New Issues on Cetuximab Mechanism of Action in Epidermal Growth Factor Receptor–Negative Colorectal Cancer: The Role of Vascular Endothelial Growth Factor
Authors: Bruno Vincenzi, Daniele Santini, Giuseppe Tonini
Journal: Journal of Clinical Oncology (2006)

Cetuximab is a chimeric immunoglobulin G1 (IgG1) monoclonal antibody that binds to epidermal growth factor receptor (EGFR) with high specificity and with a higher affinity than epidermal growth factors, thus blocking ligand-induced phosphorylation of EGFR. 1 Cunningham et al 2 evaluated cetuximab alone and cetuximab plus irinotecan in patients with irinotecan-refractory colorectal cancer in a phase III trial.The response rates were 10.8% for cetuximab alone and 22.9% for cetuximab plus irinotecan.Moreover, cetuximab seems able to enhance the effects of irinotecan in experimental systems. 3Although cetuximab is indicated only for patients affected by tumors that overexpress EGFR, Chung et al 4 recently demonstrated that patients who appear to lack EGFR expression showed clinical response to cetuximab.Possible causes for this paradox include false-negative results because of poor sensitivity in the detection system, heterogeneity of EGFR expression within the tumor, and specific mutations that mediate response to the tyrosine kinase inhibitors.An unknown mechanism of action of cetuximab may represent another plausible explanation for this paradox.We evaluated modifications in circulating levels of vascular endothelial growth factor (VEGF) in a homogenous cohort of EGFRnegative, advanced-stage colorectal cancer patients treated with cetuximab (400 mg/m 2 once followed by weekly infusions of 250 mg/m 2 ) plus irinotecan (90 mg/m 2 weekly).All patients had previously received and progressed after one oxaliplatin-based chemotherapy regimen (capecitabine plus oxaliplatin or FOLFOX intravenous regimen as first-line therapy) and one irinotecan-based chemotherapy regimen (FOLFIRI regimen as second-line therapy) for at least 2 months.All patients lacked immunohistochemical evidence of EGFR expression as measured semiquantitatively in a single reference laboratory (University Campus Bio-Medico, Rome, Italy).These measurements were performed and graded using a commercially available kit (EGFRpharmDx; Dako Corp, Carpentino, CA) according to the manufacturer's instructions.We performed the present study to determine if significant VEGF modifications occur in EGFR-negative patients treated with weekly cetuximab plus irinotecan and if these modifications correlate with clinical tumor response and outcome.We evaluated 10 EGRF-negative, advanced-stage colorectal cancer patients (median age, 69 years; female, n ϭ 6; male, n ϭ 4).In six patients, we recorded a greater than 50% (range, 53% to 89%) reduction of VEGF circulating levels at 21, 50, and 90 days after the first infusion.In the other four patients, we failed to record a similar VEGF reduction (range, 2% to 35%).Three of six patients who achieved at least 50% VEGF reduction showed a partial response as the best response during treatment with cetuximab plus irinotecan.Two other patients showed disease stabilization, and only one patient showed evidence of disease progression.On the contrary, none of the four patients without significant VEGF reduction showed a tumor response; one patient remained stable, and three showed evidence of disease progression.Patients with substantial VEGF reduction showed a median disease-free progression of 6.5 months (range, 3.7 to 10.9 months), compared with 3 months (range, 2.5 to 4.5 months) in patients without significant VEGF reduction.Patients with significant VEGF reduction also showed a greater overall survival than those without (14.0 and 6.5 months, respectively).The present data, even if obtained in a small population, suggest that cetuximab may induce VEGF modifications in EGFR-negative colorectal cancer patients and that these changes may be partially responsible for the clinical efficacy of cetuximab in these patients.This evidence should be carefully considered in the complex treatment of EGFR-negative colorectal cancer patients; it could lead to a reconsideration of cetuximab use in such a population.