# Presentation: 712694

## (Epirubicin Hydrochloride)

***(Epirubicin Hydrochloride)***

*Oncologic Drugs Advisory Committee Review*
*June  7, 1999*

**EPIRUBICIN**

**Pharmacia & Upjohn**

## Presentation Agenda

- Regulatory History and Pharmacology

- Early Breast Cancer Adjuvant Therapy

- Advanced Breast Cancer Therapy

- Conclusions

- Q & A

## Epirubicin Presentation Team

**Function****	****	****Name****	****Affiliation****Medical****	****Langdon Miller, MD****	****	****P&U****	****Elena Colajori, MD****	****	****P&U**
**Biostatistical****	****Anna Petroccione, MD, PhD****	****	****P&U**
**Clinical Pharmacology****	****Italo Poggesi, PhD****	****	****P&U**
**Pharmacovigilance****	****Claudio Praga, MD****	****	****P&U**
**Investigators****	****Mark Levine, MD****	****	****NCIC****	****Kathleen Pritchard, MD****	****	****NCIC****	****Dongsheng Tu, PhD****	****	****NCIC****	****Jacques Bonneterre, MD****	****	****FESG**

## Regulatory History

**Regulatory History**

- Registered in >80 countries worldwide
- First approved in France in 1982
- Registered in most countries since 1984

- Originally approved doses
- Single-agent therapy: 60-90 mg/m2
- Combination therapy: 50-75 mg/m2
- US NDA submitted in 1984
- Small sample sizes
- Limited survival data

## Worldwide Clinical Development and Use (1984 to 1999)

**Worldwide Clinical Development and Use (1984 to 1999)**

- Extensively studied in clinical trials
- Breast cancer
- Other tumor types

- Subject of >2000 publications
- Millions of patients have received the drug worldwide

- Efficacy and safety thoroughly characterized through clinical trials and postmarketing surveillance

## Epirubicin Structure and Mechanism of Action

- OH

- NH2Cl

- O

- O

- CH3

- O

- O

- CH3

- O

- OH

- OH

- OH

- O

- Anthracycline

- 4’ epimer of doxorubicin

- Mechanism of action
- DNA intercalation
- Topoisomerase II inhibition
- Helicase inhibition
- Free-radical formation

- Metabolites relatively noncytotoxic

## Increased lipophilicity
Increased cell penetration

- Increased cell penetration

**Pharmacologic Implications of Epirubicin Structure**

- MTD redefined
- Dose can be escalated up to 180 mg/m2

## Clinical Dose Response in Advanced Breast Cancer

**0%**

**25%**

**50%**

**75%**

**100%**

**0**

**100**

**200**

**Epirubicin Starting Dose (mg/m****2****)**

**Response Rate**

**Sledge G, personal communication**

## Basis for Approval

- Early Breast Cancer -- 3 Randomized Controlled Trials
- Pivotal Study: CEF vs CMF (EBC-1/MA-5)
- Supportive Study: Epirubicin Dose-Response (EBC-2/GFEA05)
- Other Supportive Study: Epirubicin Plus Tamoxifen (EBC-3/C-4-87)

- Advanced Breast Cancer -- 4 Randomized Controlled Trials
- Pivotal Study: CEF vs CMF (ABC-1/HEPI 013)
- Supportive Study: Epirubicin Dose-Response (ABC-2/HEPI 010)
- Other Supportive Studies:  Epirubicin Dose-Response (ABC-3, 4)

## Basis for Selection of Studies

- Studies were selected in consultation with the FDA:
- Trials were conducted in women with breast cancer
- All studies were completed, well-controlled, randomized, phase III trials
- Symmetrical designs allowed for a specific evaluation of epirubicin effect
- Epirubicin was tested at starting doses of 100 mg/m2
- Full study reports were available
- Data were available electronically or could be provided on request by the study group

## Proposed Indications

- Indicated as a component of adjuvant therapy in patients with evidence of axillary-node tumor involvement following resection of primary breast cancer (Stage II & III)
- Starting doses of 100 to 120 mg/m2

- Indicated for the therapy of patients with locally advanced or metastatic breast cancer
- Starting doses of 100 to 135 mg/m2

