Jianming Xu1, Lin Shen2, Zhiwei Zhou3, Jie Li2, Chunmei Bai4, Yihebali Chi5, Zhiping Li6, Nong Xu7, Enxiao Li8, Tianshu Liu9, Yuxian Bai10, Ying Yuan11, Xingya Li12, Xiuwen Wang13, Jia Chen14, Jieer Ying15, Xianjun Yu16, Shukui Qin17, Xianglin Yuan18, Tao Zhang19, Yanhong Deng20, Dianrong Xiu21, Ying Cheng22, Min Tao23, Ru Jia24, Wei Wang3, Jing Li25, Songhua Fan25, Mengye Peng25, Weiguo Su25. 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 Gastric Surgery, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China. 4. Department of Medical Oncology, Peking Union Medical College Hospital, Beijing, China. 5. National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. 6. Department of Abdominal Oncology, West China Hospital, Sichuan University, Chengdu, China. 7. Department of Medical Oncology, The First Affiliated Hospital of Zhejiang University, Hangzhou, China. 8. Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China. 9. Department of Medical Oncology, Zhongshan Hospital of Fudan University, Shanghai, China. 10. Department of Gastrointestinal Oncology, Harbin Medical University Cancer Hospital, Harbin, China. 11. Department of Medical Oncology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. 12. Department of Medical Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China. 13. Department of Medical Oncology, Qilu Hospital of Shandong University, Jinan, China. 14. Department of Oncology, Jiangsu Cancer Hospital, Nanjing, China. 15. Department of Abdominal Oncology, Zhejiang Cancer Hospital, Hangzhou, China. 16. Department of Pancreatic and Hepatobiliary Surgery, Fudan University Shanghai Cancer Center, Shanghai, China. 17. People's Liberation Army Cancer Center of Nanjing Jinling Hospital, Nanjing, China. 18. Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. 19. Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. 20. Department of Medical Oncology, The Sixth Affiliated Hospital, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases l, Sun Yat-sen University, Guangzhou, Guangdong, China. 21. Department of General Surgery, Peking University Third Hospital, Beijing, China. 22. Department of Thoracic Oncology, Jilin Provincial Cancer Hospital, Changchun, China. 23. Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou, China. 24. Department of Gastrointestinal Oncology, The Fifth Medical Center, Chinese PLA General Hospital, Beijing, China. 25. Department of Clinical Development and Regulatory Affairs, Hutchison MediPharma, Shanghai, China.
Abstract
BACKGROUND: Therapeutic options for advanced neuroendocrine tumours (NETs) are limited. We investigated the efficacy and safety of surufatinib (HMPL-012, sulfatinib) in patients with extrapancreatic NETs. METHODS: SANET-ep was a randomised, double-blind, placebo-controlled, phase 3 trial undertaken at 24 hospitals across China. Patients (aged 18 years or older) with unresectable or metastatic, well differentiated, extrapancreatic NETs, with an Eastern Cooperative Oncology Group performance status of 0 or 1, and progression on no more than two types of previous systemic regimens were enrolled. Patients were centrally randomly assigned (2:1) using stratified block randomisation (block size 3) via an interactive web response system to receive oral surufatinib at 300 mg per day or matching placebo. Randomisation was stratified by tumour origin, pathological grade, and previous treatment. Patients, investigators, research staff and the sponsor study team were masked to treatment allocation. Crossover to the surufatinib group was allowed for patients in the placebo group at disease progression. The primary endpoint was investigator-assessed progression-free survival, which was analysed in the intention-to-treat population. A preplanned interim analysis was done at 70% of predicted progression-free survival events. This study was registered with ClinicalTrials.gov, NCT02588170. Follow-up is ongoing. FINDINGS: Between Dec 9, 2015, and March 31, 2019, 198 patients were randomly assigned to surufatinib (n=129) orplacebo (n=69). Median follow-up was 13·8 months (95% CI 11·1-16·7) in the surufatinib group and 16·6 months (9·2-not calculable) in the placebo group. Investigator-assessed median progression-free survival was 9·2 months (95% CI 7·4-11·1) in the surufatinib group versus 3·8 months (3·7-5·7) in the placebo group (hazard ratio 0·33; 95% CI 0·22-0·50; p<0·0001). As the trial met the predefined criteria for early discontinuation of the study at the interim analysis, the study was terminated early, as recommended by the independent data monitoring committee. The most common treatment-related adverse events of grade 3 or worse were hypertension (47 [36%] of 129 patients in the surufatinib group vs nine [13%] of 68 patients in the placebo group) and proteinuria (25 [19%] vs zero). Treatment-related serious adverse events were reported in 32 (25%) of 129 patients in the surufatinib group and nine (13%) of 68 patients in the placebo group. Treatment-related deaths occurred in three patients in the surufatinib group (disseminated intravascular coagulation and hepatic encephalopathy, liver injury, and death with unknown reason) and one patient in the placebo group (cachexia and respiratory failure). INTERPRETATION:Progression-free survival was significantly longer in patients given surufatinib compared with patients given placebo, and surufatinib has a favourable benefit-to-risk profile in patients with progressive, advanced, well differentiated extrapancreatic NETs. Our results suggest that surufatinib might be a new treatment option for this population. FUNDING: Hutchison MediPharma.
