La lenalidomide: meccanismo d azione e risultati terapeutici. F. Ferrara

La lenalidomide: meccanismo d azione e risultati terapeutici F. Ferrara

MDS: new treatment goals Emerging treatment options expected to facilitate shift from supportive care to active therapy in MDS New treatments should be pathobiology based monotherapy or novel treatment combinations treatment of subpopulations based on genetic/ipss-wpss risk groups Safe, long-term remitting activity

Haase, D. et al. Blood 2007;110:4385-4395 Copyright 2007 American Society of Hematology. Copyright restrictions may apply.

del 5q is the most common chromosomal abnormality in MDS patients* del 5q 5q- syndrome (10%)** (30%) Isolated del 5q 14% del 5q + 1 additional abnormality 5% Complex abnormalities 11% MDS with chromosomal abnormalities (52%) * Based on study of 2,124 MDS patients, of which 1,080 had cytogenetic abnormalities ** of 595 MDS classified according to WHO Haase D, et al. Blood. 2007

del(5q) MDS: median OS for the 5q- syndrome 1.0 0.9 5q syndrome: median OS, 107 months Male population Germany: median OS, 188 months Female population Germany: median OS, 244 months Cumulative survival 0.8 0.7 0.6 0.5 0.4 0.3 0.2 Blasts < 5%, n = 60 0.1 0.0 0 60 120 180 Time (months) 240 300 360 OS = overall survival. Giagounidis AAN, et al. Hematology. 2004;9:271-7.

Prognostic impact of medullary blast count in del(5q) MDS Cumulative survival 1.0 0.8 0.6 0.4 5q syndrome del(5q) with blasts 5% Blasts < 5% 0.2 Blasts 5% 0.0 0 p = 0.00005 60 120 180 240 Time (months) 300 360 Giagounidis AAN, et al. Hematology. 2004;9:271-7.

Prognostic impact of additional chromosomal aberrations on survival in del(5q) MDS Cumulative survival 1.0 0.8 0.6 0.4 0.2 0 0 del(5q) + multiple del(5q) + 1 p = 0.00005 60 120 180 240 Time (months) isolated del(5q) del(5q) + 1 additional abnormality del(5q)+ multiple abnormalities 300 isolated del(5q) 360 Giagounidis AAN, et al. Hematology. 2004;9:271-7.

Change in bone marrow microvessel density according to erythroid response

Change in apoptotic index according to erythroid response

Change in marrow proliferation index according to erythroid response

An Erythroid Differentiation Signature Predicts Response to Lenalidomide in Myelodysplastic Syndrome The response signature consisted of a cohesive set of erythroid-specific genes with decreased expression in responders, suggesting that a defect in erythroid differentiation underlies lenalidomide response Erbert et al, PLOS Med, 2008

MDS-001: study design Eligibility All FAB categories Hb < 10 g/dl or RBC transfusion 4 U/8 weeks ANC > 500/µL Platelets > 10,000/µL R E G I S T E R Lenalidomide, p.o. 25 mg once daily 10 mg once daily 10 mg for 21 days of each 28-day cycle R E S P O N S E Yes Continue No Off study Week: 0 4 8 12 16 Primary objective: haematological response (International Working Group criteria) Secondary objectives: safety, cytogenetic response, biological correlates List A, et al. N Engl J Med. 2005;352:549-57.

MDS-001: IWG-defined erythroid response 70 Intent-to-treat population (N = 43) 65% 60 54% Patients (%) 50 40 30 20 46% Major response* Minor response 10 0 25 mg/day (n = 13) 10 mg/day (n = 13) 10 mg/day, 21 days (n = 17) *20 (63%) of 32 transfusion-dependent patients became transfusion independent; 1 (9%) of 11 transfusionindependent patients had a Hb increase of > 2 g/dl. Median Hb increase = 5.3 g/dl (range 4.4 8.7); median duration of major response > 48 weeks (not reached at median follow-up of 81 weeks). IWG = International Working Group. Data from List A, et al. N Engl J Med. 2005;352:549-57.

MDS-001: erythroid response by karyotype 100 83% Erythroid response (% patients) 80 60 40 20 0 n = 12 del(5)(q31.1) 57% n = 23 Normal p = 0.007 12% n = 8 Other Karyotype Data from List A, et al. N Engl J Med. 2005;352:549-57.

