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Transcript of CC-1 Aranesp ® (darbepoetin alfa) Therapy for Oncology Patients Oncologic Drugs Advisory Committee...
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Aranesp® (darbepoetin alfa) Therapy for Oncology Patients
Oncologic Drugs Advisory CommitteeMay 4, 2004
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Amgen Guests
Jeffrey Crawford, MD Professor of Medicine Duke University School of Medicine
David DeMets, PhD Professor and Chair of BiostatisticsUniversity of Wisconsin
John Glaspy, MD, MPH Professor of MedicineUniversity of California at Los Angeles School of Medicine
Harvey Lodish, PhD Professor of Biology and Professor of Bioengineering at MITMember of Whitehead Institute
Douglas Losordo, MD Associate Professor of MedicineTufts University School of Medicine
Marc Pfeffer, MD, PhD Senior Physician in CardiologyProfessor of MedicineBrigham and Women’s Hospital
Joseph Eschbach, MD Senior Research AdvisorNorthwest Kidney CenterClinical Professor MedicineUniversity of Washington
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Independent Investigators
Principal Investigator Study Group Institution
J. Overgaard, MD The Danish Head Dept. Experimental Clinical Oncology and Neck Cancer Aarhus University HospitalStudy Group Aarhus C. Denmark(DAHANCA)
R. Delarue, MD Groupe d’Etude des Adult Hematology DeptLymphomes de l’Adulte Hospital Necker, Paris, France
A. Bosley, MD (GELA) Hematology Dept.UCL Mont Godinne, Belgium
U. Nitz, MD Westdeutschen Gynecological ClinicStudiengruppe (WSG) Dusseldorf University
Dusseldorf, Germany
S. Kahlert, MD Gynecological Clinic and Polyclinic for Oncology Study Obstetrics and Gynecology,Group (AGO) Grosshadern Clinic, Ludwig-
Maximillian UniversityMunich, Germany
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Presentation Outline
Background Dawn Viveash, MDVP of Regulatory Affairs and Safety
EPO-R Considerations Harvey Lodish, PhDProfessor of Biology andBioengineering - MIT
Clinical Observations David Parkinson, MDVP of Oncology ClinicalDevelopment
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Distinct Properties of Aranesp
Altered amino Altered amino acid sequence acid sequence permits permits attachment ofattachment of2 additional 2 additional carbohydrate carbohydrate side chains side chains
Increase in Increase in negative negative chargecharge
Increase in Increase in molecular molecular weight weight and sizeand size
5-fold reduction in 5-fold reduction in receptor binding receptor binding affinityaffinity
3-fold increase in 3-fold increase in serum half lifeserum half life
Leads to improved Leads to improved in vivo biological in vivo biological activityactivity
Molecular Differences Compared
with Epoetin
Physical Differences Compared
with Epoetin
Biological Differences Compared
with Epoetin
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Aranesp Approvals
September 2001 US Nephrology Approval– Aranesp is indicated for the treatment of anemia
associated with chronic renal failure, including patients on dialysis and patients not on dialysis
July 2002 US Oncology Approval – Aranesp is indicated for the treatment of anemia in
patients with non-myeloid malignancies where anemia is due to the effect of concomitantly administered chemotherapy
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Aranesp Product Labeling
Warnings: Cardiovascular events (including thrombotic events)– Association with high hemoglobin and rate of rise
– Description of Besarab1 study including mortality
Guidance regarding hemoglobin target and rate of rise– Adjust dose to achieve and maintain a target Hb 12 g/dL and rate of rise
of Hb not to exceed 1 g/dL in two weeks
Precautions: Theoretical concern regarding growth factor potential
Adverse reactions: Thrombotic events– Overall incidence 6.2% for Aranesp and 4.1% for placebo; specific
mention of pulmonary embolism and thrombosis
1Besarab et al. NEJM. 339(9):584;1998.
