An exploratory pharmacogenomic study of neoadjuvant cetuximab (C225, ERBITUX®) followed by cisplatin, radiotherapy, and cetuximab in women with untreated advanced cervical cancer

3533 Background: EGFR overexpression is correlated with poor prognosis and decreased survival in cervical cancer. Though EGFR expression is necessary for sensitivity to cetuximab, a monoclonal antibody directed against EGFR, not all EGFR-positive tumors will respond to cetuximab. We initiated a study to describe the antitumor activity of neoadjuvant cetuximab and to determine the safety of cetuximab with concurrent chemoradiation in women with advanced cervical carcinoma. We performed sequential tumor biopsies and FDG-PET/CT imaging to attempt to predict response to neoadjuvant cetuximab. Methods: Women with untreated advanced cervical cancer underwent a biopsy for EGFR sequencing, IHC staining, and transcriptional profiling, CT scan, and PET scan prior to 3 weekly treatments of neoadjuvant cetuximab (initial dose of 400 mg/m 2 followed by 250 mg/m 2 , Part A). They then underwent a second biopsy, CT scan, and PET scan prior to receiving concurrent therapy consisting of IMRT (PTV Final to 50 cGy) and 6 weekly HDR intracavitary implants (650 cGy/fraction) with six weekly treatments of cetuximab (250 mg/m 2 ) and cisplatin (40 mg/m 2 , Part B). Women then received 12 weekly treatments of cetuximab followed by a final biopsy, CT scan, and PET scan (Part C). Results: Nine women with Stage I-IV disease were entered. Seven completed Part A (1 opted for standard treatment and 1 refused further treatment), 3 completed Part B (3 remain in treatment and 1 opted to complete treatment closer to home), and 2 patients are presently receiving treatment on Part C. In Part A, toxicities were minimal with grade 1/2 acneiform rash in 3 and 4 patients, respectively. In Part B, hematologic toxicities included grade 3 neutropenia, anemia, and thrombocytopenia in 2, 1, and 1 patients, respectively. Non-hematologic toxicities included grade 3/4 fatigue in 4, grade 3 anorexia in 3, grade 3 nausea/vomiting in 3, grade 3 infections with neutropenia in 1 and with normal ANC in 2 patients. Grade 2 and 3 diarrhea and electrolyte abnormalities were notable in all patients requiring hospitalizations in 5 patients and/or outpatient fluid and electrolyte replacement in 3 patients. One patient each had Grade 3 small bowel obstruction and enteritis. Two patients had elevated transaminases and dilated intra- and extra-hepatic ducts by CT scans. ERCP revealed biliary sludge in 1 patient and suppurative cholangitis in the other. While no patients had a partial response by RECIST criteria after neoadjuvant cetuximab, several patients had a decrease in their disease by clinical examination. Conclusion: We noted significant gastrointestinal and metabolic toxicities and will be modifying our treatment. The results of the correlative studies on the tumor biopsies, CT scans, and PET scans before and after neoadjuvant cetuximab have not been analyzed yet and will be presented.