Clinical development of lenalidomide in MDS: completed trials del 5q MDS-001 N = 43 Phase I/II initiated Feb 2002 non-del 5q MDS-003 N = 148 Phase II initiated July 2003 MDS-002 N = 214 Phase II initiated July 2003

MDS-003: study design Multi-centre phase II study Eligibility RBC transfusion 2 U/8 weeks 16-week pre-study RBC transfusions ANC > 500/µL Platelets > 50,000/µL De novo MDS with del(5)(q31.1) R E G I S T E R Week: 0 Lenalidomide, p.o. 10 mg daily 10 mg for 21 days of each 28-day cycle R E S P O N S E 6 12 18 24 Yes Continue No Dose reduction 5 mg q.d. 5 mg q.o.d. Off study Primary end-point: transfusion independence (Hb 1 g/dl) Secondary end-points: duration of TI, frequency of minor erythroid response, cytogenetic response, pathological response, safety List A, et al. N Engl J Med. 2006;355:1456-65.

MDS-003: Response to Lenalidomide Therapy in MDS with del(5q)

MDS-003: transfusionindependence rate by cytogenetic pattern Complexity * n Transfusionindependent (N = 147) patients n (%) Isolated del 5q del 5q + 1 abnormality Complex karyotype ( 3 abnormalities) 110 25 12 79 (72) 12 (48) 8 (67) *p = 0.068. Excluding 1 patient whose cytogenetic characteristics were defined by FISH only. List A, et al. N Engl J Med. 2006;355:1456-65.

MDS-003: duration of transfusion-free period Transfusion-free patients (%) 100 90 80 70 60 50 40 30 20 10 n = 99 Median follow-up: 104 weeks Median duration of transfusion independence: > 74 weeks Range: 8.6 89+ weeks Ongoing: 53 patients Censored* 0 0 10 20 30 40 50 60 70 80 90 100 Time (weeks) Data cut-off: 15 July 2005. *Patients who remained transfusion independent at time of data cut-off or at time of study discontinuation.. List A, et al. N Engl J Med. 2006;355:1456-65.

1.0 Duration Transfusion-Free [N=97] 0.9 0.8 MDS003 Proportion Transfusion-Free 0.7 0.6 0.5 0.4 0.3 0.2 0.1 Median follow-up: 58 wks Median duration TI MDS003: >47 wks MDS002: 43 wks Range: 8.6 66+ wks MDS002 Ongoing Discontinued 0 0 10 20 30 40 50 60 70 Weeks

Features associated with longer duration of transfusion-independence Prognostic variable p value Age Gender FAB type RBC transfusions <4U/8 weeks Thrombocytopenia Neutropenia Low risk IPSS Karyotype complexity 5q syndrome NS NS NS NS NS NS 0.02 0.01 0.002 List AF et al. Presented at ASH Annual Meeting, 2006.

Sekeres et al, JCO, 2009

MDS-003: treatment-related adverse events Adverse events grade 3 % Thrombocytopenia 44 Neutropenia 55 Pruritus 3 Rash 6 Diarrhoea 3 Fatigue 3 Deaths on study 11 Neutropenic infection 3 n List A, et al. N Engl J Med. 2006;355:1456-65.

MDS-003: dose-adjustments according to schedule 102 N = 124 Patients (n) 46 *p < 0.05 Data from List A, et al. N Engl J Med. 2006;355:1456-65.

MDS-003: drug discontinuation according to schedule N = 148 Patients (n) 10 2 *p > 0.05 4 6 Data from List A, et al. N Engl J Med. 2006;355:1456-65.

Is relapse equivalent to definitive failure? Haemoglobin (g/dl) 16 14 12 10 8 6 4 2 0 Haemoglobin Lenalidomide treatment 1 5 9 13 17 21 25 29 33 37 41 Time (months)

CHARACTERISTICS OF DISEASE PROGRESSION IN 3144 PATIENTS WITH MYELODYSPLASTIC SYNDROMES Progression to AML or to more advanced MDS subtype RA/RARS: 10% RCMD: 17% 5q-: 26% RAEB I: 27% RAEB II: 36% AML evolution at 2 and 5 years RA/RARS: 4% and 8% RCMD: 11% and 19% 5q-: 10% and 18% RAEB I: 26% and 44% RAEB II: 50% and 74% CMML I: 14% and 24% CMML II: 33% and 74% RARS-T: 5% and 5% Zohren et al, EHA 2008

List et al, EHA 2008

Survival of MDS-003 and Registry Patients Median survival IPSS MDS-003 Registry Low Not reached 6.3 years Intermediate-1 3.1 years 2.8 years

MDS 002 (214 patients)

MDS-002: baseline cytogenetic profile Variable n (%) Evaluable* Normal karyotype Abnormal karyotype (non del 5q) 207 (98) 160 (77) 47 (23) Missing/inadequate 7 (3) * 20 evaluable metaphases needed to evaluate response. Raza A, et al. Presented at ASH Annual Meeting, 2006.

