Commentary (Rudin): Targeting the Epidermal Growth Factor Receptor

The epidermal growth factor receptor (EGFR) is expressed in essentially all head and neck squamous cell carcinomas, and in the large majority of non-small-cell lung carcinomas (NSCLC). EGFR is a key regulator of both proliferative and survival signaling pathways, implicated in the processes of carcinogenesis, invasion, and metastasis. It has been characterized as a determinant of metastatic potential and as a prognostic factor. As noted in the review by Saba et al, EGFR has also been exploited as a therapeutic target. High-specificity inhibitors including monoclonal antibodies and small-molecule tyrosine kinase inhibitors demonstrate significant antitumor activity in several clinical contexts.

Targeted Therapy

The promise of targeted therapy is the potential for individualized treatment focused on the key molecular alterations found in particular cancers. The clinical development of EGFR-targeted therapeutics illustrates the difficulty in defining the subset of individuals likely to benefit even from high-specificity inhibitors of well-defined molecular targets. A partial list of NSCLC patient characteristics suggested as determinants of sensitivity to the EGFR small-molecule inhibitor erlotinib (Tarceva) includes female gender, Asian ethnicity, minimal tobacco exposure, adenocarcinoma histology (particularly with bronchoalveolar features), development of a skin rash, EGFR overexpression or gene amplification, site-specific EGFR mutation, and EGFR-dependent activation of particular downstream signal transducers such as Akt and/or STAT3.

Among these features, the identification and characterization of somatic activating mutations by several research groups in 2004 generated the greatest initial interest as a defining characteristic of patient benefit.[1-3] Among the tumor types responsive to EGFR-targeted agents, preliminary data suggest that characteristic somatic EGFR mutations may be limited to lung cancers. In patients with NSCLC, EGFR mutations were found with increased frequency in women, Asians, nonsmokers, patients with adenocarcinomas, and most notably, patients with dramatic objective tumor response.

Emerging data from several groups has called into question the singular importance of EGFR mutation. Cappuzzo and colleagues recently reported that tumor classification by EGFR expression and gene amplification, based on immunohistochemistry and fluorescence in situ hybridization, was more predictive of patient survival than EGFR mutational status.[4] Retrospective analysis of tumor blocks from a subset of NSCLC patients treated on the definitive phase III BR.21 study comparing erlotinib to placebo failed to demonstrate a significant difference in outcome based on mutational status or EGFR expression, and showed a difference of borderline significance for gene amplification.[5] From the same data set, Clark and colleagues reported that, in fact, smoking history was the strongest predictor of survival among multiple factors analyzed.[6] Ad hoc subset analysis of outcome from the BR.21 study suggests a survival advantage for erlotinib recipients even among male smokers with squamous cell carcinoma-a population that would be expected to contain few if any subjects with receptor mutations.

Taken together, these retrospective analyses seem to have muddied what appeared to be clear waters regarding molecular profiling of candidates for EGFR-targeted small-molecule inhibitors. Defining a subset of patients appropriate for EGFR inhibitor therapy remains an unresolved challenge. Even for EGFR, among the best defined growth factor receptors in cancer biology and the focus of intensive interrogation over several years, the clinician is in general left giving supposedly targeted therapy without in fact knowing how to target the therapy.

Rash and Outcome

One of the more intriguing and unexpected clinical observations regarding EGFR-targeted therapy has been the association of clinical benefit with development of a skin rash. Median survival of a cohort of NSCLC patients treated with erlotinib who failed to develop a rash was a dismal 1.5 months, for those with a grade 1 rash was 8.5 months, and for grade 2/3 rash 19.6 months.[7] This was notably a retrospective analysis of a relatively small data set (N = 57), but these differences are highly statistically significant and supported by other data. A similar statistically significant association between rash and survival has been noted for patients with head and neck squamous cell carcinomas and ovarian cancer treated with erlotinib. The correlation between skin rash and patient benefit appears to extend across classes of EGFR-targeted agents: The same observation has been made in patients treated with the anti-EGFR monoclonal antibody cetuximab (Erbitux).

The biology underlying this purely clinical observation has not been defined. One explanation that has been offered is that patients incapable of mounting a robust rash may be in some way more immunologically compromised. It is not clear, however, that the rash is immunologically mediated. The consistent distribution of rash across studies in different diseases, in different stage of disease, and across performance status would appear to argue against this notion. Prospective trials testing hypothesized correlates with rash, including pharmacokinetic variability, differential pharmacodynamic effects, and pharmacogenomic differences either within the target gene EGFR or in other genetic loci have recently been completed, and correlative analyses are in progress. Ongoing clinical trials (including the current first-line NSCLC trial by the Eastern Cooperative Oncology Group) are testing one possible interpretation of this correlation-that rash serves as a cheap and dependable pharmacokinetic biomarker and a guide to appropriate dose, whereby patients should be individually dose-escalated to the development of at least a grade 2 rash.

Summary

As outlined by Saba et al, the identification of EGFR as a biologically relevant cancer target, and the development of multiple high-specificity inhibitors of this target is unquestionably a great success story for the field of molecularly targeted therapeutics. These agents offer a clear and meaningful survival benefit to patients with cancers of the lung, head and neck, and colon. Compared with traditional cytotoxics, these targeted agents, as advertised, also offer less toxic therapeutic options.

The flip side of the advertisement-that molecularly targeted therapy will offer highly refined individualized therapy-has not yet been fulfilled. Ongoing work by multiple groups, including analyses of genetic and epigenetic factors, gene-expression profiles, and proteomic profiles of tumor and patient serum, may help to further guide the administration of targeted therapy.

-Charles M. Rudin, MD, PhD

Disclosures:

The author(s) have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

1. Lynch TJ, Bell DW, Sordella R, et al: Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350:2129-2139, 2004.

2. Paez JG, Janne PA, Lee JC, et al: EGFR mutations in lung cancer: Correlation with clinical response to gefitinib therapy. Science 304:1497-1500, 2004.

3. Pao W, Miller V, Zakowski M, et al: EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci U S A 101:13306-13311, 2004.

4. Cappuzzo F, Hirsch FR, Rossi E, et al: Epidermal growth factor receptor gene and protein and gefitinib sensitivity in non-small-cell lung cancer. J Natl Cancer Inst 97:643-655, 2005.

5. Tsao MS, Sakurada A, Lorimer I, et al: Molecular analysis of the epidermal growth factor receptor gene and protein expression in patients treated with erlotinib in National Cancer Institute of Canada Clinical Trials Group trial BR.21 (abstract 7007). J Clin Oncol 23(16S):622s, 2005.

6. Clark GM, Zborowski D, Santabarbara P, et al: Smoking history is more predictive of survival benefit from erlotinib for patients with non-small cell llung cancer than EGFR expression (abstract 7033). J Clin Oncol 23(16S):628s, 2005.

7. Perez-Soler R, Chachoua A, Hammond LA, et al: Determinants of tumor response and survival with erlotinib in patients with non-small-cell lung cancer. J Clin Oncol 22:3238-3247, 2004.