Epidermal Growth Factor Receptor Inhibitors in Lung Cancer: Smaller or Larger Molecules, Selected or Unselected Populations?

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Epidermal growth factor receptor (EGFR) inhibitors, including the small-molecule tyrosine kinase inhibitors (EGFR TKIs) erlotinib (Tarceva; OSI Pharmaceuticals Inc, Melville, NY) and gefitinib (Iressa; AstraZeneca, Macclesfield, United Kingdom), and the monoclonal antibodies directed at the receptor such as cetuximab (Erbitux; BristolMyers Squibb, Princeton, NJ), have demonstrated promising effects in some patients with non–small-cell lung cancer (NSCLC) and other solid tumors. In patients with NSCLC, both erlotinib and gefitinib produced objective response in a minority of patients (9% to 20%). In subsequent randomized trials comparing these agents versus placebo, erlotinib produced a significant survival benefit (hazard ratio [HR] 0.73), but gefitinib failed to produce a significant survival advantage (HR 0.89) in unselected patients. Data on cetuximab have been more sparse. Table 1 lists published, ongoing, and planned NSCLC studies with cetuximab. As a single-agent treatment in chemotherapy-refractory patients, Hanna et al reported an objective response rate of 4.5% and a disease control rate of 35%, which is similar to but numerically lower than that reported from the phase II studies with EGFR TKIs. In this issue of Journal of Clinical Oncology, Robert et al present results of a phase I/II a study of cetuximab in combination with carboplatin and gemcitabine in patients with advanced NSCLC who were EGFR positive by immunohistochemistry (IHC). The drug combination was well tolerated, with acceptable toxicity. Objective response was reported in 10 of 35 patients (28.6%) and an additional 21 patients had stable disease, yielding a disease control rate of 88.6%. As listed in Table 1, the combination studies so far reported have given consistent objective responses of 26% to 35% and median survivals of 7 to 11 months. The question is whether these results are better than chemotherapy alone in unselected or selected patient populations. With cetuximab, there are as yet no phase III study results reported. In a randomized phase II study, which compared vinorelbine/cisplatin alone with the same combination plus cetuximab, the addition of cetuximab resulted in a slightly superior response and survival, leading to initiation of an ongoing randomized phase III trial. Currently, several other randomized studies are ongoing or completed accrual, and more results are waiting. Combination of cytotoxic chemotherapy with EGFR TKIs failed to improve outcome in advanced NSCLC, but there might be significant differences in the mechanisms of sensitivity between monoclonal antibodies and the EGFR TKIs. For example, a recent study showed that EGFR mutations were associated with gefitinib sensitivity in vitro, but this was not the case for cetuximab. Much has to be learned about the combinations of chemotherapy and targeted therapies, and some of the questions that need to be resolved include the following. Do the EGFR monoclonal antibodies provide synergy in combination with chemotherapy? What is the optimal scheduling of chemotherapy and EGFR inhibitors in combination? (A targeted therapy given concomitantly with chemotherapy might produce antagonism, whereas sequential treatment might give synergy as demonstrated in breast cancer and antihormonal therapy.) What is the importance of selecting subgroups of patients to these treatments? The study by Robert et al was performed in an enriched population based on EGFR protein expression detected by IHC. The role of EGFR protein expression for prediction of outcome after EGFR inhibitors has been a subject of debate. In patients with colorectal cancer, the US Food and Drug Administration (FDA) label indicates that patient selection by a Dako test kit (Dako A/S, Glostrup, Denmark) should be used for this particular indication, but JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 23 NUMBER 36 DECEMBER 2