MDS-002: erythroid response (ITT) Daily dose 21-Day dose All patients n = 100 n = 114 N = 214 Erythroid response, n (%) 41 (41) 51 (45) 92 (43) TI 26 (26) 30 (26) 56 (26) Minor (> 50% decrease) 15 (15) 21 (18) 36 (17) Time to initial response, weeks Median 6.4 3.6 4.5 Range 4.1 9.0 2.3 6.4 2.7 6.7 Lenalidomide eliminated or reduced transfusion requirements in 43% of MDS patients without del 5q cytogenetic abnormalities Patients who responded to lenalidomide had a median increase in Hb of 3.2 g/dl Raza A, et al. Presented at ASH Annual Meeting, 2006.

MDS-002: duration of transfusion-free period Transfusion-free patients (%) 100 90 80 70 60 50 40 30 20 10 n = 56 Censored Median duration TI: 41 weeks Range: 8.0 136.4+ weeks 35 patients TI 24 weeks 20 patients TI 52 weeks 19 patients ongoing 0 0 25 50 75 100 125 150 Time (weeks) Raza A, et al. Presented at ASH Annual Meeting, 2006.

MDS-002: transfusion independence by IPSS diagnosis (ITT) Patients (%) Erythroid response is similar in Low- and Int-1-risk MDS patients Raza A, et al. Presented at ASH Annual Meeting, 2006.

MDS-002: transfusion independence by FAB diagnosis (ITT) Patients (%) Data cut-off: July 2006 Erythroid response is similar in RA, RARS, RAEB, and CMML Raza A, et al. Presented at ASH Annual Meeting, 2006.

MDS-002: most common drugrelated adverse events (NCI Adverse event CTC) All grades n (%) Grade 3 n (%) Neutropenia 60 (28) 53 (25) Thrombocytopenia 56 (26) 43 (20) Rash 47 (22) 9 (4) Pruritis 45 (21) 2 (1) Fatigue 33 (15) 8 (4) Diarrhea 32 (15) 3 (1) Neutropenia and thrombocytopenia were manageable with dose reduction or interruption NCI CTC = National Cancer Institute Common Toxicity Criteria. Raza A, et al. Presented at ASH Annual Meeting, 2006.

Venous Thromboembolism in Myelodysplastic Syndrome Patients Receiving Lenalidomide: Results from Postmarketing Surveillance and Data Mining Techniques Yang et al, 2009

n i d n o p s e R t n e c r e P 100 Lenalidomide in MDS Transfusion-independence duration MDS001 and MDS003 studies 90 80 70 60 50 40 30 20 10 min, max = 0.2, 4.8+ years 73 TI response! 1 years 47 TI response! 2 years 50 ongoing responders Maximum Hb, g/dl [range] Baseline 7.8 [5.3 10.4] Lenalidomide 13.4 [9.2 18.6] Median Hb 5.4 [1.1 11.4] 0 0 1 2 3 4 5 Years Median duration TI = 2.2 years Median F/U: 2.8 yr Unpublished data, courtesy of Alan List

Survival correlates to cytogenetic response to lenalidomide Cumulative Survival 100 90 80 70 60 50 40 30 20 10 0 P<0.0001 PR cytogen, N=35, Median OS not reached CR cytogen, N=55, Median OS not reached NR cytogen/not evaluable, N=78, OS=28 months 0 24 48 72 96 120 144 168 192 216 240 Weeks Unpublished data, courtesy of Alan List

AML evolution correlates to cytogenetic response to lenalidomide Cum Incidence of AML Evolution 100 90 80 70 60 50 40 30 20 10 0 P=0.010 N=168 NR cytogen/not evaluable (9/77) 15% CR cytogen/pr cytogen (7/89) 0 24 48 72 96 120 144 168 192 216 240 Weeks 67% Unpublished data, courtesy of Alan List

Lenalidomide in higher risk MDS with 5q deletion 13/47 Responses (27%) Ades et al, Blood, prepublished Nov. 5. 2008

Lenalidomide in higher risk MDS Ades et al, Blood, prepublished Nov. 5. 2008

Lenalidomide in higher risk MDS Ades et al, Blood, prepublished Nov. 5. 2008

Unanswered questions with lenalidomide treatment of MDS with del 5q What is the optimal dose of lenalidomide? Can we improve management or prevention of side effects? How long should treatment be administered in responders? Has lenalidomide an impact on survival in MDS with del 5q? Is lenalidomide cost-effective?

