Multi-targeted inhibition of the epidermal growth factor (EGFR) and vascular endothelial growth factor receptor (VEGFR) pathways: A phase I study of cetuximab (C), erlotinib (E), and bevacizumab (B) in patients with solid tumors

3005 Background: Complex interrelationships exist between the EGFR and VEGFR pathways. EGFR activation elicits cell proliferation, and downstream effects increase expression of VEGF. In renal cell carcinoma, mutations increase hypoxia inducible factor-1alpha, stimulating VEGF and transforming growth factor expression. Moreover, there is additive tumor inhibition from combined EGFR targeting with C, and a tyrosine kinase inhibitor. To maximally inhibit EGFR, and then inhibit downstream VEGFR activity, this phase I study was initiated to determine the maximum tolerated dose (MTD) of E with a fixed dose of C, and then the MTD of B with combined E and C in patients with advanced malignancies. Methods: Patients with advanced malignancies likely to express EGFR were entered in part 1 to daily oral E (starting at 100mg, planned initially to increase to 150 mg), with fixed dose C (400 mg/m2 loading and 250 mg/m2 IV weekly). Once the MTD was determined for E in combination C, part 2 incorporated the addition of es...