Impact on Quality of Life of Adding Cetuximab Impact on Quality of Life of Adding Cetuximab to Irinotecan in Patients to Irinotecan in Patients Who Have Failed Prior Who Have Failed Prior Oxaliplatin-Based Therapy: Results From the Oxaliplatin-Based Therapy: Results From the

EPIC TrialEPIC Trial

Cathy EngCathy Eng11, J. Maurel, J. Maurel22, W. Scheithauer, W. Scheithauer33, L. Wong, L. Wong44, M. Lutz, M. Lutz55, G. Middleton, G. Middleton66, R. , R. StollerStoller77, A. Zubel, A. Zubel88, H. Lu, H. Lu99, A. F. Sobrero, A. F. Sobrero1010

11Gastrointestinal Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX, Gastrointestinal Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX, 22Hospital Clinic I Provincial, Barcelona, Hospital Clinic I Provincial, Barcelona, SPAIN, SPAIN, 33Universitatesklinik, Wien, AUSTRIA, Universitatesklinik, Wien, AUSTRIA, 44Scott &White Hospital, Temple, TX, Scott &White Hospital, Temple, TX, 55Caritasklinik St. Theresia, Saarbrücken, GERMANY, Caritasklinik St. Theresia, Saarbrücken, GERMANY, 66St Luke's St Luke's

Cancer Centre, Guildford, UNITED KINGDOM, Cancer Centre, Guildford, UNITED KINGDOM, 77University of Pittsburgh Cancer Center, Pittsburgh, PA, University of Pittsburgh Cancer Center, Pittsburgh, PA, 88Gastrointestinal Medical Oncology, Merck Gastrointestinal Medical Oncology, Merck KGaA, Darmstadt, GERMANY, KGaA, Darmstadt, GERMANY, 99Bristol-Myers-Squibb, Wallingford, CT, Bristol-Myers-Squibb, Wallingford, CT, 1010Ospedale San Martino, Genova, ITALYOspedale San Martino, Genova, ITALY

Quality of Life As An Endpoint in mCRCQuality of Life As An Endpoint in mCRCSimilar QoL Reported in Control and Experimental ArmsSimilar QoL Reported in Control and Experimental Arms

Irinotecan After 5FU FailureIrinotecan After 5FU Failure• As single agent (vs BSC, except for worse diarrhea scores)As single agent (vs BSC, except for worse diarrhea scores)• Added to 5FUAdded to 5FU

(Cunningham 1998, Rougier 1998)(Cunningham 1998, Rougier 1998)

Irinotecan Added to FUIrinotecan Added to FU (Delayed Deterioration of QoL)(Delayed Deterioration of QoL)

(Saltz 2000, Douillard 2000)(Saltz 2000, Douillard 2000)

Oxaliplatin Added to FUOxaliplatin Added to FU(De Gramont 2000)(De Gramont 2000)

Bevacizumab Added to FU or IFLBevacizumab Added to FU or IFL(Chawla 2005)(Chawla 2005)

First-line mCRCFirst-line mCRC

Pre-Treated mCRCPre-Treated mCRC

19981998 20002000 20022002 20042004 20062006

Rationale for EPIC Study DesignRationale for EPIC Study DesignFocus on mCRC patients after oxaliplatin failureFocus on mCRC patients after oxaliplatin failure Irinotecan is the approved standard of careIrinotecan is the approved standard of care

Phase II data indicated that irinotecan +cetuximab is an Phase II data indicated that irinotecan +cetuximab is an effective combination effective combination Saltz 2001, Cunningham 2004Saltz 2001, Cunningham 2004

Inclusion of quality of life as endpoint in mCRCInclusion of quality of life as endpoint in mCRC Survival time has increased from 10 to 20 months in last Survival time has increased from 10 to 20 months in last

10 years10 years Long-term survival = increased importance in QoL Long-term survival = increased importance in QoL

EPIC Study DesignEPIC Study Design

Cetuximab / Irinotecan Cetuximab / Irinotecan

IrinotecanIrinotecan

Failure of Failure of Oxaliplatin-Based Oxaliplatin-Based

TherapyTherapySurvivalSurvival

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, Secondary Endpoints: PFS, RR, DCR, Safety, QoLQoL• Sample Size: 1298 patients in 221 centersSample Size: 1298 patients in 221 centers

N = 648 N = 648

N = 650 N = 650

QoL AssessmentQoL Assessment

Baseline, Week 4, Week 10 then every other cycle (Q 6 weeks)Baseline, Week 4, Week 10 then every other cycle (Q 6 weeks)

