# Presentation: 792170

**Evolving Safety Issues Associated With Erythropoietin Products ****Oncology Drugs Advisory Committee****May 4, 2004**
**Harvey Luksenburg, M.D. ****Division of Therapeutic Biological Oncology Products,****ODE 6/OND/CDER**

## FDA Team

**Harvey Luksenburg, M.D., Clinical**
**Kaushik Shastri, M.D., Clinical**
**Ellis Unger, M.D., Clinical**
**Andrea Weir, Ph.D., Pharm/Tox**
**Clare Gnecco, Ph.D., Statistics**
**Mark Rothmann, Ph.D., Statistics**
**Ruth Wager, Ph.D., Product**
**Emily Shacter, Ph.D., Product**

## Background 

**Two large randomized studies in cancer patients on chemotherapy ****± EPO**** have shown**
**Shorter OS **
**Shorter PFS**
****** ****incidence of thrombotic/cardiovascular events**
**in the groups assigned to EPO**

**The EPO products used in these two studies are not licensed in U.S. **
**Used a treatment strategy to achieve  hemoglobin ******** 12 gm/dL [higher than recommended in the labeling for U.S. licensed products]**

**Background**

## Background 

**Clinical trials for U.S. licensed EPO products were **_**not**_** designed to assess **_**impact on**_
**Response rate **
**  ****(except N93-004)**
**TTP/PFS **
**OS**

## Goals (1) 

**Safety issues observed with EPREX and NeoRecormon may also apply to U.S. licensed products**
**Review results of trials with EPREX and NeoRecormon (non-U.S. licensed) regarding safety concerns**

## Goals (2)

**Review data available regarding safety from trials of EPOGEN / Procrit and Aranesp (U.S. licensed)**
**To come to agreement on design of future studies regarding safety **

## Safety Issues With Recombinant Erythropoietins

**Thrombotic and cardiovascular adverse events **
**Tumor progression **
**Survival**

## Recombinant EPO Products (U.S. Licensed)

**Epoetin alfa manufactured by Amgen**
**EPOGEN (marketed by Amgen Inc.)**
**Procrit (marketed by Ortho BioTech L.P.)**
**Darbepoetin alfa**
**   ****(Aranesp; Amgen, Inc.)**

## Recombinant EPO Products(Not Licensed in U.S.)

**Epoetin alfa (EPREX, Ortho Biologics)**
**Epoetin beta (NeoRecormon; Hoffmann-La Roche) **

## EPOs as a Class 

**FDA considers **_**all**_** of these products members of the same product class**
**These evolving safety issues are assumed to apply to all products unless adequate and well-controlled trials demonstrate otherwise**

## Differences

**Epoetin alfa and beta have same amino acid sequence but differ in glycosylation**
**Aranesp differs in amino acid sequence (5) and degree of glycosylation  **

## Similarities

**All exert principal clinical effect by binding to the EPO receptor**
**All have similar  pharmacodynamic effects when used at recommended dosages**
**Similar toxicity profile across products (except PRCA)**

**Labels for EPOGEN/Procrit and Aranesp have dosage guidelines based on safety data from registration studies performed in patients with chronic renal failure (CRF)  **

**Target Hemoglobin: Background**

## Recommended Hgb/Hct

**EPOGEN/Procrit**
**“****Suggested Target Hct. Range: 30% to 36%” **
**Aranesp**
**“****The dose should be adjusted for each patient to achieve and maintain a target hemoglobin not to exceed 12 g/dL”**

## Dosing Recommendations

**For rapid increase in Hgb greater than 1.0 g/dL (or 4 points in Hct) in any 2 week period dose should be reduced**
**Hold if Hgb > 13 g/dL, until Hgb falls **_**<**_** 12 g/dL, and restart dose at 25% below**** ****previous dose.**

## Thrombotic and Cardiovascular Adverse Events 

## Slide 18

|  | Thrombotic events | Tumor progression | OS |
| --- | --- | --- | --- |
| “NL Hct Study” (EPOGEN) in CRF | X |  |  |
| BEST
(EPREX) | X | X | X |
| Henke et al
(NeoRecormon) | X | X | X |
| Procrit
Pooled Studies | X |  |  |
| Procrit N93-004  | X | X | X |
| Aranesp 980297 | X | X | X |

## Thrombotic Events with EPO

**Licensing studies for EPOGEN**
**  ****/ Procrit and Aranesp demonstrated baseline risk of thrombotic & cardiovascular adverse events at labeled target Hgb (10-12 g/dL)**

