1 (Epirubicin Hydrochloride) Oncologic Drugs Advisory Committee Review June 7, 1999 EPIRUBICIN Pharmacia & Upjohn

1

(Epirubicin Hydrochloride)(Epirubicin Hydrochloride)

Oncologic Drugs Advisory Committee ReviewOncologic Drugs Advisory Committee ReviewJune 7, 1999June 7, 1999

EPIRUBICINEPIRUBICIN

Pharmacia & UpjohnPharmacia & Upjohn

2

Presentation AgendaPresentation Agenda

Regulatory History and PharmacologyRegulatory History and Pharmacology

Early Breast Cancer Adjuvant TherapyEarly Breast Cancer Adjuvant Therapy

Advanced Breast Cancer TherapyAdvanced Breast Cancer Therapy

ConclusionsConclusions

Q & AQ & A

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Epirubicin Presentation TeamEpirubicin Presentation Team

FunctionFunction NameName AffiliationAffiliation

MedicalMedical Langdon Miller, MDLangdon Miller, MD P&UP&UElena Colajori, MDElena Colajori, MD P&UP&U

BiostatisticalBiostatistical Anna Petroccione, MD, PhDAnna Petroccione, MD, PhD P&UP&U

Clinical PharmacologyClinical Pharmacology Italo Poggesi, PhDItalo Poggesi, PhD P&UP&U

PharmacovigilancePharmacovigilance Claudio Praga, MDClaudio Praga, MD P&UP&U

InvestigatorsInvestigators Mark Levine, MDMark Levine, MD NCICNCICKathleen Pritchard, MDKathleen Pritchard, MD NCICNCICDongsheng Tu, PhDDongsheng Tu, PhD NCICNCICJacques Bonneterre, MDJacques Bonneterre, MD FESGFESG

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Regulatory HistoryRegulatory History

Registered in >80 countries worldwideRegistered in >80 countries worldwide

– First approved in France in 1982First approved in France in 1982

– Registered in most countries since 1984Registered in most countries since 1984

Originally approved dosesOriginally approved doses

– Single-agent therapy: 60-90 mg/mSingle-agent therapy: 60-90 mg/m22

– Combination therapy: 50-75 mg/mCombination therapy: 50-75 mg/m22

US NDA submitted in 1984US NDA submitted in 1984

– Small sample sizesSmall sample sizes

– Limited survival dataLimited survival data

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

Extensively studied in clinical trialsExtensively studied in clinical trials

– Breast cancerBreast cancer

– Other tumor typesOther tumor types

Subject of >2000 publicationsSubject of >2000 publications

Millions of patients have received the drug worldwide Millions of patients have received the drug worldwide

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

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Epirubicin Structure and Epirubicin Structure and Mechanism of ActionMechanism of Action

OH

NH2Cl

O O

CH3 O

OCH3

O OH

OH

OH

O

AnthracyclineAnthracycline

4’ epimer of doxorubicin4’ epimer of doxorubicin

Mechanism of actionMechanism of action

– DNA intercalationDNA intercalation

– Topoisomerase II inhibitionTopoisomerase II inhibition

– Helicase inhibitionHelicase inhibition

– Free-radical formationFree-radical formation

Metabolites relatively Metabolites relatively noncytotoxicnoncytotoxic

HO

Epirubicin

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Increased lipophilicityIncreased lipophilicity

– Increased cell penetrationIncreased cell penetration

Pharmacologic Implications of Pharmacologic Implications of Epirubicin StructureEpirubicin Structure

0.1

1.0

10.0

100.0

1000.0

10000.0

0 50 100 150

Time (hours)

Me

an

P

las

ma

Co

nc

en

tra

tio

n +

SD

(n

g/m

L)

Doxorubicin 60 mg/m2 (N=8)

Epirubicin 60 mg/m2 (N=8)

Camaggi, Cancer Chemother Pharmacol 21:221-8, 1988

Additional glucuronidation Additional glucuronidation pathwaypathway

– More rapid clearanceMore rapid clearance

– Shorter terminal half-lifeShorter terminal half-life

MTD redefinedMTD redefined

– Dose can be escalated up to Dose can be escalated up to 180 mg/m180 mg/m22

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Clinical Dose Response Clinical Dose Response in Advanced Breast Cancerin Advanced Breast Cancer

0%

25%

50%

75%

100%

0 100 200

Epirubicin Starting Dose (mg/m2)

Res

po

nse

Rat

e

Single-agentResponse Rate

Sledge G, personal communication

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Basis for ApprovalBasis for Approval

Early Breast Cancer -- 3 Randomized Controlled Trials Early Breast Cancer -- 3 Randomized Controlled Trials

– Pivotal Study: CEF vs CMF (EBC-1/MA-5)Pivotal Study: CEF vs CMF (EBC-1/MA-5)

– Supportive Study: Epirubicin Dose-Response (EBC-2/GFEA05)Supportive Study: Epirubicin Dose-Response (EBC-2/GFEA05)

– Other Supportive Study: Epirubicin Plus Tamoxifen (EBC-3/C-4-87)Other Supportive Study: Epirubicin Plus Tamoxifen (EBC-3/C-4-87)

Advanced Breast Cancer -- 4 Randomized Controlled TrialsAdvanced Breast Cancer -- 4 Randomized Controlled Trials

– Pivotal Study: CEF vs CMF (ABC-1/HEPI 013)Pivotal Study: CEF vs CMF (ABC-1/HEPI 013)

