Impact on Quality of Life of Adding Cetuximab to Irinotecan in Patients Who Have Failed Prior...
-
Upload
prosper-mills -
Category
Documents
-
view
218 -
download
0
Transcript of Impact on Quality of Life of Adding Cetuximab to Irinotecan in Patients Who Have Failed Prior...
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