## “Normal Hematocrit Study” (Besarab et al, NEJM 1998)

**1,233 patients with chronic renal failure on dialysis with clinical evidence of CHF or ischemic heart disease**
** **
**EPOGEN at baseline in order to achieve/maintain Hct 27-33% **

## “Normal Hematocrit Study” 

**Both arms received EPOGEN but randomized to different treatment strategies**
**Achieve Hct of 42% (****±3) (“normal Hct”)**
**Maintain Hct of 30% ****(****±3) **
**	****(“low Hct”)**

## “Normal Hematocrit Study”

|  | Normal Hct 
N=618 | Low Hct
N=615 |
| --- | --- | --- |
| Deaths | 183 (30%) | 150 (24%) |
| Non-fatal MI | 19 (3.1%) | 14 (2.3%) |
| Vascular access thrombosis  | 39% | 29% |

## Probability of Death/Non-Fatal MI

**Probability of Death/Non-Fatal MI**

## Slide 24

|  | Thrombotic events | Tumor progression | OS |
| --- | --- | --- | --- |
| “NL Hct Study” (EPOGEN) in CRF | X |  |  |
| BEST
(EPREX) | X | X | X |
| Henke et al
(NeoRecormon) | X | X | X |
| Procrit
Pooled Studies | X |  |  |
| Procrit N93-004  | X | X | X |
| Aranesp 980297 | X | X | X |

## Breast Cancer Erythropoietin Trial (BEST) (EPREX [Epoetin alfa])

**Randomized, DB, Placebo controlled **
**939 women w/ metastatic breast cancer**
**1****st**** line therapy **
**+/- EPREX for 12 mos**
**Therapy started Hgb < 13 g/dL**

## BEST Trial

**Primary objective to demonstrate superior survival at 12 months.**
**Target Hgb 12-14 g/dL**
**Stopped by IDMC based on first 4 mos safety data**

## BEST Trial 

**At 4 months**
****** ****incidence of fatal thrombotic and cardiovascular events **
**  ****EPREX    2.3% **
**  ****Placebo   0.4%**

## Henke et al (Lancet 2003) (NeoRecormon [Epoetin beta])

**Randomized, DB, PC**
**351 patients w/ head and neck cancer**
**Concurrent radiotherapy**
**Anemic  < 12 g/dL women **
**	****	****	****       ****< 13 g/dL men**

## Henke et al

**Primary Objective**
**	****To demonstrate superior locoregional PFS**
**Target Hgb   ****≤****14 g/dL women**
**	****	****	****           ≤****15 g/dL men**

## Henke et al 

**Hypertension, hemorrhage, venous thrombosis, pulmonary embolism, CVA**
**   ****Epoetin beta     11% **
**   ****Placebo               5%  **
**Patients who died of “cardiac disorders” **
**   ****Epoetin beta    5.5%**
**   ****Placebo ****	****       3%**

## Slide 31

|  | Thrombotic events | Tumor progression | OS |
| --- | --- | --- | --- |
| “NL Hct Study” (EPOGEN-CRF) | X |  |  |
| BEST
(EPREX) | X | X | X |
| Henke et al
(NeoRecormon) | X | X | X |
| Procrit
Pooled Studies | X |  |  |
| Procrit N93-004  | X | X | X |
| Aranesp 980297 | X | X | X |

## Registration Studies-Procrit

**Pooled analyses of six multicenter, randomized, DB, placebo-controlled studies **
**131 patients **
**– ****Various primary cancers**
**Platinum (n=59)  & non-platinum (n=72)**
**Anemic**
**Primary endpoint: Proportion patients tranfused**

## Registration Studies-Procrit 

**Incidence of thrombotic & cardiovascular events  (pooled data)**
**Placebo    12%  (8/68)**
**Procrit        3%  (2/63)**

## Study N93-004 (Procrit [Epoetin alfa])

**Post-marketing commitment **
**Randomized, DB, PC, non-inferiority study**
**Intended to enroll 400 patients with SCLC**
**First line therapy **
**Baseline Hgb < 14 g/dL**

## Study N93-004 

**Primary Endpoint: Objective RR after 3 cycles chemo to rule out decrement of 15% in ORR with Procrit **
**No target Hgb, Procrit dose reduced for Hgb **_**>**_** 16 g/dL**
**Study terminated for poor accrual at 224 patients**

