Emerging Role of EGF (Epidermal Growth Factor) Receptor-Directed Therapy of Colon Cancer

Walter Sall, MD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: November 12, 2003

Faculty Disclosure: Howard S. Hochster, M.D.
In this presentation by Dr. Hochster there is discussion of cetuximab (C 225) and erlotinib (Tarceva) for the treatment of colorectal cancer which is not FDA approved and gefitinib (Iressa) for the treatment of colorectal cancer which is an off label use.

Presenter: Howard S. Hochster, M.D.
Affiliation: New York University

The epidermal growth factor receptor (erbB1)is a dimeric membrane bound protein responsible for an array of downstream growth factor activation after ligand binding. Its overexpression has been documented in a wide variety of tumor types, including 70% of colorectal cancers. Cetuximab (Erbitux, C225) is a chimeric, monoclonal antibody directed against the extra-cellular domain of the EGFR receptor which prevents ligand binding and receptor activation. In vitro data shows anti-tumor activity of cetuximab, especially in combination with chemotherapy and/or radiation. Small molecule inhibitors of the EGFR tyrosine kinase have also been developed. These agents include gefitinib and erlotinib which bind to the intracellular portion of the EGFR molecule. Because of promising pre-clinical data, many trials of these agents in colorectal cancer have been completed.

Combination cetuximab and irinotecan have been tested in heavily pre-treated patients with at least 1+ EGFR staining by immunohistochemistry. American and European studies show partial response rates of approximately 20% with the combination vs. 11% for cetuximab alone. Toxicity with cetuximab has been mainly limited to acneiform rash. Contrary to expectations, there has been no correlation seen between the level of EGFR expression and response. However, grade III or higher rash has been seen to correlate with a doubling of survival and response rates.

Phase II/III protocols of cetuximab with various chemotherapy regimens are currently underway. The EPIC protocol (CA225-006) will test irinotecan with or without cetuximab. The EXPLORE protocol (CA225-014) will test FOLFOX chemotherapy with or without cetuximab. CALGB 80203 is a 2x2 study of FOLFIRI vs. FOLFOX-4 each arm with a second randomization with or without cetuximab.

Gefitinib (Iressa) is a small molecule EGFR tyrosine kinase inhibitor recently FDA approved for refractory non-small cell lung cancer. It has been found to have a favorable toxicity profile in colorectal cancer both as a single agent and combined with full dose 5-FU/ leucovorin and FOLFOX-4. Minimal objective tumor responses have been seen, however. Phase II studies are underway to better assess response rates. Erlotinib (Tarceva) is another tyrosine kinase inhibitor that has been tested as monotherapy in the phase II setting. No objective responses have been seen to date.

Cetuximab shows very promising activity in chemotherapy refractory colorectal cancer with an 11% response rate as monotherapy and a 20% response rate with irinotecan. It has a favorable toxicity profile when combined with full dose FOLFIRI and IFL chemotherapy regimens. Further phase III data will be required before the role of cetuximab is fully elucidated, especially in light of the impressive results of anti-VEGF antibodies in the same patient cohort. Cetuximab is currently being evaluated by the FDA for the treatment of colorectal cancer.

The role of gefitinib and erlotinib is less clear given the modest activity seen to date. Perhaps combination with chemotherapy will demonstrate a role for these drugs in colorectal cancer.