All Randomized PatientsAll Randomized Patients Cetuximab + Irinotecan Cetuximab + Irinotecan

N = 648 (%)N = 648 (%)

Irinotecan Irinotecan

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

GENDERGENDER Male / FemaleMale / Female 405 ( 62.5) / 243 ( 37.5)405 ( 62.5) / 243 ( 37.5) 411 ( 63.2) / 239 ( 36.8)411 ( 63.2) / 239 ( 36.8)

AGE (years)AGE (years) MedianMedian 61.061.0 62.062.0

Minimum-MaximumMinimum-Maximum 23.0 – 85.023.0 – 85.0 21.0 – 90.021.0 – 90.0

≥ ≥ 65 years65 years 255 (39.4)255 (39.4) 275 (42.3)275 (42.3)

ECOG ECOG Performance Performance

StatusStatus

00 348 (53.7)348 (53.7) 316 (48.6)316 (48.6)

11 260 (40.1)260 (40.1) 295 (45.4)295 (45.4)

22 35 (5.4)35 (5.4) 35 (5.4)35 (5.4)

Not ReportedNot Reported 5 (0.8)5 (0.8) 4 (0.6)4 (0.6)

Demographic Characteristics*Demographic Characteristics*

* EGFR detectable (by IHC)* EGFR detectable (by IHC)* Failed an oxaliplatin based regimen * Failed an oxaliplatin based regimen - Failure = progression of disease or intolerance; ≤ 6 months of last dose of any agent- Failure = progression of disease or intolerance; ≤ 6 months of last dose of any agent

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

Perc

enta

ge (%

)

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

Cetuximab Cetuximab ++

Irinotecan Irinotecan

N (%)N (%)

IrinotecanIrinotecan

N (%)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 = <0.0001p-value = <0.0001

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

p-value = <0.0001p-value = <0.0001

PR

OP

OR

TIO

N P

RO

GR

ES

SIO

N F

RE

EP

RO

PO

RT

ION

PR

OG

RE

SS

ION

FR

EE

0.00.0

0.20.2

0.40.4

0.60.6

0.80.8

1.01.0

00 33 66 99 1212 1515 1818

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

CETUXIMAB + IRINOTECAN CETUXIMAB + IRINOTECAN

N = 648N = 648

PR

OP

OR

TIO

N A

LIV

EP

RO

PO

RT

ION

AL

IVE

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)

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

Overall SurvivalOverall Survival

Median OSMedian OS 10.71 mo10.71 mo 9.99 mo9.99 mo

Post-Study Post-Study TherapyTherapy

AnyAny 57%57% 65%65%

CetuximabCetuximab 11%11% 47%47%

BevacizumabBevacizumab 16%16% 14%14%

IRINOTECAN IRINOTECAN

N = 650N = 650

Grade 3 / 4 Adverse EventsGrade 3 / 4 Adverse Events

Toxicity Toxicity Cetuximab + Cetuximab + Irinotecan Irinotecan

N = 638N = 638

IrinotecanIrinotecan

N = 629N = 629

Any 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 Other Grade 3/4 ToxicityToxicity

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

QoL Assessments: EORTC QLQ – C30 (v. 3.0)QoL Assessments: EORTC QLQ – C30 (v. 3.0) Global Health StatusGlobal Health Status

Functional Functional ScalesScales

— PhysicalPhysical — CognitiveCognitive

— RoleRole — SocialSocial

— EmotionalEmotional

Symptom ScalesSymptom Scales —FatigueFatigue — NauseaNausea

— PainPain — VomitingVomiting

Single ItemsSingle Items — DyspneaDyspnea — ConstipationConstipation

— InsomniaInsomnia — DiarrheaDiarrhea

— Appetite LossAppetite Loss — Financial ProblemsFinancial Problems

Statistical ConsiderationsStatistical Considerations

The primary comparison of QoL changes used a Wei-The primary comparison of QoL changes used a Wei-Lachin nonparametric testLachin nonparametric test The robustness of the test was evaluated by The robustness of the test was evaluated by

longitudinal modeling longitudinal modeling

Descriptive statistics were calculated for baseline and Descriptive statistics were calculated for baseline and change from baseline QoL scores at each time pointchange from baseline QoL scores at each time point

QoL ComplianceQoL Compliance

Irinotecan + CetuximabIrinotecan + Cetuximab IrinotecanIrinotecan

BaselineBaseline 543/648 (83.8)543/648 (83.8) 563/650 (86.6)563/650 (86.6)

