Shukui Qin1, Qiu Li2, Shanzhi Gu3, Xiaoming Chen4, Lizhu Lin5, Zishu Wang6, Aibing Xu7, Xi Chen8, Cuncai Zhou9, Zhenggang Ren10, Lin Yang11, Li Xu12, Yuxian Bai13, Lei Chen14, Jun Li15, Hongming Pan16, Bangwei Cao17, Weijia Fang18, Wei Wu19, Ge Wang20, Ying Cheng21, Zhuang Yu22, Xu Zhu23, Da Jiang24, Yinying Lu25, Huaming Wang26, Jianming Xu27, Li Bai28, Yunpeng Liu29, Hailan Lin30, Changping Wu31, Yang Zhang32, Ping Yan33, Chunlei Jin33, Jianjun Zou33. 1. Department of Medical Oncology, Cancer Center of Bayi Hospital, Nanjing Chinese Medicine University, Nanjing, China. Electronic address: qinsk@csco.org.cn. 2. Cancer Center, West China Hospital, Sichuan University, Chengdu, China. 3. Department of Intervention, Hunan Cancer Hospital, Changsha, China. 4. Department of Invasive Technology, Guangdong Provincial People's Hospital, Guangzhou, China. 5. Cancer Center, The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou, China. 6. Department of Medical Oncology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China. 7. Department of Interventional Therapy, Nantong Tumor Hospital, Nantong, China. 8. Department of Oncology, The 900th Hospital of Joint Logistics Support Force, Fuzhou, China. 9. Department of Hepatobiliary Interventional, Jiangxi Cancer Hospital, Nanchang, China. 10. Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China. 11. Department of Medical Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. 12. Department of Hepatobiliary and Pancreatic Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China. 13. Department of Gastroenterology, Harbin Medical University Cancer Hospital, Harbin, China. 14. Department of Oncology, Cancer Hospital of Shantou University Medical College, Shantou, China. 15. Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China. 16. Department of Oncology, Sir Run Run Shaw Hospital Zhejiang University School of Medicine, Hangzhou, China. 17. Department of Oncology, Beijing Friendship Hospital, Capital Medical University, Beijing, China. 18. Department of Oncology, The First Affiliated Hospital, Zhejiang University, Hangzhou, China. 19. Department of Hepatopathy, The Sixth People's Hospital of Shenyang, Shenyang, China. 20. Cancer Center, Daping Hospital, Army Medical University, Chongqing, China. 21. Department of Internal Medicine-Oncology, Jilin Cancer Hospital, Changchun, China. 22. Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao, China. 23. Department of Interventional Therapy Unit, Beijing Cancer Hospital, Beijing, China. 24. Department of Oncology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China. 25. Comprehensive Liver Cancer Centre, The Fifth Medical Center of the Chinese PLA General Hospital, Beijing, China. 26. Department of Interventional Therapy, The Fifth Medical Center of the Chinese PLA General Hospital, Beijing, China. 27. Department of Digestive Oncology, The Fifth Medical Center of the Chinese PLA General Hospital, Beijing, China. 28. Department of Oncology, Chinese PLA General Hospital, Beijing, China. 29. Department of Oncology, The First Hospital of China Medical University, Shenyang, China. 30. Department of Intervention, Fujian Cancer Hospital, Fuzhou, China. 31. Department of Medical Oncology, The First People's Hospital of Changzhou, Changzhou, China. 32. Department of Oncology, The Second Affiliated Hospital of Dalian Medical University, Dalian, China. 33. Clinical Research and Development, Jiangsu Hengrui Medicine, Shanghai, China.
