Cetuximab prolongs survival in patients with locoregionally advanced squamous cell carcinoma of head and neck: A phase III study of high dose radiation therapy with or without cetuximab

5507 Background: The majority of head and neck cancers overexpress the epidermal growth factor receptor (EGFR), which is associated with aggressive tumor behavior and poor clinical outcome. Preclinical in vitro and in vivo model systems demonstrate radiosensitization following molecular inhibition of EGFR signaling. Promising phase I/II clinical results were achieved when radiation was combined with the EGFR blocking antibody, cetuximab, in patients with locoregionally advanced squamous cell carcinoma (SCC) of the head and neck (H&N). This phase III international trial was designed to examine the impact of combining cetuximab with high dose radiation on locoregional disease control and survival in patients with locally advanced H&N cancer. Methods: Patients with locoregionally advanced SCC of the oropharynx, hypopharynx or larynx with measurable disease were eligible to enroll. Patients were stratified by Karnofsky score 60–80 vs. 90–100, node positive vs. negative, T1–3 vs. T4, radiation fractionation regimen (once-a-day vs. twice-a-day vs. concomitant boost), and were randomized to receive either radiation alone for 6–7 weeks, or radiation plus weekly cetuximab. Following completion of treatment, patients were followed by physical examination and radiographic imaging every 4 months for 2 years, and then every 6 months up to 5 years. Results: From 04/99 to 03/02, 424 patients were randomized on this trial in the USA (61%), Europe (28%), and other countries. Median age was 57; 80% were male; 69% had KPS 90–100; 60% had oropharyngeal, 25% laryngeal, and 15% hypopharyngeal primary tumors. The two treatment arms were well balanced with regard to patient characteristics and stratification factors. The two arms were also well balanced with respect to radiation dose and fractions received, use of post-radiotherapy neck dissection, and secondary cancer therapy. Minimum and median durations of follow-up were 24 and 38 months, respectively. Median survival times, two and three-year survival rates derive from Kaplan-Meier estimates. Survival and selected safety results are as follows: The overall toxicity profile was dominated by classic known effects of high dose H&N radiation, although some additional toxicity was attributed to cetuximab. Locoregional control assessment is ongoing. Conclusions: The addition of cetuximab to high dose radiation in patients with locoregionally advanced SCC of H&N demonstrated a statistically significant prolongation in overall survival. This clinical benefit was achieved with minimal enhancement in the overall toxicity profile associated with curative-intent radiation therapy. These results corroborate the promising preclinical and earlier phase clinical results supporting the use of EGFR blockade in combination with radiation for advanced SCC of H&N. Furthermore, this combination treatment should be explored in other common epithelial malignancies demonstrating EGFR overexpression. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration ImClone Systems ImClone Systems ImClone Systems ImClone Systems