Jianming Xu1, Lin Shen2, Chunmei Bai3, Wei Wang4, Jie Li2, Xianjun Yu5, Zhiping Li6, Enxiao Li7, Xianglin Yuan8, Yihebali Chi9, Yongmei Yin10, Wenhui Lou11, Nong Xu12, Yuxian Bai13, Tao Zhang14, Dianrong Xiu15, Xiuwen Wang16, Ying Yuan17, Jia Chen18, Shukui Qin19, Ru Jia20, Ming Lu2, Yuejuan Cheng3, Zhiwei Zhou4, Jing Li21, James He21, Weiguo Su21. 1. Department of Gastrointestinal Oncology, The Fifth Medical Center, Chinese PLA General Hospital, Beijing, China. Electronic address: jmxu2003@yahoo.com. 2. Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China. 3. Department of Medical Oncology, Peking Union Medical College Hospital, Beijing, China. 4. Department of Gastric Surgery, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China. 5. Department of Pancreatic and Hepatobiliary Surgery, Fudan University Shanghai Cancer Center, Shanghai, China. 6. Department of Abdominal Oncology, West China Hospital, Sichuan University, Chengdu, China. 7. Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China. 8. Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. 9. National Cancer Center and Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. 10. Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China. 11. Department of General Surgery, Zhongshan Hospital of Fudan University, Shanghai, China. 12. Department of Medical Oncology, The First Affiliated Hospital of Zhejiang University, Hangzhou, China. 13. Department of Gastrointestinal Oncology, Harbin Medical University Cancer Hospital, Harbin, China. 14. Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. 15. Department of General Surgery, Peking University Third Hospital, Beijing, China. 16. Department of Medical Oncology, Qilu Hospital of Shandong University, Jinan, China. 17. Department of Medical Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. 18. Department of Oncology, Jiangsu Cancer Hospital, Nanjing, China. 19. People's Liberation Army Cancer Center of Nanjing Jinling Hospital, Nanjing, China. 20. Department of Gastrointestinal Oncology, The Fifth Medical Center, Chinese PLA General Hospital, Beijing, China. 21. Department of Clinical and Regulatory Affairs, Hutchison MediPharma, Shanghai, China.
Abstract
BACKGROUND:Surufatinib showed superior efficacy in extrapancreatic neuroendocrine tumours (NETs) in the phase 3 SANET-ep study. In SANET-p, we aimed to assess the efficacy and safety of surufatinib in patients with advanced pancreatic NETs. METHODS: SANET-p was a multicentre, randomised, double-blind, placebo-controlled, phase 3 study, done in 21 hospitals across China. Eligible patients were adults (aged 18 years or older) with progressive, advanced, well differentiated pancreatic NETs, Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and progression on up to two kinds of previous systemic regimens for advanced disease. Patients were randomly assigned (2:1) via an interactive web response system to receive 300 mg of surufatinib or placebo, taken orally once per day in consecutive 4-week treatment cycles until disease progression, intolerable toxicity, withdrawal of consent, poor compliance, use of other antitumour medication, pregnancy, loss to follow-up, or if the investigator deemed discontinuation in the patient's best interest. Randomisation was done centrally using stratified block randomisation (block size three), stratified by pathological grade, previous systemic antitumour treatment, and ECOG performance status score. Patients, investigators, research staff, and the sponsor study team were masked to treatment allocation. Crossover to surufatinib was permitted for patients in the placebogroup with disease progression. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population, which included all patients in randomisation. A pre-planned interim analysis was done at 70% of the predicted progression-free survival events. This study is registered at ClinicalTrials.gov, NCT02589821. FINDINGS: Between Feb 18, 2016, and Nov 11, 2019, of 264 patients who were screened, 172 (65%) patients were randomly assigned to receive surufatinib (n=113) or placebo (n=59). The median follow-up was 19·3 months (95% CI 9·3-19·4) in the surufatinib group and 11·1 months (5·7-35·9) in the placebo group. The median investigator-assessed progression-free survival was 10·9 months (7·5-13·8) for surufatinib versus 3·7 months (2·8-5·6) for placebo (hazard ratio 0·49, 95% CI 0·32-0·76; p=0·0011). The trial met the early stopping criteria at the interim analysis and was terminated on recommendation from the independent data monitoring committee. The most common grade 3 or worse treatment-related adverse events were hypertension (43 [38%] of 113 with surufatinib vs four [7%] of 59 with placebo), proteinuria (11 [10%] vs one [2%]), and hypertriglyceridaemia (eight [7%] vs none). Treatment-related serious adverse events were reported in 25 (22%) patients in the surufatinib group and four (7%) patients in the placebo group. There were three on-treatment deaths in the surufatinib group, including two deaths due to adverse events (gastrointestinal haemorrhage [possibly treatment-related] and cerebral haemorrhage [unlikely to be treatment-related]), and one death attributed to disease progression. One on-treatment death in the placebo group was attributed to disease progression. INTERPRETATION:Surufatinib significantly improves progression-free survival and has an acceptable safety profile in patients with progressive, advanced pancreatic NETs, and could be a potential treatment option in this patient population. FUNDING: Hutchison MediPharma.