Greenberg PL et al, J Natl Compr Canc Netw. 2008 Oct;6(9):942-53.

Costs of potentially anemiaaltering drugs in MDS An evaluation of the costs of specific drugs (r-huepo, azacytidine, decitabine, lenalidomide) and their sequential use in the lower-risk IPSS (low and intermediate-1) subgroups based on the NCCN guidelines Results estimate an average annual cost for potentially anemia-altering drugs of $ 63,577 per patient, ranging from $ 26,000 to $ 95,000, depending on the specific therapies. In patients for whom the therapies fail, annual costs for iron chelation plus red blood cell transfusions are estimated to average $ 41,412 The economic impact of drug therapy should be weighed against the patient's potential for improvement in clinical outcomes, quality of life, and transfusion requirements. Greenberg PL et al, J Natl Compr Canc Netw. 2008 Oct;6(9):942-53.

Ongoing and future trials

MDS-004: study design Planned N = 162 Eligibility IPSS Low/Int-1 del 5q Transfusion dependent Stratify IPSS Complexity S T R A T I F Y R A N D O M I Z E Lenalidomide, p.o. 10 mg/day, for 21 days of each 28-day cycle Lenalidomide, p.o. 5 mg/day, for 28 days of each 28-day cycle Placebo Double-blind phase Week 0 4 8 12 16 R E S P O N S E Response: Continue for up to 52 weeks No response: Open-label treatment Primary end-point: transfusion independence 24 weeks Secondary end-points: duration of transfusion independence, cytogenetic and histological responses, quality of life

MDS-005: Study design Screening (day -56 to day 1) MDS IPSS low or int -1 Any karyotype excluding del 5q Trans fusion -dependent anemia R A N D O M I Z A T I O N 2:1 Oral Lenalidomide 10mg once daily Matching oral placebo 6 M O N T H S Erythroid response** No erythroid response Continue to erythroid relapse or PD* Discontinue l enalidomide *PD = progressive disease, d/c=discontinue **Erythroid response (as per IWG 2006) is defined as a Hb increase by > 1.5 g/dl, OR a reduction of units of RBC transfusions by an absolute number of at least 4 RBC transfusion in 8 weeks compared to the pre -treatment transfusion number in the previous 8 weeks; responses must last >56 days; i.e., Study Days 113 through 168 inclusively

ECOG-2905: study design Eligibility IPSS Low/Int-1 Hb < 9.5 g/dl Poor EPO response Stratify del 5q sepo S T R A T I F Y R A N D O M I Z E A. Lenalidomide 10 mg/day x 21 days B. Lenalidomide + darbepoetin alfa Week 0 4 8 12 16 R E S P O N S E MER No Continue Combination (only arm A) Primary end-point: major erythroid response (MER) Secondary end-points: MER duration, time to MER, cytogenetic EPO = erythropoietin; sepo = serum erythropoietin. response

LENALIDOMIDE AND MDS: OTHER STUDIES L + SGN 33 L + BORTEZOMIB L + 5-AZA L + AMG 531 L + rh-scf L + LDARA-C (unfit elderly AML)

Phase I trial: lenalidomide plus azacitidine in higher risk MDS, w/o del5q Cohort Lenalidomide dose, mg Azacitidine dose, mg/m 2 1 5, days 1 14 75, days 1 5 2 5, days 1 21 75, days 1 5 3 10, days 1 21 75, days 1 5 4 5, days 1 14 50, days 1 5, 8 12 Responses (n = 12/17, 71%) Response n (%) Complete response 7 (41) Partial Response Hematol. Improvement 1 (6) 3 (18) Marrow Response 1 (6) 5 5, days 1 21 50, days 1 5, 8 12 No DLTs occurred in any dosing 6 10, days 1 21 50, days 1 5, 8 12 cohort, and the MTD was not reached Day 1 5 8 12 14 21 28 Lenalidomide Lenalidomide Azacitidine Azacitidine Sekeres MA, et al. ASH 2008