## Study N93-004

**Incidence of Thrombotic Vascular Events**
**Procrit****	****   ****	****22% (24/109)**
**Placebo****	****23% (27/115)**
**Includes “chest pain”, MI, angina, stroke, cardiac arrest, peripheral ischemia, cardiovascular disorder, thrombosis, DVT, PE, phlebitis **

## Thrombotic / Vascular Events

|  | Including “Chest Pain” | Not Including “Chest Pain” |
| --- | --- | --- |
| Procrit | 22% (24/109) | 14% (15/109) |
| Placebo  | 23% (27/115) | 9.5% (11/115) |

**Thrombotic / Vascular Events**

## Aranesp 980297

**Randomized, DB, PC**
**320 pts with lung cancer**
**Platinum-containing chemotherapy **
**Anemic (< 11 g/dL)**

## Aranesp 980297

**Primary endpoint: Proportion transfused between week 5 and week 12 or end of treatment period (EOTP) **
**Aranesp held for Hgb **_**>**_** 14 g/dL women & Hgb **_**>**_** 15 g/dL men**

## Aranesp 980297

**Thrombotic events**
**Aranesp   5% (7/155)**
**Placebo   3%  (5/159)**

## Thrombotic/Vascular Events

| “NL Hct Study” (EPOGEN)
(N=1,233) | Non-fatal MI 3.1% vs.  2.3% 
Vasc access thrombosis 
39% vs.  29%  |
| --- | --- |
| BEST
(EPREX)
(N=939) | Fatal thrombotic events
2.3% vs.  0.4% (Placebo) |
| Henke (NeoRecormon)
(N=351) | CV & thrombotic events
11% vs.  5% (Placebo) |

**Thrombotic/Vascular Events**
**Studies w/ Signal**** **

## Thrombotic/Vascular Events

| Procrit Pooled Studies (N=131)  | 3% (Procrit) vs. 12% (Placebo) |
| --- | --- |
| Procrit N93-004
(N=224) | * 22% (Procrit) vs.  23% (Placebo)  |
| Aranesp 980297 (N=320) | 5% (Aranesp) vs.  3% (Placebo) |

**Thrombotic/Vascular Events**
**Studies w/o Signal**** **

## In September 2003 three placebo controlled clinical trials in oncology patients in which one arm received EPO to target a higher hemoglobin were terminated because of unexpected rates of thrombotic events in the EPO arm

**Higher Target Hemoglobin**

## Higher Target Hemoglobin

| Primary Cancer | Target Hgb (g/dL) | TVE |
| --- | --- | --- |
| SCLC
(N=106) | 14-16  | 34% (EPREX) 6% (Placebo) |
| Cervical cancer
(N=113) | 13-14 | 16% (Procrit) 5% (Placebo) |
| Gastric or rectal cancer 
(N=60) | 14-15 | 24% (Procrit) 6% (Placebo) |

**Higher Target Hemoglobin**

## Tumor progression 

## Preclinical Studies 

**EPO receptors (EPO-R) are present on some tumor cell lines & tumor vasculature (endothelial cells)**** **

## Preclinical Studies

**EPO is reported to**
**Inhibit apoptosis  **
**Stimulate angiogenesis; endothelial cell growth, migration, and proliferation **
**Reduce survival in tumor xenograft models**

## Tumor Stimulation

**Studies supporting approval of Procrit and Aranesp for the treatment of anemia in cancer patients on chemotherapy **_**not**_** designed to assess impact on **
**Tumor response **
**Tumor progression**
**Survival**

## Slide 49

|  | Thrombotic events | Tumor progression | Survival |
| --- | --- | --- | --- |
| BEST
EPREX | X | X | X |
| Henke 
NeoRecormon | X | X | X |
| N93-004 
Procrit | X | X | X |
| Aranesp 980297 | X | X | X |

## Breast Cancer Erythropoietin Trial (BEST) (EPREX [Epoetin alfa])

**Randomized, DB, Placebo controlled **
**939 women w/ metastatic breast cancer**
**1****st**** line therapy **
**+/- 12 mo EPREX**
**Therapy started Hgb < 13 g/dL**

## Breast Cancer Erythropoietin Trial (BEST) (EPREX [Epoetin alfa])

**Primary objective to demonstrate superior survival at 12 months.**
**Target Hgb 12-14 g/dL**
**Stopped by IDMC based on first 4 mos safety data**