Abstract
BACKGROUND: Inhibition of vascular endothelial growth factor receptor (VEGFR) has shown antitumour activity in advanced hepatocellular carcinoma, but few studies of VEGFR inhibitors have been done in populations with a high prevalence of hepatitis B virus infection. The aim of this study was to evaluate the efficacy and safety of apatinib in patients with pretreated advanced hepatocellular carcinoma. METHODS:AHELP was a randomised, double-blind, placebo-controlled, phase 3 trial done at 31 hospitals in China, in patients (aged ≥18 years) with advanced hepatocellular carcinoma who had previously been refractory or intolerant to at least one line of systemic chemotherapy or targeted therapy. Patients were randomly assigned (2:1) to receive apatinib 750 mg or placebo orally once daily in 28-day treatment cycles. Group allocation was done with a central randomisation system, with a block size of six, and was stratified by Eastern Cooperative Oncology Group performance status, previous sorafenib treatment, and presence of vascular invasion or extrahepatic metastasis. The primary endpoint was overall survival, which was defined as time from randomisation to death from any cause, and was analysed in patients who were randomly assigned and received at least one dose of the study drug. Safety analyses were done in patients who received at least one dose of the study treatment and had post-dose safety assessments. This trial is registered with ClinicalTrials.gov, NCT02329860. FINDINGS:Between April 1, 2014, and May 3, 2017, 400 eligible patients were randomly assigned to receive apatinib (n=267) or placebo (n=133). Seven patients (six in the apatinib group and one in the placebo group) did not receive study treatment and were excluded from efficacy analyses. Overall survival was significantly improved in the apatinib group compared with the placebo group (median 8·7 months [95% CI 7·5‒9·8] vs 6·8 months [5·7‒9·1]; hazard ratio 0·785 [95% CI 0·617‒0·998], p=0·048). 387 patients (257 in the apatinib group and 130 in theplacebo group) had a safety assessment after study treatment and were included in safety analyses. The most common treatment-related adverse events of grade 3 or 4 were hypertension (71 [28%] patients in the apatinib group vs three [2%] in the placebo group), hand-foot syndrome (46 [18%] vs none), and decreased platelet count (34 [13%] vs one [1%]). 24 (9%) patients in the apatinib group and 13 (10%) in the placebo group died due to adverse events, but none of these deaths were deemed to be related to treatment by investigators. INTERPRETATION: Apatinib significantly improved overall survival in patients with pretreated advanced hepatocellular carcinoma compared with placebo, with a manageable safety profile. FUNDING: Jiangsu Hengrui Medicine.
RCT Entities:
BACKGROUND: Inhibition of vascular endothelial growth factor receptor (VEGFR) has shown antitumour activity in advanced hepatocellular carcinoma, but few studies of VEGFR inhibitors have been done in populations with a high prevalence of hepatitis B virus infection. The aim of this study was to evaluate the efficacy and safety of apatinib in patients with pretreated advanced hepatocellular carcinoma. METHODS: AHELP was a randomised, double-blind, placebo-controlled, phase 3 trial done at 31 hospitals in China, in patients (aged ≥18 years) with advanced hepatocellular carcinoma who had previously been refractory or intolerant to at least one line of systemic chemotherapy or targeted therapy. Patients were randomly assigned (2:1) to receive apatinib 750 mg or placebo orally once daily in 28-day treatment cycles. Group allocation was done with a central randomisation system, with a block size of six, and was stratified by Eastern Cooperative Oncology Group performance status, previous sorafenib treatment, and presence of vascular invasion or extrahepatic metastasis. The primary endpoint was overall survival, which was defined as time from randomisation to death from any cause, and was analysed in patients who were randomly assigned and received at least one dose of the study drug. Safety analyses were done in patients who received at least one dose of the study treatment and had post-dose safety assessments. This trial is registered with ClinicalTrials.gov, NCT02329860. FINDINGS: Between April 1, 2014, and May 3, 2017, 400 eligible patients were randomly assigned to receive apatinib (n=267) or placebo (n=133). Seven patients (six in the apatinib group and one in the placebo group) did not receive study treatment and were excluded from efficacy analyses. Overall survival was significantly improved in the apatinib group compared with the placebo group (median 8·7 months [95% CI 7·5‒9·8] vs 6·8 months [5·7‒9·1]; hazard ratio 0·785 [95% CI 0·617‒0·998], p=0·048). 387 patients (257 in the apatinib group and 130 in the placebo group) had a safety assessment after study treatment and were included in safety analyses. The most common treatment-related adverse events of grade 3 or 4 were hypertension (71 [28%] patients in the apatinib group vs three [2%] in the placebo group), hand-foot syndrome (46 [18%] vs none), and decreased platelet count (34 [13%] vs one [1%]). 24 (9%) patients in the apatinib group and 13 (10%) in the placebo group died due to adverse events, but none of these deaths were deemed to be related to treatment by investigators. INTERPRETATION:Apatinib significantly improved overall survival in patients with pretreated advanced hepatocellular carcinoma compared with placebo, with a manageable safety profile. FUNDING: Jiangsu Hengrui Medicine.
Authors: Alexandre A Jácome; Ana Carolina G Castro; João Paulo S Vasconcelos; Maria Helena C R Silva; Marco Antônio O Lessa; Eduardo D Moraes; Aline C Andrade; Frederico M T Lima; João Paulo F Farias; Roberto A Gil; Gabriel Prolla; Bernardo Garicochea Journal: JAMA Netw Open Date: 2021-12-01