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Comprehensive Risk Assessment:Preclinical Data with Darbepoetin alfa
Not genotoxic1
No proliferative or hyperplastic signals inlong-term animal toxicology studies1
No tumor progression in tumor xenograft models2,3
Beneficial effect (decrease in tumor progression) in association with radiotherapy3
1Amgen data on file.2Kirkpatrick et al. 2003.3Ning et al. 2003.
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Comprehensive Risk Assessment:Clinical Data
Epidemiological analysis of thrombotic events
Review of completed and ongoing Aranesp trials
Post-marketing oncology experience
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Aranesp Safety Observations
No detrimental effect on survival
No tumor progression signal
Thrombotic event rate consistent across pre-and post-approval studies
Product label appropriately represents relevant safety information
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Presentation Outline
Background Dawn Viveash, MDVP of Regulatory Affairs and Safety
EPO-R Considerations Harvey Lodish, PhDProfessor of Biology andBioengineering - MIT
Clinical Observations David Parkinson, MDVP of Oncology ClinicalDevelopment
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Characteristics of Established Oncogenes
Chromosome translocation
Gene amplification
Gene mutation
Protein over-expression
Protein truncation
Auto-phosphorylation
Signaling in absence of ligand
Transforming
Prognostic indicator
Therapeutic target
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The EPO-R and Tumorgenicity
The EPO-R is not an oncogene– No amplification of the EPO-R gene in any tumor except
for 2 erythroleukemic cell lines– No activating EPO-R point mutations in any human or
animal tumor
Humans with EPO-R truncations are hypersensitive to EPO but have no increase in tumor incidence
EPO transgenic mice and humans over-expressing EPO are polycythemic but have no increase in tumor incidence
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EPO-R Expression in Erythroid Cells
Over 90% of receptors are in the cytoplasm, not on the cell surface
Only 1000 - 2000 receptors are present on the cell surface
Surface expression requires JAK-2 and possibly other accessory proteins
2 EPO-R:1 EPO complex is required for signaling
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Measuring EPO-R in Fixed or Frozen Primary Tumor Biopsies
RT-PCR – Measures EPO-R transcripts, not functional EPO-R
mRNA, EPO-R protein, or functional receptor– Requires separation of tumor from other cells
Immunohistochemistry– Measures EPO-R in the cytoplasm and on the cell
surface– Too insensitive to detect cell surface EPO-R– Existing antibodies not sufficiently specific
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Measuring EPO-R in Fresh Primary Tumor Biopsies All methods require purifying tumor cells from other cells and at least 108 cells
per sample
Binding with radio-labeled EPO– Difficult to detect specific, saturable binding to EPO-R versus non-specific, non-
saturable binding– Difficult to detect low numbers of low-affinity
(Kd >1 nM) receptors
Proliferation in response to EPO– Fresh tumor cells generally are not viable in culture
EPO-induced signal transduction pathways– EPO-induced phosphorylation of EPO-R, JAK-2, STAT-5, etc– Requires immunoprecipitation – Western blot analysis– Very insensitive, low signal to background ratio in
non-erythroid cells
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Presentation Outline
Background Dawn Viveash, MDVP of Regulatory Affairs and Safety
EPO-R Considerations Harvey Lodish, PhDProfessor of Biology andBioengineering - MIT
Clinical Observations David Parkinson, MDVP of Oncology ClinicalDevelopment
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Clinical Observations
Benefits associated with treatment of anemia
Thrombotic Events Analyses in Oncology– Epidemiology
– Clinical trials
Survival Analyses of Aranesp Clinical Trials
Ongoing Aranesp Clinical Trials in Oncology– Amgen-sponsored
– Independent-investigator sponsored
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Anemia is a Significant Complication of Chemotherapy Treatment in Patients with Cancer
Anemia is a highly prevalent comorbidity1-5 – ~90% of chemotherapy patients will develop anemia (grade
1-4)– Up to 30% of patients develop grade 3-4 anemia
Anemia has a significant impact in quality of life and commonly results in transfusions6
– 40 - 60% of anemic patients will require transfusions7,8
– 61% of patients believe fatigue affects their quality of life more than pain
– 78% of patients with cancer experience fatigue
1Chau L, et al. Br J Haem. 2003;120:970-977; 2Louvet C, et al. J Clin Oncol. 2002;20:4543-4548; 3Scheithauer W, et al. J Clin Oncol. 2003;21:1307-1312; 4Hitt R, et al. Ann Oncol. 2002;13:1665-1673; 5Schiller JH, et al. N Engl J Med 2002;346:92-98; 6 Vogelzang N, et al. Semin Hematol. 1997;34(suppl 2):4–12; 7Tandem audit; 8Amgen data on file.