– Supportive Study: Epirubicin Dose-Response (ABC-2/HEPI 010)Supportive Study: Epirubicin Dose-Response (ABC-2/HEPI 010)

– Other Supportive Studies: Epirubicin Dose-Response (ABC-3, 4)Other Supportive Studies: Epirubicin Dose-Response (ABC-3, 4)

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Basis for Selection of StudiesBasis for Selection of Studies

Studies were selected in consultation with the FDA:Studies were selected in consultation with the FDA:

– Trials were conducted in women with breast cancerTrials were conducted in women with breast cancer

– All studies were completed, well-controlled, randomized, phase III trialsAll studies were completed, well-controlled, randomized, phase III trials

– Symmetrical designs allowed for a specific evaluation of epirubicin effect Symmetrical designs allowed for a specific evaluation of epirubicin effect

– Epirubicin was tested at starting doses of Epirubicin was tested at starting doses of 100 mg/m100 mg/m22

– Full study reports were availableFull study reports were available

– Data were available electronically or could be provided on request by Data were available electronically or could be provided on request by the study groupthe study group

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Proposed IndicationsProposed Indications

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

– Starting doses of 100 to 120 mg/mStarting doses of 100 to 120 mg/m22

Indicated for the therapy of patients with locally advanced or metastatic Indicated for the therapy of patients with locally advanced or metastatic breast cancerbreast cancer

– Starting doses of 100 to 135 mg/mStarting doses of 100 to 135 mg/m22

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Adjuvant Therapy of Adjuvant Therapy of Early Breast CancerEarly Breast Cancer

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Overview of Epirubicin StudiesOverview of Epirubicin Studiesin Early Breast Cancer (N=1885)in Early Breast Cancer (N=1885)

MenopausalMenopausal IntensiveIntensiveStudyStudy StatusStatus Epirubicin (N)Epirubicin (N) Control (N)Control (N)

PivotalPivotal

EBC-1EBC-1 Pre/PeriPre/Peri CEF-120CEF-120 CMFCMF(MA-5)(MA-5) (356)(356) (360)(360)

SupportiveSupportive

EBC-2EBC-2 Pre/PostPre/Post CEF-100CEF-100 CEF-50CEF-50(GFEA05)(GFEA05) (276)(276) (289)(289)

Other SupportiveOther Supportive

EBC-3EBC-3 PostPost E-100 + TE-100 + T TT(C-4-87) (C-4-87) (303)(303) (301)(301)

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

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Intensive CEF vs CMF as Adjuvant Therapy Intensive CEF vs CMF as Adjuvant Therapy for Premenopausal Patients With Axillary for Premenopausal Patients With Axillary

Node-Positive Breast CancerNode-Positive Breast Cancer

Results of an NCIC-CTG-Sponsored Results of an NCIC-CTG-Sponsored Phase III Multicenter Randomized Phase III Multicenter Randomized

Controlled Trial (EBC-1/MA-5)Controlled Trial (EBC-1/MA-5)

NCIC-CTG=National Cancer Institute of Canada Clinical Trials Group

Number of sites: 37Enrollment dates: 1989-1993

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

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

RRAANNDDOOMMIIZZAATTIIOONN

CEF-120 q 4 wk for 6 cycles*CEF-120 q 4 wk for 6 cycles*• C, 75 mg/mC, 75 mg/m22 orally, d 1-14 orally, d 1-14• E, 60 mg/mE, 60 mg/m22 IV, d 1 + 8 IV, d 1 + 8• F, 500 mg/mF, 500 mg/m22 IV, d 1 + 8 IV, d 1 + 8 (plus antibiotic prophylaxis)(plus antibiotic prophylaxis)

Stratification:Stratification:

• Total vs partialTotal vs partial mastectomy mastectomy

• Receptor statusReceptor status

• Number of positiveNumber of positive nodes nodes

CMF q 4 wk for 6 cycles*CMF q 4 wk for 6 cycles*• C, 100 mg/mC, 100 mg/m22 orally, d 1-14 orally, d 1-14• M, 40 mg/mM, 40 mg/m22 IV, d 1 + 8 IV, d 1 + 8• F, 600 mg/mF, 600 mg/m22 IV, d 1 + 8 IV, d 1 + 8

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CMF q 4 wk for 6 cyclesCMF q 4 wk for 6 cycles• C, 100 mg/mC, 100 mg/m22 orally, d 1-14 orally, d 1-14• M, 40 mg/mM, 40 mg/m22 IV, d 1 + 8 IV, d 1 + 8• F, 600 mg/mF, 600 mg/m22 IV, d 1 + 8 IV, d 1 + 8

CMF CMF An Adjuvant StandardAn Adjuvant Standard

CCEEF vs CF vs CMMF comparison allowed isolation of F comparison allowed isolation of epirubicin effect against a standard regimenepirubicin effect against a standard regimen

CMF -- an adjuvant standardCMF -- an adjuvant standard– Prior to start of EBC-1 in 1989Prior to start of EBC-1 in 1989

– Currently in 1999Currently in 1999

Current CMF usage in USCurrent CMF usage in US 23,600 patients with Stage II early breast cancer on 23,600 patients with Stage II early breast cancer on

treatmenttreatment

39% are receiving adjuvant CMF39% are receiving adjuvant CMF

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PrimaryPrimary– Relapse-free survivalRelapse-free survival

