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Stimulation of the epidermal growth factor receptor (EGFR) activates several proliferative signaling pathways that are associated with anti-apoptotic, pro-proliferative signaling processes. This pathway is among the most advanced in targeted therapy development. It can be interrupted with monoclonal antibodies that block EGFR on the cell surface or by inhibiting the intracellular tyrosine kinase, the enzyme activated by EGFR stimulation (Figure 1).

Source: Reproduced with permission of Bristol-Myers Squibb Oncology.

"Given the potential for anti-apoptotic, pro-proliferative signaling, and given the observation of frequent EGFR expression in a variety of malignancies, the EGFR has become a prime target for therapeutic intervention in clinical oncology in general, and in gastrointestinal oncology in particular," reported Leonard B. Saltz, MD, at the 20^th annual meeting of the Chemotherapy Foundation. Although Dr. Saltz was concentrating on the potential for targeted EGFR therapies in colorectal cancer, he acknowledged that overexpression of EGFR is common in a wide variety of other solid tumors.

EGFR Overexpression: A Poor Prognostic Marker
EGFR overexpression is not only common but also a poor prognostic marker in colorectal, head and neck, non-small cell lung cancers (NSCLC), and cancers of the breast, bladder, and pancreas. The premise that overexpression of EGFR facilitates processes that allow tumor cell proliferation is supported by preclinical trials that have associated monoclonal antibody blockade of EGFR with dramatic downregulation of cell growth (Table 1).

Source: Reproduced with permission of Bristol-Myers Squibb Oncology.

EGFR Targeted Therapies Not Interchangeable
Although monoclonal antibodies targeted to the EGFR and tyrosine kinase inhibitors that prevent EGFR stimulation of protein phosphorylation work along the same pathway, it is likely that these are not interchangeable. One reason is that inhibition at different points along the pathway may have different effects on feedback or compensatory signaling. Although there are no direct clinical comparisons of monoclonal antibodies and tyrosine kinase inhibitors, independent studies suggest that anti-tumor effects may be different.

"Different EGFR antagonist agents may have different activity spectra. I don't think we can be comfortable that one agent is interchangeable with another or that the tyrosine kinase inhibitors are interchangeable with the antibody receptor blockers. We simply do not know the answers," Dr. Saltz reported.

Response Rates in Colorectal Cancer Trials
In phase I and II trials of colorectal cancer, objective response rates are more pronounced with monoclonal antibodies directed at EGFR than small molecules that inhibit tyrosine kinase. Patients who had previously not responded to irinotecan (CPT-11) showed a 23% objective response rate in a phase II trial of cetuximab combined with irinotecan. This result led to a large randomized phase III trial of cetuximab in 300 irinotecan-refractory patients. The study is nearing completion, and will be followed by a second phase III trial of cetuximab in 1,900 patients on one of two 5-fluorouracil (5-FU)-based regimens.

In contrast, results in colorectal cancer with ZD-1839, a tyrosine kinase inhibitor, "have been a little less exciting. So far, there have not been any major overt objective responses in 2 small phase III trials, although there have been some minor responses and stabilization of disease," Dr. Saltz reported. Two ongoing phase II trials of OSI-774, another tyrosine kinase inhibitor, show "no major objective responses". A study combining OSI-774 with a 5-FU-containing chemotherapy regimen is planned.

"The monoclonal antibodies targeted at EGFR and the small molecule inhibitors of tyrosine kinase represent completely different drug classes and should not be lumped together," suggested Robert A. Figlin, MD, from the David Geffen School of Medicine, University of California, Los Angeles. Although these agents inhibit the same pathway, there is a difference in their effects and their potential benefits.

Monoclonal antibodies and tyrosine kinase inhibitors have unique activities. This is further supported by preliminary evidence showing additive benefits of both types of agents when used in combination. The combined use of monoclonal antibodies and small molecule inhibitors of tyrosine kinase is an intriguing avenue for future research as it has the potential to more completely suppress the EGFR signaling pathway as well as related signaling events.

Potential Differences Between Classes of Anti-EGFR Agents
Monoclonal antibodies for EGFR may not only differ from tyrosine kinase inhibitors but also from each other. While cetuximab is the most advanced in clinical testing, another monoclonal antibody, ABX-EGF has entered clinical testing. However unlike cetuximab, ABX-EGF has not been shown to date to have an effect on the immune system to produce antibody-dependent cellular toxicity, according to Dr. Figlin. He suggested that this difference might prove to be clinically meaningful. At this time, however, there are no direct comparisons between the cetuximab and ABG-EGF antibody therapies.

The tyrosine kinase inhibitors now in clinical trials, ZD-1839 and OSI-774, appear to be far more similar in their characteristics and mode of action than monoclonal antibodies in development. While tyrosine kinase inhibitors have not been compared directly against each other either, there are a number of potential variables, such as relative ability to reach the intracellular space, which could affect their clinical activity. One side effect of all agents that target the EGFR pathway is an acneiform skin rash. This side effect may be considered a surrogate marker for relative inhibition of EGFR, and several trials have demonstrated a correlation between the grade of skin rash and clinical response rates.

Unanswered Questions to Consider
A number of important questions regarding clinical applications of EGFR antagonists remain unanswered. For example, it is not known yet whether a high degree of EGFR expression in the target tumor is necessary for these agents to be active. In addition, it is likely that the role of these agents will evolve as they continue to be studied. Another question concerns the combined use of EGFR antibodies and tyrosine kinase inhibitors. While there is compelling experimental evidence that these agents are more effective when used in combination, the direction of research must be first to apply them in conjunction with conventional chemotherapy, Dr. Saltz said.

"EGFR antagonists will have a role in the treatment of gastrointestinal malignancies," Dr. Saltz reported, adding that trials are moving in a positive direction to identify the specific clinical application of these agents.

A similar statement might be appropriate for a wide variety of other cancers in which EGFR appears to be a mediator of tumor cell proliferation. Response rates with cetuximab, ABX-EGF, ZD-1839 and OSI-774 in pancreatic cancer, renal cell carcinoma, and lung cancer have been modest. Nonetheless, they are impressive, considering they were tested in advanced stages of these malignancies. Objective responses have been seen even in patients who are highly resistant to conventional cytotoxic agents. Recounting a "striking" response in one irinotecan-refractory patient who received cetuximab on a compassionate basis, Dr. Saltz suggested that these drugs have the potential to prolong the lives of patients.

Key Points In Focus:

The EGFR pathway is one of the most rapidly advancing areas of targeted therapy. Large, randomized trials are underway or planned for cetuximab, ZD-1839, and OSI-774 in colorectal cancer and in a variety of solid tumors.
Although the monoclonal antibodies cetuximab and ABX-EGF and the tyrosine kinase inhibitors ZD-1839 and OSI-774 target the EGFR pathway, their clinical effects may not be interchangeable. Significant clinical differences may exist between or even within these different anti-EGFR agents.
There are now a number of clinical trials investigating the effect of cetuximab in combination with currently available chemotherapy regimens, including a 1,900-patient phase III trial in patients with advanced colorectal cancer with cetuximab. However, there is also significant interest in developing combination regimens that include both monoclonal antibodies directed against the EGFR and small molecule inhibitors of tyrosine kinase as well as with other targeted therapies.

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