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Aranesp Increases Hemoglobin and Reduces Transfusions
RBC Transfusions from week 5 to 13
314 1487 77315N =
PlaceboQWK
Q2WKQ3WK
0.0
0.2
0.4
0.6
0.8
1.0
Pro
po
rtio
n +
95%
CI
328 1462 81330N = 0.0
0.2
0.4
0.6
0.8
1.0
PlaceboQWK
Q2WKQ3WK
Pro
po
rtio
n +
95%
CI
Hematopoietic response
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Evidence-Based Clinical Practice Guidelines by ASH/ASCO and NCCN
Confirmed the benefits of anemia treatment regarding transfusion requirements and improvement in HRQOL1-5
Guidelines provide recommendations regarding:– Hemoglobin target (11 – 12 g/dL)4
– Thresholds for withholding erythropoietic protein therapy
Amgen supports these independent evidence-based guidelines– They are consistent with the US package insert
for Aranesp
1Seidenfeld et al. 2001; 2Bohlius. 2003; 3Crawford et al. 2002; 4Sabbatini et al. 2004; 5Rizzo et al. 2001.
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Clinical Observations
Benefits associated with treatment of anemia
Thrombotic Events Analyses in Oncology– Epidemiology
– Clinical trials
Survival Analyses of Aranesp Clinical Trials
Ongoing Aranesp Clinical Trials in Oncology– Amgen-sponsored
– Independent-investigator sponsored
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Analysis of Thrombotic Events in Oncology Patients
Thrombotic event terms as defined in approved US product label
Methods:– Analysis of epidemiologic databases
• General Practice Research Database (108,000 patient-years)
• Medstat Marketscan Database (~7,000 patient years)
– Analysis of Amgen clinical trial data• 11 Aranesp oncology trials completed by November 2003
• 1,807 Aranesp and 444 Placebo subjects
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Patients with Cancer Receiving Epoetin alfa and Epoetin beta Have a Higher than Background Risk of Thrombotic Events
Amgen analysis of Medstat Claims Database(1,305 patients)– Adjusted RR1 = 1.40 [95% CI: 0.90-2.16]
Bohlius et al. [2003]2 meta-analysis: 12 controlled trials (1,737 patients)– RR = 1.55 [95% CI: 0.93-2.59]– Does not include BEST or ENHANCE studies
Amgen analysis (Aranesp)– Confirms stable rate since approval– Prior TE history and poor performance status are independent risk
factors
1Adjusted for age, sex, cancer type, and comorbidities2Bohlius, et al. Blood. 2003;102:203a. Abstract 709.
