CALGB 80403 / ECOG 1206: Randomized Phase II Study of Standard
Chemotherapy + Cetuximab for Metastatic Esophageal Cancer
PC Enzinger, BA Burtness, DR Hollis, D Niedzwiecki, DH Ilson, AB Benson 3rd,
RJ Mayer, RM Goldberg
• NCI-sponsored Esophageal Cancer Strategy Meeting of the GI Intergroup:
• No superior regimen or molecularly targeted agent for esophagogastric cancer.
• Randomized Phase II.
• Response rate is primary endpoint - fastest.
• Best regimen phase III vs best “standard”.
CALGB 80403 / ECOG E1206: Background
CALGB 80403 / ECOG E1206: BackgroundRegimen Phase Tumor
SitesResponse Survival Reference
ECF III Esoph GEJ Stomach
45% 8.9 mos Webb.J Clin Oncol 1997
ECF III Esoph GEJ Stomach
42.4% 9.4 mos Ross.J Clin Oncol 2002
ECF III Esoph GEJ Stomach
40.7% 9.9 mos Cunningham. N Engl J Med 2008
IC II EsophGEJ
57% 14.6 mos Ilson. J Clin Oncol 1999
IC II GEJ Gastric
58% 9 mos Ajani. Cancer 2002
FOLFOX II Esoph GEJ Cardia
40% 7.1 mos Mauer. Ann Oncol 2005
FLO III GEJ Gastric
41.3% 10.7 mos Al-Batran. J Clin Oncol 2008
• Cetuximab: chimerized monoclonal antibody - EGFR (oropharyngeal cancer , NSCLC, and colorectal cancer)
• EGFR expression – 3/4 of ADC and SCC 1-5
• EGFR expression correlates with prognosis in esophagogastric ADC and SCC 1-5
• KRAS mutations occur in approx. 2% of esophageal cancers6
CALGB 80403 / ECOG E1206: Background
1-5 Mukaida. Cancer 1991; Itakura. Cancer 1994; Yacoub. Mod Pathol 1997; Torzewski. Anticancer Res 1997; Koyama. J Cancer Res Clin Oncol 1999; 6 Lea. Carcinogenesis 2007
CALGB 80403 / ECOG E1206: Statistics
• Response Rate: met esophageal ADC (cisplatin/ 5-FU) is approx. 25% in randomized trials.
• Simon’s Optimal Two-Stage Design
• Null Hypothesis vs. Alternative Hypothesis RR = 0.25 vs. RR = 0.40
• Regimen is efficacious if 21+ responses among 64 patients treated in each arm.
• Power: 90% Significance Level: 0.1
CALGB 80403 / ECOG E1206: Eligibility• Metastatic ADC or SCC of the esophagus or GE
junction (Siewert AEG Type I-II).
• Measurable disease required.
• No prior chemotherapy, radiotherapy, or therapy that targets the EGFR pathway.
• ECOG PS 0-2.
• Adequate total caloric intake to maintain body weight.
• No ≥ grade 2 peripheral neuropathy or ≥ grade 2 diarrhea.
CALGB 80403 / ECOG E1206: Schema
Stratification:ECOG 0-1 vs 2ADC vs. SCC
ARM A: (ECF + cetuximab); 1 cycle = 21 days
Cetuximab 400 250mg/m2 IV, weeklyEpirubicin 50 mg/m2 IV, day 1Cisplatin 60mg/m2 IV, day 1Fluorouracil 200mg/m2/day, days 1-21
ARM B: (IC + cetuximab); 1 cycle = 21 days
Cetuximab 400 250mg/m2 IV, weeklyCisplatin 30 mg/m2 IV, days 1 and 8Irinotecan 65 mg/m2 IV, days 1 and 8
ARM C: (FOLFOX + cetuximab); 1 cycle = 14 days
Cetuximab 400 250mg/m2 IV, weeklyOxaliplatin 85 mg/m2 IV, day 1Leucovorin 400 mg/m2, day 1Fluorouracil 400 mg/m2 IV bolus, day 1Fluorouracil 2400 mg/m2 IV over 46hrs (days 1-2)
Randomized (n=245)
Arm A: ECF-C (n=82)
Arm B: IC-C (n=83)
Arm C: FOLFOX-C (n=80)
Adenocarcinomas (n=74)
Adenocarcinomas (n=74)
Adenocarcinomas (n=74)
Never treated (n=6) No data submitted (n=1)
Never treated (n=2) No data submitted (n=1)
