NEJM 2010;362:2380\

Background Non–small-cell lung cancer with sensitive mutations of the epidermal growth factor receptor (EGFR) is highly responsive to EGFR tyrosine kinase inhibitors such as gefitinib, but little is known about how its efficacy and safety profile compares with that of standard chemotherapy.

Methods We randomly assigned 230 patients with metastatic, non–small-cell lung cancer and EGFR mutations who had not previously received chemotherapy to receive gefitinib or carboplatin–paclitaxel. The primary end point was progression-free survival; secondary end points included overall survival, response rate, and toxic effects.

Results In the planned interim analysis of data for the first 200 patients, progression-free survival was significantly longer in the gefitinib group than in the standard-chemotherapy group (hazard ratio for death or disease progression with gefitinib, 0.36), resulting in early termination of the study. The gefitinib group had a significantly longer median progression-free survival (10.8 months, vs. 5.4 months in the chemotherapy group; hazard ratio, 0.30), as well as a higher response rate (73.7% vs. 30.7%). The median overall survival was 30.5 months in the gefitinib group and 23.6 months in the chemotherapy group. The most common adverse events in the gefitinib group were rash (71.1%) and elevated aminotransferase levels (55.3%), and in the chemotherapy group, neutropenia (77.0%), anemia (64.6%), appetite loss (56.6%), and sensory neuropathy (54.9%). One patient receiving gefitinib died from interstitial lung disease.

Conclusions First-line gefitinib for patients with advanced non–small-cell lung cancer who were selected on the basis of EGFR mutations improved progression-free survival, with acceptable toxicity, as compared with standard chemotherapy.

In May 2004, two pivotal studies showed that the presence of somatic mutations in the kinase domain of EGFR strongly correlates with increased responsiveness to EGFR tyrosine kinase inhibitors in patients with non–small-cell lung cancer It was later found that subgroups of patients with non–small-cell lung cancer who had sensitivity to gefitinib had a high incidence of EGFR mutations. In Japan, 30% or more of patients with mutated-EGFR non–small-cell lung cancer are male or have a history of smoking. Therefore, we hypothesized that selecting patients on the basis of EGFR mutations rather than clinical factors would result in a population with a greater sensitivity to gefitinib.

Our previous prospective, phase 2 studies of gefitinib therapy in patients with advanced non–small-cell lung cancer and EGFR mutations revealed a response rate of more than 70% and progression-free survival of 9 to 10 months.

Discussion

Previous phase 2 studies have suggested that EGFR tyrosine kinase inhibitors are highly effective against mutated-EGFR non–small-cell lung cancer. The current phase 3, prospective, randomized study showed that the use of gefitinib results in progression-free survival that is twice as long as that obtained with the use of carboplatin–paclitaxel in patients with mutated-EGFR non–small-cell lung cancer, with a tolerable toxicity profile, including less hematologic toxicity and neurotoxicity than is seen with chemotherapy.

The IPASS, which was conducted in Asia, compared gefitinib with carboplatin–paclitaxel as the first-line treatment for advanced non–small-cell lung cancer in patients selected on the basis of clinical characteristics that included a history of no smoking or light smoking as well as histologic evidence of adenocarcinoma. Although IPASS showed the overall superiority of gefitinib (rate of 1-year progression-free survival, 24.9%, vs. 6.7% with chemotherapy; hazard ratio for death or disease progression, 0.74; P<0.001), the most impressive result emerged from subgroup analysis: as compared with chemotherapy, gefitinib was effective in patients with mutant EGFR (hazard ratio for death or disease progression, 0.48) but was ineffective in those with wild-type EGFR (hazard ratio, 2.85). This finding suggested that the presence of EGFR mutations is the best criterion for selection of patients who benefit from gefitinib, an idea that is validated by the present study. Recently, another Japanese phase 3 study (WJTOG3405; University Hospital Medical Information Network Clinical Trials Registry [UMIN-CTR] number, UMIN000000539) compared gefitinib to cisplatin–docetaxel as the first-line treatment for advanced non–small-cell lung cancer with EGFR mutations.Although this study also showed the superiority of gefitinib over standard chemotherapy with respect to progression-free survival, the magnitude of the benefit was somewhat smaller than in our study, possibly because of differences in the characteristics of the patients (since 41% of patients in WJTOG3405 had had surgery, vs. only 9% in our study) and the duration of follow-up (median, 81 days in WJTOG3405 vs. 527 days in our study).

The best timing of treatment with an EGFR tyrosine kinase inhibitor for patients with EGFR mutations remains undetermined. A recent study showed that overall survival did not differ significantly between first-line and second-line treatments with erlotinib. Overall survival is considered to be influenced by the second-line or later treatment. In the current study, 95% of the patients in whom first-line carboplatin–paclitaxel failed crossed over to gefitinib therapy. Such a high crossover rate has not been reported in previous studies of EGFR tyrosine kinase inhibitors. For example, in IPASS, only 39% of patients in the first-line chemotherapy group later received an EGFR-tyrosine kinase inhibitor. Considering that in our study the median overall survival in the gefitinib group was 7 months longer than that in the chemotherapy group (30.5 months vs. 23.6 months), in which virtually all patients were given gefitinib as the second-line treatment, and that the rate of response to gefitinib was slightly worse in the second-line setting than in the first-line setting (58.5% vs. 73.7%), first-line gefitinib may be more effective than gefitinib as second-line or later therapy. This idea needs to be tested in studies with large samples or in a meta-analysis.

Predictable toxicity profiles were observed with gefitinib and with carboplatin–paclitaxel in the current study. Diarrhea and rash were seen more often in the gefitinib group, whereas hematologic and neurologic toxic effects were more common in the chemotherapy group. Gefitinib appears to be less toxic than carboplatin–paclitaxel. The only exception was interstitial lung disease; there were three cases of severe interstitial lung disease (grade 3) in the gefitinib group and none in the chemotherapy group; one of the cases was fatal. The patient who died was a woman who had no history of smoking and thus had a relatively low risk of interstitial lung disease. Gefitinib sometimes causes diffuse alveolar or interstitial damage, especially during the first 3 months of treatment. The estimated incidence of interstitial lung disease is low in many countries (e.g., 0.3% in United States) but is relatively high (4 to 6%) in Japan. Every patient treated with an EGFR tyrosine kinase inhibitor should be carefully monitored for this toxic effect.

In conclusion, the efficacy of first-line gefitinib was superior to that of standard chemotherapy, with acceptable toxicity, in patients with advanced non–small-cell lung cancer harboring sensitive EGFR mutations. Selection of patients on the basis of EGFR-mutation status is strongly recommended.