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Clinical Observations
Benefits associated with treatment of anemia
Thrombotic Events Analyses in Oncology– Epidemiology
– Clinical trials
Survival Analyses of Aranesp Clinical Trials
Ongoing Aranesp Clinical Trials in Oncology– Amgen-sponsored
– Independent-investigator sponsored
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Survival Analysis in Aranesp Randomized, Placebo-Controlled Trials in CIA
1Vansteenkiste J, et al. J Natl Cancer Inst. 2002;94:1211-1220. (Study 980297)2Hedenus M, et al. Br J Haematol. 2003;122:394-403. (Study 20000161)3Hedenus M, et al. Br J Haematol. 2002;119:79-86. (Study 980291)4Kotasek D, et al. Eur J Cancer. 2003;39:2026-2034. (Study 990114)
Studies: Characteristics:
Lung cancer1 N = 314 Homogeneous patient populationPlatinum-based therapyLong-term follow-up
Lymphoid malignancies2 N = 344 Less homogeneous patient populationsLong-term follow-up
Mixed solid tumor3 N = 405 Heterogeneous patient populationLymphoid malignancies4 N = 66 Follow-up (16 weeks)
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Aranesp Lung Cancer Study
RandomizationN = 314
Chemotherapy1
Aranesp 2.25 µg/kg/week
for 12 weeks
Chemotherapy1 Placebo
for 12 weeks
Endpoint
RBC
Transfusion
Long-termFollow-up
for Survival And Progression
Median follow up time:16 months
Placebo Aranesp
Number of patients 159 155
HistologyNSCLC 114 (72%) 108 (70%)SCLC 45 (28%) 47 (30%)
1Platinum-basedStudy 980297
Hb entry: 11 g/dLWithhold dose: Hb >14g/dL
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Aranesp
Placebo
Pe
rce
nt
20
40
60
80
100
Months from 1st Dose0 3 6 9 12 15 18 21 24
Subjects at risk:
PlaceboAranesp
159155
114116
5063
2635
1416
713
46
15
Progression-free Survival in Lung Cancer Patients
Study 9802971Adjusted for histology
Total Events
Aranesp 155 131
Placebo 159 145
Hazard Ratio1
0.81 (95% CI: 0.64, 1.03)
0
01
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Overall Survival in Lung Cancer Patients
Placebo
Aranesp
20
40
60
80
100
0 3 6 9 12 15 18 21 24
Subjects at risk:
PlaceboAranesp
159155
127133
8694
5874
4449
3034
1616
37
Total Deaths
Aranesp 155 100
Placebo 159 119
Hazard Ratio1
0.78 (95% CI: 0.60, 1.01)Pe
rce
nt
Months from 1st Dose
0
01
Study 9802971Adjusted for histology
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Aranesp Lymphoid Malignancy Study
Median follow-up time:27 months
Placebo Aranesp
Number of patients 169 175NHL 45 (27%) 39 (22%)
HD 9 (5%) 12 (7%)CLL 26 (15%) 29 (17%)MM 83 (49%) 90 (51%)Waldenstrom’s 6 (4%) 5 (3%)
RandomizationN = 344
Chemotherapy +Aranesp
2.25 µg/kg/weekfor 12 weeks
Chemotherapy +Placebo
for 12 weeks
Endpoint
RBC
Transfusion
Long-termFollow-up
for Survival And Progression
Study 20000161
Hb entry: 11 g/dLWithhold dose: Hb >14g/dL
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Aranesp Lymphoid Malignancy Study: Baseline Characteristics
Placebo AranespN = 169 N = 175n (%) n (%)
Non-Hodgkin’s lymphoma 45 (27) 39 (22)Indolent 29 (64) 20 (51)Aggressive 16 (36) 17 (44)
International Prognostic Index0 – 2 30 (67) 22 (56)3 – 5 15 (33) 17 (44)
Multiple myeloma 83 (49) 90 (51)Stage I + II 28 (34) 36 (40)Stage IIIA + B 55 (66) 54 (60)
Chronic lymphocytic leukemia 26 (15) 29 (17)Stage A + B 14 (54) 11 (34)Stage C 11 (42) 17 (59)
Study 20000161
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Progression-free Survival in Patients with Lymphoid Malignancies
Study 200001611Adjusted for disease type, stage and IPI score
Aranesp
Placebo
Pe
rce
nt
20
40
60
80
100
Months from 1st Dose0 3 6 9 12 15 18 21 24
Subjects at risk:
PlaceboAranesp
169175
150146
119125
104109
96100
8585
7172
6360
Total Events
Aranesp 175 120
Placebo 169 113
Hazard Ratio1
1.11 (95% CI: 0.85, 1.44)
0
4943
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Overall Survival in Patients withLymphoid Malignancies
Aranesp
Placebo
20
40
60
80
100
0 3 6 9 12 15 18 21 24
Subjects at risk:
PlaceboAranesp
169175
160162
146150
135136
132126
124122
116117
113101
Total Deaths
Aranesp 175 80
Placebo 169 61Hazard Ratio1
1.33 (95% CI: 0.95, 1.86)
Pe
rce
nt
Months from 1st Dose