3 Weeks3 Weeks 399/638 (62.5)399/638 (62.5) 356/629 (56.6)356/629 (56.6)

9 Weeks9 Weeks 356/608 (58.6)356/608 (58.6) 313/593 (52.8)313/593 (52.8)

15 Weeks15 Weeks 295/524 (56.3)295/524 (56.3) 267/476 (56.1)267/476 (56.1)

21 Weeks21 Weeks 188/382 (49.2)188/382 (49.2) 144/282 (51.1)144/282 (51.1)

27 Weeks27 Weeks 134/283 (47.3)134/283 (47.3) 82/172 (47.7)82/172 (47.7)

33 Weeks33 Weeks 100/195 (51.3)100/195 (51.3) 49/103 (47.6)49/103 (47.6)* Information was collected until patients’ first follow-up evaluation for toxicity. For time points * Information was collected until patients’ first follow-up evaluation for toxicity. For time points beyond 33 weeks, compliance was comparable between the arms.beyond 33 weeks, compliance was comparable between the arms.

N (%) of Patients with QoL Data*N (%) of Patients with QoL Data*

Baseline QoL Scores ComparisonBaseline QoL Scores Comparison

Most baseline QoL scores were balanced between treatment arms

Exceptions in favor of irinotecan + cetuximab include:

Functional Scale: Social functioning

Symptoms: Fatigue

Single Items: Dyspnea, Appetite loss

On Treatment Comparison of QoL On Treatment Comparison of QoL ChangesChanges from Baseline Between Treatment Armsfrom Baseline Between Treatment Arms

Wei-Lachin TestWei-Lachin Test

P-value (two-sided)P-value (two-sided) ComparisonComparison

Global health statusGlobal health status 0.0490.049

Functional Functional

ScalesScales

PhysicalPhysical 0.0020.002

RoleRole 0.0030.003

EmotionalEmotional 0.0020.002

CognitiveCognitive <0.001<0.001

SocialSocial 0.7740.774 No differenceNo difference

Favor irinotecan + Favor irinotecan + cetuximabcetuximab

P-value (two-sided)P-value (two-sided)

SymptomsSymptoms FatigueFatigue 0.005 0.005

Nausea/vomitingNausea/vomiting < 0.001< 0.001

PainPain < 0.001< 0.001

ItemsItems DiarrheaDiarrhea 0.0170.017

InsomniaInsomnia 0.0350.035

Appetite lossAppetite loss 0.1330.133

ConstipationConstipation 0.2760.276

DyspneaDyspnea 0.3680.368

Financial problemsFinancial problems 0.5590.559

On Treatment Comparison of QoL On Treatment Comparison of QoL ChangesChanges fromfrom Baseline Between Treatment Arms Baseline Between Treatment Arms

Favor irinotecan + Favor irinotecan + cetuximabcetuximab

No differenceNo difference

Wei-Lachin TestWei-Lachin Test ComparisonComparison

Overall QoL and Functional ScalesOverall QoL and Functional Scales

Mean values and 95% CIMean values and 95% CI

BetterBetter

WorseWorse

Symptom ScalesSymptom Scales

Mean values and 95% CIMean values and 95% CI

WorseWorse

BetterBetter

ConclusionsConclusionsThe combination of cetuximab + irinotecan resulted in The combination of cetuximab + irinotecan resulted in better QoL despite increased toxicities (diarrhea and better QoL despite increased toxicities (diarrhea and fatigue) when compared to irinotecan alone.fatigue) when compared to irinotecan alone.

Although there was no difference in OS between the Although there was no difference in OS between the arms, PFS, and RR arms, PFS, and RR were significantly better with the were significantly better with the addition of cetuximab.addition of cetuximab.

This is This is the first studythe first study in which the addition of a biologic in which the addition of a biologic agent to a cytotoxic platform in mCRC provides better agent to a cytotoxic platform in mCRC provides better QoL than the cytotoxic regimen alone.QoL than the cytotoxic regimen alone.

AcknowledgementsAcknowledgementsEnrolled and randomized patients and their Enrolled and randomized patients and their caregiverscaregivers

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

Merck KGaA Merck KGaA Oliver Kisker, Michael Oliver Kisker, Michael SchlichtingSchlichting

Bristol-Myers SquibbBristol-Myers Squibb Justin Kopit, Bonnie Donato, Lucinda OrsiniJustin Kopit, Bonnie Donato, Lucinda Orsini

ImClone Systems Incorporated ImClone Systems Incorporated