Never treated (n=1) No data submitted (n=1)
Analyzed (n=67)
Analyzed (n=71)
Analyzed (n=72)
CALGB 80403/ECOG 1206: Consort Diagram
September 2006 to May 2009
CALGB 80403 / ECOG E1206: Patient Characteristics
ECF-CN=67
IC-CN=71
FOLFOX-CN=72
TotalN=210
Age: median 57.7 60.3 59.2 59.3range 33-86 33-80 30-83 30-86
Sex:Male 59 (88%) 58 (82%) 67 (93%) 184 (88%)Female 8 (12%) 13 (18%) 5 ( 7%) 34 (14%)
PS:0 31 (46%) 35 (49%) 35 (49%) 101 (48%)1 33 (49%) 34 (48%) 35 (49%) 102 (49%)2 3 ( 4%) 2 ( 3%) 2 ( 3%) 7 ( 3%)
Primary Site*:Esophagus 43 (64%) 32 (44%) 41 (57%) 116 (55%)GE junction 23 (34%) 38 (54%) 28 (39%) 89 (42%)Unknown 1 ( 1%) 1 ( 1%) 3 ( 4%) 5 ( 2%)
*No locally advanced*7 cases post esophagectomy
CALGB 80403/ECOG 1206: Response
ECF-C N=64
IC-C N=68
FOLFOX-C N=69
Response CR 0 1 ( 1%) 2 ( 3%)
PR 37 (58%) 30 (44%) 35 (51%)
SD 15 (23%) 23 (34%) 19 (28%)
PD 4 ( 6%) 10 (15%) 8 (12%)
Not eval / unknown 5 / 3 (8% /5%) 2 / 2 (3% /3%) 3 / 2 (4% /3%) Objective Response Rate*
(CR+PR)/total 57.8 45.6 53.6
(90% C.I.) 46.8 68.3 35.2 56.3 43.1 64.0
p vs. H0<0.25 <.0001 <.0001 <.0001 Response duration (mos) median 6.1 5.3 5.7
range 0.5 - 22.7 0.5 - 20.1 2.4 - 18.2
*RECIST - confirmed; restaging every 6 weeks
ECF-C IC-C FOLFOX-C Total N=67 N=71 N=72 N=210
Mos 95% c.i. Mos 95% c.i. Mos 95% c.i. Mos 95% c.i. OS median 11.5 (8.1,12.5) 8.9 (6.2,13.1) 12.4 (8.8,13.9) 11.0 (8.8,12.3) # dead 51 52 51 154 PFS median 5.9 (4.5,8.3) 5.0 (3.9,6.0) 6.7 (5.5,7.4) 5.8 (5.1,6.8) # dead/pd 57 64 63 184 TTF median 5.5 (3.9,7.2) 4.5 (3.6,5.6) 6.7 (4.8,7.2) 5.5 (4.5,5.9)
#dead/pd/ off forAE 58 66 64 188
CALGB 80403/ECOG 1206: Survival
0 5 10 15 20 25
Months from Study Entry
0.0
0.2
0.4
0.6
0.8
1.0
Pro
po
rtio
n S
urv
ivin
g ECF-C (n=67)IC-C (n=71)FOLFOX-C (n=72)
CALGB 80403/ECOG 1206: Overall Survival by Arm
0 5 10 15 20 25
Months from Study Entry
0.0
0.2
0.4
0.6
0.8
1.0
Pro
po
rtio
n P
rog
res
sio
n-F
ree
ECF-C (n=67)IC-C (n=71)FOLFOX-C (n=72)
CALGB 80403/ECOG 1206: Progression-Free Survival by Arm
CALGB 80403/ECOG 1206: Grade 3-4 Heme Toxicity*
P = NS for all comparisons*No grade 5 hematologic toxicity
ECF-CECF-C IC-CIC-C FOLFOX-CFOLFOX-CHematologicHematologic49%49% 58%58% 46%46%
NeutropeniaNeutropenia 48%48% 49%49% 42%42%LeukocytopeniaLeukocytopenia 7%7% 21%21% 13%13%
AnemiaAnemia 4%4% 13%13% 6%6%ThrombocytopeniaThrombocytopenia 4%4% 8%8% 1%1%
* Includes 4 deaths** Includes 2 deaths† Indicates a death
CALGB 80403/ECOG 1206: Grade 3-5 Non-Heme Toxicity
P = NS except as noted
ECF-CECF-C IC-CIC-C FOLFOX-CFOLFOX-CNon-HematologicNon-Hematologic 66%*66%* 77%**77%** 65%65%
Constitutional symptomsConstitutional symptoms 13%13% 18%18% 17%17%DermatologicDermatologic 16%16% 11%11% 19%19%GastrointestinalGastrointestinal 28%28% 42%†42%† 22%22%InfectionInfection 13%13% 8%8% 7%7%MetabolicMetabolic 16%16% 34%34% 22%22%NeurologicNeurologic 12%12% 4%4% 17%17%PainPain 9%9% 1%1% 3%3%PulmonaryPulmonary 4%4% 1%†1%† 0%0%VascularVascular 6%6% 7%7% 4%4%Death; no CTCAE definedDeath; no CTCAE defined 6%6% 0%0% 0%0%
Total (Heme + Non-Heme)Total (Heme + Non-Heme) 75%75% 86%86% 79%79%
