Gefitinib Alone vs Gefitinib Plus Chemotherapy in EGFR-Mutated Metastatic NSCLC

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In the Japanese phase III NEJ009 trial reported in the Journal of Clinical Oncology, Hosomi et al found that the addition of first-line gefitinib to carboplatin/pemetrexed improved progression-free survival vs gefitinib alone in patients with EGFR-mutated metastatic non–small cell lung cancer (NSCLC).

Study Details

In the multicenter trial, 345 patients were randomly assigned between October 2011 and September 2015 to receive gefitinib alone (n = 173) or gefitinib plus carboplatin/pemetrexed (n = 172). Treatment consisted of gefitinib 250 mg once daily alone or with carboplatin AUC = 5 and pemetrexed 500 mg/m2 in 3-week cycles for up to six cycles followed by concurrent gefitinib and pemetrexed maintenance.

The primary endpoints were progression-free survival, progression-free survival-2 (defined as the period from the date of randomization until both platinum-based therapy and gefitinib became ineffective conceptually), and overall survival sequentially analyzed according to hierarchical statistical testing.

Treatment Outcomes


  • Gefitinib plus chemotherapy was associated with improved progression-free survival and overall survival vs gefitinib alone.
  • The observed overall survival benefit with combination treatment requires additional validation.

Median follow-up was 45 months. Median progression-free survival was 20.9 months in the gefitinib plus chemotherapy group vs 11.9 months in the gefitinib alone group (hazard ratio [HR] = 0.490, P < .001). Median progression-free survival-2 was 20.9 vs 18.0 months (HR = 0.99, P = .092). Overall survival analysis was considered exploratory due to the lack of significance of the progression-free survival-2 comparison; median overall survival was 50.9 vs 38.8 months (HR = 0.722, P = .021). Objective response rates were 84% vs 67% (P < .001).

Subsequent treatment included platinum-based chemotherapy (as recommended by protocol) in the gefitinib group (77.4% of patients). Osimertinib was used in 23.3% of the gefitinib group and 21.8% of the combination group. Among patients receiving osimertinib, median overall survival was 74.4 months in the gefitinib group and not reached in the combination group, vs 29.8 and 43.8 months among patients not receiving osimertinib.

Adverse Events

Treatment-related grade ≥ 3 adverse events occurred in 65.3% of the combination group vs 31.0% of the gefitinib group. Some grade 3 or 4 adverse events were more common in the combination group—such as neutropenia (31.2% vs 0.6%), anemia (21.2% vs 2.3%), and thrombocytopenia (17.1% vs 0%)—whereas grade 3 or 4 liver toxicity was more common in the gefitinib group (22.2% vs 12.4%). Treatment was discontinued due to adverse events in 10.7% of the combination group and 9.9% of the gefitinib group. A fatal adverse event (infection) occurred in one patient in the combination group.

The investigators concluded, “Compared with gefitinib alone, gefitinib combined with carboplatin plus pemetrexed improved [progression-free survival] in patients with untreated advanced NSCLC with EGFR mutations with an acceptable toxicity profile, although its [overall survival] benefit requires further validation.”

Akira Inoue, MD, PhD, of Tohoku University School of Medicine, Sendai, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by the Japan Society for Promotion of Science and Japanese Foundation for the Multidisciplinary Treatment of Cancer. For full disclosures of the study authors, visit

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