Randomized Phase III Trial of Cetuximab Randomized Phase III Trial of Cetuximab Plus Irinotecan vs Irinotecan Alone for Plus Irinotecan vs Irinotecan Alone for Metastatic Colorectal Cancer (mCRC) Metastatic Colorectal Cancer (mCRC) after Failing Prior Oxaliplatin-based after Failing Prior Oxaliplatin-based

Therapy: Therapy: The EPIC TrialThe EPIC Trial

Alberto F. SobreroAlberto F. Sobrero11, Louis Fehrenbacher, Louis Fehrenbacher22, Fernando , Fernando RiveraRivera33, Ernst-Ulrich Steinhauer, Ernst-Ulrich Steinhauer44, Jana Prausova, Jana Prausova55, , Christophe BorgChristophe Borg66, Yousif Abubakr, Yousif Abubakr77, Angela Zubel, Angela Zubel88, ,

Christiane LangerChristiane Langer99, Howard Burris III, Howard Burris III1010 11Ospedale San Martino, Genova, Italy; Ospedale San Martino, Genova, Italy; 22Kaiser Permanente Medical Center, Vallejo, CA; Kaiser Permanente Medical Center, Vallejo, CA; 33Hospital Universitario Hospital Universitario

Marques de Valdecilla, Santander, Spain; Marques de Valdecilla, Santander, Spain; 44Klinikum Kassel, Kassel, Germany; Klinikum Kassel, Kassel, Germany; 55Motol University Hospital, Prague, Motol University Hospital, Prague, Czech Republic; Czech Republic; 66CHU Besancon, Besancon, France; CHU Besancon, Besancon, France; 77Florida Oncology Associates, Jacksonville, FL; Florida Oncology Associates, Jacksonville, FL; 88Merck Merck

KGaAKGaA,, Darmstadt, Germany; Darmstadt, Germany; 99Bristol-Myers-Squibb, Wallingford, CT; Bristol-Myers-Squibb, Wallingford, CT; 1010The Sarah Cannon Cancer Center, The Sarah Cannon Cancer Center, Nashville, TN Nashville, TN

DisclosuresDisclosuresAuthorAuthor EmploymentEmployment Consultant /Consultant /

AdvisorAdvisorStock OwnerStock Owner HonorariaHonoraria

AF SobreroAF Sobrero Merck KGaA*, Roche, Merck KGaA*, Roche, Pfizer, Sanofi Aventis, Pfizer, Sanofi Aventis, AmgenAmgen

Merck KGaA*, Roche, Merck KGaA*, Roche, Pfizer, Sanofi Aventis, Pfizer, Sanofi Aventis, AmgenAmgen

A ZubelA Zubel Merck KGaA*Merck KGaA*

C LangerC Langer Bristol-Myers SquibbBristol-Myers Squibb Bristol-Myers SquibbBristol-Myers Squibb

H BurrisH Burris Bristol-Myers SquibbBristol-Myers Squibb Bristol-Myers SquibbBristol-Myers Squibb

L FehrenbacherL Fehrenbacher No conflicts of interest to discloseNo conflicts of interest to disclose

F RiveraF Rivera No conflicts of interest to discloseNo conflicts of interest to disclose

E U SteinhauerE U Steinhauer No conflicts of interest to discloseNo conflicts of interest to disclose

J PrausovaJ Prausova No conflicts of interest to discloseNo conflicts of interest to disclose

C BorgC Borg No conflicts of interest to discloseNo conflicts of interest to disclose

Y AbubakrY Abubakr No conflicts of interest to discloseNo conflicts of interest to disclose

*Darmstadt, Germany

CETUXIMAB : Clinical Development ProgramCETUXIMAB : Clinical Development Program

33rd line and beyond BOND, NCIC C0.17

2nd line EPIC

1st line CRYSTAL

Adjuvant PETACC 8, NCCTG N0147

Cetuximab: Cetuximab: Multiple Mechanisms of ActionMultiple Mechanisms of Action

IgG1 monoclonal antibodyIgG1 monoclonal antibody Competitively inhibits ligand binding to EGFR Competitively inhibits ligand binding to EGFR Blocks receptor dimerization, TK phosphorylation, and signal Blocks receptor dimerization, TK phosphorylation, and signal

transductiontransduction IgG1-induced Antibody-Dependent Cell CytotoxicityIgG1-induced Antibody-Dependent Cell Cytotoxicity

EGFRADCC

EPIC Study DesignEPIC Study Design

Cetuximab / Irinotecan

Irinotecan

Failure of Oxaliplatin-Based

TherapySurvival

WHY?