p=0.05
p=0.03
p=0.06
p=0.01
P-value
p=0.05
p=0.03
p=0.06
p=0.01
P-value
CALGB 80403/ECOG 1206: Tolerability
ECF-CN=67
IC-CN=71
FOLFOX-CN=72
TotalN=210
Reason off treatment
Progression 35 (52%) 41 (58%) 42 (58%) 118 (56%)
Adverse event 10 (10%) 12 (16%) 8 ( 9%) 30 (14%)
Death on treatment 4 ( 6%) 6 ( 8%) 3 ( 4%) 13 ( 6%)
Withdrew 7 (10%) 6 ( 8%) 8 (11%) 21 (10%)
Alternate therapy 3 ( 4%) 3 ( 4%) 3 ( 4%) 9 ( 4%)
Other reason 5 ( 7%) 1 ( 1%) 3 ( 4%) 10 ( 4%)
Unknown 2 ( 3%) 1 ( 1%) 2 ( 3%) 5 ( 2%)
Still on treatment 1 ( 1%) 1 ( 1%) 3 ( 4%) 5 ( 2%)
Treatment modification 60 (90%) 61 (86%) 52 (72%) 173 (82%)
p=0.03
CALGB 80403/ECOG 1206: Discussion
Response Survival Response Survival
ECF
41-45% 8.9-9.9 mos
ECF-C
57.8% 11.5 mos
IC (Phase II)
57-58% 9-14.6 mos
IC-C
45.6% 8.9 mos
FOLFOX
40-41% 7.1-10.7 mos
FOLFOX-C 53.6% 12.4 mos
Random Phase II* Regimen Pts Response PFS OS
1st line therapy for esophageal SCC
Cis/5-FU 30 13% 3.6 5.5
CF + Cetux 32 19% 5.9 9.5
Is there a signal for cetuximab in esophageal cancer?
*Lorenzen. Ann Oncol 2009
15%
2.5mo
-10%
-2mo
Vs.
CALGB 80403/ECOG 1206: DiscussionIs there a signal for EGFR antibodies in esophagogastric cancer?
* http://clinicaltrials.gov/ct2/show/NCT00824785
**http://clinicaltrials.gov/ct2/show/NCT00678535
REAL 3*
EXPAND**
EOX
EOX + Panitumumab
Cape / Cis
Cape / Cis + Cetuximab
CALGB 80403/ECOG 1206: Conclusions
• Primary endpoint: all 3 regimens > 40% RR
• IC-C: appeared to have lowest response and survival & most adverse events.
• ECF-C: appeared to have highest response, but highest treatment-related mortality and most treatment-related modifications.
• FOLFOX-C: good response and survival and best tolerated – best for phase III development.
AcknowledgementsThank you to the 245 patients and all the investigators
who participated at the following sites:
4Sanford1CINJ4VCC6MGH
9Carle CCOP
6Michigan CCOP2W. Mich.4SECCC1Kansas CCOP
8Wichita CCOP13Abbott1RPCI6Iowa U.
10Iowa Onc.2Indiana1RIH8IORA
2Geisinger1Wisconsin10OSUMC1Illinois
3Duluth12NWestern2N.ShoreU.2HOACNY
2Cedar Rapids12U. Penn.5NICRC7Georgetown
4N.Shore16Fox Chase3Nebraska7DFCI
1Penn State4Case W.3NCRF3Dartmouth
1St. Vincent2Tufts2MVCC26U. Chicago
1Scott White2Mayo 1MSKCC7Chapel Hill
5Decatur5Hopkins2Minnesota5CCHLTH
Patients Enrolled
ECOG Institutions
Patients Enrolled
ECOG Institutions
Patients Enrolled
CALGB Institutions
Patients Enrolled
CALGB Institutions
4Sanford1CINJ4VCC6MGH
9Carle CCOP
6Michigan CCOP2W. Mich.4SECCC1Kansas CCOP
8Wichita CCOP13Abbott1RPCI6Iowa U.
10Iowa Onc.2Indiana1RIH8IORA
2Geisinger1Wisconsin10OSUMC1Illinois
3Duluth12NWestern2N.ShoreU.2HOACNY
2Cedar Rapids12U. Penn.5NICRC7Georgetown
4N.Shore16Fox Chase3Nebraska7DFCI
1Penn State4Case W.3NCRF3Dartmouth
1St. Vincent2Tufts2MVCC26U. Chicago
1Scott White2Mayo 1MSKCC7Chapel Hill
5Decatur5Hopkins2Minnesota5CCHLTH
Patients Enrolled
ECOG Institutions
Patients Enrolled
ECOG Institutions
Patients Enrolled
CALGB Institutions
Patients Enrolled
CALGB Institutions
Supported by CA314946, Bristol-Myers Squibb, Pfizer, and Sanofi-Aventis
Thank You!