Hongyun Zhao1, Wenxiu Yao2, Xuhong Min3, Kangsheng Gu4, Guohua Yu5, Zhonghan Zhang6, Jiuwei Cui7, Liyun Miao8, Li Zhang23, Xia Yuan10, Yong Fang11, Xiuhua Fu12, Chengping Hu13, Xiaoli Zhu14, Yun Fan15, Qitao Yu16, Gang Wu17, Ou Jiang18, Xiuping Du19, Jiwei Liu20, Wei Gu21, Zhiguo Hou22, Quanren Wang22, Rongrong Zheng22, Xianfeng Zhou22, Li Zhang23. 1. Department of Clinical Research, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China. 2. Department of Thoracic Oncology, Sichuan Cancer Hospital, Chengdu, China. 3. Department of Tumor Radiotherapy, Anhui Chest Hospital, Hefei, China. 4. Department of Medical Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China. 5. Department of Medical Oncology, Weifang People's Hospital, Weifang, China. 6. Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China. 7. Oncology Department of Oncology Center, First Hospital of Jilin University, Changchun, China. 8. Department of Respiratory, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing, China. 9. Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital of Chinese Academy of Medical Sciences, Beijing, China. 10. Department of Medical Oncology, Huizhou Municipal Central Hospital, Huizhou, China. 11. Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China. 12. Department of Respiratory and Critical Care Medicine, The Affiliated Hospital of Inner Mongolia Medical University, Hohhot, China. 13. Department of Respiratory Medicine, Xiangya Hospital, Central South University, Changsha, China. 14. Department of Respiratory, Zhongda Hospital, Southeast University, Nanjing, China. 15. Department of Thoracic Medical Oncology, Zhejiang Cancer Hospital, Hangzhou, China. 16. Department of Respiratory Oncology, Guangxi Medical University Affiliated Tumor Hospital, Nanning, China. 17. Department of Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. 18. Center of Oncology, Neijiang Second People's Hospital, Neijiang, China. 19. Department of Medical Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China. 20. Department of Oncology, The First Affiliated Hospital of Dalian Medical University, Dalian, China. 21. Department of Respiratory, Nanjing First Hospital, Nanjing, China. 22. Jiangsu Hengrui Pharmaceuticals Co., Ltd., Shanghai, China. 23. Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China. Electronic address: zhangli@sysucc.org.cn.
Abstract
INTRODUCTION:Blocking vascular endothelial growth factor (VEGF) pathway can enhance the efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in EGFR-mutant non-small cell lung cancer (NSCLC). ACTIVE is the first phase III study conducted in China, evaluating apatinib, a VEGFR2 TKI, plus gefitinib as first-line therapy in EGFR-mutant NSCLC. METHODS:Treatment-naïve patients with stage IIIB/IV non-squamous NSCLC, an ECOG PS of 0/1 and EGFR ex19del or ex21L858R mutation were randomized 1:1 to receive oral gefitinib (250 mg/day), plus apatinib (500 mg/day; A+G group) or placebo (P+G group). Stratification factors: mutation type, sex and PS. The primary endpoint was PFS by blinded independent radiology review committee (IRRC). Secondary endpoints: investigator-assessed PFS, OS, quality of life (QoL), safety, etc. Next-generation sequencing was used to explore efficacy predictors and acquired resistance. RESULTS:313 patients were assigned to the A+G (n=157) or P+G group (n=156). Median IRRC-PFS in the A+G group was 13.7 months vs 10.2 months in the P+G group (HR 0.71; P=.0189). Investigator- and IRRC-assessed PFS were similar. OS was immature. The most common treatment-emergent adverse events ≥grade 3 were hypertension (46.5%) and proteinuria (17.8%) in the A+G group and increased ALT (10.4%) and AST (3.2%) in the P+G group. QoL in the two groups had no statistical differences. Post-hoc analysis showed PFS benefits tended to favor the A+G group in patients with TP53 ex8 mutation. CONCLUSIONS: Apatinib+gefitinib as first-line therapy demonstrated superior PFS in advanced EGFR-mutant NSCLC vs placebo+gefitinib. Combination therapy brought more adverse events but did not interfere QoL.
RCT Entities:
INTRODUCTION: Blocking vascular endothelial growth factor (VEGF) pathway can enhance the efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in EGFR-mutant non-small cell lung cancer (NSCLC). ACTIVE is the first phase III study conducted in China, evaluating apatinib, a VEGFR2 TKI, plus gefitinib as first-line therapy in EGFR-mutant NSCLC. METHODS: Treatment-naïve patients with stage IIIB/IV non-squamous NSCLC, an ECOG PS of 0/1 and EGFR ex19del or ex21L858R mutation were randomized 1:1 to receive oral gefitinib (250 mg/day), plus apatinib (500 mg/day; A+G group) or placebo (P+G group). Stratification factors: mutation type, sex and PS. The primary endpoint was PFS by blinded independent radiology review committee (IRRC). Secondary endpoints: investigator-assessed PFS, OS, quality of life (QoL), safety, etc. Next-generation sequencing was used to explore efficacy predictors and acquired resistance. RESULTS: 313 patients were assigned to the A+G (n=157) or P+G group (n=156). Median IRRC-PFS in the A+G group was 13.7 months vs 10.2 months in the P+G group (HR 0.71; P=.0189). Investigator- and IRRC-assessed PFS were similar. OS was immature. The most common treatment-emergent adverse events ≥grade 3 were hypertension (46.5%) and proteinuria (17.8%) in the A+G group and increased ALT (10.4%) and AST (3.2%) in the P+G group. QoL in the two groups had no statistical differences. Post-hoc analysis showed PFS benefits tended to favor the A+G group in patients with TP53 ex8 mutation. CONCLUSIONS:Apatinib+gefitinib as first-line therapy demonstrated superior PFS in advanced EGFR-mutant NSCLC vs placebo+gefitinib. Combination therapy brought more adverse events but did not interfere QoL.