Originally published as JCO Early Release 10.1200/JCO.2004.04.934 on June 21 2004

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

Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Rockville, MD

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.

In this issue of the Journal of Clinical Oncology, Rowinsky et al describe the results of a phase II study¹¹ of the monoclonal EGFR-targeting antibody ABX-EGF, a high-affinity human monoclonal antibody produced by a genetically engineered mouse. ABX-EGF blocks ligand binding and promotes rapid internalization of the receptor. In this well-executed study, 88 patients for whom immunotherapy had failed or was contraindicated were treated with ABX-EGF doses of 1.0, 1.5, 2.0, or 2.5 mg/kg weekly. Of the 76 patients tumors tested for EGFR, 91% expressed the receptor; 90% of patients had a prior nephrectomy; and 85% of patients had received prior interleukin-2. Three patients had objective tumor responses, and the median progression-free survival (PFS) was 100 days (95% CI, 58 to 150 days). There was no correlation between dose and response; however, compared with patients with clear-cell histology, those with non–clear-cell carcinomas were more likely to have objective responses (two of 14 patients v a presumed, but not explicitly stated, one of 74 patients) and longer median PFS (92 v 56 days), albeit the latter comparison is not statistically significantly different between the subgroups. Interestingly, 100% of patients treated at the highest dose level developed acneiform rash, with a trend toward longer PFS in patients with more severe rash.

What conclusions may be drawn from this study? First, ABX-EGF is well tolerated and has predictable and consistent pharmacokinetics. The incidence of severe rash is slightly higher than reported with other EGFR inhibitors, with 90% of patients expected to have rash at doses 1.5 mg/kg. Second, the correlation between severity of rash and survival is consistent with other uncontrolled trials of EGFR inhibitors¹² and may be a marker predictive of therapeutic effect or underlying patient prognosis. However, a retrospective comparison of patients with rash and longer survival, with patients without rash and poor survival, is inherently biased, as those patients with the least favorable prognosis are unlikely to remain on study long enough to develop rash or have rash reported as an adverse event. Only randomized studies comparing patients administered escalating doses of EGFR inhibitor to intolerable rash compared with those with less frequent or severe rash due to less intensive EGFR inhibitor dosing, or treatment to maximum rash followed by randomization to continue or discontinue EGFR inhibitor could definitively address the value of rash as a possible predictive marker of clinical benefit of these agents. Third, single-agent activity of EGFR inhibitors in RCC patients with metastatic clear-cell carcinomas is limited, and activity in patients with papillary carcinomas is uncertain. Fourth, the single-agent activity of EGFR inhibitors in RCC patients with papillary histology requires further evaluation; however, further evaluations of EGFR inhibitors in clear-cell carcinoma patients should be limited to studies of combinations selected based on compelling data from nonclinical studies.

ABX-EGF is the third agent targeting EGFR to be tested in patients with RCC, and the third to yield unimpressive single-agent results.^13,14 The single complete response seen in a patient with clear-cell carcinoma reported in the Rowinsky study is intriguing, as it is the first objective response seen among RCC patients with this histology treated on EGFR-inhibitor trials. This response may reflect the antitumor effect of ABX-EGF; however, a 6.6% response rate has been reported from a randomized trial of RCC patients with metastases without systemic treatment.^15,16 Thus, the possibility of a spontaneous remission cannot be excluded. The low response rate and relatively short PFS seen in the Rowinsky study is consistent with the results of other phase II EGFR-inhibitor studies. There were no objective responses, and the median time to progression was 57 days among 54 RCC patients treated with cetuximab.^13,14 Similarly, none of the 18 patients treated with gefitinib 500 mg daily had complete or partial responses, and 13 (81%) of 18 patients had progressive disease within 4 months of start of therapy.¹³ Unfortunately, neither of these reports describes the histological subtypes of tumors among the enrolled patients. However, it is likely that the majority of patients on these two studies had clear-cell carcinomas, found in 75% to 85% of tumors, rather than papillary carcinomas, which occur in 14% of renal cancers.¹⁷

Why have EGFR inhibitors failed to induce objective responses or delay progression in significant numbers of RCC patients? Certainly, the molecular heterogeneity of RCC likely contributes to the low frequency of activity of single-agent EGFR inhibitors. Activating mutations or amplification of EGFR are rarely seen, and EGFR is only one of many growth factors expressed in RCC. If aberrant EGFR signaling is not driving tumor proliferation, it is unlikely that solely inhibiting the receptor will have antitumor activity. In addition, the frequent biallelic silencing of the von Hippel Lindau (VHL) tumor suppressor gene in clear-cell, relative to papillary tumors,^18,19 may contribute to the relative resistance of clear-cell carcinomas to EGFR inhibitors. Loss of VHL protein function is associated with dysregulation of the transcription factor hypoxia-inducible factor and constitutive expression of mRNAs encoding hypoxia-inducible proteins, including vascular endothelial growth factor (VEGF), and the EGFR ligand TGF.^20,21 Generation of TGF and VEGF as a consequence of VHL inactivation in renal epithelial cells may provide the uncontrolled growth stimulus necessary for the initiation of tumorigenesis.²¹ However, inhibiting EGFR may not sufficiently disrupt signaling through this paracrine loop to result in antitumor activity. One in vitro study showed that cetuximab caused only a modest decrease in growth rate of clear-cell RCC-derived cell lines lacking VHL in contrast with non–clear-cell RCC-derived cell lines that retained VHL.²² Transfection of VHL into VHL-negative RCC cell lines restored responsiveness to cetuximab, indicating that this tumor suppressor gene is required for effective EGFR blockade. Additional nonclinical studies have reported that acquired resistance to anti-EGFR antibodies in vivo can emerge by selecting tumor cell subpopulations with increased angiogenic potential through elevated expression of VEGF,²³ and that dual inhibition of EGFR and VEGF may overcome resistance to EGFR inhibitors.²⁴

These nonclinical studies suggest that EGFR inhibitors are unlikely to have significant antitumor effects in patients with clear-cell carcinomas with VHL mutations due to dysregulated expression of proteins normally under VHL control; they may, however, have greater potential for benefit to those patients with papillary carcinomas with wild-type VHL. The activity of the EGFR inhibitor erlotinib in patients with papillary carcinomas is being assessed in Southwest Oncology Group study S0317. For RCC patients with clear-cell histology, combining agents targeting both VEGF and EGFR may be more effective, and is a strategy being tested in a phase II trial of erlotinib and bevacizumab (http://www.ClinicalTrials.gov), and, arguably, in the phase III study of BAY 43-9006, an agent that inhibits Raf kinase, a downstream protein of EGFR signaling pathway and VEGF receptor-2 (http://www.ClinicalTrials.gov). Rather than inhibiting growth factors, potentially greater benefit may be derived from directly inhibiting hypoxia-inducible factor, and the identification of molecules that inhibit this target is being pursued. Leads generated from studies of RCC pathophysiology will likely identify additional targets of therapeutic interest. A more comprehensive understanding of the spectrum of proliferative, survival, resistance, and antiapoptotic pathways will undoubtedly lead to more efficient clinical therapeutics development, and to improved survival for patients with metastatic RCC.

Author's Disclosures of Potential Conflicts of Interest

The author indicated no potential conflicts of interest.

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