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Can Acquired Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors Be Overcome by Different Small-Molecule Tyrosine Kinase Inhibitors?

University of Colorado Health Sciences Center; University of Colorado Cancer Center, Denver, CO

The introduction of inhibitors of the epidermal growth factor receptor (EGFR) pathway marked a new chapter in the treatment of lung cancer patients. Before 1990, no systemic therapy was proven to prolong survival in patients with non–small-cell lung cancer (NSCLC), the leading cause of cancer death in the US. Meta-analyses of studies of systemic chemotherapy (primarily platinum-based doublets) conducted in the 1980s and 1990s demonstrated that chemotherapy improved survival in stage II to IV NSCLC.¹

The EGFR has been known to be overexpressed in the majority of NSCLC tumors for many years.² Phase I and II trials of the small-molecule EGFR tyrosine kinase inhibitors (TKIs) erlotinib and gefitinib as well as the anti-EGFR monoclonal antibody cetuximab demonstrated that objective responses occurred in 10% to 15% of patients with advanced NSCLC and other solid tumors.^3-6 Dose-limiting toxicities included skin rash, other cutaneous toxicities, diarrhea, and other GI toxicities. Allergic reactions occurred in some patients receiving cetuximab, and rare patients receiving EGFR TKIs were reported to develop interstitial lung disease.

Randomized single-agent studies versus best supportive care in the second- and third-line setting demonstrated that erlotinib (hazard ratio [HR], 0.73; P .001) and gefitinib (HR, 0.89; P = .087) were associated with improved survival, but this was significant only for erlotinib.^7,8 The reasons for the superior HR for erlotinib are unknown, but likely include the higher relative dose and patient selection factors. Retrospective molecular marker studies from these randomized trials indicated that patients whose tumors had high EGFR expression by gene copy number, or by protein expression, were more likely to have survival benefit; that patients with EGFR mutations were more likely to respond; and that patients with K-ras mutations were less likely to respond.^9,10

Trials combining EGFR TKIs with chemotherapy in unselected, previously untreated NSCLC patients yielded uniformly negative results, and single-agent EGFR TKI trials in unselected patients suggested that outcome might be superior with chemotherapy.^11,12 In marked contrast, prospective patient selection trials using molecular biomarkers have shown high response rates, long progression-free survival, and long survival rates.^13,14 The results of randomized trials in biomarker-selected patients are eagerly awaited.

An exciting advancement in our understanding of acquired resistance to EGFR TKIs was the discovery of additional mutations in exon 20 (T790M) of the EGFR in patients with preexisting activating EGFR mutations. These T790M mutations block binding of erlotinib and gefitinib to the receptor.^15,16 New irreversible EGFR TKIs have been shown to bind to the mutated EGFR and have preclinical activity in such tumors.^17,18 Clinical studies are in progress. The mechanisms of acquired mutations in tumors with wild-type receptors are undefined, and T790M resistance mutations appear to be uncommon in these tumors. It is thus unknown whether these irreversible inhibitors will have activity in acquired resistance not associated with T790M.

Anecdotal reports of responses to a different EGFR inhibitor in patients with acquired resistance and presumed wild-type receptors have been reported.^19,20 The article by Cho et al²¹ in this issue of the Journal of Clinical Oncology is the first reported study of erlotinib after gefitinib therapy. In this report, 21 patients who progressed after gefitinib (apparently while receiving gefitinib or within 4 months of discontinuing gefitinib) were treated with standard doses of erlotinib. The objective response rate was 9.5%, and 29% of patients had a response or stable disease. The median duration of disease control was 125 days. The highest rates of disease control and the longest progression-free survival were observed in patients with wild-type EGFR who had stable disease on gefitinib and were likely not to have resistance resulting from T790M mutations. After disease progression during treatment with erlotinib, two patients were treated with cetuximab, and one had an objective response. It is unclear whether the observed responses to erlotinib were a result of its relatively higher dose schedule or whether the drug was active for other reasons. The overall response to cetuximab as a single agent is only 5%. The response after treatment failure with EGFR TKIs is of interest, and studies evaluating cetuximab with and after erlotinib are reasonable. Studies of newer irreversible EGFR tyrosine kinase inhibitors will undoubtedly be conducted both in patients with and without EGFR mutations, and we can expect to see responses in some patients. It will be important to develop biomarkers for the selection of patients most likely to benefit in this situation.

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author indicated no potential conflicts of interest.

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