RCT Entities:
BACKGROUND:Surufatinib showed superior efficacy in extrapancreatic neuroendocrine tumours (NETs) in the phase 3 SANET-ep study. In SANET-p, we aimed to assess the efficacy and safety of surufatinib in patients with advanced pancreatic NETs. METHODS:SANET-p was a multicentre, randomised, double-blind, placebo-controlled, phase 3 study, done in 21 hospitals across China. Eligible patients were adults (aged 18 years or older) with progressive, advanced, well differentiated pancreatic NETs, Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and progression on up to two kinds of previous systemic regimens for advanced disease. Patients were randomly assigned (2:1) via an interactive web response system to receive 300 mg of surufatinib or placebo, taken orally once per day in consecutive 4-week treatment cycles until disease progression, intolerable toxicity, withdrawal of consent, poor compliance, use of other antitumour medication, pregnancy, loss to follow-up, or if the investigator deemed discontinuation in the patient's best interest. Randomisation was done centrally using stratified block randomisation (block size three), stratified by pathological grade, previous systemic antitumour treatment, and ECOG performance status score. Patients, investigators, research staff, and the sponsor study team were masked to treatment allocation. Crossover to surufatinib was permitted for patients in the placebo group with disease progression. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population, which included all patients in randomisation. A pre-planned interim analysis was done at 70% of the predicted progression-free survival events. This study is registered at ClinicalTrials.gov, NCT02589821. FINDINGS: Between Feb 18, 2016, and Nov 11, 2019, of 264 patients who were screened, 172 (65%) patients were randomly assigned to receive surufatinib (n=113) or placebo (n=59). The median follow-up was 19·3 months (95% CI 9·3-19·4) in the surufatinib group and 11·1 months (5·7-35·9) in the placebo group. The median investigator-assessed progression-free survival was 10·9 months (7·5-13·8) for surufatinib versus 3·7 months (2·8-5·6) for placebo (hazard ratio 0·49, 95% CI 0·32-0·76; p=0·0011). The trial met the early stopping criteria at the interim analysis and was terminated on recommendation from the independent data monitoring committee. The most common grade 3 or worse treatment-related adverse events were hypertension (43 [38%] of 113 with surufatinib vs four [7%] of 59 with placebo), proteinuria (11 [10%] vs one [2%]), and hypertriglyceridaemia (eight [7%] vs none). Treatment-related serious adverse events were reported in 25 (22%) patients in the surufatinib group and four (7%) patients in the placebo group. There were three on-treatment deaths in the surufatinib group, including two deaths due to adverse events (gastrointestinal haemorrhage [possibly treatment-related] and cerebral haemorrhage [unlikely to be treatment-related]), and one death attributed to disease progression. One on-treatment death in the placebo group was attributed to disease progression. INTERPRETATION:Surufatinib significantly improves progression-free survival and has an acceptable safety profile in patients with progressive, advanced pancreatic NETs, and could be a potential treatment option in this patient population. FUNDING: Hutchison MediPharma.
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