The epidermal growth factor receptor (EGFR) family is part of a complex signal-transduction network that is central to several critical cellular processes. Since EGFR is often found in non–small-cell lung cancer cells, it has been the focus of efforts to develop new agents that target the EGFR pathway. Erlotinib (Tarceva, OSI Pharmaceuticals) and gefitinib (Iressa, AstraZeneca) inhibit the tyrosine kinase activity of EGFR and have been studied extensively.

In randomized phase 2 trials of gefitinib (Iressa Dose Evaluation in Advanced Lung Cancer [IDEAL] 1 and 2), the tumors of 10 to 20 percent of patients who were previously treated with platinum-based regimens responded, and in a phase 2 trial of erlotinib among previously treated patients with non–small-cell lung cancer in which 10 percent or more of the cells expressed EGFR, the response rate was 12.3 percent.These promising rates are perhaps higher than those possible with other forms of chemotherapy, but it is unknown whether treatment with an EGFR inhibitor prolongs survival. For this reason, the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) conducted a trial (BR.21) to compare erlotinib with placebo after the failure of standard chemotherapy for non–small-cell lung cancer. The inclusion of a control group receiving placebo was considered ethical in view of the lack of benefit from further chemotherapy after the failure of standard treatment.

Patients with stage IIIB or IV non–small-cell lung cancer, with performance status from 0 to 3, were eligible if they had received one or two prior chemotherapy regimens, and were randomly assigned in a 2:1 ratio to receive oral erlotinib, at a dose of 150 mg daily, or placebo.

Results The median age of the 731 patients who underwent randomization was 61.4 years; 49 percent had received two prior chemotherapy regimens, and 93 percent had received platinum-based chemotherapy. The response rate was 8.9 percent in the erlotinib group and less than 1 percent in the placebo group (P<0.001); the median duration of the response was 7.9 months and 3.7 months, respectively. Progression-free survival was 2.2 months and 1.8 months, respectively (hazard ratio, 0.61, adjusted for stratification categories; P<0.001). Overall survival was 6.7 months and 4.7 months, respectively (hazard ratio, 0.70; P<0.001), in favor of erlotinib. Five percent of patients discontinued erlotinib because of toxic effects.

Conclusions Erlotinib can prolong survival in patients with non–small-cell lung cancer after first-line or second-line chemotherapy.

Expression of EGFR is common in non–small-cell lung cancer. Several agents that target EGFR are in various phases of clinical evaluation. The orally active EGFR tyrosine kinase inhibitors gefitinib and erlotinib have been evaluated in several trials. In the IDEAL 1 trial, patients with non–small-cell lung cancer with disease progression after platinum-based chemotherapy were randomly assigned to receive gefitinib, at a dose of 250 mg or 500 mg daily. There were no differences between the two doses with respect to response rate, time to progression, or median survival. The response rates were also similar whether gefitinib was used as second-line treatment (17.9 percent of patients) or third-line treatment (19.8 percent of patients). In the IDEAL 2 trial, which enrolled symptomatic patients in whom two or more chemotherapy regimens containing platinum and docetaxel had failed, the response rates were 12 percent and 9 percent, respectively, for the two dose levels. More adverse events were seen with the dose of 500 mg in both trials, but discontinuation of treatment because of toxic effects was uncommon at either dose. In a phase 2 trial of erlotinib, the response rate was 12 percent, and response did not correlate with level of EGFR in the tumor.

In our trial, the response rate of 8.9 percent was similar to rates reported for erlotinib and gefitinib. Some investigators have reported that responsiveness to EGFR inhibitors correlates with sex, histologic type, race or ethnic origin, and smoking status. We also found that response was higher among Asians, women, patients with adenocarcinoma, and lifetime nonsmokers. Contrary to previous reports, the response rate in our trial was higher when 10 percent or more of tumor cells expressed EGFR.

Activating mutations in the EGFR gene have been found to predict a response to gefitinib. The results of our assays for the number of copies and mutation status of the EGFR gene are published in this issue of the Journal. Higher response rates were found among patients with high numbers of gene copies and mutations, but the difference was significant only for gene copies.

Because none of the early trials had a placebo control group, it is not possible to determine whether EGFR-inhibitor therapy was superior to palliative treatment. In our placebo-controlled trial, erlotinib did provide clinically meaningful prolongation of survival. According to the Kaplan–Meier estimates, the median survival was prolonged by two months, and 31 percent of patients treated with erlotinib were alive at one year, as compared with 22 percent in the placebo group. The two-month prolongation of survival is similar to that achieved with docetaxel in the setting of second-line chemotherapy,  even though half the patients in our trial were treated after both first-line and second-line chemotherapy. In this trial and another trial, a significant prolongation of survival was achieved despite response rates of less than 10 percent, perhaps because a high proportion of the patients had durable stable disease while receiving treatment. Survival in this trial appears to be longer than what was achieved in a similar trial of gefitinib, although the response rates were similar in both studies. The characteristics of the patients in these two trials, however, may have differed somewhat.

Exploratory multivariate analyses showed that only Asian origin, adenocarcinoma on histologic examination, and a history of not smoking were significant independent predictors of survival after adjustment for treatment and other potential predictors. Erlotinib had a beneficial effect on survival in almost all subgroups tested, but only the interaction between smoking status and treatment was significantly predictive of a differential effect on survival. Notably, the presence of EGFR gene mutations was not predictive of a survival benefit from erlotinib in our study.

In the IDEAL 2 trial, gefitinib rapidly reduced symptoms in 35 percent to 43 percent of patients. In our trial, significantly more patients in the erlotinib group than in the placebo group had reductions in dyspnea, pain, and cough. Furthermore, the time to exacerbation of these symptoms was significantly longer in the erlotinib group. The analysis of the quality of life showed that symptom improvement was also associated with significantly improved physical function.

Rash and diarrhea are the main toxic effects of EGFR inhibitors. They led to dose reduction in 12 percent and 5 percent of patients, respectively, in our trial. Pneumonitis has been reported mainly in Japan following treatment with gefitinib. However, four trials of gefitinib or erlotinib combined with chemotherapy for non–small-cell lung cancer reported similar rates of pneumonitis in active-treatment and placebo groups. We rarely encountered pneumonitis or pulmonary fibrosis.