Commentary (Collins/Hurwitz)-Epidermal Growth Factor Receptor Inhibitors for the Treatment of Colorectal Cancer: A Promise Fulfilled?

Damjanov and Meropol have done an excellent job of reviewing both the complex biology of epidermal growth factor signaling and the current status of epidermal growth factor receptor (EGFR, ErbB-1) inhibition for the treatment of colorectal cancer. As they point out, several factors have made EGFR a potentially high-value target in cancer therapy. In addition, they review several phase II studies that have demonstrated clinical activity for anti-EGFR antibodies in patients with advanced colorectal cancer.

One of these agents, cetuximab (Erbitux), was recently approved by the US Food and Drug Administration (FDA) for use in combination with irinotecan (Camptosar) in advanced colorectal cancer. That said, the preclinical promise of EGFR inhibition has not yet been fully achieved in patients. The challenge for researchers in the field now is to answer the question, How can we capitalize on these promising early results?

Improving Results in the Clinic

We can improve the clinical activity of targeted therapies, including EGFR inhibitors, in three primary ways: (1) better selection of patients for characteristics that predict response, (2) development of more effective drugs against a specific target, and (3) the combined use of complementary targeted therapies.

One promise still to be fully realized is the goal of identifying patients who will respond to a given targeted therapy based on the presence of the target itself. In the case of EGFR inhibition, the level of EGFR expression alone has not proven to be predictive of response. This finding is consistent with a complex signaling network, where the activation state of the many pathways may be more relevant than the state of one signaling node in isolation. Part of this difficulty may also relate to the significant heterogeneity in the biology between primary tumors and metastases or among different metastatic sites. With greater experience and improving technologies, the goal is being changed from the search for one factor to the identification of a set of factors or a "molecular fingerprint" that might be used to predict response.

Ongoing Process

The development of more potent inhibitors with more favorable pharmacokinetic properties is an ongoing process. Each molecule has its own unique pharmacokinetic characteristics, which may limit the achievement of ideal tissue drug levels. In addition, there are theoretical reasons why pan-ErbB inhibitors may be more effective than selective EGFR inhibitors. Alternatively, receptor recycling and signaling biology may favor antibody- based approaches in some settings as well.[1]

We still need to learn how to combine this class of agents with existing therapies-either with classical cytotoxic agents or with other targeted therapies. In patients with refractory colorectal cancer, the anti-EGFR antibody cetuximab used as monotherapy had a modest response rate of 10.8%. While this in itself is noteworthy, the results were even better when combined with chemotherapy. Although patients had previously been treated with irinotecan, the combination of cetuximab with irinotecan resulted in a significantly improved response rate of 22.9%,[2] suggesting a favorable interaction with the combination of anti-EGFR therapy and chemotherapy. Interestingly, this pattern of activity appears different from that of gefitinib in non- small-cell lung cancer, where firstline combinations with chemotherapy were no more effective than chemotherapy alone. Elucidating the mechanisms underlying these interactions with chemotherapy will certainly be important to the planning of future clinical trials.

In addition to chemotherapy combinations, there is considerable preclinical rationale for the combination of EGFR inhibitors with other targeted therapies. To some degree, a variety of potential combination strategies should be expected, as tumor growth is dependent upon the disruption of many interrelated pathways. However, a large number of permutations for these combination therapies quickly come to mind, particularly if one considers dose and scheduling issues. As with the combination of EGFR inhibitors and traditional chemotherapy, empiric clinical validation of safety and efficacy is needed for even the most "rational" of combinations. Nevertheless, we are fortunate that these clinical reagents are now available, so that we can address these issues with deliberate and rational approaches.

Conclusions

Although the promise of EGFR inhibition has not yet been fully achieved, we have seen meaningful successes. With the recent FDA approval of cetuximab in combination with irinotecan for colorectal cancer (and gefitinib for non-small-cell lung cancer), there is at least proof of principle for the value of EGFR as a target in human cancer. Clinical trials addressing the role of EGFR inhibitors in other settings and combinations are ongoing. As the number of active agents for colorectal cancer continues to grow, new empiric and mechanism-based combination regimens will need to be evaluated. Recent improvements in imaging, molecular diagnostics, and drug design should help this process. For now, the optimal use of EGFR inhibitors remains a work in progress.

Financial Disclosure: Dr. Hurwitz is a consultant for Genentech.

References:

1.

Arteaga CL: ErbB-targeted therapeuticapproaches in human cancer. Exp Cell Res284:122-130, 2003.

2.

Cunningham D, Humblet Y, Siena S, etal: Cetuximab (C225) alone or in combinationwith irinotecan (CPT-11) in patients with epidermalgrowth factor receptor (EGFR)-positive,irinotecan-refractory metastatic colorectal cancer(MCRC) (abstract 1012). Proc Am Soc ClinOncol 22:252, 2003.