## BEST Trial  

**At 4 months**
**2-fold increase in disease progression **
**   ****EPREX      6% (28/469)**
**   ****Placebo    3% (13/470) **

## BEST Trial (EPREX [Epoetin alfa])

**At 4 months **
**2.5-fold increase in early mortality **
**	****EPREX    8.7% (41/469) **
**	****Placebo  3.4% (16/470)**

## Henke et al (Lancet 2003) (NeoRecormon [Epoetin beta])

**Randomized, DB, PC**
**351 patients w/ head & neck cancer **
**Concurrent radiotherapy**
**Anemic: Hgb < 12 g/dL women **
**	****	****	****       ****Hgb < 13 g/dL men**

## Henke et al 

**Primary Objective to demonstrate superior locoregional PFS**
**Target Hgb  ****≤ ****14 g/dL women**
**	****	****	****          ≤**** ****15 g/dL men**

## Henke et al

**For Locoregional PFS **
**NeoRecormon vs.  Placebo **
**                 ****RR 1.62 **
**(95% CI 1.22, 2.14, p=0.0008)**

## Henke et al

**For Locoregional progression**
**NeoRecormon vs.  Placebo **
**                   ****RR 1.69 **
**(95% CI 1.16-2.47;  p=0.007) **

## Study N93-004 (Procrit [Epoetin alfa])

**Post-marketing commitment**
**Randomized, DB, PC, non-inferiority study**
**Intended to enroll 400 patients with SCLC**
**First line therapy **
**Baseline Hgb < 14 g/dL**

## Study N93-004 

**Primary Endpoint: Objective RR after 3 cycles chemo to rule out 15% decrement in ORR in Procrit arm**
**No target Hgb, Procrit dose reduced for Hgb **_**>**_** 16 g/dL**
**Study terminated at 225/400 for poor accrual**

## Procrit N93-004

**Not designed to assess impact on TTP**
**Survival a secondary endpoint - no formal hypothesis testing **

## Procrit N93-004  Response Rate 

|  | Placebo
(n=115) | Procrit
(n=109) |
| --- | --- | --- |
| ORR | 67% | 72% |
| 95% CI around observed difference | 
- 6%, 18%  |  |

**Procrit N93-004  Response Rate**

## Aranesp 980297

**Randomized, DB, PC**
**320 pts with lung cancer**
**Platinum-containing chemotherapy **
**Anemic (Hgb < 11 g/dL)**

## Aranesp 980297

**Primary endpoint: Proportion transfused between week 5 and week 12 (or EOTP) **
**Aranesp held for Hgb **_**>**_** 14 g/dL women &  **_**>**_** 15 g/dL men**

## Aranesp 980297

**Median PFS (95% CI)**
**  ****Aranesp  5 months (4, 7 mos)**
**  ****Placebo  4 months (4, 5 mos)**
**Not designed to assess impact on PFS**

## Study 980297 Progression-free survival 

**Study 980297 Progression-free survival **

## Tumor Stimulation 

| BEST
EPREX
(N=939) | 4 mo Deaths due to Disease Progression
6% (EPREX) vs.  
3% (Placebo) |
| --- | --- |
| Henke
NeoRecormon
(N=351) | RR for locoregional PFS 
NeoRecormon vs. Placebo  1.62 |

**Tumor Stimulation **
**Studies w/ Signal**

## Tumor Stimulation

| Procrit 
N93-004 
(N=224) | ORR (95% CI):
Procrit 72% vs. (64, 81)
Placebo 67% (58, 76) |
| --- | --- |
| Aranesp 980297 (N=320) | Median PFS (95% CI):
Aranesp 4 months (4, 7) vs.  Placebo 5 months (4, 5) |

**Tumor Stimulation**
**Studies w/o Signal**

## Survival

## Slide 69

|  | Thrombotic events | Tumor progression | Survival |
| --- | --- | --- | --- |
| BEST
EPREX | X | X | X |
| Henke 
NeoRecormon | X | X | X |
| N93-004 
Procrit | X | X | X |
| Aranesp 980297 | X | X | X |

## Breast Cancer Erythropoietin Trial (BEST) (EPREX [Epoetin alfa])

**Randomized, DB, Placebo controlled **
**939 women w/ metastatic breast cancer**
**1****st**** line therapy **
**+/- EPREX for 12 mos**
**Study drug started at Hgb < 13 g/dL**

## BEST Trial

**Primary objective: To demonstrate superior survival at 12 months.**
**Target Hgb 12-14 g/dL**
**Stopped by IDMC based on 4 mo safety data **

