PHILADELPHIA-In a phase III randomized trial, the addition of cetuximab(Drug information on cetuximab) (Erbitux) to standard radiotherapy resulted in improved locoregional disease control and enhanced survival in patients with advanced squamous cell carcinoma of the head and neck, according to a poster presentation (poster B106) at the annual AACR/NCI/EORTC International Conference on Molecular Targets and Cancer Therapeutics.
The initial 38-month results of this trial were presented at ASCO in 2004. The current report, based on a review by an independent committee and with nearly 1 year of additional follow-up, "continues to demonstrate significant benefit in survival and locoregional disease control" with cetuximab added to radiotherapy, said principal investigator James A. Bonner, MD, professor and chairman, Department of Radiation Oncology, University of Alabama at Birmingham. Furthermore, cetuximab did not exacerbate the most debilitating toxicities commonly associated with radiotherapy of the head and neck.
"This report represents the first showing improved efficacy for radiotherapy when it has been combined with a new targeted therapy," Dr. Bonner said. Cetuximab is a monoclonal antibody that blocks the epidermal growth factor receptor (EGFR), which is highly expressed by cancer cells and is an adverse prognostic marker in carcinoma of the head and neck. Preclinical studies indicated that EGFR blockade leads to radiosensitization of cancer cells via a mechanism not yet completely characterized.
Participants in the phase III trial were 424 patients with resectable or unresectable locoregionally advanced (stage III or IV) head and neck carcinoma. Patients were randomly assigned to receive individualized definitive radiotherapy alone or with cetuximab. The antibody was administered at 400 mg/m2 IV one week before beginning radiotherapy and then 250 mg/m2 every week throughout radiation treatment. Radiotherapy could be given once daily, twice daily, or as a concomitant boost.
Treatment outcome was analyzed after a median follow-up of 45 months by an external committee blinded to patients' treatment assignment, using prospectively developed uniform guidelines. According to this analysis, the addition of cetuximab to radiotherapy was associated with a longer median duration of locoregional control, the primary study outcome. Control was achieved for a median of 24.4 months with radiation plus cetuximab vs 14.9 months for radiation alone (P = .005). Adding cetuximab to radiotherapy reduced the risk of locoregional failure by 32%.
Median overall survival was increased by 19.7 months, from 29.3 months with radiation alone to 49 months with the addition of cetuximab (P = .03), representing a 26% reduction in the risk of mortality from this disease. Survival rates at 3 years were 45% with radiation alone and 56% with radiation plus cetuximab.
"These end results are of substantial clinical significance for patients with this disease," Dr. Bonner said in a press conference. Furthermore, the frequency of most grade 3-4 toxicities was similar in the two treatment groups except for the previously reported increase in acneiform rashes and infusion reactions that occurred with cetuximab. "Therefore cetuximab can be given with radiation therapy and not accentuate the toxicities that are most likely to inhibit adequate delivery of this therapy," he said. In addition, the trial showed that cetuximab can be given with once- or twice daily radiotherapy, Dr. Bonner said. A recent meta-analysis showed a survival advantage for twice-daily (or altered fractionated) radiotherapy.
It is not clear whether cetuximab can enhance the effects of other, more aggressive treatments that may be used in these patients with advanced disease. "It is our belief these results will provide additional therapeutic options for patients with locoregionally advanced head and neck carcinoma," possibly using radiation plus cetuximab as a basis for more aggressive approaches, he said.
Cetuximab, currently approved in combination with irinotecan(Drug information on irinotecan) (Camptosar) to treat metastatic colorectal cancer, was accepted by the FDA for priority review of the new indication for head and neck cancer on October 31, 2005.