in MDSStudy MDS-001 R E G I S T E R R E S P O N S E Eligibility All FAB/IPSS Hgb < 10 g/dL ANC > 500/µLPlatelets > 10,000/µL Activation: 3-1-02 Cohorts25 mg po qd 10 mg po qd 10 mg × 21/28 days Yes→Continue No→Off study Wk: 4 8 16 0 12 Primary endpoint: erythroid response (IWG criteria) Secondary endpoints: cytogenetic response, biologic correlates List A, et al. N Engl J Med. 2005;352:549-557.

  4. DV 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 Updated from MAS: DV complete by MAS

  5. Phase 2 Study of Lenalidomide MDS Del 5q (MDS-003) R E G I S T E R R E S P O N S E Activation date: 7-15-03Cohorts 10 mg × 21 days10 mg po qd Treatment until progression/relapse Wk: 0 4 8 12 16 20 24

  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

  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

  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

  9. Study ConductDel 5q (MDS-003) • Initially, CBC q2 wk × 8 wk, then q1 mo • Amended to include weekly CBC, wk 1-8 • Concomitant medications • rhu-EPO excluded • Myeloid growth factors permitted • RBC transfusion guidelines • Hgb ≤ 8.0/Hct 25 or • Pre-study threshold

  10. Patient Baseline Characteristics Del 5q (MDS-003)

  11. IPSS/FAB by Central ReviewDel 5q (MDS-003) IPSS FAB AML 0.7% Atypical CML 2% CMML 2% Unclass11% Unclass14% Int-2/High5% Low37% RA52% RAEB20% Int-144% RARS12%

  12. Prior Therapy for MDSDel 5q (MDS-003)

  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)

  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

  15. NDA submission9-15-04 Updated data3-31-05 ITT, N = 148 Overall, n 95 (64%) 99 (67%) 95% CI 55.9, 71.9 58.7, 74.4 Median time to response, wk (range) 4.1 (1 - 19) 4.6 (1 - 49) Modified ITT, N = 94 Overall, n 57 (61%) 60 (64%) 95% CI 50.0, 70.6 53.3, 73.5 Median time to response, wk (range) 4.7 (1 - 19) 5.1 (1 - 49) Transfusion Independence Response Del 5q (MDS-003) See BD for data

  16. 6 4 pRBC, units 2 0 –16 - –9 –8 - 0 1 - 8 9 - 16 17 - 24 25 - 32 33 - 40 41 - 48 Study wk Mean Number of RBC Units Transfused per Patient by 56-Day Periods (8 Wk) (ITT)Responders Del 5q (MDS-003) (3-31-05) Pretreatment Treatment 4.7 4.6 3.9 0.7 0.4 0.3 0.3 0.2 N = 92 95 95 95 92 88 59 28

  17. 0 Mean Untransfused§ Hgb (g/dL) by Cycle (ITT)Del 5q (MDS-003) (3-31-05) N = 148 Responders Non-responders 14 12 Median time to response Normalized, per NCCN Guideline Hgb, g/dL 10 8 6 2 4 6 8 10 12 14 16 18 Cycle, 28 days 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.

  18. 12.5 10.0 7.5 Hgb change from baseline Median = 5.3 5.0 2.5 0.0 Hemoglobin Improvement forTI Responders (ITT) Del 5q (MDS-003) (3-31-05) N = 99

  19. 110 § Censored 100 90 80 70 60 Percent responding Median not yet reached 50 40 min, max = 8, 75 wk 30 ³ 83 TI response 24 wk 20 ³ 52 TI respon se 52 wk 10 57 ongoing responders 0 0 10 20 30 40 50 60 70 80 Wk 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.

  20. UPDATED 29 AUG 05 dv TI Response by Baseline Cytogenetics Del 5q (MDS-003) (3-31-05) § Excludes 1 patient defined by FISH only.

  21. UPDATED 29 AUG 05 dv Cytogenetic ResponseDel 5q (MDS-003) (NDA) § Evaluated patients on 20 or more metaphases at baseline and follow-up based on IWG guidelines.

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

  23. Marrow Histologic ResponseDel 5q (MDS-003)(NDA) § 28/29 CRs are major erythroid (TI) responders. Put in script

  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