0
Study 200001611Adjusted for disease type, stage and IPI score
9376
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Number of Patients Tumor Type
314 Lung cancer
410 Lymphoid cancer
405 Mixed Solid Tumor
1,129
(708 Aranesp, 421 Placebo)
933 Patient-years of follow-up
Pooled Analysis of Four Amgen Completed Trials Concerning Tumor Progression and Survival
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Progression-free Survival in Four Pooled1 Placebo Controlled Trials – 16 Week Data
Pe
rce
nt
80
85
90
95
100
Weeks After 1st Dose0 4 8 12 16
Subjects at risk:
PlaceboAranesp
421708
405680
372642
349572
Placebo
Aranesp
Hazard Ratio2
1.02 (95% CI: 0.78, 1.33)
1Studies 980297, 20000161, 980291, 9901142Adjusted for study, disease type, stage and IPI score
0
252313
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Overall Survival in Four Pooled1 Placebo Controlled Trials – 16 Week Data
Placebo
Aranesp
80
85
90
95
100
Weeks After 1st Dose0 4 8 12 16
Subjects at risk:
PlaceboAranesp
421708
411687
387660
368600
294358
Hazard Ratio2
1.02 (95% CI: 0.67, 1.54)
0
Pe
rce
nt
1Studies 980297, 20000161, 980291, 9901142Adjusted for study, disease type, stage and IPI score
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Pooled1 Analyses: Progression-free Survival Hazard Ratios Associated with Aranesp (A) vs Placebo (P) by Tumor Type
1Studies 980297, 20000161, 980291, 990114
Hazard Ratio (95% CI)0.1 1.0 10
Ovarian (A = 11/49, P = 3/12)
Breast (A = 16/94, P = 6/23)
GI Other (A = 15/54, P = 4/13)
SCLC (A = 40/60, P = 42/47)
NSCLC (A = 99/146, P = 109/130)
Lymphoma (A = 29/70, P = 32/60)
Myeloma (A = 66/105, P = 57/86)
CLL (A = 26/39, P = 22/28)
Other (A = 23/91, P = 5/22)
Overall (A = 325/708, P = 280/421)
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No Negative Impact on Progression or Survival Outcomes with Hb 13 g/dL or 1 g/dL in 14 Days
Pooled analyses of Aranesp trials; Studies 980297, 20000161, 980291, 990114;Models stratified by study; adjusted for treatment therapy and baseline Hb value;Hb increase and Hb target were time-dependent covariates; Hb values within 28 days of a transfusion are excluded.
HazardEndpoint ratio 95% CI
1 g/dL Hb Progression-increase in 14 days free Survival 0.51 0.42, 0.62
Survival 0.43 0.34, 0.56
Achieved Hb of Progression-13 g/dL free Survival 0.66 0.51, 0.84
Survival 0.56 0.40, 0.79
(857/1129)
(272/1129)
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Summary of Safety Experience with Aranesp®
Thrombotic event rate is appropriately represented in the Aranesp prescribing information
No effect on tumor progression or survival has been observed in Aranesp oncology clinical trials
Safety profile of Aranesp remains unchanged and excellent since its approval for oncology and nephrology indications
Benefit / Risk of Aranesp remains favorable
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Clinical Observations
Benefits associated with treatment of anemia
Thrombotic Events Analyses in Oncology– Epidemiology
– Clinical trials
Survival Analyses of Aranesp Clinical Trials
Ongoing Aranesp Clinical Trials in Oncology– Amgen-sponsored
– Independent-investigator sponsored
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Rationale for the Investigation of Anemia Treatment on Tumor Progression and Survival
Well-established association between anemia and decreased survival in multiple malignancies– Overall increase in mortality risk: RR = 1.65 (1.54, 1.77)1
Pre-clinical correlations between anemia, tumor oxygenation, tumor response and survival in the setting of radiotherapy2-4
Trends toward improved survival in some chemotherapy induced anemia trials in oncology– Observed with Aranesp in SCLC [RR = 0.62 (0.38,1.01)]5
– Cochrane Meta-analysis with epoetin alfa and beta also suggest a benefit [RR = 0.80 (0.65, 1.00)]6
1 Caro et al. Cancer. 2001;91:2214; 2 Grogan M, et al. Cancer. 1999;86:1528–1536; 3 Overgaard J. Sem. Rad. Oncol. 1996;6:10-21; 4 Glaser CM. Int.J.Radiat.Oncol.Biol.Phys. 2001;50:705-715; 5 Vansteenkiste J, et al. J NCI 2002;94:1211-1220; 6 Bohlius et al, Blood. 2003;102:203a, abs 709.