SecondarySecondary– Overall survivalOverall survival

– SafetySafety

– Quality of life (Breast Cancer Chemotherapy Quality of life (Breast Cancer Chemotherapy Questionnaire [BCQ], McMaster University) Questionnaire [BCQ], McMaster University)

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

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HypothesisHypothesis

– 10% absolute improvement in 5-year relapse-free survival10% absolute improvement in 5-year relapse-free survival Assumed rate in CMF arm: 55% Assumed rate in CMF arm: 55% Expected rate in CEF arm: 65%Expected rate in CEF arm: 65%

Statistical testStatistical test

– Stratified 2-tailed log-rank test with Stratified 2-tailed log-rank test with =0.05=0.05

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

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Pre- or perimenopausalPre- or perimenopausal

Histologically proven breast cancer treated with Histologically proven breast cancer treated with total or partial mastectomytotal or partial mastectomy

Histologically positive axillary nodesHistologically positive axillary nodes

No distant metastasesNo distant metastases

No prior hormonal or cytotoxic therapyNo prior hormonal or cytotoxic therapy

LVEF LVEF 45%45%

Adequate hematological, renal, and liver functionAdequate hematological, renal, and liver function

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

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Assessments at baseline and during chemotherapyAssessments at baseline and during chemotherapy

– CXR, bone scan (baseline)CXR, bone scan (baseline)

– CBC (baseline, weekly)CBC (baseline, weekly)

– PE, AEs, QoL (baseline and monthly)PE, AEs, QoL (baseline and monthly)

– LFTs (baseline, 3 and 6 months)LFTs (baseline, 3 and 6 months)

– Echocardiogram or MUGA scan (baseline, 6 months)Echocardiogram or MUGA scan (baseline, 6 months)

Follow-up assessmentsFollow-up assessments– PE, CBC, LFTs, survival (every 3 months x 2 years, every 6 months xPE, CBC, LFTs, survival (every 3 months x 2 years, every 6 months x

5 years, yearly thereafter)5 years, yearly thereafter)

– Mammogram, CXR (yearly)Mammogram, CXR (yearly)

– Echocardiogram or MUGA scan (6, 12, 36, and 60 months)Echocardiogram or MUGA scan (6, 12, 36, and 60 months)

– QoL (every 3 months x 2 years)QoL (every 3 months x 2 years)

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

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Patients randomizedPatients randomizedN=716N=716

CEFCEFN=356*‡N=356*‡

CMFCMFN=360*N=360*

* Includes 1 patient who never received treatment* Includes 1 patient who never received treatment‡ Includes 1 patient who was erroneously treated with CMF‡ Includes 1 patient who was erroneously treated with CMF

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

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CEFCEF CMFCMFN=356N=356 N=360N=360

Median age (yr)Median age (yr) 44.544.5 44.544.5[range][range] [26-56][26-56] [23-57][23-57]

ECOG performance status (%)ECOG performance status (%)00 7878 838311 21 21 171722 11 11

Menopausal status (%)Menopausal status (%)PremenopausalPremenopausal 7878 7979PerimenopausalPerimenopausal 2222 2121

Clinical stage (%)Clinical stage (%)II 3838 4040IIII 5050 4848IIIIII 44 66UnknownUnknown 88 66

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

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% of Patients% of PatientsCEFCEF CMFCMF

N=356N=356 N=360N=360

Surgery typeSurgery typePartial mastectomyPartial mastectomy 4949 4949Total mastectomyTotal mastectomy 5151 5151

Nodes examinedNodes examined1-51-5 88 996-106-10 3636 3838

>10>10 5656 5454

Positive nodes at surgeryPositive nodes at surgery1-31-3 6161 61614-104-10 3232 3333>10>10 66 77

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

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% of Patients % of Patients CEFCEF CMFCMF

N=356N=356 N=360N=360

Estrogen Estrogen ER positive*ER positive* 6060 6060ER negativeER negative 2929 2727UnknownUnknown 1111 1313

ProgesteroneProgesteronePR positive*PR positive* 63635959PR negativePR negative 25252828UnknownUnknown 12121414

* 10 fmol/mg

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

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CEFCEF CMFCMFN=354N=354 N=360N=360

Patients completing 6 cycles (%)Patients completing 6 cycles (%) 9696 9797

Median dose intensity, mg/mMedian dose intensity, mg/m22/wk /wk (Median relative dose intensity, %) (Median relative dose intensity, %)

CyclophosphamideCyclophosphamide 219 (83)219 (83) 325 (96)325 (96)

Epirubicin/MethotrexateEpirubicin/Methotrexate 24 (80) 24 (80) 19 (96) 19 (96)

FluorouracilFluorouracil 199 (80)199 (80) 282 (96)282 (96)

Radiotherapy (%)Radiotherapy (%) 4545 4646

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

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CMFCMF

0.40.4

0.50.5

0.60.6

0.70.7

0.80.8

0.90.9

1

11 22 33 44 5 66 770000

CEFCEF

0.10.10.10.1

0.20.20.20.2

0.30.30.30.3

YearsYears

Pro

bab

ilit

yP

rob

abil

ity

CEFCEF CMFCMF

No. of patientsNo. of patients 356356 3603605-year RFS5-year RFS 62%62% 53%53%Log-rank probabilityLog-rank probability p=0.013p=0.013

