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!