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PC Enzinger, BA Burtness, DR Hollis, D Niedzwiecki, DH Ilson, AB Benson 3rd,

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. CALGB 80403 / ECOG E1206: Background.

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PC Enzinger, BA Burtness, DR Hollis, D Niedzwiecki, DH Ilson, AB Benson 3rd,

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  1. 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

  2. CALGB 80403 / ECOG E1206: Background • 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”.

  3. CALGB 80403 / ECOG E1206: Background

  4. CALGB 80403 / ECOG E1206: Background • 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 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

  5. 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

  6. 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.

  7. CALGB 80403 / ECOG E1206: Schema 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 Stratification: ECOG 0-1 vs 2 ADC vs. SCC 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)

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

  9. CALGB 80403 / ECOG E1206: Patient Characteristics *No locally advanced *7 cases post esophagectomy

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

  11. CALGB 80403/ECOG 1206: Survival

  12. CALGB 80403/ECOG 1206: Overall Survival by Arm

  13. CALGB 80403/ECOG 1206: Progression-Free Survival by Arm

  14. ECF ECF - - C C IC IC - - C C FOLFOX FOLFOX - - C C Hematologic Hematologic 49% 49% 58% 58% 46% 46% Neutropenia Neutropenia 48% 48% 49% 49% 42% 42% Leukocytopenia Leukocytopenia 7% 7% 21% 21% 13% 13% Anemia Anemia 4% 4% 13% 13% 6% 6% Thrombocytopenia Thrombocytopenia 4% 4% 8% 8% 1% 1% CALGB 80403/ECOG 1206: Grade 3-4 Heme Toxicity* P = NS for all comparisons *No grade 5 hematologic toxicity

  15. P - value p=0.03 p=0.03 p=0.05 p=0.05 p=0.06 p=0.06 4% 17% 17% Pain Pain 9% 9% 1% 1% 3% 3% Pulmonary Pulmonary 4% 4% 1% 1% † † 0% 0% Vascular Vascular 6% 6% 7% 7% 4% 4% p=0.01 Death; no CTCAE defined Death; no CTCAE defined 6% 6% 0% 0% 0% 0% Total ( Total ( Heme Heme + Non + Non - - Heme Heme ) ) 75% 75% 86% 86% 79% 79% CALGB 80403/ECOG 1206: Grade 3-5 Non-Heme Toxicity P - value ECF ECF - - C C IC IC - - C C FOLFOX FOLFOX - - C C Non Non - - Hematologic Hematologic 66%* 66%* 77%** 77%** 65% 65% Constitutional symptoms Constitutional symptoms 13% 13% 18% 18% 17% 17% Dermatologic Dermatologic 16% 16% 11% 11% 19% 19% † † Gastrointestinal Gastrointestinal 28% 28% 42% 42% 22% 22% Infection Infection 13% 13% 8% 8% 7% 7% Metabolic Metabolic 16% 16% 34% 34% 22% 22% Neurologic Neurologic 12% 12% 4% p=0.01 * Includes 4 deaths ** Includes 2 deaths † Indicates a death P = NS except as noted

  16. CALGB 80403/ECOG 1206: Tolerability

  17. CALGB 80403/ECOG 1206: Discussion Is there a signal for cetuximab in esophageal cancer? 15% -10% Vs. 2.5mo -2mo *Lorenzen. Ann Oncol 2009

  18. CALGB 80403/ECOG 1206: Discussion Is there a signal for EGFR antibodies in esophagogastric cancer? EOX REAL 3* EOX + Panitumumab Cape / Cis EXPAND** Cape / Cis + Cetuximab * http://clinicaltrials.gov/ct2/show/NCT00824785 **http://clinicaltrials.gov/ct2/show/NCT00678535

  19. 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.

  20. AcknowledgementsThank 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

  21. Thank You!

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