## Adjuvant Therapy of Early Breast Cancer

***Adjuvant Therapy of Early Breast Cancer***

## Overview of Epirubicin Studiesin Early Breast Cancer (N=1885)

**	****	****Menopausal****	****	****Intensive****	****Study****	****Status****	****	****Epirubicin (N)****	****	****Control (N)**
**Pivotal**
**	****EBC-1****	****Pre/Peri****	****	****CEF-120****	****	****CMF****	****(MA-5)****	****	****	****(356)****	****	****(360)**
**Supportive**
**	****EBC-2****	****Pre/Post****	****	****CEF-100****	****	****CEF-50****	****(GFEA05)****	****	****	****(276)****	****	****(289)**
**Other Supportive**
**	****EBC-3****	****Post****	****	****E-100 + T****	****	****T****(C-4-87)   ****	****	****	****(303)****	****	****(301)**

**C=cyclophosphamide, E=epirubicin, F=fluorouracil, M=methotrexate, T=tamoxifen**

## Intensive CEF vs CMF as Adjuvant Therapy for Premenopausal Patients With Axillary Node-Positive Breast Cancer

**Results of an NCIC-CTG-Sponsored ****Phase III Multicenter Randomized Controlled Trial (EBC-1/MA-5)**

***NCIC-CTG=National Cancer Institute of Canada Clinical Trials Group***
**Number of sites:  37****Enrollment dates:  1989-1993**

## Study Schema(EBC-1/MA-5)

***Women with partial mastectomy underwent radiotherapy after chemotherapy C=cyclophosphamide, E=epirubicin, F=fluorouracil, M=methotrexate**

## CMF  An Adjuvant Standard

**CMF q 4 wk for 6 cycles**
** ****C, 100 mg/m****2**** orally, d 1-14**
** ****M, 40 mg/m****2**** IV, d 1 +  8**
** ****F, 600 mg/m****2**** IV, d 1 + 8**

**CMF  ****An Adjuvant Standard**

- CEF vs CMF comparison allowed isolation of epirubicin effect against a standard regimen
- CMF -- an adjuvant standard
- Prior to start of EBC-1 in 1989
- Currently in 1999
- Current CMF usage in US
- 23,600 patients with Stage II early breast cancer on treatment
- 39% are receiving adjuvant CMF

## Primary
Relapse-free survival
Secondary
Overall survival
Safety
Quality of life (Breast Cancer Chemotherapy Questionnaire [BCQ], McMaster University) 

- Relapse-free survival
- Secondary
- Overall survival
- Safety
- Quality of life (Breast Cancer Chemotherapy Questionnaire [BCQ], McMaster University)

**Study Endpoints****(EBC-1/MA-5)**

## Hypothesis
10% absolute improvement in 5-year relapse-free survival
Assumed rate in CMF arm:  55% 
Expected rate in CEF arm:  65%
Statistical test
Stratified 2-tailed log-rank test with =0.05

- 10% absolute improvement in 5-year relapse-free survival
- Assumed rate in CMF arm:  55%
- Expected rate in CEF arm:  65%
- Statistical test
- Stratified 2-tailed log-rank test with =0.05

**Statistical Considerations****(EBC-1/MA-5)**

## Pre- or perimenopausal
Histologically proven breast cancer treated with total or partial mastectomy
Histologically positive axillary nodes
No distant metastases
No prior hormonal or cytotoxic therapy
LVEF 45%
Adequate hematological, renal, and liver function

- Histologically proven breast cancer treated with total or partial mastectomy
- Histologically positive axillary nodes
- No distant metastases
- No prior hormonal or cytotoxic therapy
- LVEF 45%
- Adequate hematological, renal, and liver function

**Eligibility Criteria****(EBC-1/MA-5)**

## Assessments at baseline and during chemotherapy
CXR, bone scan (baseline)
CBC (baseline, weekly)
PE, AEs, QoL (baseline and monthly)
LFTs (baseline, 3 and 6 months)
Echocardiogram or MUGA scan (baseline, 6 months)
Follow-up assessments
PE, CBC, LFTs, survival (every 3 months x 2 years, every 6 months x5 years, yearly thereafter)
Mammogram, CXR (yearly)
Echocardiogram or MUGA scan (6, 12, 36, and 60 months)
QoL (every 3 months x 2 years)

- CXR, bone scan (baseline)
- CBC (baseline, weekly)
- PE, AEs, QoL (baseline and monthly)
- LFTs (baseline, 3 and 6 months)
- Echocardiogram or MUGA scan (baseline, 6 months)
- Follow-up assessments
- PE, CBC, LFTs, survival (every 3 months x 2 years, every 6 months x5 years, yearly thereafter)
- Mammogram, CXR (yearly)
- Echocardiogram or MUGA scan (6, 12, 36, and 60 months)
- QoL (every 3 months x 2 years)