StudyStudy NN TreatmentTreatmentEfficacyEfficacy

ORRORR PFSPFS OSOS

Oxaliplatin failureOxaliplatin failureTournigand 2004Tournigand 2004 6969 FOLFIRIFOLFIRI 44 2.5 2.5 NRNR

Irinotecan failureIrinotecan failure

Rothenberg 2003Rothenberg 2003 152152 FOLFOXFOLFOX 9.99.9 4.6 4.6 NRNR

Tournigand 2004Tournigand 2004 6969 FOLFOXFOLFOX 1515 4.2 4.2 NRNR

Giantonio 2005Giantonio 2005290290289289243243

FOLFOXFOLFOXFOLFOX+BFOLFOX+B

BevacizumabBevacizumab

9.29.221.821.83.03.0

4.84.87.27.22.72.7

10.810.812.9 12.9 10.810.8

Phase III Data in 2Phase III Data in 2ndnd Line mCRC Line mCRC

Rowland K, ASCO 05, 3519

Phase III Data in 3Phase III Data in 3rdrd Line mCRC Line mCRC

NN 94 94 126 126RRRR 4% 4% 16% 16%PFSPFS 2.7 months 2.7 months 5.0 months 5.0 monthsOS OS 8.7 months 8.7 months 10.0 months 10.0 months

1 FU

2 FOLFOX

3 Irinotecan

1 FU

2 Irinotecan

3 FOLFOX

EPIC Study DesignEPIC Study Design

Cetuximab / Irinotecan

Irinotecan

Failure of Oxaliplatin-Based

TherapySurvival

WHY?

WHY?

Prewett M, et al. Proc AACR . 2001;42: Abstract 1543.

Cetuximab + Irinotecan Cetuximab + Irinotecan in mCRC Xenografts in mCRC Xenografts

HT-29HT-29

0

1000

2000

3000

4000

5000

6000

0 5 10 15 20 25 30 35 40 45 50DaysDays

SalineSaline

Irinotecan +Irinotecan +

CetuximabCetuximab

IrinotecanIrinotecan

CetuximabCetuximab

Mea

n Tu

mor

Vol

ume

(mm

Mea

n Tu

mor

Vol

ume

(mm 33

))

Phase II Studies N Phase II Studies N

EfficacyEfficacy

ORRORR TTPTTP

Irinotecan failureIrinotecan failure

Cunningham D.Cunningham D.N Eng J MedN Eng J Med 2004 2004 218218 22.9%22.9% 4.1 mo4.1 mo

Saltz L.Saltz L.Proc ASCOProc ASCO 2001 2001 121121 17%17% NRNR

Cetuximab + Irinotecan Cetuximab + Irinotecan in Heavily Pre-Treated mCRC in Heavily Pre-Treated mCRC

Why OS as Primary EndpointWhy OS as Primary Endpoint

RelevanceRelevance

Time of Study (2002)Time of Study (2002) 1990 - OS advantage of 1° line FU vs BSC1990 - OS advantage of 1° line FU vs BSC 1997 - OS advantage of 2° line IRI vs BSC1997 - OS advantage of 2° line IRI vs BSC 2007 - OS advantage of 3° line CET vs BSC 2007 - OS advantage of 3° line CET vs BSC

(NCIC)(NCIC)

FDA RequestFDA Request

EPIC Study DesignEPIC Study Design

Cetuximab / Irinotecan

Irinotecan

Failure of Oxaliplatin-Based

TherapySurvival

Stratified by:Stratified by: Study site Study site ECOG PS (0 - 1, 2)ECOG PS (0 - 1, 2)

• Primary Endpoint: SurvivalPrimary Endpoint: Survival

• Secondary Endpoints: PFS, RR, DCR, Safety, QoLSecondary Endpoints: PFS, RR, DCR, Safety, QoL

• Sample Size: 1298 patients in 221 centersSample Size: 1298 patients in 221 centers

N = 648 N = 648

N = 650 N = 650

Sample size and powerSample size and power One interim analysis of survival (DSMB) based on O’Brien One interim analysis of survival (DSMB) based on O’Brien

and Fleming alpha spending functionand Fleming alpha spending function 850 deaths required (90% power for declaring significance 850 deaths required (90% power for declaring significance

given a hazard ratio of 0.80)given a hazard ratio of 0.80) 1300 subjects planned1300 subjects planned

Survival analysisSurvival analysis Two-sided log-rank test stratified by ECOG PS 0-1 vs 2Two-sided log-rank test stratified by ECOG PS 0-1 vs 2 Kaplan-Meier curves Kaplan-Meier curves

