Small molecule epidermal growth factor receptor (EGFR) tyrosine kinase (TK) inhibitors (erlotinib - Tarceva and  gefitinib - Iressa) were initially developed for use as second-line therapy after failure with a cytotoxic chemotherapy regimen. In this setting, erlotinib was shown to increase survival, with the magnitude of benefit similar to that with second-line chemotherapy. Multiple clinical and molecular markers are useful in predicting which patients are most likely to benefit from therapy with this class of agents, both for the initial and second-line therapy in patients with advanced NSCLC.

Abnormalities in several cell signaling pathways have been identified in NSCLC.  Briefly, tumor growth and progression are dependent upon the activity of cell surface membrane receptors that control the intracellular signal transduction pathways regulating proliferation, apoptosis, angiogenesis, adhesion, and motility. One such family of cell surface receptors is the receptor tyrosine kinases (TKs), which include the epidermal growth factor receptor (EGFR, also called HER1 or erbB-1). EGFR exists as a monomer on the cell surface, and it must dimerize to activate the TK.

While the TK activity of EGFR is tightly controlled in normal cells, in malignant cells, the genes encoding these receptors have escaped from their usual intracellular inhibitory mechanisms through amplification, overexpression, or mutation.

PREDICTORS OF RESPONSIVENESS — Both clinical and molecular parameters are helpful in predicting which patients with advanced NSCLC are most likely to benefit from treatment with EGFR TK inhibitors. The presence of these characteristics may define a subset of patients with a more favorable prognosis rather than a responsiveness to these agents. Subsequent analyses of larger trials have confirmed that these parameters also predict responsiveness to these agents.

• Adenocarcinoma
• Women
• Nonsmokers
• Asian ethnicity

Many of these clinical parameters may be mediated through differences in the frequency of EGFR and k-ras mutations. As an example, EGFR mutations are more common in those with adenocarcinoma and in Asian populations, and k-ras mutations are less frequent in both of these groups  However, these factors are not absolute. Even for poor prognosis subsets (ie, men, non-adenocarcinoma histology, non-Asian ethnicity, and current or former smokers), there was a reduction in the hazard ratio for death among patients treated with erlotinib.

Molecular markers

EGFR abnormalities — Clinical correlation studies have found that specific activating mutations in the TK domain of the EGFR (exon 19 deletions, L858R point mutation in exon 21) are associated with increased responsiveness to either erlotinib or gefitinib. One study that included 197 patients with EGFR mutations found that deletions in exon 19 are associated with a significantly higher response rate compared to the L858R point mutation. The impact of EGFR mutations on prognosis may be modified by the presence of nuclear expression of estrogen receptor beta (ER-beta). Multiple studies have shown that ER-beta is expressed in more than one-half of patients with NSCLC. In a Japanese study of 447 patients with resected adenocarcinoma of the lung, ER-beta expression was significantly more frequent in those with an EGFR mutation than in those with EGFR wild-type tumors (70 versus 37 percent). Furthermore, those with an EGFR mutation and strong ER-beta expression had a significantly better prognosis than those with an EGFR mutation but without ER-beta expression. ER-beta expression did not affect prognosis in those without an EGFR mutation.

EGFR protein overexpression and gene amplification have also been studied, and appear to be predictive of response to EGFR TK inhibitors.

Primary resistance: K-ras mutations — Preexisting somatic mutations in k-ras are associated with primary resistance to this class of agents. Furthermore, mutations in k-ras only rarely occur in conjunction with mutations in EGFR.

SUMMARY — The decision of whether or not to use an epidermal growth factor receptor (EGFR) tyosine kinase (TK) inhibitor such as erlotinib or gefitinib should incorporate information about both clinical and molecular predictive factors, as well as a consideration of the tolerance for and likelihood of response to other treatment options.

• Clinical factors associated with increased responsiveness to these agents include adenocarcinoma, women, nonsmokers, and Asian ethnicity
• Molecular factors predicting responsiveness to these agents include activating mutations in the EGFR receptor (deletions in exon 19, L858R in exon 21), EGFR protein overexpression, and EGFR gene amplification. In contrast, primary resistance to these agents is associated with mutations in k-ras. Secondary resistance after initial responsiveness has been associated with acquired mutations or with MET oncogene overexpression.