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Amgen-Sponsored and Investigator-Initiated Studies of Aranesp in Oncology
Purpose:– Testing hypothesis of potential Aranesp survival benefit for multiple
oncology settings Process: – All Aranesp oncology studies worldwide reviewed
• Hemoglobin baseline, target, dosing algorithms• Safety monitoring• Design appropriateness for survival assessment
Outcome:– Five large randomized, controlled trials comprise a survival focused
clinical development program• One Amgen sponsored • Four investigator initiated, independently conducted, cooperative group trials
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Ongoing Survival Clinical Trials Program: Design Elements Randomized, controlled– Aranesp vs. placebo (double-blind) or
Aranesp vs. no epoetin (open-label) Aranesp administration during chemotherapy
or radiotherapy Progression and survival endpoints Safety endpoints monitored including thrombotic and
cardiovascular events Homogeneous populations Stratification for prognostic variables Long-term follow-up
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Ongoing Survival Clinical Trials Program: Sample Size and Tumor Type
Patient Population
Follow-up: over 9,000 patient-years
# of Patients Tumor Type
1,720 Breast cancer (2 trials)600 Head and neck cancer600 Lymphoma600 Small-cell lung cancer
3,520
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Amgen Small Cell Lung Cancer Study
RandomizationDouble-blind
N = 600
Cis/Carboplatin +Etoposide + Aranesp Endpoint
Survival
Follow-up
Study endpoints:• Survival• Change in Hb• FACT-F
Cis/Carboplatin +Etoposide + Placebo
Hb entry: 9 - 13 g/dLWithhold dose: Hb >14g/dL
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AGO Breast Cancer StudyDr. M. Untch et al.
RandomizationN = 720
SequentialTherapy(ECT)
SequentialDose-intensified
Therapy(ETCMF)
Endpoint
Relapse-freeand
OverallSurvival
Follow-up
Aranesp
Supportivecare
Aranesp S u
r g
e r
y
Study endpoints:• Relapse-free and overall survival• Complete pathological response• Quality of lifeE = epirubicin
C = cyclophosphamideT = paclitaxelM = methotrexateF = flourouracil
Withhold dose: Hb >14g/dL
Supportivecare
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WSG Adjuvant Breast Cancer StudyDr. U. Nitz et al.
RandomizationN = 1000
CEF or TAC+ radiotherapy
+ Aranesp
CEF or TAC + radiotherapy only
Endpoint
Relapse-freeSurvival
Follow-up
CEF = cyclophosphamide/epirubicin/5-floururacilTAC = taxotere/Adriamycin/cyclophosphamide
Study Endpoints:• Relapse-free survival• Overall survival• Hemoglobin response• Cognitive function
Surgery
Hb entry: 13.5 g/dLWithhold dose: Hb >14g/dL
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GELA Diffuse Large Cell Lymphoma StudyDr. R. Delarue, Dr. A. Bosley et al.
RandomizationN = 600
R-CHOP-14
R-CHOP-21
Endpoint
Relapse-freesurvival
Follow-up
Aranesp
Aranesp
Study endpoints:• Relapse-free survival• Overall survival• Disease-free survival• Response rateHb entry: 13 g/dLWithhold dose: Hb >14 g/dL
Supportivecare
Supportivecare
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DAHANCA Head and Neck Cancer StudyDr. J. Overgaard et al.