RCT Entities:
BACKGROUND: Therapeutic options for advanced neuroendocrine tumours (NETs) are limited. We investigated the efficacy and safety of surufatinib (HMPL-012, sulfatinib) in patients with extrapancreatic NETs. METHODS: SANET-ep was a randomised, double-blind, placebo-controlled, phase 3 trial undertaken at 24 hospitals across China. Patients (aged 18 years or older) with unresectable or metastatic, well differentiated, extrapancreatic NETs, with an Eastern Cooperative Oncology Group performance status of 0 or 1, and progression on no more than two types of previous systemic regimens were enrolled. Patients were centrally randomly assigned (2:1) using stratified block randomisation (block size 3) via an interactive web response system to receive oral surufatinib at 300 mg per day or matching placebo. Randomisation was stratified by tumour origin, pathological grade, and previous treatment. Patients, investigators, research staff and the sponsor study team were masked to treatment allocation. Crossover to the surufatinib group was allowed for patients in the placebo group at disease progression. The primary endpoint was investigator-assessed progression-free survival, which was analysed in the intention-to-treat population. A preplanned interim analysis was done at 70% of predicted progression-free survival events. This study was registered with ClinicalTrials.gov, NCT02588170. Follow-up is ongoing. FINDINGS: Between Dec 9, 2015, and March 31, 2019, 198 patients were randomly assigned to surufatinib (n=129) or placebo (n=69). Median follow-up was 13·8 months (95% CI 11·1-16·7) in the surufatinib group and 16·6 months (9·2-not calculable) in the placebo group. Investigator-assessed median progression-free survival was 9·2 months (95% CI 7·4-11·1) in the surufatinib group versus 3·8 months (3·7-5·7) in the placebo group (hazard ratio 0·33; 95% CI 0·22-0·50; p<0·0001). As the trial met the predefined criteria for early discontinuation of the study at the interim analysis, the study was terminated early, as recommended by the independent data monitoring committee. The most common treatment-related adverse events of grade 3 or worse were hypertension (47 [36%] of 129 patients in the surufatinib group vs nine [13%] of 68 patients in the placebo group) and proteinuria (25 [19%] vs zero). Treatment-related serious adverse events were reported in 32 (25%) of 129 patients in the surufatinib group and nine (13%) of 68 patients in the placebo group. Treatment-related deaths occurred in three patients in the surufatinib group (disseminated intravascular coagulation and hepatic encephalopathy, liver injury, and death with unknown reason) and one patient in the placebo group (cachexia and respiratory failure). INTERPRETATION: Progression-free survival was significantly longer in patients given surufatinib compared with patients given placebo, and surufatinib has a favourable benefit-to-risk profile in patients with progressive, advanced, well differentiated extrapancreatic NETs. Our results suggest that surufatinib might be a new treatment option for this population. FUNDING: Hutchison MediPharma.
Authors: Chandra K Maharjan; Po Hien Ear; Catherine G Tran; James R Howe; Chandrikha Chandrasekharan; Dawn E Quelle Journal: Cancers (Basel) Date: 2021-10-12 Impact factor: 6.639
Authors: Fangdi Sun; James P Grenert; Lisa Tan; Jessica Van Ziffle; Nancy M Joseph; Claire K Mulvey; Emily Bergsland Journal: JCO Precis Oncol Date: 2022-06