**Patient Evaluation****(EBC-1/MA-5)**

## Intent-to-Treat Study Population(EBC-1/MA-5)

**Intent-to-Treat Study Population****(EBC-1/MA-5)**

## Patient Characteristics(EBC-1/MA-5)

**	****	****N=356****	****	****N=360**
**Median age (yr)****	****44.5****	****	****44.5**
**	****[range]****	****[26-56]****	****          ****	****[23-57]**
**ECOG performance status (%)**
**	****0****	****78****	****	****83**
**	****1****	****  21  ****	****	****17**
**	****2****	****1****	****	****1**
**Menopausal status (%)**
**	****Premenopausal****	****78****	****	****79**
**	****Perimenopausal****	****22****	****	****21**
**Clinical stage (%)**
**	****I****	****38****	****	****40**
**	****II****	****50****	****	****48**
**	****III****	****4****	****	****6**
**	****Unknown****	****8****	****	****6**
**	**

**Patient Characteristics****(EBC-1/MA-5)**

## Surgical Findings(EBC-1/MA-5)

**	****	****CEF****	****CMF**
**	****	****N=356****	****N=360**
**Surgery type****	****	**
**	****Partial mastectomy****	****49****	****49**
**	****Total mastectomy****	****51****	****51**
**Nodes examined**
**	****1-5****	****8****	****9**
**	****6-10****	****36****	****38**
**       ****>10****	****56****	****54**
**Positive nodes at surgery**
**	****1-3****	****61****	****61**
**	****4-10****	****32****	****33**
**	****>10****	****6****	****7**
**	**

**Surgical Findings****(EBC-1/MA-5)**

## Receptor Status(EBC-1/MA-5)

**	****	****CEF****	****CMF**
**	****	****N=356****	****N=360**
**Estrogen ****	****	**
**	****ER positive*****	****60****	****60**
**	****ER negative****	****29****	****27**
**	****Unknown****	****11****	****13**
**Progesterone**
**PR positive*****	****63****	****59**
**PR negative****	****25****	****28**
**Unknown****	****12****	****14**

***  ********10 fmol/mg**

**Receptor Status****(EBC-1/MA-5)**

## Treatment Administration(EBC-1/MA-5)

**Treatment Administration****(EBC-1/MA-5)**

## Relapse-Free Survival(EBC-1/MA-5)

**CMF**

**0.4**

**0.5**

**0.6**

**0.7**

**0.8**

**0.9**

**1**

**1**

**2**

**3**

**4**

**5**

**6**

**7**

**0**

**0**

**CEF**

**0.1**

**0.1**

**0.2**

**0.2**

**0.3**

**0.3**

**Years**

**Probability**

**	****CEF****	****	****CMF**
**No. of patients****	****356****	****	****360****5-year RFS****	****62%****	****	****53%****Log-rank probability****	****	****p=0.013**

**Relapse-Free Survival****(EBC-1/MA-5)**

## Multivariate Analysis:  Treatment Effect on Relapse-Free Survival Adjusted for Prognostic Factors (EBC-1/MA-5)

**	****	****Conditional ****	**
**Factors*****	****	****Risk Ratio****	****p-value**
**Baseline characteristics**
**   ****Tumor Size****	**** ********T****3****	****2.5****	****<0.001**
**   ****Nodal Status****	**** ********4****	****1.7****	****<0.001**
**Treatment ****	****   CEF/CMF****	****  0.76****	****  0.021**

*** Factors evaluated in the modeling process were menopausal ****  status, type of surgery, tumor size, receptor status, and nodal****  status**

## Overall Survival(EBC-1/MA-5)

**CEF**

**CMF**

**0**

**0.1**

**0.2**

**0.3**

**0.4**

**0.5**

**0.6**

**0.7**

**0.8**

**0.9**

**1**

**0**

**1**

**2**

**3**

**4**

**5**

**6**

**7**

**Years**

**Probability**

**	****CEF****	****	****CMF**
**No. of patients****	****356****	****	****360****5-year survival****	****77%****	****	****70%****Log-rank probability****	****	****p=0.043**