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

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Multivariate Analysis: Treatment Effect on Multivariate Analysis: Treatment Effect on Relapse-Free Survival Adjusted for Relapse-Free Survival Adjusted for

Prognostic Factors (EBC-1/MA-5)Prognostic Factors (EBC-1/MA-5)

Conditional Conditional Factors*Factors* Risk RatioRisk Ratio p-valuep-value

Baseline characteristicsBaseline characteristics

Tumor SizeTumor Size TT33 2.52.5 <0.001<0.001

Nodal StatusNodal Status 44 1.71.7 <0.001<0.001

Treatment Treatment CEF/CMF CEF/CMF 0.76 0.76 0.021 0.021* Factors evaluated in the modeling process were menopausal * Factors evaluated in the modeling process were menopausal status, type of surgery, tumor size, receptor status, and nodal status, type of surgery, tumor size, receptor status, and nodal status status

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CEFCEF

CMFCMF

00

0.10.1

0.20.2

0.30.3

0.40.4

0.50.5

0.60.6

0.70.7

0.80.8

0.90.9

11

00 11 22 33 44 55 66 77

YearsYears

Pro

bab

ilit

yP

rob

abil

ity

CEFCEF CMFCMF

No. of patientsNo. of patients 356356 3603605-year survival5-year survival 77%77% 70%70%Log-rank probabilityLog-rank probability p=0.043p=0.043

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

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Conditional Conditional Factors*Factors* Risk RatioRisk Ratio p-valuep-value

Baseline characteristicsBaseline characteristics

Tumor sizeTumor size TT33 2.52.5 <0.001<0.001

Receptor statusReceptor status NegativeNegative 2.02.0 <0.001<0.001

Nodal statusNodal status 44 1.71.7 <0.001<0.001

Treatment Treatment CEF/CMFCEF/CMF 0.71 0.71 0.034 0.034

Multivariate Analysis: Treatment Effect on Overall Multivariate Analysis: Treatment Effect on Overall Survival Adjusted for Prognostic FactorsSurvival Adjusted for Prognostic Factors

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

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

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CEFCEF CMFCMF

Grade 3/4 EventsGrade 3/4 Events N=354N=354 N=360N=360

Hematologic Events (%) Hematologic Events (%) Neutropenia Neutropenia 9595 6060 + fever or infection+ fever or infection 11 11 2 2AnemiaAnemia 1010 1 1ThrombocytopeniaThrombocytopenia 9 9 4 4HemorrhageHemorrhage 1 1 0 0

Non-hematological Events (%) Non-hematological Events (%) Alopecia Alopecia 4242 7 7StomatitisStomatitis 13 13 2 2Vomiting Vomiting 1212 5 5Asthenia Asthenia 3 3 0 0Diarrhea Diarrhea 1 1 3 3CutaneousCutaneous 1 1 0 0

Discontinuations (N [%])Discontinuations (N [%]) 6 [1.7] 6 [1.7] 2 [0.6] 2 [0.6]Drug-related deaths (N [%])Drug-related deaths (N [%]) 0 0 0 0

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

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CEFCEF CMFCMF

EventEvent N=354N=354 N=360N=360

Cardiac toxicity (N [%])Cardiac toxicity (N [%]) 12 [3.4]12 [3.4] 4 [1.1]4 [1.1]

Asymptomatic Asymptomatic LVEF ( LVEF (40%) 40%) 7 [2.0] 7 [2.0] 3 [0.8]3 [0.8]Congestive heart failure (CHF)Congestive heart failure (CHF) 5 [1.4] 5 [1.4] 1 [0.3]1 [0.3]

Acute leukemia (N [%])Acute leukemia (N [%])

Acute myelogenous leukemia (AML)Acute myelogenous leukemia (AML) 4 [1.1]4 [1.1] 1 [0.3]1 [0.3]

Acute lymphocytic leukemia (ALL)Acute lymphocytic leukemia (ALL) 1 [0.3]1 [0.3] 00

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

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Overall Survival

AML-Free Survival

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

CEFCMF

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Breast Cancer Chemotherapy Questionnaire (BCQ)Breast Cancer Chemotherapy Questionnaire (BCQ)

– Designed to assess quality of life during adjuvant therapyDesigned to assess quality of life during adjuvant therapy

30 questions30 questions

– Focus on emotional and physical symptomsFocus on emotional and physical symptoms

– 7-point scale for each question7-point scale for each question

Mean summary score computed using information from all scalesMean summary score computed using information from all scales

<0.5 change is considered clinically inconsequential<0.5 change is considered clinically inconsequential

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

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

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Time (mo)Time (mo) 00 11 22 33 44 55 66 99 1212 1515 1818 2121 2424

CMF (N)CMF (N) 276276 322322 324324 322322 326326 324324 251251 270270 277277 268268 256256 227227 220220

CEF (N)CEF (N) 270270 322322 325325 321321 315315 316316 252252 288288 265265 244244 239239 233233 217217

00

11

22

33

44

55

66

7

00 33 66 99 1212 1515 1818 2121 2424

Months From RandomizationMonths From Randomization

BC

Q M

ea

n S

um

ma

ry S

co

re

BC

Q M

ea

n S

um

ma

ry S

co

re ++

S.E

. S

.E.

