# Presentation: 399127

## Aranesp® (darbepoetin alfa) Therapy for Oncology Patients

**Oncologic Drugs Advisory Committee****May 4, 2004**

## Amgen Guests

**Jeffrey Crawford, MD****	****Professor of Medicine ****	****Duke University School of Medicine**** **
**David DeMets, PhD****	****Professor and Chair of Biostatistics****	****University of Wisconsin**
**John Glaspy, MD, MPH****	****Professor of Medicine****	****University of  California at Los Angeles ****	****School of Medicine**
**Harvey Lodish, PhD****	****Professor of Biology and Professor of ****	****Bioengineering at MIT****	****Member of Whitehead Institute**
**Douglas Losordo, MD****	****Associate Professor of Medicine****	****Tufts University School of Medicine**** **
**Marc Pfeffer, MD, PhD****	****Senior Physician in Cardiology****	****Professor of Medicine****	****Brigham and Women’s  Hospital**
**Joseph Eschbach, MD****	****Senior Research Advisor****	****Northwest Kidney Center****	****Clinical Professor Medicine****	****University of Washington**

## Independent Investigators

**Principal Investigator****	****Study Group****	****Institution**
**J. Overgaard, MD**	**The Danish Head****	****Dept. Experimental Clinical Oncology  ****	****and Neck Cancer ****	****Aarhus University Hospital****	****Study Group****	****Aarhus C. Denmark****	****(DAHANCA)**
**R. Delarue, MD**	**Groupe d’Etude des****	****Adult Hematology Dept**	**Lymphomes de l’Adulte****	****Hospital Necker, Paris, France****A. Bosley, MD**	**(GELA)****	****Hematology Dept.****	****	****UCL Mont Godinne, Belgium**
**U. Nitz, MD**	**Westdeutschen****	****Gynecological Clinic****	****Studiengruppe (WSG)****	****Dusseldorf University****	****	****Dusseldorf, Germany**
**S. Kahlert, MD**	**Gynecological****	****Clinic and Polyclinic for ****	****Oncology Study****	****Obstetrics and Gynecology,****	****	****Group (AGO)****	****Grosshadern Clinic, Ludwig-****	****	****Maximillian University****	****	****Munich, Germany**

## Presentation Outline

**	**

**Background ****	****Dawn Viveash, MD**	VP of Regulatory Affairs 	and Safety
**EPO-R Considerations**	**Harvey Lodish, PhD**	Professor of Biology and	Bioengineering - MIT
**Clinical Observations****	****David Parkinson, MD**	VP of Oncology Clinical	Development

## Distinct Properties of Aranesp 

- Altered amino acid sequence permits attachment of2 additional carbohydrate side chains

- Increase in negative charge
- Increase in molecular weight and size

- 5-fold reduction in receptor binding affinity
- 3-fold increase in serum half life
- Leads to improved in vivo biological activity

**Molecular Differences Compared with Epoetin***** ***

**Physical Differences Compared with Epoetin**

**Biological Differences Compared ****with Epoetin**** **

## 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

## 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

**1****Besarab et al. *****NEJM*****. 339(9):584;1998.**

## 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

**1****Amgen data on file.**
**2****Kirkpatrick et al. 2003.****3****Ning et al. 2003.**

## Comprehensive Risk Assessment:Clinical Data

- Epidemiological analysis of thrombotic events
- Review of completed and ongoing Aranesp trials
- Post-marketing oncology experience

## 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

## Presentation Outline

**	**

**Background ****	****Dawn Viveash, MD**	VP of Regulatory Affairs 	and Safety
**EPO-R Considerations**	**Harvey Lodish, PhD**	Professor of Biology and	Bioengineering - MIT
**Clinical Observations****	****David Parkinson, MD**	VP of Oncology Clinical	Development

## 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

## 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

## 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

## 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

## 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

## Presentation Outline

**	**

**Background ****	****Dawn Viveash, MD**	VP of Regulatory Affairs 	and Safety
**EPO-R Considerations**	**Harvey Lodish, PhD**	Professor of Biology and	Bioengineering - MIT
**Clinical Observations****	****David Parkinson, MD**	VP of Oncology Clinical	Development