Statistical ConsiderationsStatistical Considerations

EPIC Study RegimensEPIC Study Regimens

CetuximabR

ando

miz

atio

nR

ando

miz

atio

n400 mg/m²

Initial dose week 1 of cycle

1

250 mg/m² Weekly starting

week 2

Irinotecan350 mg/m2 Q 3 wks*

Irinotecan350 mg/m2 Q 3 wks*

* or 300 mg/m* or 300 mg/m22 Q 3 weeks in patients Q 3 weeks in patients >> 70, prior RT, ECOG 2 70, prior RT, ECOG 2

Histologically documented mCRCHistologically documented mCRC

Bi-dimensionally measurable diseaseBi-dimensionally measurable disease

EGFR detectable (by IHC)EGFR detectable (by IHC)

Failed an oxaliplatin based regimen Failed an oxaliplatin based regimen Failure = progression of disease or intoleranceFailure = progression of disease or intolerance ≤≤ 6 months after the last dose of any agent6 months after the last dose of any agent

Key Eligibility CriteriaKey Eligibility Criteria

All Randomized PatientsAll Randomized Patients Cetuximab + Cetuximab + Irinotecan Irinotecan N = 648 (%)N = 648 (%)

Irinotecan Irinotecan N = 650 (%)N = 650 (%)

GenderGender MaleMale 62.562.5 63.263.2

FemaleFemale37.537.5 36.836.8

Age (years)Age (years) MedianMedian 61.061.0 62.062.0≥ ≥ 65 years65 years 39.439.4 42.342.3

ECOG PSECOG PS 00 53.753.7 48.648.6 11 40.140.1 45.445.4 22 5.45.4 5.45.4

Not reportedNot reported 0.80.8 0.60.6

Baseline Demographic CharacteristicsBaseline Demographic Characteristics

Prior Anti-Cancer Prior Anti-Cancer TherapyTherapy

Cetuximab + Cetuximab + IrinotecanIrinotecanN = 648 (%)N = 648 (%)

IrinotecanIrinotecanN = 650 (%)N = 650 (%)

OxaliplatinOxaliplatin 99.599.5 99.599.5

FluoropyrimidineFluoropyrimidine 97.897.8 97.297.2

BevacizumabBevacizumab 13.013.0 12.612.6

Prior Anti-Cancer TherapyPrior Anti-Cancer Therapy

Treatment ExposureTreatment Exposure

CetuximabCetuximab(N = 603)(N = 603)

IrinotecanIrinotecan(N = 634)(N = 634)

IrinotecanIrinotecan(N = 629)(N = 629)

Relative Dose Intensity Relative Dose Intensity ≥ 80%≥ 80% 78%78% 80%80% 86%86%

* One cycle = 3 weeks* One cycle = 3 weeks

Cetuximab + IrinotecanCetuximab + IrinotecanN = 638N = 638

IrinotecanIrinotecanN = 629N = 629

Median weeksMedian weeks 1414 13.113.1 9.99.9

Median number of Median number of cycles*cycles* 55 33

Median irinotecan Median irinotecan cumulative dosecumulative dose 1,395.2 mg/m1,395.2 mg/m22 1,048.2 mg/m1,048.2 mg/m22

Safety in Treated SubjectsSafety in Treated SubjectsGrade 3/4 Toxicity Grade 3/4 Toxicity Cetuximab + Irinotecan Cetuximab + Irinotecan

N = 638N = 638IrinotecanIrinotecan

N = 629N = 629Any AE > 5%Any AE > 5% 457 (71.6)457 (71.6) 357 (56.8)357 (56.8)

DiarrheaDiarrhea 184 (28.8)184 (28.8) 102 (16.2)102 (16.2)VomitingVomiting 39 (6.1)39 (6.1) 40 (6.4)40 (6.4)FatigueFatigue 59 (9.2)59 (9.2) 31 (4.9)31 (4.9)

Other Grade 3/4 ToxicityOther Grade 3/4 Toxicity Acneform Rash*Acneform Rash* 52 (8.2%)52 (8.2%) 3 (0.5%)3 (0.5%)

Infusion Reaction*Infusion Reaction* 9 (1.4%)9 (1.4%) 5 (0.8%)5 (0.8%) Hypomagnesemia** Hypomagnesemia**

9 (3.3%)9 (3.3%) 1 (0.4%)1 (0.4%)

* Composite term ** Percentages are calculated relative to the number of patients who received the given laboratory test

