Purpose: There remains a great need for novel therapeutic agents and treatment strategies for advanced esophagogastric cancer. Preclinical and clinical studies have demonstrated increased EGFR expression in a significant proportion of both esophageal and gastric carcinomas. Inactivation of EGFR through use of a monoclonal antibody in preclinical models has resulted in inhibition of tumor growth. Agents designed to block the EGFR pathway have demonstrated disease control among previously treated patients with metastatic esophageal and gastric cancer. The proposed mechanism of action for cetuximab is its ability to effectively disrupt EGFR-mediated signal transduction pathways that ultimately leads to halting cell cycle progression, induces apoptosis, and also inhibits processes important for tumor growth, such as cell invasion and angiogenesis.

OBJECTIVES:

Primary - To assess the response rate of single-agent cetuximab in patients with advanced esophageal or gastric cancer who have failed 1-2 prior chemotherapy regimens given in the metastatic setting.

Secondary

• To evaluate the duration of response, progression-free survival and overall survival.
• To assess the safety of cetuximab.

Exploratory

- To assess whether levels of EGFR expression and/or EGFR mutation status correlates with response and toxicity of cetuximab.

STATISTICAL DESIGN:

This study used a two-stage design to evaluate efficacy of cetuximab based on overall response (OR) defined as complete response (CR) or partial response (PR). The null and alternative OR rate were 5% and 15%. If one or more patients enrolled in the stage one cohort (n=20 patients) achieved PR or better than accrual would proceed to stage two (n=16 patients). There was 36% probability of stopping the trial at stage one if the true OR rate was 5%. The probability that the regimen would be considered promising if the true OR rate was 5% was 10% and 80% if the true OR rate was 15%.

Inclusion Criteria:

• Histologically confirmed, unresectable or metastatic stage IV esophageal or gastric adenocarcinoma. Tumors with squamous cell differentiation, including those with a mixture of squamous and adenomatous differentiation, are excluded.
• Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) criteria, greater than or equal to 1 cm (longest diameter) by spiral computed tomography (CT) scan or greater than or equal to 2 cm by other radiographic technique. Disease in an irradiated field as only site of measurable disease is acceptable if there has been a clear progression of the lesion.
• Patients must have at least one paraffin block or twenty unstained slides available for analysis of epidermal growth factor receptor (EGFR) status.
• Treatment with 1-2 prior chemotherapy regimens given in the metastatic setting for unresectable or metastatic esophageal or gastric carcinoma.
• ECOG performance status 0-2.
• Life expectancy greater or equal to 12 weeks.
• Age 18 years or older.
• Ability to sign an informed consent document.
• Neutrophils greater than or equal to 1,000/mm3.
• Platelets greater than or equal to 75,000/mm3.
• Serum bilirubin less than or equal to 2.0 mg/dl.
• Serum creatinine less than or equal to 1.5 mg/dl.
• Aspartate aminotransferase (AST or SGOT) less than or equal to 2.5 x upper institutional normal limit.

Exclusion Criteria:

• Pregnant or lactating women. Women of childbearing potential must have a negative serum or urine pregnancy test within 14 days of initiation of therapy. Men and women of reproductive potential may not participate unless they have agreed to use an effective contraceptive method while in this study.
• Subjects should have no other active malignancy other than non-melanoma skin cancer or in-situ cervical carcinoma. A resected cancer (other than in-situ carcinoma) must have demonstrated no evidence of recurrence for at least 3 years.
• Subjects should not have a significant history of cardiac disease, i.e., uncontrolled hypertension; unstable angina; congestive heart failure; myocardial infarction less than 6 months prior to registration; or serious uncontrolled cardiac arrhythmia.
• Subjects must not have received prior cetuximab or other therapy that specifically and directly targets the EGFR pathway. Prior therapy with bevacizumab is permissible.
• Subjects must not have experienced prior severe infusion reaction to a monoclonal antibody.
• Subjects must not have received any chemotherapy regimen or radiation therapy within 28 days prior to study entry.
• Patients must have completed any major surgery 4 weeks or any minor surgery 2 weeks prior to the first infusion of cetuximab. Patients must have fully recovered from the procedure.
• No concurrent use of chemotherapy, radiation, or other investigational agents is allowed while participating in this study.

The analysis dataset is comprised of eligible and treated patients.

Assessed each cycle throughout treatment from time of first dose and up to day 30 post-treatment.

Maximum grade toxicity by type was first calculated. Serious AEs were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher per CTCAEv3. Other AEs were defined as events with treatment-attribution of possible, probable or definite and grades 1 or 2 per CTCAEv3.