A phase I trial finds that the combination of cetuximab (Erbitux) and gefitinib (Iressa) produces responses in patients with advanced solid cancers expressing the epidermal growth factor receptor (EGFR)—especially colorectal cancer.
ATLANTAA phase I trial finds that the combination of cetuximab (Erbitux) and gefitinib (Iressa) produces responses in patients with advanced solid cancers expressing the epidermal growth factor receptor (EGFR)especially colorectal cancer. José Baselga, MD, of Vall d'Hebron Hospital, Barcelona, presented the results at the American Society of Clinical Oncology 42nd Annual Meeting (abstract 3006).
The rationale for combining cetuximab (an anti-EGFR monoclonal antibody) and gefitinib (an anti-EGFR tyrosine kinase inhibitor) in the clinical setting was strong evidence of synergy of the combination against EGFR-positive tumors in preclinical studies.
The study included patients with advanced, EGFR-expressing colorectal cancer (24 patients), head and neck cancer (17), or non-small-cell lung cancer (17) that had not responded to standard therapy. Patients could not have received any prior anti-EGFR therapy.
They were given cetuximab monotherapy (400 mg/m2 IV loading dose, 250 mg/m2 IV weekly dose), gefitinib monotherapy (250 mg PO daily), or combination therapy according to a set of dose escalation schemes (cetuximab loading dose, 320 to 400 mg/m2; cetuximab weekly dose, 200 to 250 mg/m2; gefitinib, 100 to 500 mg daily). Thus far, 43 patients have been treated, including three newly enrolled in the expansion study.
Among the 40 patients in the initial study, dose-limiting toxicities during the first 28 days of treatment included grade 4 interstitial lung disease with gefitinib monotherapy, and grade 3 reversible deafness, anorexia, nausea, and fatigue with combination therapy. Dose-limiting toxicities documented after that period were grade 3 anorexia and fatigue with the combination.
Based on the results, Dr. Baselga said, "the recommended dose of both agents is the same as when administered as single agents, so we can give the full dose of both therapies." As expected, skin rash was the most common toxicity, but it was not dose-limiting in any cases.
Colorectal Cancer Responses
Among the 40 evaluable patients, the overall response rate was 21%, he reported. When the analysis was restricted to the 26 patients given combination therapy, the rate increased to 28%. More strikingly, Dr. Baselga noted, the overall response rate was 32% in all 21 patients with colorectal cancer, and 50% in the 11 given the combination.
"If you compare this rate with historical data in colorectal cancer, with cetuximab as a single agent, the response rate is in the range of 10%, and with gefitinib the response rate is 0%," he said. Dr. Baselga added that the study is being expanded to include 20 additional patients with colorectal cancer.
Results concerning tumor markers are preliminary, Dr. Baselga cautioned, but thus far, significant differences in tumor protein expression across treatments favoring combination therapy over monotherapy have been found for pAKT, the proliferation marker Ki-67, and the apoptosis marker TUNEL.
Early data suggest that responders share a specific "gene signature," Dr. Baselga said. Gefitinib monotherapy was associated with a change in expression of 111 genes; cetuximab monotherapy, 221 genes; and combination therapy, 311 genes. "There is some overlap, but not much," he said. "That to me is an indication that these therapies are probably working through nonoverlapping mechanisms of action, or at least partially nonoverlapping mechanisms."