## 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

## 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

**1****Chau L, et al. *****Br J Haem.***** 2003;120:970-977; ****2****Louvet C, et al. *****J Clin Oncol. *****2002;20:4543-4548; ****3****Scheithauer W, et al. *****J Clin Oncol.***** 2003;21:1307-1312; ****4****Hitt R, et al. *****Ann Oncol.***** 2002;13:1665-1673; ****5****Schiller JH, et al. *****N Engl J Med***** 2002;346:92-98; ****6**** Vogelzang N, et al. *****Semin Hematol.***** 1997;34(suppl 2):4–12; ****7****Tandem audit; ****8****Amgen data on file.**

## Aranesp Increases Hemoglobin and Reduces Transfusions 

## 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

**1****Seidenfeld et al. 2001; ****2****Bohlius. 2003; ****3****Crawford et al. 2002; ****4****Sabbatini et al. 2004; ****5****Rizzo et al. 2001.**

## 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

## 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

## 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

**1****Adjusted for age, sex, cancer type, and comorbidities**
**2****Bohlius, et al. *****Blood*****. 2003;102:203a. Abstract 709. **

## 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

## Survival Analysis in Aranesp Randomized, Placebo-Controlled Trials in CIA

**1****Vansteenkiste J, et al. *****J Natl Cancer Inst. ***** 2002;94:1211-1220. (Study 980297)**
**2****Hedenus M, et al.  *****Br J Haematol. ***** 2003;122:394-403.**** (Study 20000161)**
**3****Hedenus M, et al. *****Br J Haematol. ***** 2002;119:79-86.**** (Study 980291)**
**4****Kotasek D, et al. *****Eur J Cancer. ***** 2003;39:2026-2034.**** (Study 990114)**

**Studies:****	****Characteristics:**
**Lung cancer****1 ****N = 314****	****Homogeneous patient population****	****	****Platinum-based therapy****	****	****Long-term follow-up**
**Lymphoid malignancies****2 ****N = 344****	****Less homogeneous patient populations****	****	****Long-term follow-up**
**Mixed solid tumor****3 ****N = 405 ****	****Heterogeneous patient population****Lymphoid malignancies****4 ****N = 66****	****Follow-up (16 weeks)**

## Aranesp Lung Cancer Study

**Randomization****N = 314**

**Chemotherapy****1**
**Aranesp **
**2.25 ****μg/kg/week**
**for 12 weeks**

**Chemotherapy****1**** **
**Placebo **
**for 12 weeks**

_**Endpoint**_
**RBC**
**Transfusion**

**Long-term**
**Follow-up**
**for Survival **
**And Progression**

**Median follow up time:****16 months**

**	****	****	****	****	****Placebo****	****Aranesp **
**Number of patients****	****159****	****155**
**Histology****	****NSCLC****	****114 (72%)****	****108 (70%)****	****SCLC****	****45 (28%)****	****47 (30%)**

**1****Platinum-based**
**Study 980297**

**Hb entry: ********11 g/dL**
**Withhold dose: Hb >14g/dL **

## Progression-free Survival in Lung Cancer Patients

**Placebo**

**Percent**

**20**

**40**

**60**

**80**

**100**

**Months from 1st Dose**

**0**

**3**

**6**

**9**

**12**

**15**

**18**

**21**

**24**

**Subjects at risk:**

**Placebo**

**Aranesp**

**159**

**155**

**114**

**116**

**50**

**63**

**26**

**35**

**14**

**16**

**7**

**13**

**4**

**6**

**1**

**5**

**Study 980297**
**1****Adjusted for histology**

**	****Total ****	****Events**
**Aranesp****	****155****	****131**
**Placebo****	****159****	****145**

**Hazard Ratio****1**
**0.81 (95% CI: 0.64, 1.03)**

**0**

**0**

**1**

## Overall Survival in Lung Cancer Patients

**Placebo**

**20**

**40**

**60**

**80**

**100**

**0**

**3**

**6**

**9**

**12**

**15**

**18**

**21**

**24**

**Subjects at risk:**

**Placebo**

**Aranesp**

**159**

**155**

**127**

**133**

**86**

**94**

**58**

**74**

**44**

**49**

**30**

**34**

**16**

**16**

**3**

**7**

**	****Total ****	****Deaths**
**Aranesp****	****155****	****100**
**Placebo****	****159****	****119**

**Hazard Ratio****1**
**0.78 (95% CI: 0.60, 1.01)**

**Percent**

**Months from 1st Dose**

**0**

**0**

**1**

**Study 980297**
**1****Adjusted for histology**

## Aranesp Lymphoid Malignancy Study

**Median follow-up time:****27 months**

**	****	****Placebo****	****Aranesp**
**Number of patients****	****169****	****175****	****NHL****	****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%)****	**