**Overall Survival****(EBC-1/MA-5)**

## Multivariate Analysis:  Treatment Effect on Overall Survival Adjusted for Prognostic Factors (EBC-1/MA-5)

**Factors*****	****	****Risk Ratio****	****p-value**
**Baseline characteristics**
**   ****Tumor size****	****    ********T****3****	****2.5****	****<0.001**
**   ****Receptor status****	****Negative****	****2.0****	****<0.001**
**   ****Nodal status****	**** ********4****	****1.7****	****<0.001**
**Treatment ****	****CEF/CMF****	****  0.71****	****  0.034**

**Multivariate Analysis:  Treatment Effect on Overall Survival Adjusted for Prognostic Factors**** (EBC-1/MA-5)**

*** Factors evaluated in the modeling process were menopausal status,****  type of  surgery, tumor size, receptor status, and nodal status**

## On-Treatment Adverse Events(EBC-1/MA-5)

**On-Treatment Adverse Events****(EBC-1/MA-5)**

## Late Adverse Events(EBC-1/MA-5)

**Late Adverse Events****(EBC-1/MA-5)**

## Life-Table Analysis of AML-Free and Overall Survival(EBC-1)

**Overall Survival**

**AML-Free Survival**

**Life-Table Analysis of AML-Free and Overall Survival****(EBC-1)**

**CEF****CMF**

## Breast Cancer Chemotherapy Questionnaire (BCQ)
Designed to assess quality of life during adjuvant therapy
30 questions
Focus on emotional and physical symptoms
7-point scale for each question
Mean summary score computed using information from all scales
<0.5 change is considered clinically inconsequential

- Designed to assess quality of life during adjuvant therapy
- 30 questions
- Focus on emotional and physical symptoms
- 7-point scale for each question
- Mean summary score computed using information from all scales
- <0.5 change is considered clinically inconsequential

**Quality of Life (BCQ)****(EBC-1/MA-5)**

- Levine *et al*.  *J Clin Oncol* 1988;6:1798-1810

## Quality of Life (BCQ)(EBC-1/MA-5)

**CMF (N)****	****276****	****322****	****324****	****322****	****326****	****324****	****251****	****270****	****277****	****268****	****256****	****227****	****220**
**CEF (N)****	****270****	****322****	****325****	****321****	****315****	****316****	****252****	****288****	****265****	****244****	****239****	****233****	****217****	**

**0**

**1**

**2**

**3**

**4**

**5**

**6**

**7**

**0**

**3**

**6**

**9**

**12**

**15**

**18**

**21**

**24**

**Months From Randomization**

**BCQ Mean Summary Score **_**+**_** S.E. **

**Quality of Life (BCQ)****(EBC-1/MA-5)**

## Compared to CMF, CEF-120 improved:
Relapse-free survival
Overall survival

- Relapse-free survival
- Overall survival

- Toxicities were manageable and outweighed by benefits
- 96% of patients completed CEF-120 therapy
- No on-treatment CEF-120-related deaths occurred
- QoL was clinically similar between the 2 treatments

- Epirubicin was the critical component of the CEF regimen

**Conclusions****(EBC-1/MA-5)**

## Results of an FESG-Sponsored Phase III Multicenter Randomized Controlled Trial (EBC-2/GFEA05)

***FESG=French Epirubicin Study Group***
**Number of sites:  20****Enrollment dates:  1990-1993**

**Randomized Dose-Response Study of CEF-100 vs CEF-50 as Adjuvant Therapy for Patients With Axillary Node-Positive Breast Cancer**

## Study Schema(EBC-2/GFEA05)

**  ****Radiotherapy was administered at the completion of chemotherapy**
**  ****C=cyclophosphamide, E=epirubicin, F=fluorouracil**

**CEF-100 q 3 wk for 6 cycles***
** ****C, 500 mg/m****2**** IV, d 1**
** ****E, 100 mg/m****2**** IV, d 1**
** ****F, 500 mg/m****2**** IV, d 1 **

**Patient Population:**
** ****Pre-/post-****  menopausal**
** ****Positive axillary****  nodes**
**Stratification:**
** ****Study center**
** ****Number of****  positive nodes**

**CEF-50 q 3 wk for 6 cycles***
** ****C, 500 mg/m****2**** IV, d 1**
** ****E,   50 mg/m****2**** IV, d 1**
** ****F, 500 mg/m****2**** IV, d 1**

