Colorectal cancer remains a common disease in the United States. The projected incidence for 2007 is 153,760 cases, and 52,180 deaths are expected. Advances were made in the systemic therapy of metastatic colorectal cancer after the introduction of the novel cytotoxics irinotecan(Drug information on irinotecan) (Camptosar) and oxaliplatin(Drug information on oxaliplatin) (Eloxatin), extending median survival for metastatic disease from 9 months with fluorouracil(Drug information on fluorouracil) (5-FU) and leucovorin, to longer than 17 months with first-line use of oxaliplatin together with 5-FU, and longer than 20 months for patients who are well enough to receive, and who have access to, all three drugs at some time in their treatment course.[2-4]
Novel targets are also being explored. A clear survival advantage has been demonstrated for the addition of bevacizumab(Drug information on bevacizumab) (Avastin), a monoclonal antibody that targets the vascular endothelial growth factor (VEGF).* Also active, but less well-studied in front-line therapy, are agents that target the epidermal growth factor receptor (EGFR). Such drugs are the focus of this review.
Epidermal Growth Factor Receptor
The epidermal growth factor receptor (EGFR or HER1) is a 170-kd polypeptide tyrosine kinase growth factor receptor. Along with HER2, HER3, and HER4, it is a member of the HER receptor family and an important mediator of cell proliferation, differentiation, and survival. The extracellular region of the EGFR contains both a ligand-binding domain and a dimerization loop; the tyrosine kinase domain is located in the molecule's cytoplasmic region. A putative nuclear localization sequence has been identified in the juxtamembrane domain. Endogenous ligands include epidermal growth factor (EGF), transforming growth factor (TGF)-alpha, amphiregulin, heparin(Drug information on heparin)-binding EGF, and betacellulin, although the two most important stimulatory ligands are EGF and TGF-alpha.[8-10]
Binding of ligand leads to dimerization of the receptor with another HER molecule, followed by autophosphorylation of intracellular tyrosine residues. Signal transduction cascades via the Ras, ERK1/2, PI3K/Akt, and STAT pathways are activated. Cellular proliferation, adhesion, differentiation, angiogenesis, and apoptosis result.[6,8,10]
Pharmacologic inhibition of EGFR signaling can be achieved through competitive inhibition of ligand-binding, or by direct tyrosine kinase inhibition. Both of these approaches have undergone extensive clinical development. Two monoclonal antibodies that interfere with ligand-binding have been approved for use in metastatic colorectal cancercetuximab (Erbitux) and panitumumab (Vectibix).
Cetuximab (C225, IMC-225) was developed as a human-murine chimeric antibody derived from the murine antibody M225, which binds specifically to the ligand-binding domain of EGFR. Cetuximab(Drug information on cetuximab)-bound EGFR is not available for binding by natural ligand, and ligand-dependent signaling is reduced. Antibody-bound receptor is internalized, albeit by an alternative and possibly slower process than is ligand-bound receptor. Cetuximab upregulates expression of the cell-cycle inhibitor p27(kip1), resulting in G1 arrest. Reduced proliferation, substantial antitumor effect, and enhanced apoptosis have been demonstrated in cetuximab-treated A431 vulvar carcinoma xenografts. The murine antiepidermal growth factor antibody M225, from which cetuximab was derived by chimerization, substantially enhanced the antitumor effects of doxorubicin(Drug information on doxorubicin) in established xenografts of EGFR-expressing tumor cells.
Phase I testing of cetuximab established that therapy with cetuximab is well-tolerated, with acneiform rash and hypersensitivity reactions as the predominant toxicities. Subsequently, hypomagnesemia has also been recognized as an adverse effect of cetuximab. The recommended phase II doses were a loading dose of cetuximab at 400 mg/m2 in week 1, followed by a maintenance dose of 250 mg/m2 given weekly. Clearance was saturated at this dose and schedule, but an optimum biologic dose was not demonstrated, formal determination of the maximum tolerated dose was not achieved, and alternative schedules such as every-other-week dosing are only now being explored.
Cetuximab in Chemotherapy-Refractory Disease
The phase II experience with cetuximab in colon cancer began with testing in patients with irinotecan-refractory disease, at a time when oxaliplatin was not commercially available in the United States. Patients with disease progression on irinotecan-containing therapy continued the dose and schedule of irinotecan given at the time of progression, with the addition of cetuximab. Objective responses were observed in 22% of patients.
This finding was later confirmed in a large randomized phase II study by Cunningham and colleagues, in a similar population of irinotecan-refractory patients. A total of 329 such patients were randomly assigned to receive either cetuximab and irinotecan (218 patients) or cetuximab monotherapy (111 patients). Objective responses were observed in 22.9 % (confidence interval [CI] = 17.5%-29.1%) of patients treated with the combination, compared with 10.8% of those who received cetuximab alone (CI = 5.7%-18.1%, P = .007). Median time to progression was 4.1 months for patients who received the combination, compared with 1.5 months for those who received the monotherapy (P < .001). Median overall survival was 8.6 months in the combination-therapy group and 6.9 months for patients who received cetuximab alone (P = .48).
Similar objective response rates for cetuximab monotherapy were described in two additional studies: a response rate of 9% among 57 patients with irinotecan-refractory metastatic colorectal cancer treated in a multicenter study, and of 11.6% among 346 patients with irinotecan- and oxaliplatin-refractory disease.[20,21]
A randomized trial of irinotecan with or without cetuximab for patients with metastatic, fluoropyrimidine- and oxaliplatin-refractory colorectal cancer has been completed. The study randomized 1,298 patients between irinotecan and irinotecan/cetuximab. Confirmed responses are reported in 4% of irinotecan, and 16% of irinotecan/cetuximab-treated patients. Median progression-free survival was 2.6 months for irinotecan and 4.0 months for irinotecan/cetuximab (hazard ratio [HR] = 0.69, stratified log-rank P < .0001). However, these improved initial outcome measures were not matched by a comparable advance in overall survival: Median survival was 10.0 months for irinotecan-treated patients and 10.7 months for patients who received irinotecan/cetuximab (P = .7). There was no clear explanation for this discrepancyone might hypothesize that the survival impact of cetuximab at the time of progression in the control patients was sufficient for survival to match that seen in patients assigned to early cetuximab. The possibility of postprogression acceleration of disease also cannot be excluded on the basis of these data.
Likewise, a comparison of cetuximab with best supportive care for patients with chemotherapy-refractory colon cancer has also been completed, by the National Cancer Institute of Canada (NCIC) and the Australasian Gastrointestinal Trials Group. Patients who had progressed after (or were not candidates for) treatment with a fluoropyrimidine, oxaliplatin, and irinotecan received cetuximab monotherapy or best supportive care, following random assignment. The median survival for patients receiving best supportive care was 4.6 months, compared with 6.1 months for those receiving cetuximab (HR = 0.77, P = .005).
Activity of the cetuximab/irinotecan combination has also been demonstrated when the agents are given on an every-other-week schedule. In a phase II study enrolling patients who had disease progression after treatment with fluorouracil, irinotecan, and oxaliplatinwithout requiring evidence of EGFR expressioncetuximab was given as a loading dose of 400 mg/m2 in week 1, 250 mg/m2 in week 2, and then 500 mg/m2 every second week. A response rate of 23% and a median time to progression of 4.7 months were observed in 40 patients. These results are similar to the response and progression data obtained with weekly cetuximab added to irinotecan in the Cunningham study described above.