**Randomization****N = 344**

**Chemotherapy**** ****+**
**Aranesp **
**2.25 ****μg/kg/week**
**for 12 weeks**

**Chemotherapy**** ****+****Placebo **
**for 12 weeks**

_**Endpoint**_
**RBC**
**Transfusion**

**Long-term**
**Follow-up**
**for Survival **
**And Progression**

**Study 20000161**

**Hb entry: ********11 g/dL**
**Withhold dose: Hb >14g/dL **

## Aranesp Lymphoid Malignancy Study: Baseline Characteristics

**	****	****Placebo****	****Aranesp****	****	****N = 169****	****N = 175****	****	****n (%)****	****n (%)**
**Non-Hodgkin’s lymphoma****	****45 (27)****	****39 (22)****	****	****Indolent****	****   29 (64)****	****   20 (51)****	****Aggressive****	****   16 (36)****	****   17 (44)**
**International Prognostic Index****	****	****0 – 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**

## Progression-free Survival in Patients with Lymphoid Malignancies

**Study 20000161**
**1****Adjusted for disease type, stage and IPI score**

**Aranesp**

**Placebo**

**Percent**

**20**

**40**

**60**

**80**

**100**

**Months from 1st Dose**

**0**

**3**

**6**

**9**

**12**

**15**

**18**

**21**

**24**

**Subjects at risk:**

**Placebo**

**Aranesp**

**169**

**175**

**150**

**146**

**119**

**125**

**104**

**109**

**96**

**100**

**85**

**85**

**71**

**72**

**63**

**60**

**	****Total ****	****Events**
**Aranesp****	****175****	****120**
**Placebo****	****169****	****113**

**Hazard Ratio****1**
**1.11 (95% CI: 0.85, 1.44)**

**0**

**49**

**43**

## Overall Survival in Patients withLymphoid Malignancies

- Overall Survival in Patients withLymphoid Malignancies

**Placebo**

**20**

**40**

**60**

**80**

**100**

**0**

**3**

**6**

**9**

**12**

**15**

**18**

**21**

**24**

**Subjects at risk:**

**Placebo**

**Aranesp**

**169**

**175**

**160**

**162**

**146**

**150**

**135**

**136**

**132**

**126**

**124**

**122**

**116**

**117**

**113**

**101**

**	****Total ****	****Deaths**
**Aranesp****	****175****	****80**
**Placebo****	****169****	****61**

**Hazard Ratio****1**
**1.33 (95% CI: 0.95, 1.86)**

**Percent**

**Months from 1st Dose**

**0**

**Study 20000161**
**1****Adjusted for disease type, stage and IPI score**

**93**

**76**

## Pooled Analysis of Four Amgen Completed Trials Concerning Tumor Progression and Survival

- 	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

## Progression-free Survival in Four Pooled1 Placebo Controlled Trials – 16 Week Data

**Percent**

**80**

**85**

**90**

**95**

**100**

**Weeks After 1st Dose**

**0**

**4**

**8**

**12**

**16**

**Subjects at risk:**

**Placebo**

**Aranesp**

**421**

**708**

**405**

**680**

**372**

**642**

**349**

**572**

**Hazard Ratio****2**
**1.02 (95% CI: 0.78, 1.33)**

**1****Studies 980297, 20000161, 980291, 990114**
**2****Adjusted for study, disease type, stage and IPI score**

**0**

**252**

**313**

## Overall Survival in Four Pooled1 Placebo Controlled Trials – 16 Week Data

**80**

**85**

**90**

**95**

**100**

**Weeks After 1st Dose**

**0**

**4**

**8**

**12**

**16**

**Subjects at risk:**

**Placebo**

**Aranesp**

**421**

**708**

**411**

**687**

**387**

**660**

**368**

**600**

**294**

**358**

**Hazard Ratio****2**
**1.02 (95% CI: 0.67, 1.54)**

**0**

**Percent**

**1****Studies 980297, 20000161, 980291, 990114**
**2****Adjusted for study, disease type, stage and IPI score**

## Pooled1 Analyses: Progression-free Survival Hazard Ratios Associated with Aranesp (A) vs Placebo (P) by Tumor Type

**1****Studies 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)**

## 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.**

**	****	****Hazard****	****Endpoint****	****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)**

## 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

## 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**

## 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.**

## 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

## 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

## 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 cancer	600	Lymphoma	600	Small-cell lung cancer
- 	3,520

