Irinotecan Plus Cetuximab Shows Promise Against Colon Cancer

NEW YORK CITY—Promising early data are emerging from a phase II colon cancer trial of irinotecan (Camptosar) plus cetuximab (IMC-C225), a chimeric monoclonal antibody that targets the epidermal growth factor receptor (EGFR), reported Leonard Saltz, MD. He is associate attending physician on the Gastrointestinal Oncology Service at Memorial Sloan-Kettering Cancer Center in New York City.

EGFR is emerging as an important area of colon cancer research because preventing activation of this receptor prevents transduction of signals that favor cell growth and survival. Current attempts to block EGFR function include monoclonal antibodies and tyrosine kinase inhibitors (both of which block signal transduction), toxin conjugates (which cause cell death after they are internalized), and antisense molecules (which interfere with protein synthesis).

Cetuximab blocks the binding of growth factor to the receptor and prevents tyrosine kinase-mediated cell signaling. The rationale for combining cetuximab with irinotecan was preclinical evidence of synergy between the two compounds. "There was also a striking response in irinotecan-refractory patients that received cetuximab plus irinotecan on a compassionate release protocol," Dr. Saltz said.

Updated Data

Dr. Saltz updated data from a phase II irinotecan/cetuximab study he presented earlier this year at the American Society of Clinical Oncology annual meeting. The trial included 120 patients with documented progressive disease on irinotecan and a parallel group of 18 patients who had stable disease on irinotecan. Dr. Saltz said the stable-disease group was included in the protocol "to keep the study group pure for irinotecan resistance."

All patients had measurable metastatic colorectal cancer and EGFR expression on tumor samples documented by immunohistochemistry. Patients had no intercurrent chemotherapy between irinotecan failure and protocol entry.

Patients were treated with cetuximab plus the same dose and schedule of irinotecan on which they had previously progressed. Patients were premedicated with diphenhydramine, and cetuximab was given as a 20 mg test dose on day 1, followed by a 400 mg/m² loading dose and then biweekly doses of 250 mg/m².

Treatment of previously irinotecan-resistant patients with cetuximab plus irinotecan produced partial responses in 27 (22.5%, 95% CI 15%-31%) and stable disease lasting a minimum of 12 weeks in 9 (7%). Median duration of response in the 27 responding patients was 186 days.

Response did not appear to vary with increasing intensity of EGFR expression. Dr. Saltz said that a simple positive/negative EGFR assessment is currently the most useful in clinical terms. EGFR quantitation is currently not well standardized.

The investigators also hope to test cetuximab/irinotecan in EGFR-negative patients, since low levels of EGFR expression might be associated with even more response to EGFR-blockade if lower levels of EGFR are associated with fewer cell-signaling pathways to block.

The investigators saw responses in both the weekly and q30 day schedules of C225. "We saw responses in large refractory tumors. These were not small, equivocal responses," Dr. Saltz said. These included responses in patients who had hepatic metastases and pulmonary metastases.

Reduced Toxicity

Toxicity in this trial was less than in previously published studies of irinotecan as first-line or second-line single-agent therapy. "These problems were well within the degree of toxicity we expect for regimens we currently use in treating colorectal cancer," Dr. Saltz said. Toxicity of irinotecan does not appear to be increased by concurrent administration of cetuximab.

Cetuximab was associated with grade 3/4 allergic reactions that required discontinuation of therapy in 3% of patients. These occurred primarily on the first day of treatment. Cetuximab was also associated with an acne-like skin rash that caused grade 3 itching or pain in 12% of patients. Dr. Saltz said that the rash may actually be a positive response indicator, since 29% of patients who developed the rash had antitumor responses, compared to one patient who did not develop the rash.

"This acneiform skin problem appears to be a class phenomenon with EGFR-targeted agents," Dr. Saltz said. "It suggests that there is a narrow therapeutic window, and patients may have to tolerate the rash to get the benefits."