Study Shows Dramatic Response Rates in Advanced Head and Neck Cancers

BIRMINGHAM, Alabama—Combining the monoclonal antibody C225, which targets epidermal growth factor receptor (EGFr), with radiation dramatically increased response rate and durability in patients with advanced, unresectable, head and neck squamous cell carcinomas.

James A. Bonner, MD, and his colleagues at the University of Alabama, Birmingham, found an overall response rate of 100%, including complete remissions in 13 of 15 patients, in their phase IA/IIB trial. Dr. Bonner reported the results at the ASCO annual meeting.

“C225 is a chimeric monoclonal antibody that acts by binding a tyrosine kinase receptor, thereby causing inhibition of cellular proliferation by blocking access of growth factors,” Dr. Bonner explained.

“We felt that this combination might be very exciting in squamous cell carcinomas of the head and neck, as the majority of these tumors overexpress the EGF receptor,” Dr. Bonner said.

Present Response Rates

“For truly unresectable disease, the complete response rate with radiation alone is 25% to 30%. For resectable disease treated with radiation therapy alone, the response rates are 45% to 60%. Unfortunately, locoregional control rates at 1 and 2 years fall below 50% for both groups when radiation therapy is used alone,” Dr. Bonner said.

The aim of this trial of C225 antibody in combination with radiation was to increase tumor cell death by damaging tumor cells, blocking cell cycles, and inhibiting tumor cells’ ability to perform DNA repair.

The Regimens

Patients received 70 Gy of radiation in 35 once-daily fractions administered over approximately 7 weeks, or 74.4 Gy administered in twice-daily fractions of 120 cGy. “Patients also received weekly C225 injections on Monday, beginning 1 week prior to radiation,” Dr. Bonner said.

This was a dose-escalation trial with five treatment groups having three patients in each group. Loading doses ranged from 100 mg/m² to 500 mg/m² of C225. Weekly maintenance doses ranged from 100 mg/m² to 250 mg/m².

A related study confirmed that saturation kinetics occurred with a loading dose of 400 mg/m² and 250 mg/m² weekly dosing, so this schedule was used for treatment group 5. In that group, the radiation schedule was also changed to the twice-daily regimen.

Patients had histologically confirmed stage III (n = 3) or stage IV (n = 13) squamous cell carcinoma that was unresectable. Patients could have had no prior radiation or chemotherapy for active cancer and no previous monoclonal antibody therapy.

Sixteen patients were enrolled, and 14 had evaluable assessment of EGF receptor status. All expressed EGFr.

Unique Side Effects

“The adverse events were similar to what one would expect with an aggressive radiation therapy alone regimen,” Dr. Bonner said. There was one episode of grade 4 mucositis, and one grade 4 allergic response.

“The C225 antibody does have one unique side effect,” he continued. “It causes a follicular rash over the facial and upper thoracic regions. Almost all patients get some rash during the 8-week treatment. It does not interfere with the delivery of radiation to the head and neck region. The rash resolves without scarring when treatment is discontinued.”

Thirteen of the 15 evaluable patients had a complete response to therapy. Two of the 15 had a partial response, for an overall response rate of 100%. “We have nine patients living without evidence of disease, and the 2-year actuarial survival rate is about 60%,” Dr. Bonner said.

He concluded that the regimen has an acceptable safety profile, with 100% response rate and median duration of response of 16.9 months. Seven patients were in complete response at more than 2 years, and nine patients are currently free of disease at greater than 1.5 years.

“Based on this information, we felt that a phase III trial was warranted, and one is ongoing,” Dr. Bonner said.