Epidermal Growth Factor Receptor and Epidermal Growth Factor Receptor Therapies in Renal Cell Carcinoma: Do We Need a Better Mouse Trap?

For many patients with metastatic renal cell carcinoma (RCC), successful therapy remains elusive. Despite earlier diagnosis and extensive efforts to develop more effective therapies, the outcome remains poor, with less than 10% of patients with metastases surviving 5 years. 1 Complete resection of metastases can result in long-term survival in some individuals, while removal of the primary tumor in patients with disseminated disease has also been shown to improve survival in selected patients receiving systemic immunotherapy. 2 While cytokine-based immunotherapies with interleukin-2 or interferon-alfa are the mainstays of treatment, response rates are 15% to 20%, and long-term survival rates are 6% to 8%. Thus, the systemic treatment of this disease remains unsatisfactory, and the need for more effective therapies is urgent. The rationale for testing epidermal growth factor receptor (EGFR) inhibitors in patients with advanced RCC is compelling. Multiple studies have documented that the overexpression of EGFR and its ligands epidermal growth factor (EGF) and transforming growth factor-alpha (TGF) in RCC occurs frequently. 3-6 Autocrine and paracrine signaling loops are associated with the development and progression of RCC metastases. 7,8 Most significantly for drug development decisions, EGFR signaling blockade decreases the proliferation of RCC cells in vitro and in vivo. 9,10 Current knowledge regarding the frequency of EGFR expression in human RCC and its successful manipulation in nonclinical human RCC models provides a sound basis for the clinical testing of EGFR inhibitors in RCC patients. However, results from clinical trials evaluating these agents to date have been unimpressive.