RandomizationN = 600
Radiotherapy+ Aranesp
Radiotherapyalone
Endpoint
Local-RegionalControl
Follow-up
Study endpoints:• Local-regional control (T+N)• Overall survival• Hemoglobin response
Hb entry: 13 g/dLWithhold dose: Hb >15 g/dL
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Amgen-Sponsored Trial and Independent-Investigator Trials
Accrual Detectable Sponsor/ Tumor through Projected DifferencesInvestigator type April ‘04 Control (80% power)
GELA/R. Delarue, NHL 22/600 62% atA. Bosley 3 years 11%
AGO/ Neo-adjuvant 80% atM.Untch Breast 400/720 5 years 10%
WSG/ Adjuvant 12/1000 75% atU. Nitz Breast 5 years 7%
DAHANCA/ Head/Neck 260/600 60% atJ. Overgaard 5 years 11%
Amgen SCLC 213/600 50% at9 months 11%
Overall Survival
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Amgen-Sponsored and Investigator-Initiated Trials
0
10
20
30
40
50
60
70
80
90
100
GELA
AGO
WSG
DAHANCA
Amgen
1.0 1.1 1.2 1.3 1.4 1.5
Po
we
r
Hazard Ratio
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Amgen-Sponsored and Investigator-Initiated Trials: Patient Experience
2003 2005 2007 2009 2011
1000
2000
3000
4000
5000
6000
7000
8000
9000
0
Projected Patients
Projected CumulativePatient-years of Follow-up
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Amgen-Sponsored and Investigator-Initiated Trials
Meta Analysis of all 5 trials
0
10
20
30
40
50
60
70
80
90
100
1.0 1.1 1.2 1.3 1.4 1.5
Po
we
r
Hazard Ratio
A meta-analysis with results from all five trials has 80% power to detect a hazard ratio of 1.15 or greater
BEST Survival HR = 1.31ENHANCE Survival HR = 1.39
Meta Analysis for the twobreast cancer studies
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Strengths of the Ongoing Aranesp Clinical Trials Program Design elements involve either double-blind, placebo-controlled or Aranesp
vs. no epoetin with pre-defined survival or tumor progression endpoints
Ongoing trials across multiple tumor types – 1700 breast cancer (2 studies)
– 600 head and neck cancer
Cumulative meta-analyses of 3500 patients will provide assessment over time of tumor progression and survival– Over 900 patients accrued to date
Studies include appropriate safety monitoring, including collection of thrombotic events– Head and neck study interim performed at 260 patients
AGO breast cancer trial incorporates tissue collection
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Conclusions
After detailed review of Aranesp pre-clinical and clinical experience, no significant survival or tumor progression signal observed
Benefits from treatment of CIA with Aranesp are well-established
Thrombotic event rate remains consistent with label
Substantial clinical trials program in place to further investigate survival outcomes
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Aranesp® (darbepoetin alfa) Therapy for Oncology Patients
Oncologic Drugs Advisory CommitteeMay 4, 2004
CC-57
Aranesp Group (Target hemoglobin 13 g/dL)
Placebo Group
Study Population• Hemoglobin 11 g/dL• GFR 20-60 mL/min/1.73m2
• Type 2 DM
N = 2000
N = 2000
Enrollment 1.5 years Follow-up period 2.5 years
Final Analysis
Baseline
Primary Endpoint- Time to the composite event, comprising:
• Mortality
• Non-fatal cardiovascular events: Myocardial infarction, acute myocardial ischemia, congestive heart failure, cerebrovascular accident
TREAT: Trial to Reduce Cardiovascular Events with Aranesp Therapy
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Pooled Oncology Analysis: Potential Interaction between Prior TE and Treatment
% of Subjects
NESP(N=1807)
Placebo(N=444)
No Prior Thrombotic Event
6%
(97/1703)
3%
(11/412)
Prior Thrombotic Event 13%
(14/104)
12%
(4/32)