Dongsheng Yue1, Shidong Xu2, Qun Wang3, Xiaofei Li4, Yi Shen5, Heng Zhao6, Chun Chen7, Weimin Mao8, Wei Liu9, Junfeng Liu10, Lanjun Zhang11, Haitao Ma12, Qiang Li13, Yue Yang14, Yongyu Liu15, Haiquan Chen16, Changli Wang17. 1. Department of Lung Cancer, Lung Cancer Center, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center of Cancer, Tianjin, China. 2. Harbin Medical University, Cancer Hospital, Heilongjiang, China. 3. Fudan University, Zhongshan Hospital, Shanghai, China. 4. The Fourth Military Medical University, Tangdu Hospital, Xi'an, China. 5. The Affiliated Hospital of Qingdao University, Qingdao, China. 6. Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai, China. 7. Fujian Medical University Union Hospital, Fujian, China. 8. Zhejiang Cancer Hospital, Hangzhou, China. 9. The First Bethune Hospital of Jilin University, Changchun, China. 10. Tumor Hospital of Hebei Province, Shijiazhuang, China. 11. Cancer Hospital, Sun Yat-Sen University, Guangzhou, China. 12. The First Affiliated Hospital of Suzhou University, Jiangsu, China. 13. Sichuan Cancer Hospital & Institute, Chengdu, China. 14. Peking University Cancer Hospital, Beijing, China. 15. Liaoning Cancer Hospital, Shenyang, China. 16. Fudan University, Shanghai Cancer Center, Shanghai, China. 17. Department of Lung Cancer, Lung Cancer Center, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center of Cancer, Tianjin, China. Electronic address: wangchangli9@163.com.
Abstract
BACKGROUND:Adjuvant 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. METHODS: In 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 IIIA EGFR mutation-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/m2 intravenously on days 1 and 8 of each 21-day cycle] plus cisplatin [75 mg/m2 intravenously on day 1 of each 21-day cycle]). Randomisation was done by Simon's minimisation with a random element and was stratified by EGFR activating mutation type (exon 19 vs 21), histology (adenocarcinoma vs non-adenocarcinoma), and smoking status (smoker vs non-smoker). The primary endpoint in the unblinded intention-to-treat analysis was 2-year disease-free survival. This ongoing study is registered with ClinicalTrials.gov, number NCT01683175. FINDINGS: Between 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. INTERPRETATION:Adjuvant erlotinib improved 2-year disease-free survival in patients with EGFR mutation-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 in EGFR mutation-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. FUNDING: National Key Research and Development Program of China and Shanghai Roche Pharmaceuticals Ltd.
RCT Entities:
BACKGROUND: Adjuvant 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. METHODS: In 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 IIIA EGFR mutation-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/m2 intravenously on days 1 and 8 of each 21-day cycle] plus cisplatin [75 mg/m2 intravenously on day 1 of each 21-day cycle]). Randomisation was done by Simon's minimisation with a random element and was stratified by EGFR activating mutation type (exon 19 vs 21), histology (adenocarcinoma vs non-adenocarcinoma), and smoking status (smoker vs non-smoker). The primary endpoint in the unblinded intention-to-treat analysis was 2-year disease-free survival. This ongoing study is registered with ClinicalTrials.gov, number NCT01683175. FINDINGS: Between 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. INTERPRETATION: Adjuvant erlotinib improved 2-year disease-free survival in patients with EGFR mutation-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 in EGFR mutation-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. FUNDING: National Key Research and Development Program of China and Shanghai Roche Pharmaceuticals Ltd.