**N=565**

**Study Schema****(EBC-2/GFEA05)**

## Treatment Administration(EBC-2/GFEA05)

**	****	****CEF-100****	****CEF-50**
**	****	****N=266****	****N=280**
**Patients completing 6 cycles (%)****	****94****	****95**
**Median dose intensity, mg/m****2****/wk ****(Median relative dose intensity, %)**
**	****Cyclophosphamide****	****153 (92)****	****157 (94)**
**	****Epirubicin****	****  31 (92)****	****  16 (94)**
**	****Fluorouracil****	****153 (92)****	****157 (94)**
**Radiotherapy (%)****	****97****	****94**

## Relapse-Free Survival(EBC-2/GFEA05)

**No. of patients****	****276****	****	****289****5-year RFS****	****65%****	****	****52%****Log-rank probability****	****	****p=0.007****	**

**CEF-50**

**CEF-100**

**0.0**

**0.1**

**0.2**

**0.3**

**0.4**

**0.5**

**0.6**

**0.7**

**0.8**

**0.9**

**1.0**

**Years**

**Probability**

**Relapse-Free Survival****(EBC-2/GFEA05)**

## Overall Survival(EBC-2/GFEA05)

**0.0**

**0.1**

**0.2**

**0.3**

**0.4**

**0.5**

**0.6**

**0.7**

**0.8**

**0.9**

**1.0**

**Years**

**Probability**

**	****CEF-100****	****	****CEF-50**
**No. of patients****	****276****	****	****289****5-year survival****	****76%****	****	****65%****Log-rank probability****	****	****p=0.007****	**

**CEF-50**

**CEF-100**

**Overall Survival****(EBC-2/GFEA05)**

## On-Treatment Adverse Events(EBC-2/GFEA05)

**On-Treatment Adverse Events****(EBC-2/GFEA05)**

## Late Adverse Events(EBC-2/GFEA05)

**	****CEF-100****	****CEF-50**
**Event**** ****	****N=266****	****N=280**
**Cardiac events (N [%])****	****8 [3.0]****	****5 [1.7]**
**   ****Congestive heart failure (CHF)****	****4 [1.5]****	****1 [0.3]**
**   ****Other events****	****4 [1.5]****	****4 [1.4]**
**Acute leukemia (N [%])**
**   ****Acute myelogenous leukemia****	****1 [0.4]****	****0**
**   ****Acute lymphocytic leukemia ****	****0****	**** 1 [0.4] ****	**

**Late Adverse Events****(EBC-2/GFEA05)**

## Compared with CEF-50, CEF-100 significantly:
Improved relapse-free survival
Improved overall survival

- Improved relapse-free survival
- Improved overall survival

- Toxicities were manageable
- 94% of patients completed CEF-100 therapy
- Relative dose intensity was 90%
- No on-treatment CEF-100-related deaths occurred

- EBC-2 strongly corroborates EBC-1, confirming the clinical benefits of epirubicin-based therapy

**Conclusions****(EBC-2/GFEA05)**

## Results of an ICCG-Sponsored Phase III Multicenter Randomized Controlled Trial (EBC-3/C-4-87)

***ICCG=International Collaborative Cancer Group***
**Number of sites:  13****Enrollment dates:  1988-1995**

**Randomized Study of Epirubicin-100 Plus Tamoxifen vs Tamoxifen Alone as Adjuvant Therapy for Postmenopausal Patients With Axillary Node-Positive Breast Cancer **

## Study Schema(EBC-3/C-4-87)

*** Women with partial mastectomy underwent radiotherapy after chemotherapy**
**E=epirubicin, T=tamoxifen**

**E + T**
** ****E, 50 mg/m****2**** IV, d 1 + 8 every 4 wks x 6 cycles**
** ****T, 20 mg/day orally for 4 years**

**Patient Population:**
** ****Post-****  menopausal**
** ****Positive axillary****  nodes**
**Stratification:**
** ****Study center**

**T alone**
** ****T, 20 mg/day orally for 4 years**

**N=604**

## Relapse-Free Survival(EBC-3/C-4-87)

**0**

**10**

**20**

**30**

**40**

**50**

**60**

**70**

**80**

**90**

**100**

**0**

**1**

**2**

**3**

**4**

**5**

**6**

**7**

**8**

**% Probability**

**E-100 + T**

**T alone **

**	****E-100 + T****	****	****T alone **
**No. of patients****	****303****	****	****301****5-year survival****	****74%****	****	****62%****Log-rank probability****	****	****p=0.023****	**