Reasons for Treatment DiscontinuationReasons for Treatment Discontinuation

6%8%7%5%

67%

6%7%5%4%

68%

0

10

20

30

40

50

60

70

80

Progression Death Toxicity Preference Deterioration

Percentage of Patients

Cetuximab + Irinotecan Irinotecan

Response and Disease Control RatesResponse and Disease Control Rates

61.4

16.4

45.8

4.20

10

20

30

40

50

60

70

Response rate Disease Control

Percentage (%)

Cetuximab + Irinotecan (N=648) Irinotecan (N=650)

Cetuximab +Cetuximab +Irinotecan Irinotecan

N (%)N (%)

IrinotecanIrinotecanN (%)N (%)

CRCR 9 (1.4)9 (1.4) 1 ( 0.2)1 ( 0.2)

PRPR 97 (15)97 (15) 26 ( 4.0)26 ( 4.0)p-value = <0.0001

p-value = <0.0001

(CR + PR) (CR + PR + SD)

PRO

POR

TIO

N P

RO

GR

ESSI

ON

FR

EE

0.0

0.2

0.4

0.6

0.8

1.0

0 3 6 9 12 15 18

4.0 mo4.0 mo2.6 mo2.6 mo

MONTHSMONTHS

HR = 0.692 HR = 0.692 95% CI = 0.617 – 0.77695% CI = 0.617 – 0.776

CETUXIMAB + IRINOTECAN; N = 648CETUXIMAB + IRINOTECAN; N = 648

IRINOTECAN ALONE; N = 650IRINOTECAN ALONE; N = 650

STRATIFIED LOGRANK P-VALUE = < 0.0001STRATIFIED LOGRANK P-VALUE = < 0.0001

Progression Free SurvivalProgression Free Survival

PRO

POR

TIO

N A

LIVE

PRO

POR

TIO

N A

LIVE

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

MONTHSMONTHS00 33 66 99 1212 1515 1818 2121 2424 2727 3030 3333 3636 3939

HR = 0.975 HR = 0.975 (95.03% CI = 0.854 – 1.114)(95.03% CI = 0.854 – 1.114)

CETUXIMAB + IRINOTECAN; N = 648CETUXIMAB + IRINOTECAN; N = 648Median OS = 10.71 moMedian OS = 10.71 mo

IRINOTECAN; N = 650IRINOTECAN; N = 650Median OS = 9.99 moMedian OS = 9.99 mo

STRATIFIED LOGRANK P-VALUE = 0.7115STRATIFIED LOGRANK P-VALUE = 0.7115

Overall SurvivalOverall Survival

Post-Study TherapyPost-Study Therapy

Post-Study TherapyPost-Study Therapy Cetuximab + Cetuximab + IrinotecanIrinotecan(N = 648)(N = 648)

Irinotecan* Irinotecan* (N = 650) (N = 650)

Any 3Any 3rdrd Line Rx Line Rx 57%57% 65%65%

Cetuximab*Cetuximab* 11%11% 47%47%

BevacizumabBevacizumab 16%16% 14%14%

* Majority of patients received irinotecan + cetuximab

PRO

POR

TIO

N A

LIVE

PRO

POR

TIO

N A

LIVE

0.00.0

0.50.5

1.01.0

00 33 66 99 1212 1515 1818 2121 2424 2727 3030 3333 3636 3939MONTHMONTHSS

11.7 mo11.7 mo5.8 mo5.8 mo15.6 mo15.6 mo

Correlation of Rash and OSCorrelation of Rash and OSCetuximab + Irinotecan ArmCetuximab + Irinotecan Arm

Gr 0; N = 148Gr 0; N = 148Median OS = 5.8 moMedian OS = 5.8 mo95% CI = 4.8 – 7.195% CI = 4.8 – 7.1

Gr 1-2; N = 448Gr 1-2; N = 448Median OS = 11.7 moMedian OS = 11.7 mo95% CI = 11.1 – 13.095% CI = 11.1 – 13.0

Gr 3-4; N = 52Gr 3-4; N = 52Median OS = 15.6 moMedian OS = 15.6 mo95% CI = 13.2 – 19.395% CI = 13.2 – 19.3

SummarySummary

Progression Free SurvivalProgression Free Survival Prolonged - 4.0 vs 2.6 monthsProlonged - 4.0 vs 2.6 months Extent of benefitExtent of benefit Impressive Impressive

Absolute valueAbsolute value Incremental Incremental

Overall Response RateOverall Response Rate Higher - 16% vs 4%Higher - 16% vs 4%

CRCR Appealing Appealing

Overall SurvivalOverall Survival Unchanged - 10.7 vs 9.9 monthsUnchanged - 10.7 vs 9.9 months Impact of post-trial CETImpact of post-trial CET SubstantialSubstantial Correlation with rashCorrelation with rash StrongStrong

Time on TreatmentTime on Treatment ProlongedProlonged ToxicityToxicity Higher incidence of rash, diarrheaHigher incidence of rash, diarrhea QoLQoL Pending reporting later in 2007Pending reporting later in 2007

CONCLUSION #1CONCLUSION #1

There was no difference in overall survival.There was no difference in overall survival.