## BEST Trial 

**Estimated 12-month survival **
**  ****EPREX:  70% (148 deaths/469)**
**  ****Placebo: 76% (115 deaths/470)**
**RR of death=1.4**
**(95% CI 1.07,1.74; p=0.012)**

## BEST:  Time to Death w/in 12 Months

**BEST:  Time to Death w/in 12 Months**

## Henke et al (Lancet 2003) (NeoRecormon [Epoetin beta])

**Randomized, DB, PC**
**351 patients w/ head and neck cancer **
**Concurrent radiotherapy**
**Anemic < 12 Hgb g/dL women **
**	****	****	****      ****< 13 Hgb g/dL men**

## Henke et al

**RR of death*****:  *****1.4 **
**   ****(95% CI 1.05-1.84, p=0.02 Cox)**
**Median overall survival**
**   ****NeoRecormon   605 days **
**Placebo             928 days  **
**   ****(p=0.09, logrank)**

## Study N93-004 (Procrit [Epoetin alfa])

**Randomized, DB, PC, non-inferiority study**
**Intended to enroll 400 patients with SCLC**
**First line therapy **
**Baseline Hgb < 14 g/dL**
**Not designed to assess impact on survival**

## Study N93-004 (Procrit [Epoetin alfa])

**Median survival**** **
**Procrit    10.5 months (95% CI: 9, 13)**
**Placebo  10.4 months (95% CI: 8, 13)**
**Overall mortality rate**
**Procrit    92% (100/109)**
**Placebo  88% (101/115)**

## N93-004 Survival Over Time (ITT)

**N93-004 Survival Over Time (ITT)**

## Aranesp 980297

**Randomized, DB, PC**
**320 pts with lung cancer**
**Platinum-containing chemotherapy **
**Anemic (< 11 g/dL)**
**Not designed to address impact on survival**

## Aranesp 980297 

**Median overall survival**
**Aranesp 10 mos (95% CI: 9, 12 mos)**
**Placebo   8 mos (95% CI: 7, 9 mos) **
**Overall mortality rate**
**Aranesp    14% (22/155)**
**Placebo     12% (19/159)**

## Aranesp 980297 Overall Survival

**Aranesp 980297 Overall Survival**

## Survival:  Studies w/ Signal

| BEST
EPREX 
(N=939) | 12 mo Survival Rate
70% (EPREX) vs. 
76% (Placebo) (p=0.012) |
| --- | --- |
| Henke
NeoRecormon
(N=351) | Median Overall Survival
605 days (NeoRecormon) vs. 
928 days (Placebo) (p=0.09) |

**Survival:  Studies w/ Signal**

## Survival:  Studies w/o Signal

| N93-004 
Procrit 
(N=224) | 10.5 months (Procrit) vs.  
10.4 months (Placebo) |
| --- | --- |
| Aranesp 980297
(N=320) | 10 months (Aranesp) vs.  
8 months (Placebo) |

**Survival:  Studies w/o Signal**

## Summary

**Two large, multicenter studies (BEST & Henke) designed to show superior survival or PFS demonstrated **
**Increased thrombotic events **
**Shorter PFS**
**Shorter OS **
**Used a treatment strategy to achieve hemoglobin levels **_**>**_** 12 g/dL**

## Summary

**Multicenter, placebo-controlled trials**
**	****Procrit (N93-004) and Aranesp (980297)**
**Smaller in size**
**Not designed to assess impact on PFS or OS**
**Treatment strategy varied – Procrit held **_**>**_** Hgb 14 g/dL **
**  ****(label recommends 12 g/dL)**

## Conclusions

**Evolving safety concerns**
**Current dosing recommendations adequate to minimize risks of thrombotic events**
**Insufficient information for OS and PFS for U.S. licensed products at approved doses to assess risks**
**Amgen, Ortho Biotech and FDA agree on need for further studies**

## FDA Recommended Elements

**Homogenous primary tumor type**
**Homogenous chemotherapy or radiotherapy regimens**
**Study designed to detect clinically meaningful decrements in response rate, PFS, and survival**

## FDA Recommended Elements

**Prespecified definitions of cardiovascular and thrombotic events**
**DSMB oversight**

## FDA Recommended Elements

**Determination of expression and **
**ligand affinity of EPO-R on **
**specific primary tumor types**
**Preferably through analysis of clinical tissue specimens or**
**Pre-existing tissue repositories representing common tumor types**