Randomized Phase III Trial of Randomized Phase III Trial of Cetuximab Plus Irinotecan vs Cetuximab Plus Irinotecan vs Irinotecan Alone for Metastatic Irinotecan Alone for Metastatic Colorectal Cancer (mCRC) after Colorectal Cancer (mCRC) after Failing Prior Oxaliplatin-based Failing Prior Oxaliplatin-based Therapy: Therapy: The EPIC Trial The EPIC Trial Alberto F. Sobrero Alberto F. Sobrero 1 , Louis Fehrenbacher , Louis Fehrenbacher 2 , , Fernando Rivera Fernando Rivera 3 , Ernst-Ulrich Steinhauer , Ernst-Ulrich Steinhauer 4 , , Jana Prausova Jana Prausova 5 , Christophe Borg , Christophe Borg 6 , Yousif , Yousif Abubakr Abubakr 7 , Angela Zubel , Angela Zubel 8 , Christiane Langer , Christiane Langer 9 , , Howard Burris III Howard Burris III 10 10 1 Ospedale San Martino, Genova, Italy; Ospedale San Martino, Genova, Italy; 2 Kaiser Permanente Medical Center, Vallejo, CA; Kaiser Permanente Medical Center, Vallejo, CA; 3 Hospital Universitario Marques de Valdecilla, Santander, Spain; Hospital Universitario Marques de Valdecilla, Santander, Spain; 4 Klinikum Kassel, Kassel, Klinikum Kassel, Kassel, Germany; Germany; 5 Motol University Hospital, Prague, Czech Republic; Motol University Hospital, Prague, Czech Republic; 6 CHU Besancon, Besancon, CHU Besancon, Besancon, France; France; 7 Florida Oncology Associates, Jacksonville, FL; Florida Oncology Associates, Jacksonville, FL; 8 Merck KGaA Merck KGaA, Darmstadt, Germany; Darmstadt, Germany; 9 Bristol-Myers-Squibb, Wallingford, CT; Bristol-Myers-Squibb, Wallingford, CT; 10 10 The Sarah Cannon Cancer Center, Nashville, TN The Sarah Cannon Cancer Center, Nashville, TN
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Randomized Phase III Trial of Cetuximab Plus Irinotecan vs Irinotecan Alone for Metastatic Colorectal Cancer (mCRC) after Failing Prior Oxaliplatin-based.
CETUXIMAB : Clinical Development Program 3 3 rd line and beyond BOND, NCIC C nd line EPIC 1 st line CRYSTAL Adjuvant PETACC 8, NCCTG N0147
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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
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
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)
• 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
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
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
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)