ImplicationImplication

In patients failing oxaliplatin-based first line In patients failing oxaliplatin-based first line therapy, irinotecan-based therapy remains the therapy, irinotecan-based therapy remains the standard of care.standard of care.

CONCLUSION #2CONCLUSION #2 Cetuximab plus irinotecan resulted in moderately higher toxicity.Cetuximab plus irinotecan resulted in moderately higher toxicity.

RR and PFS were significantly better with the addition of cetuximab.RR and PFS were significantly better with the addition of cetuximab.

Extensive post trial use of cetuximab provides a plausible Extensive post trial use of cetuximab provides a plausible explanation for the lack of OS difference.explanation for the lack of OS difference.

ImplicationImplication

These data confirm that, despite a moderate increase in toxicity, These data confirm that, despite a moderate increase in toxicity, cetuximab is a key therapeutic agent for the cetuximab is a key therapeutic agent for the optimaloptimal treatment of treatment of advanced colorectal cancer.advanced colorectal cancer.

AcknowledgementsAcknowledgements Enrolled and randomized patients and their

caregivers

Investigator teams across 221 sites in Europe, United States, Australia, and Hong Kong

Merck KGaA – Michael Schlichting, Marie-Louice Wilberg , Oliver Kisker

Bristol-Myers Squibb– Justin Kopit, Kathleen Williams

ImClone Systems Incorporated

Back-Up SlidesBack-Up Slides

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0.10.1

0.20.2

0.30.3

0.40.4

0.50.5

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0.90.9

1.01.0

Survival Time [Months]Survival Time [Months]

00 33 66 99 1212 1515 1818 2121 2424 2727 3030

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Post-Hoc Survival AnalysisPost-Hoc Survival AnalysisSubjects with Post-Study Cetuximab ExcludedSubjects with Post-Study Cetuximab Excluded

IRINOTECAN; N = 345IRINOTECAN; N = 345

CETUXIMAB + IRINOTECAN; N = 575CETUXIMAB + IRINOTECAN; N = 575

PRO

POR

TIO

N A

LIVE

PRO

POR

TIO

N A

LIVE

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

MONTHSMONTHS

0 3 6 9 12 15 18 21 24

SUBJECTS AT RISKCET+IRIN 233 135 65 29 5 3 1 0 0

IRINO 118 59 18 8 2 1 1 0226

Post-Hoc Survival Analysis Post-Hoc Survival Analysis Prior to Cetuximab CommercializationPrior to Cetuximab Commercialization

CETUXIMAB + IRINOTECAN; n = 233CETUXIMAB + IRINOTECAN; n = 233Median OS = 10.5 moMedian OS = 10.5 mo95% CI = 7.8 – 11.395% CI = 7.8 – 11.3CENSORED (No. DEAD = 64)CENSORED (No. DEAD = 64)

IRINOTECAN; n = 226IRINOTECAN; n = 226Median OS = 8.6 moMedian OS = 8.6 mo95% CI = 7.0 – 10.995% CI = 7.0 – 10.9

CENSORED (No DEAD = 59CENSORED (No DEAD = 59))

Post-Hoc Survival AnalysisPost-Hoc Survival Analysis Irinotecan Arm Post-Study: Irinotecan Arm Post-Study:

Cetuximab vs. Therapy Without Cetuximab vs. No TherapyCetuximab vs. Therapy Without Cetuximab vs. No TherapySubseq. Cet.; n = 305Median OS = 13.0 mo 95% CI = 12.2 - 15.0

CENSORED (No. Dead = 188)

Subseq. Rx, No Cet.; n = 116Median OS = 10.1 mo 95% CI = 9.0 – 13.2CENSORED (No. Dead = 77)

No Subseq. Rx; n = 229Median OS = 3.9 mo 95% CI = 3.5 – 4.9CENSORED (No. Dead = 164)

PRO

POR

TIO

N A

LIVE

PRO

POR

TIO

N A

LIVE

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

MONTHSMONTHS0 3 6 9 12 15 18 21 24 27 30 33