CEFCEF

CMFCMF

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

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Compared to CMF, CEF-120 improved:Compared to CMF, CEF-120 improved:

– Relapse-free survivalRelapse-free survival

– Overall survivalOverall survival

Toxicities were manageable and outweighed by benefitsToxicities were manageable and outweighed by benefits

– 96% of patients completed CEF-120 therapy 96% of patients completed CEF-120 therapy

– No on-treatment CEF-120-related deaths occurredNo on-treatment CEF-120-related deaths occurred

– QoL was clinically similar between the 2 treatmentsQoL was clinically similar between the 2 treatments

Epirubicin was the critical component of the CEF regimenEpirubicin was the critical component of the CEF regimen

ConclusionsConclusions(EBC-1/MA-5)(EBC-1/MA-5)

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

FESG=French Epirubicin Study Group


Randomized Dose-Response Study of CEF-100 vs Randomized Dose-Response Study of CEF-100 vs CEF-50 as Adjuvant Therapy for Patients With CEF-50 as Adjuvant Therapy for Patients With

Axillary Node-Positive Breast CancerAxillary Node-Positive Breast Cancer

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* Tamoxifen was administered to postmenopausal women* Tamoxifen was administered to postmenopausal women Radiotherapy was administered at the completion of chemotherapyRadiotherapy was administered at the completion of chemotherapy C=cyclophosphamide, E=epirubicin, F=fluorouracilC=cyclophosphamide, E=epirubicin, F=fluorouracil


CEF-100 q 3 wk for 6 cycles*CEF-100 q 3 wk for 6 cycles*• C, 500 mg/mC, 500 mg/m22 IV, d 1 IV, d 1• E, 100 mg/mE, 100 mg/m22 IV, d 1 IV, d 1• F, 500 mg/mF, 500 mg/m22 IV, d 1 IV, d 1

Patient Population:Patient Population:

• Pre-/post-Pre-/postmenopausal menopausal

• Positive axillaryPositive axillary nodes nodes


• Study centerStudy center

• Number ofNumber of positive nodes positive nodes

CEF-50 q 3 wk for 6 cycles*CEF-50 q 3 wk for 6 cycles*• C, 500 mg/mC, 500 mg/m22 IV, d 1 IV, d 1• E, 50 mg/mE, 50 mg/m22 IV, d 1 IV, d 1• F, 500 mg/mF, 500 mg/m22 IV, d 1 IV, d 1

N=565

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

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Treatment AdministrationTreatment Administration(EBC-2/GFEA05)(EBC-2/GFEA05)

CEF-100CEF-100 CEF-50CEF-50N=266N=266 N=280N=280

Patients completing 6 cycles (%)Patients completing 6 cycles (%) 9494 9595

Median dose intensity, mg/mMedian dose intensity, mg/m22/wk /wk (Median relative dose intensity, %)(Median relative dose intensity, %)

CyclophosphamideCyclophosphamide 153 (92)153 (92) 157 (94)157 (94)

EpirubicinEpirubicin 31 (92) 31 (92) 16 (94) 16 (94)

FluorouracilFluorouracil 153 (92)153 (92) 157 (94)157 (94)

Radiotherapy (%)Radiotherapy (%) 9797 9494

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CEF-100 CEF-50

No. of patients 276 2895-year RFS 65% 52%Log-rank probability p=0.007

CEF-50CEF-50CEF-100CEF-100

0.00.0

0.10.1

0.20.2

0.30.3

0.40.4

0.50.5

0.60.6

0.70.7

0.80.8

0.90.9

1.01.0

YearsYears

Pro

bab

ilit

yP

rob

abil

ity

00 11 22 33 44 55 66 77 88

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

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00 11 22 33 44 55 66 77 88

0.00.0

0.10.1

0.20.2

0.30.3

0.40.4

0.50.5

0.60.6

0.70.7

0.80.8

0.90.9

1.01.0

YearsYears

Pro

bab

ilit

yP

rob

abil

ity

CEF-100CEF-100 CEF-50CEF-50


CEF-50CEF-50CEF-100CEF-100

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

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Grade 3/4 EventsGrade 3/4 Events N=266N=266 N=280N=280

Hematologic Events (%) Hematologic Events (%) Neutropenia Neutropenia 2525 11 11 + fever or infection+ fever or infection 4 4 0 0AnemiaAnemia 1 1 0 0ThrombocytopeniaThrombocytopenia 0 0 0 0

Non-hematologic Events (%) Non-hematologic Events (%) Alopecia Alopecia 7676 19 19Nausea/VomitingNausea/Vomiting 34 34 22 22 StomatitisStomatitis 4 4 0 0Diarrhea Diarrhea 0 0 0 0CutaneousCutaneous 0 0 0 0

Discontinuations (N [%])Discontinuations (N [%]) 11 [4.1] 11 [4.1] 5 [1.8] 5 [1.8]Drug-related deaths (N [%])Drug-related deaths (N [%]) 0 0 0 0

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

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CEF-100CEF-100 CEF-50CEF-50EventEvent N=266N=266 N=280N=280

Cardiac events (N [%])Cardiac events (N [%]) 8 [3.0]8 [3.0] 5 [1.7]5 [1.7]

Congestive heart failure (CHF)Congestive heart failure (CHF) 4 [1.5]4 [1.5] 1 [0.3]1 [0.3]

Other eventsOther events 4 [1.5]4 [1.5] 4 [1.4]4 [1.4]