**Years**

**Relapse-Free Survival****(EBC-3/C-4-87)**

## Overall Survival(EBC-3/C-4-87)

**E-100 + T**

**	****E-100 + T****	****	****T alone **
**No. of patients****	****303****	****	****301****5-year survival****	****81%****	****	****77%****Log-rank probability****	****	****p=0.46****	**

**2**

**3**

**4**

**5**

**6**

**7**

**8**

**Years**

**% Probability**

**0**

**10**

**20**

**30**

**40**

**50**

**60**

**70**

**80**

**90**

**100**

**0**

**1**

**Overall Survival****(EBC-3/C-4-87)**

## On-Treatment Adverse Events(EBC-3/C-4-87)

*** Patients with at least 1 on-treatment follow-up assessment**

**On-Treatment Adverse Events****(EBC-3/C-4-87)**

## Late Adverse Events(EBC-3/C-4-87)

**Late Adverse Events****(EBC-3/C-4-87)**

## Combination therapy with epirubicin and tamoxifen significantly improved relapse-free survival over tamoxifen therapy alone

- On-treatment toxicities of epirubicin were modest

- Benefits of epirubicin in postmenopausal patients were further documented

**Conclusions****(EBC-3/C-4-87)**

## 5-Year Relapse-Free Survival in Early Breast Cancer Studies

**	****	****Treatment****	****Control****	****Study Therapy****	****(%)****	**** (%)**
**CEF combination:**
**	****EBC-1/MA-5****	**** 62%****	****53%****	****p=0.013***
**	****EBC-2/GFEA05****	**** 65%****	****52%****	****p=0.007‡**
**Chemo-hormonal**
**	****EBC-3/C-4-87****	****74%****	****62%****	****p=0.023‡**
**	****	**
**	**

*** Stratified log-rank test****‡ Unstratified log-rank test**

## 5-Year Overall Survival in Early Breast Cancer Studies

**	****	****Treatment****	****Control****	****Study Therapy****	****(%)****	**** (%)**
**CEF combination:**
**	****EBC-1/MA-5****	**** 77%****	****70%****	****p=0.043***
**	****EBC-2/GFEA05****	**** 76%****	****65%****	****p=0.007‡**
**Chemo-hormonal:**
**	****EBC-3/C-4-87****	****81%****	****77%****	****p=0.46‡**

*** Stratified log-rank test****‡ Unstratified log-rank test**

## Therapy of Advanced Breast Cancer

***Therapy of Advanced Breast Cancer***

## Overview of Studies in Advanced Breast Cancer (N=1231)

**	****	****Prior  ****	****	****	****Study****	****Therapy****	****	****Treatment (N)****	****	****Control (N)**
**Pivotal**
**	****ABC-1****	****Adjuvant****	****	****CEF-100****	****	****CMF****	****(HEPI 013)****	****permitted****	****	****(223)****	****	****(237)**
**Supportive**
**	****ABC-2****	****Adjuvant****	****	****CEF-100****	****	****CEF-50****	****(HEPI 010)****	**** permitted ****	****	****(214)****	****	****(242)**
**Other Supportive**
**	****ABC-3****	****Adjuvant****	****	**** CEF-100 ****	****	**** CEF-50 ****	****       ****	**** permitted ****	****	****(84)****	****	****(80)**
**	****ABC-4****	****CMF for ****	****	****E-135****	****	****E-75****	****	****metastatic disease****	****	****(74) ****	****	****(77)**

**C=cyclophosphamide, E=epirubicin, F=fluorouracil, M=methotrexate**

## Study Schema(ABC-1/HEPI 013)

**CEF-100 q 3 wk **
** ****C, ****	****400 mg/m****2**** IV, d 1 + 8**
** ****E, ****	****  50 mg/m****2**** IV, d 1 + 8**
** ****F, ****	****500 mg/m****2**** IV, d 1 + 8**

**Patient Population:**
** ****First-line therapy**
** ****Metastatic disease**
**Stratification:**
** ****Study center**
** ****Presence of****  visceral ****  metastases**
** ****Number of organs****  with metastases **
** ****Prior adjuvant****  chemotherapy**

**CMF q 3 wk **
** ****C,****	****500 mg/m****2**** IV, d 1 + 8**
** ****M,****	****  40 mg/m****2**** IV, d 1 + 8**
** ****F,****	****600 mg/m****2**** IV, d 1 + 8**