## Amgen Small Cell Lung Cancer Study

**Randomization****Double-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/dL**
**Withhold dose: Hb >14g/dL **

## AGO Breast Cancer StudyDr. M. Untch et al.

**Randomization****N = 720**

**Sequential****Therapy****(EC********T)**

**Sequential****Dose-intensified****Therapy****(E********T********CMF)**

_**Endpoint**_
**Relapse-free****and ****Overall****Survival**

**Follow-up**

**Aranesp**

**Supportive****care**

**Aranesp**

- S u r g e r y

**Study endpoints:**
**Relapse-free and overall survival**
**Complete pathological response**
**Quality of life**

**E = epirubicin**
**C = cyclophosphamide**
**T = paclitaxel**
**M = methotrexate**
**F = flourouracil**

**Withhold dose: Hb >14g/dL **

**Supportive****care**

## WSG Adjuvant Breast Cancer StudyDr. U. Nitz et al.

**Randomization**
**N = 1000**

**CEF or TAC****+ radiotherapy****+ Aranesp**

**CEF or TAC ****+ radiotherapy only**

_**Endpoint**_
**Relapse-free****Survival**

**Follow-up**

**CEF = cyclophosphamide/epirubicin/5-floururacil**
**TAC = taxotere/Adriamycin/cyclophosphamide**

**Study Endpoints:**
**Relapse-free survival**
**Overall survival**
**Hemoglobin response**
**Cognitive function**

**Surgery**

**Hb entry: ********13.5 g/dL**
**Withhold dose: Hb >14g/dL **

## GELA Diffuse Large Cell Lymphoma StudyDr. R. Delarue, Dr. A. Bosley et al.

**Randomization****N = 600**

**R-CHOP-14**

**R-CHOP-21**

_**Endpoint**_
**Relapse-free****survival**

**Follow-up**

**Aranesp**

**Aranesp**

**Study endpoints:**
**Relapse-free survival**
**Overall survival**
**Disease-free survival**
**Response rate**

**Hb entry: ********13 g/dL**
**Withhold dose: Hb >14 g/dL **

**Supportive****care**

**Supportive****care**

## DAHANCA Head and Neck Cancer StudyDr. J. Overgaard et al.

**Randomization**
**N = 600**

**Radiotherapy****+ Aranesp**

**Radiotherapy****alone**

_**Endpoint**_
**Local-Regional****Control**

**Follow-up**

**Study endpoints:**
**Local-regional control (T+N)**
**Overall survival**
**Hemoglobin response**

**Hb entry: ********13 g/dL**
**Withhold dose: Hb >15 g/dL **

## Amgen-Sponsored Trial and Independent-Investigator Trials

**	****	****Accrual****	****	****Detectable ****Sponsor/****	****Tumor****	****through****	****Projected****	****Differences****Investigator****	****type****	****April ‘04****	****Control****	****(80% power)**
**GELA/****	****	****	****R. Delarue, ****	****NHL****	****22/600****	****62% at****	****A. Bosley****	****	****	****3 years****	****11%****	**
**AGO/****	****Neo-adjuvant****	****	****80% at****	****M.Untch****	****Breast****	****400/720****	****5 years****	****10%**
**WSG/****	****Adjuvant****	****12/1000****	****75% at****	****U. Nitz****	****Breast****	****	****5 years****	****7%****	**
**DAHANCA/****	****Head/Neck****	****260/600****	****60% at****	****J. Overgaard****	****	****	****5 years****	****11%****	**
**Amgen****	****SCLC****	****213/600****	****50% at****	****	****	****	****	****9 months****	****11%****	**

**Overall Survival **

## 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**

**Power**

**Hazard Ratio**

## 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 Cumulative****Patient-years of Follow-up**

## Amgen-Sponsored and Investigator-Initiated Trials

**0**

**10**

**20**

**30**

**40**

**50**

**60**

**70**

**80**

**90**

**100**

**1.0**

**1.1**

**1.2**

**1.3**

**1.4**

**1.5**

**Power**

**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 = 1.31**

**ENHANCE Survival HR = 1.39**

## 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

## 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

## Aranesp® (darbepoetin alfa) Therapy for Oncology Patients

**Oncologic Drugs Advisory Committee****May 4, 2004**

## TREAT:  Trial to Reduce Cardiovascular Events with Aranesp Therapy 

**Aranesp Group (Target hemoglobin 13 g/dL)**

**Placebo Group**

**Study Population**
** ****Hemoglobin ******** 11 g/dL**
** ****GFR 20-60 mL/min/1.73m****2**
** ****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

## 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)