Acute myelogenous leukemiaAcute myelogenous leukemia 1 [0.4]1 [0.4] 00

Acute lymphocytic leukemia Acute lymphocytic leukemia 00 1 [0.4] 1 [0.4]

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

43

Compared with CEF-50, CEF-100 significantly:Compared with CEF-50, CEF-100 significantly:

– Improved relapse-free survivalImproved relapse-free survival

– Improved overall survivalImproved overall survival

Toxicities were manageableToxicities were manageable

– 94% of patients completed CEF-100 therapy94% of patients completed CEF-100 therapy

– Relative dose intensity was 90%Relative dose intensity was 90%

– No on-treatment CEF-100-related deaths occurredNo on-treatment CEF-100-related deaths occurred

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

ConclusionsConclusions(EBC-2/GFEA05)(EBC-2/GFEA05)

44

Results of an ICCG-Sponsored Results of an ICCG-Sponsored Phase III Multicenter Randomized Phase III Multicenter Randomized

Controlled Trial (EBC-3/C-4-87)Controlled Trial (EBC-3/C-4-87)

ICCG=International Collaborative Cancer Group


Randomized Study of Epirubicin-100 Plus Tamoxifen vs Randomized Study of Epirubicin-100 Plus Tamoxifen vs Tamoxifen Alone as Adjuvant Therapy for Postmenopausal Tamoxifen Alone as Adjuvant Therapy for Postmenopausal

Patients With Axillary Node-Positive Breast Cancer Patients With Axillary Node-Positive Breast Cancer

45

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

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


E + TE + T• E, 50 mg/mE, 50 mg/m22 IV, d 1 + 8 every 4 wks x 6 cycles IV, d 1 + 8 every 4 wks x 6 cycles• T, 20 mg/day orally for 4 yearsT, 20 mg/day orally for 4 years


• Post-Post- menopausal menopausal

• Positive axillaryPositive axillary nodes nodes



T aloneT alone• T, 20 mg/day orally for 4 yearsT, 20 mg/day orally for 4 years

N=604

46

0

1020

3040

50

6070

8090

100

0 1 2 3 4 5 6 7 8

% P

rob

abili

ty

E-100 + T

T alone

E-100 + TE-100 + T T alone T alone


Years

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

47

T alone

E-100 + T

E-100 + TE-100 + T T alone T alone


2 3 4 5 6 7 8

Years

% P

rob

abili

ty

0

10

20

30

40

50

60

70

80

90

100

0 1

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

48

E+TE+T TT

Grade 3/4 Events Grade 3/4 Events N=298*N=298* N=292*N=292*

Hematologic Events (%)Hematologic Events (%)Leukopenia Leukopenia 2 2 0 0 + fever or infection + fever or infection 0 0 0 0ThrombocytopeniaThrombocytopenia 1 1 0 0AnemiaAnemia 0 0 0 0

Non-hematologic Events (%) Non-hematologic Events (%) Alopecia Alopecia 4646 0 0Nausea/VomitingNausea/Vomiting 15 15 1 1 StomatitisStomatitis 2 2 0 0

Discontinuations (N [%])Discontinuations (N [%]) 18 [5.9] 18 [5.9] -- --Drug-related deaths (N [%])Drug-related deaths (N [%]) 1 [0.3] 1 [0.3] 0 0

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

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

49

E+TE+T TTEventEvent N=303N=303 N=301N=301

Congestive heart failure (N [%])Congestive heart failure (N [%]) 4 [1.3]4 [1.3] 00


Acute myelogenous leukemiaAcute myelogenous leukemia 2 [0.7]2 [0.7] 00

Acute lymphocytic leukemia Acute lymphocytic leukemia 00 00

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

50

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

On-treatment toxicities of epirubicin were modestOn-treatment toxicities of epirubicin were modest

Benefits of epirubicin in postmenopausal patients were Benefits of epirubicin in postmenopausal patients were further documentedfurther documented

ConclusionsConclusions(EBC-3/C-4-87)(EBC-3/C-4-87)

51

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

TreatmentTreatment ControlControlStudy TherapyStudy Therapy (%)(%) (%) (%)

CEF combination:CEF combination:

EBC-1/MA-5EBC-1/MA-5 62% 62% 53%53% p=0.013*p=0.013*

EBC-2/GFEA05EBC-2/GFEA05 65% 65% 52%52% p=0.007‡p=0.007‡

Chemo-hormonalChemo-hormonal

EBC-3/C-4-87EBC-3/C-4-87 74%74% 62%62% p=0.023‡p=0.023‡

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

52

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

TreatmentTreatment ControlControlStudy TherapyStudy Therapy (%)(%) (%) (%)

CEF combination:CEF combination:

EBC-1/MA-5EBC-1/MA-5 77% 77% 70%70% p=0.043*p=0.043*

EBC-2/GFEA05EBC-2/GFEA05 76% 76% 65%65% p=0.007‡p=0.007‡

Chemo-hormonal:Chemo-hormonal:

EBC-3/C-4-87EBC-3/C-4-87 81%81% 77%77% p=0.46‡p=0.46‡

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

53

Therapy of Advanced Therapy of Advanced Breast CancerBreast Cancer

54

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

Prior Prior StudyStudy TherapyTherapy Treatment (N)Treatment (N) Control (N)Control (N)

PivotalPivotal

ABC-1ABC-1 AdjuvantAdjuvant CEF-100CEF-100 CMFCMF(HEPI 013)(HEPI 013) permittedpermitted (223)(223) (237)(237)

