CALGB / 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 / ECOG E1206: Background

RegimenPhaseTumor Sites ResponseSurvivalReference ECFIIIEsoph GEJ Stomach 45%8.9 mosWebb. J Clin Oncol 1997 ECFIIIEsoph GEJ Stomach 42.4%9.4 mosRoss. J Clin Oncol 2002 ECFIIIEsoph GEJ Stomach 40.7%9.9 mosCunningham. N Engl J Med 2008 ICIIEsoph GEJ 57%14.6 mosIlson. J Clin Oncol 1999 ICIIGEJ Gastric 58%9 mosAjani. Cancer 2002 FOLFOXIIEsoph GEJ Cardia 40%7.1 mosMauer. Ann Oncol 2005 FLOIIIGEJ Gastric 41.3%10.7 mosAl-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 cancers 6 CALGB / 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 / 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 / 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 / ECOG E1206: Schema Stratification: ECOG 0-1 vs 2 ADC vs. SCC ARM A: (ECF + cetuximab); 1 cycle = 21 days Cetuximab 400  250mg/m2 IV, weekly Epirubicin 50 mg/m2 IV, day 1 Cisplatin 60mg/m2 IV, day 1 Fluorouracil 200mg/m2/day, days 1-21 ARM B: (IC + cetuximab); 1 cycle = 21 days Cetuximab 400  250mg/m2 IV, weekly Cisplatin 30 mg/m2 IV, days 1 and 8 Irinotecan 65 mg/m2 IV, days 1 and 8 ARM C: (FOLFOX + cetuximab); 1 cycle = 14 days Cetuximab 400  250mg/m2 IV, weekly Oxaliplatin 85 mg/m2 IV, day 1 Leucovorin 400 mg/m2, day 1 Fluorouracil 400 mg/m2 IV bolus, day 1 Fluorouracil 2400 mg/m2 IV over 46hrs (days 1-2)

CALGB 80403/ECOG 1206: Consort Diagram September 2006 to May 2009

CALGB / ECOG E1206: Patient Characteristics ECF-C N=67 IC-C N=71 FOLFOX-C N=72 Total N=210 Age:median range Sex: Male59 (88%)58 (82%)67 (93%)184 (88%) Female 8 (12%)13 (18%)5 ( 7%)34 (14%) PS: 031 (46%)35 (49%) 101 (48%) 133 (49%)34 (48%)35 (49%)102 (49%) 23 ( 4%)2 ( 3%) 7 ( 3%) Primary Site * : Esophagus43 (64%)32 (44%)41 (57%)116 (55%) GE junction23 (34%)38 (54%)28 (39%)89 (42%) Unknown1 ( 1%) 3 ( 4%) 5 ( 2%) *No locally advanced *7 cases post esophagectomy

CALGB 80403/ECOG 1206: Response *RECIST - confirmed; restaging every 6 weeks

CALGB 80403/ECOG 1206: Survival

CALGB 80403/ECOG 1206: Overall Survival by Arm

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

* 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-C -CIC-C -CFOLFOX-C -C Non-HematologicNon-Hematologic66%* 77%** 65% Constitutional symptoms 13% 18% 17% Dermatologic 16% 11% 19% Gastrointestinal 28% 42% † † 22% Infection 13% 8% 7% Metabolic 16% 34% 22% Neurologic 12% 4% p=0.01 P-value

CALGB 80403/ECOG 1206: Tolerability ECF-C N=67 IC-C N=71 FOLFOX-C N=72 Total N=210 Reason off treatment Progression35(52%)41(58%)42(58%)118(56%) Adverse event10(10%)12(16%) 8( 9%)30(14%) Death on treatment4( 6%)6( 8%) 3( 4%)13( 6%) Withdrew7(10%)6( 8%) 8(11%)21(10%) Alternate therapy3( 4%)3 3 9 Other reason5( 7%)1( 1%)3( 4%)10( 4%) Unknown2( 3%)1( 1%) 2( 3%)5( 2%) Still on treatment1( 1%)1 3( 4%) 5( 2%) Treatment modification60(90%)61(86%)52(72%)173(82%) p=0.03

CALGB 80403/ECOG 1206: Discussion ResponseSurvivalResponseSurvival ECF 41-45% mos ECF-C 57.8%11.5 mos IC (Phase II) 57-58% mos IC-C 45.6% 8.9 mos FOLFOX 40-41% mos FOLFOX-C 53.6% 12.4 mos Random Phase II*RegimenPtsResponsePFSOS 1 st line therapy for esophageal SCC Cis/5-FU3013% CF + Cetux3219% Is there a signal for cetuximab in esophageal cancer? *Lorenzen. Ann Oncol % 2.5mo -10% -2mo Vs.

CALGB 80403/ECOG 1206: Discussion Is there a signal for EGFR antibodies in esophagogastric cancer? * ** 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.

Acknowledgements Thank you to the 245 patients and all the investigators who participated at the following sites: Supported by CA314946, Bristol-Myers Squibb, Pfizer, and Sanofi-Aventis

Thank You!