**N=460**

**Study Schema****(ABC-1/HEPI 013)**

## Overview of Efficacy Results*(ABC-1/HEPI 013)

**	****	**** ****	**
**	****CEF-100****	****CMF****	**
**	****N=223****	****N=237****	**
**Response rate (%)****	****57.4****	****44.7****	****p=0.007**
**Median response duration (mo)****	****8.8****	****7.2****	****p=0.07**
**Median time to tumor progression (mo)****	****8.7****	****6.3****	****p=0.01**
**Median time to treatment failure (mo)****	****6.2****	****5.0****	****p=0.01**
**Median survival (mo)****	****20.1****	****18.2****	****p=NS**

*** Based on intent-to-treat population**

## 			CEF-100	CMFAgent	N=223	N=237
		Epirubicin	  16 (7%)	 44 (19%)
		Doxorubicin	    5 (2%)	 41 (17%)	
		Mitoxantrone	  19 (9%)	20  (8%)
		Total	40 (18%)	105 (44%)

**	****	****Epirubicin****	****  16 (7%)****	**** 44 (19%)**
**	****	****Doxorubicin****	****    5 (2%)****	**** 41 (17%)****	**
**	****	****Mitoxantrone****	****  19 (9%)****	****20  (8%)**
**	****	****Total****	****40 (18%)****	****105 (44%)**

**Subsequent Anthracycline or Anthracenedione Use ****(ABC-1/HEPI 013)**

## Study Schema(ABC-2/HEPI 010)

**CEF-100 q 3 wk **
** ****C, ****	****500 mg/m****2**** IV, d 1 **
** ****E, ****	****100 mg/m****2**** IV, d 1 **
** ****F, ****	****500 mg/m****2**** IV, d 1 **

**Patient Population:**
** ****First-line therapy**
** ****Metastatic disease**
**Stratification:**
** ****Study center**
** ****Presence of****  visceral ****  metastases**
** ****Number of organs****  with metastases **

**CEF-50 q 3 wk **
** ****C,****	****500 mg/m****2**** IV, d 1**
** ****E,****	****  50 mg/m****2**** IV, d 1 **
** ****F,****	****500 mg/m****2**** IV, d 1 **

**N=456**

**Study Schema****(ABC-2/HEPI 010)**

## Overview of Efficacy Results*(ABC-2/HEPI 010)

**	****	**** ****	**
**	****CEF-100****	****CEF-50****	**
**	****N=214****	****N=242****	**
**Response rate (%)****	****48.1****	****36.0****	****p=0.009**
**Median response duration (mo)****	****9.1****	****9.3****	****p=NS**
**Median time to tumor progression (mo)****	****7.5****	****7.0****	****p=NS**
**Median time to treatment failure (mo)****	****5.7****	****5.3****	****p=NS**
**Median survival (mo)****	****18.0****	****17.0****	****p=NS**

*** Based on intent-to-treat population**

## Study Schema(ABC-3)

**CEF-100 q 3 wk **
** ****C, ****	****500 mg/m****2**** IV, d 1**
** ****E, ****	****  50 mg/m****2**** IV, d 1+ 8 **
** ****F, ****	****500 mg/m****2**** IV, d 1 **

**Patient Population:**
** ****First-line therapy**
** ****Locally advanced****  or metastatic****  disease**
**Stratification:**
** ****Study center**
** ****Menopausal****  status**
** ****Locally advanced****  or metastatic****  disease **

**CEF-50 q 3 wk **
** ****C,****	****500 mg/m****2**** IV, d 1**
** ****E,****	****  50 mg/m****2**** IV, d 1 **
** ****F,****	****500 mg/m****2**** IV, d 1 **

**N=164**

**Study Schema****(ABC-3)**

## Overview of Efficacy Results*(ABC-3)

**	**** ****	**
**	****CEF-100****	****CEF-50****	**
**	****N=84****	****N=80****	**
**Response rate (%)****	****57.1****	****36.3****	****p=0.008**
**Median response duration (mo)****	****22.1****	****14.0****	****p<0.01**
**Median time to tumor progression (mo)****	****--****	****--****	****    --**
**Median time to treatment failure (mo)****	****19.2****	****8.0****	****p<0.02**
**Median survival (mo)****	****27.1****	****20.8****	****p=NS**