SupportiveSupportive

ABC-2ABC-2 AdjuvantAdjuvant CEF-100CEF-100 CEF-50CEF-50(HEPI 010)(HEPI 010) permitted permitted (214)(214) (242)(242)

Other SupportiveOther Supportive

ABC-3ABC-3 AdjuvantAdjuvant CEF-100 CEF-100 CEF-50 CEF-50 permitted permitted (84)(84) (80)(80)

ABC-4ABC-4 CMF for CMF for E-135E-135 E-75E-75metastatic diseasemetastatic disease (74) (74) (77)(77)

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

55C=cyclophosphamide, E=epirubicin, F=fluorouracil, M=methotrexateC=cyclophosphamide, E=epirubicin, F=fluorouracil, M=methotrexate


CEF-100 q 3 wk CEF-100 q 3 wk • C, C, 400 mg/m400 mg/m22 IV, d 1 + 8 IV, d 1 + 8• E, E, 50 mg/m 50 mg/m22 IV, d 1 + 8 IV, d 1 + 8• F, F, 500 mg/m500 mg/m22 IV, d 1 + 8 IV, d 1 + 8


• First-line therapyFirst-line therapy

• Metastatic diseaseMetastatic disease



• Presence ofPresence of visceral visceral metastases metastases

• Number of organsNumber of organs with metastases with metastases

• Prior adjuvantPrior adjuvant chemotherapy chemotherapy

CMF q 3 wk CMF q 3 wk • C,C, 500 mg/m500 mg/m22 IV, d 1 + 8 IV, d 1 + 8• M,M, 40 mg/m 40 mg/m22 IV, d 1 + 8 IV, d 1 + 8• F,F, 600 mg/m600 mg/m22 IV, d 1 + 8 IV, d 1 + 8

N=460

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

56

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

CEF-100CEF-100 CMFCMFN=223N=223 N=237N=237

Response rate (%)Response rate (%) 57.457.4 44.744.7 p=0.007p=0.007

Median response duration (mo)Median response duration (mo) 8.88.8 7.27.2 p=0.07p=0.07

Median time to tumor progression (mo)Median time to tumor progression (mo) 8.78.7 6.36.3 p=0.01p=0.01

Median time to treatment failure (mo)Median time to treatment failure (mo) 6.26.2 5.05.0 p=0.01p=0.01

Median survival (mo)Median survival (mo) 20.120.1 18.218.2 p=NSp=NS

* Based on intent-to-treat population

57

CEF-100CEF-100 CMFCMFAgentAgentN=223N=223 N=237N=237

EpirubicinEpirubicin 16 (7%) 16 (7%) 44 (19%) 44 (19%)

DoxorubicinDoxorubicin 5 (2%) 5 (2%) 41 (17%) 41 (17%)

MitoxantroneMitoxantrone 19 (9%) 19 (9%) 20 (8%)20 (8%)

TotalTotal 40 (18%)40 (18%) 105 (44%)105 (44%)

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

58

C=cyclophosphamide, E=epirubicin, F=fluorouracilC=cyclophosphamide, E=epirubicin, F=fluorouracil


CEF-100 q 3 wk CEF-100 q 3 wk • C, C, 500 mg/m500 mg/m22 IV, d 1 IV, d 1 • E, E, 100 mg/m100 mg/m22 IV, d 1 IV, d 1 • F, F, 500 mg/m500 mg/m22 IV, d 1 IV, d 1



• Metastatic diseaseMetastatic disease



• Presence ofPresence of visceral visceral metastases metastases

• Number of organsNumber of organs with metastases with metastases

CEF-50 q 3 wk CEF-50 q 3 wk • C,C, 500 mg/m500 mg/m22 IV, d 1 IV, d 1• E,E, 50 mg/m 50 mg/m22 IV, d 1 IV, d 1 • F,F, 500 mg/m500 mg/m22 IV, d 1 IV, d 1

N=456

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

59

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

CEF-100CEF-100 CEF-50CEF-50N=214N=214 N=242N=242


Median response duration (mo)Median response duration (mo) 9.19.1 9.39.3 p=NSp=NS

Median time to tumor progression (mo)Median time to tumor progression (mo) 7.57.5 7.07.0 p=NSp=NS

Median time to treatment failure (mo)Median time to treatment failure (mo) 5.75.7 5.35.3 p=NSp=NS

Median survival (mo)Median survival (mo) 18.018.0 17.017.0 p=NSp=NS

* Based on intent-to-treat population

60

C=cyclophosphamide, E=epirubicin, F=fluorouracilC=cyclophosphamide, E=epirubicin, F=fluorouracil


CEF-100 q 3 wk CEF-100 q 3 wk • C, C, 500 mg/m500 mg/m22 IV, d 1 IV, d 1• E, E, 50 mg/m 50 mg/m22 IV, d 1+ 8 IV, d 1+ 8 • F, F, 500 mg/m500 mg/m22 IV, d 1 IV, d 1



• Locally advancedLocally advanced or metastatic or metastatic disease disease



• MenopausalMenopausal status status

• Locally advancedLocally advanced or metastatic or metastatic disease disease

CEF-50 q 3 wk CEF-50 q 3 wk • C,C, 500 mg/m500 mg/m22 IV, d 1 IV, d 1• E,E, 50 mg/m 50 mg/m22 IV, d 1 IV, d 1 • F,F, 500 mg/m500 mg/m22 IV, d 1 IV, d 1

