Erlotinib versus vinorelbine plus cisplatin as adjuvant therapy in Chinese patients with stage IIIA EGFR mutation-positive non-small-cell lung cancer (EVAN): a randomised, open-label, phase 2 trial

摘要

BackgroundAdjuvant chemotherapy after radical resection of stage IIIA non-small-cell lung cancer (NSCLC) has quite poor outcomes. We aimed to investigate whether adjuvant erlotinib therapy improves 2-year disease-free survival compared with chemotherapy in epidermal growth factor receptor (EGFR) mutation-positive stage IIIA NSCLC. MethodsIn this randomised, open-label, phase 2 trial, eligible patients aged 18–75 years who had undergone complete (R0) resection of histologically or pathologically confirmed stage IIIAEGFRmutation-positive NSCLC and had not received any previous anticancer therapies were enrolled. Patients were randomly assigned (1:1) to receive either adjuvant erlotinib (150 mg once daily administered orally) or vinorelbine and cisplatin chemotherapy (four cycles of vinorelbine [25 mg/m2intravenously on days 1 and 8 of each 21-day cycle] plus cisplatin [75 mg/m2intravenously on day 1 of each 21-day cycle]). Randomisation was done by Simon's minimisation with a random element and was stratified byEGFRactivating mutation type (exon 19vs21), histology (adenocarcinomavsnon-adenocarcinoma), and smoking status (smokervsnon-smoker). The primary endpoint in the unblinded intention-to-treat analysis was 2-year disease-free survival. This ongoing study is registered withClinicalTrials.gov, numberNCT01683175. FindingsBetween Sept 8, 2012, and May 21, 2015, 102 patients from 16 centres across China were enrolled and randomly assigned to receive erlotinib (n=51) or chemotherapy (n=51). Median follow-up was 33·0 months (IQR 17·8–43·1). 2-year disease-free survival was 81·4% (95% CI 69·6–93·1) in the erlotinib group and 44·6% (26·9–62·4) in the chemotherapy group (relative risk 1·823 [95% CI 1·194–2·784; p=0·0054). The difference in 2-year disease-free survival between the groups was 36·7% (95% CI 15·5–58·0; p=0·0007). Adverse events of any grade occurred in 29 (58%) of 50 patients in the erlotinib group and 28 (65%) of 43 patients in the chemotherapy group. Grade 3 or worse adverse events occurred in six (12%) of 50 patients in the erlotinib group versus 11 (26%) of 43 in the chemotherapy group; the most common of these in the erlotinib group was rash (in two [4%] of 50 patients) and in the chemotherapy group were decreased neutrophil count (in seven [16%] of 43 patients) and myelosuppression (in four [9%]). No treatment-related deaths were reported. InterpretationAdjuvant erlotinib improved 2-year disease-free survival in patients withEGFRmutation-positive stage IIIA NSCLC compared with chemotherapy, with a better tolerability profile. This study suggests that tyrosine kinase inhibitors could have a potentially important role as adjuvant therapy inEGFRmutation-positive stage IIIA NSCLC. However, this trial was a phase 2 study. Mature overall survival data are also needed. Ongoing studies will hopefully confirm the role of adjuvant EGFR tyrosine kinase inhibitor therapy in patients with NSCLC. FundingNational Key Research and Development Program of China and Shanghai Roche Pharmaceuticals Ltd.