***  Based on intent-to-treat population****-- Not reported**

## Study Schema(ABC-4)

**Epirubicin, 135 mg/m****2**** IV q 3 wk**

**Patient Population:**
** ****Prior CMF therapy**
** ****Metastatic****  disease**
**Stratification:**
** ****Site of****  metastases**
** ****Response to****  prior CMF **

**N=151**

**Epirubicin, 75 mg/m****2**** IV q 3 wk**

**Study Schema****(ABC-4)**

## Overview of Efficacy Results*(ABC-4)

**	****	**** ****	**
**	****E-135****	****E-75****	**
**	****N=74****	****N=77****	**
**Response rate (%)****	****27.0****	****7.8****	****p=0.002**
**Median response duration (mo)****	**** 6.1****	****3.7****	****p=NS**
**Median time to tumor progression (mo)****	**** 4.4****	****2.5****	****p=0.003**
**Median time to treatment failure (mo)****	****--****	****--****	****     --**
**Median survival (mo)****	****10.9****	****7.9****	****p=0.065**

***  Based on intent-to-treat population****-- Not reported**

## Summary of Adverse Events(ABC-1/HEPI 013 & ABC-2/HEPI 010)

**	****	****ABC-1****	****ABC-2****	****ABC-1****	****ABC-2**
**Grade 3/4 Events****	****N=220****	****N=209****	****N=234****	****N=238**
**Hematologic events (%)****	****Neutropenia ****	****78****	****86****	****68****	****31**
**	****    ****+ fever or infection****	****15****	****11****	****12****	**** 1****	****Anemia****	****12****	****  7 ****	**** 9****	**** 1**
**	****Thrombocytopenia****	****7****	**** 6****	**** 6****	**** 2**
**Non-hematological events (%)**
**	****Alopecia ****	****66****	****71****	****  14****	****55**
**	****Nausea/Vomiting ****	****21****	****30****	****  14****	**** 26 **
**	****Stomatitis****	****12****	**** 10  ****	****  15****	**** 0**
**	****Diarrhea ****	****  1****	**** 0****	****    2****	**** 1**
**	****Cutaneous****	****  0****	**** 1****	****   0.4****	**** 0**
**Congestive heart failure****	****    6 [2.7%]****	****    1 [0.5%]****	****0****	****  2 [0.8%]**
**Drug-related deaths****	****    3 [1.4%]****	****    2 [1.0%]****	****  3 [1.2%]****	****  2 [0.8%]**

**Summary of Adverse Events****(ABC-1/HEPI 013 & ABC-2/HEPI 010)**

## Overall Response Rates in Studies in Advanced Breast Cancer

**	**** ****	****Treatment****	****Control****	****Study****	****(%)****	**** (%)**
**	****ABC-1****	**** 57.4****	****44.7****	****p=0.007**
**	****ABC-2****	**** 48.1****	****36.0****	****p=0.009**
**	****ABC-3****	**** 57.1****	****36.3****	****p=0.008 ****	**
**	****ABC-4****	**** 27.0****	****  7.8****	****p=0.002 ****	**

## Complete Response Rates in Studies in Advanced Breast Cancer

**	****	****Treatment****	****Control****	**** Study ****	****(%)****	****(%)**
**	****ABC-1****	****13.5****	****10.5**
**	****ABC-2****	****10.3****	****5.8****	**
**	****ABC-3****	****10.7****	****6.3****	**
**	****ABC-4****	**** 5.4****	****0****	**

## Time to Tumor Progression or Treatment Failure in Studies in Advanced Breast Cancer

**	****	****	****Treatment****	****Control****	**** Study ****	**** Endpoint ****	****(mo)****	****(mo)**
**	****ABC-1 ****	****TTP****	****8.7****	****6.3****	****p=0.01****	****	****TTF****	****6.2****	****5.0****	****p=0.01**
**	****ABC-2****	****TTP ****	****7.5****	****7.0****	****p=NS ****	****	****ABC-3****	****TTF ****	****19.2****	****8.0****	****p<0.02 **
**	****ABC-4****	****TTP ****	****4.4****	****2.5****	****p=0.003**

## Conclusions

- Indicated as a component of adjuvant therapy in patients with evidence of axillary-node tumor involvement following resection of primary breast cancer (Stage II & III)
- Improves relapse-free survival
- Improves overall survival

- Indicated for the therapy of patients with locally advanced or metastatic breast cancer
- Improves time to tumor progression
- Increases overall and complete response rates

## Q & A