N=164

Study SchemaStudy Schema(ABC-3)(ABC-3)

61

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


N=84N=84 N=80N=80


Median response duration (mo)Median response duration (mo) 22.122.1 14.014.0 p<0.01p<0.01

Median time to tumor progression (mo)Median time to tumor progression (mo) ---- ---- -- --

Median time to treatment failure (mo)Median time to treatment failure (mo) 19.219.2 8.08.0 p<0.02p<0.02

Median survival (mo)Median survival (mo) 27.127.1 20.820.8 p=NSp=NS* Based on intent-to-treat population-- Not reported

62


Epirubicin, 135 mg/mEpirubicin, 135 mg/m22 IV q 3 wk IV q 3 wk


• Prior CMF therapyPrior CMF therapy

• MetastaticMetastatic disease disease


• Site ofSite of metastases metastases

• Response toResponse to prior CMF prior CMF

N=151

Epirubicin, 75 mg/mEpirubicin, 75 mg/m22 IV q 3 wk IV q 3 wk

Study SchemaStudy Schema(ABC-4)(ABC-4)

63

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

E-135E-135 E-75E-75N=74N=74 N=77N=77


Median response duration (mo)Median response duration (mo) 6.1 6.1 3.73.7 p=NSp=NS

Median time to tumor progression (mo)Median time to tumor progression (mo) 4.4 4.4 2.52.5 p=0.003p=0.003

Median time to treatment failure (mo)Median time to treatment failure (mo) ---- ---- -- --

Median survival (mo)Median survival (mo) 10.910.9 7.97.9 p=0.065p=0.065* Based on intent-to-treat population-- Not reported

64

CEF-100CEF-100 CMFCMF CEF-50CEF-50ABC-1ABC-1 ABC-2ABC-2 ABC-1ABC-1 ABC-2ABC-2

Grade 3/4 EventsGrade 3/4 Events N=220N=220 N=209N=209 N=234N=234 N=238N=238

Hematologic events (%)Hematologic events (%)Neutropenia Neutropenia 7878 8686 6868 3131 + fever or infection+ fever or infection 1515 1111 1212 1 1AnemiaAnemia 1212 7 7 9 9 1 1ThrombocytopeniaThrombocytopenia 77 6 6 6 6 2 2

Non-hematological events (%)Non-hematological events (%)Alopecia Alopecia 6666 7171 14 14 5555Nausea/Vomiting Nausea/Vomiting 2121 3030 14 14 26 26 StomatitisStomatitis 1212 10 10 15 15 0 0Diarrhea Diarrhea 1 1 0 0 2 2 1 1CutaneousCutaneous 0 0 1 1 0.4 0.4 0 0

Congestive heart failureCongestive heart failure 6 [2.7%] 6 [2.7%] 1 [0.5%] 1 [0.5%] 00 2 [0.8%] 2 [0.8%]Drug-related deathsDrug-related deaths 3 [1.4%] 3 [1.4%] 2 [1.0%] 2 [1.0%] 3 [1.2%] 3 [1.2%] 2 [0.8%] 2 [0.8%]

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

65

Overall Response Rates in Studies in Overall Response Rates in Studies in Advanced Breast CancerAdvanced Breast Cancer

TreatmentTreatment ControlControlStudyStudy (%)(%) (%) (%)

ABC-1ABC-1 57.4 57.4 44.744.7 p=0.007p=0.007

ABC-2ABC-2 48.1 48.1 36.036.0 p=0.009p=0.009

ABC-3ABC-3 57.1 57.1 36.336.3 p=0.008 p=0.008

ABC-4ABC-4 27.0 27.0 7.8 7.8 p=0.002 p=0.002

66

Complete Response Rates in Studies Complete Response Rates in Studies in Advanced Breast Cancerin Advanced Breast Cancer

TreatmentTreatment ControlControl Study Study (%)(%) (%)(%)

ABC-1ABC-1 13.513.5 10.510.5

ABC-2ABC-2 10.310.3 5.85.8

ABC-3ABC-3 10.710.7 6.36.3

ABC-4ABC-4 5.4 5.4 00

67

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

TreatmentTreatment ControlControl Study Study Endpoint Endpoint (mo)(mo) (mo)(mo)

ABC-1 ABC-1 TTPTTP 8.78.7 6.36.3 p=0.01p=0.01TTFTTF 6.26.2 5.05.0 p=0.01p=0.01

ABC-2ABC-2 TTP TTP 7.57.5 7.07.0 p=NS p=NS

ABC-3ABC-3 TTF TTF 19.219.2 8.08.0 p<0.02 p<0.02

ABC-4ABC-4 TTP TTP 4.44.4 2.52.5 p=0.003p=0.003

68

ConclusionsConclusions

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

– Improves relapse-free survivalImproves relapse-free survival

– Improves overall survivalImproves overall survival

Indicated for the therapy of patients with locally advanced or metastatic breast cancerIndicated for the therapy of patients with locally advanced or metastatic breast cancer

– Improves time to tumor progressionImproves time to tumor progression

– Increases overall and complete response ratesIncreases overall and complete response rates

69

Q & AQ & A

Documents

1 (Epirubicin Hydrochloride) Oncologic Drugs Advisory Committee Review June 7, 1999 EPIRUBICIN Pharmacia & Upjohn