Yunpeng Yang1, Song Qu2, Jingao Li3, Chaosu Hu4, Mingjun Xu5, Weidong Li6, Ting Zhou1, Liangfang Shen7, Hui Wu8, Jinyi Lang9, Guangyuan Hu10, Zhanxiong Luo11, Zhichao Fu12, Shenhong Qu13, Weineng Feng14, Xiaozhong Chen15, Shaojun Lin16, Weimin Zhang17, Xiaojiang Li18, Yan Sun19, Zhixiong Lin20, Qin Lin21, Feng Lei22, Jianting Long23, Jinsheng Hong24, Xiaoming Huang25, Lingzhi Zeng26, Peiguo Wang27, Xiaohui He28, Ben Zhang29, Qing Yang29, Xiaojing Zhang29, Jianjun Zou29, Wenfeng Fang1, Li Zhang30. 1. Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China. 2. Guangxi Medical University Affiliated Tumor Hospital, Nanning, China. 3. Jiangxi Cancer Hospital of Nanchang University, Nanchang, China. 4. Fudan University Shanghai Cancer Center, Shanghai, China. 5. First Affiliated Hospital of Gannan Medical University, Ganzhou, China. 6. Guangzhou Medical University Affiliated Oncology Hospital, Guangzhou, China. 7. Xiangya Hospital Central South University, Changsha, China. 8. Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China. 9. Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China. 10. Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. 11. Liuzhou People's Hospital, Liuzhou, China. 12. 900th Hospital of The Joint Logistics Team, PLA, Fuzhou, China. 13. Guangxi Zhuang Autonomous Region People's Hospital, Nanning, China. 14. The First People's Hospital of Foshan, Foshan, China. 15. Zhejiang Cancer Hospital, Hangzhou, China. 16. Fujian Medical University Cancer Hospital & Fujian Cancer Hospital, Fuzhou, China. 17. General Hospital of Southern Theatre Command, Guangzhou, China. 18. Yunnan Cancer Hospital, Kunming, China. 19. Beijing Cancer Hospital, Beijing, China. 20. Cancer Hospital of Shantou University Medical College, Shantou, China. 21. The First Affiliated Hospital of Xiamen University, Xiamen, China. 22. Zhongshan People's Hospital, Zhongshan, China. 23. The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China. 24. The First Affiliated Hospital of Fujian Medical University/Key Laboratory of Radiation Biology, Fuzhou, China. 25. Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, China. 26. Jiujiang No.1 People's Hospital of Nanchang University, Jiujiang, China. 27. Tianjin Medical University Cancer Institute and Hospital, Tianjin, China. 28. Cancer Hospital Chinese Academy of Medical Sciences, Beijing, China. 29. Jiangsu Hengrui Pharmaceuticals, Shanghai, China. 30. 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
BACKGROUND: The addition of camrelizumab to gemcitabine and cisplatin showed promising activity as first-line therapy in patients with recurrent or metastatic nasopharyngeal carcinoma in a phase 1 trial. We therefore compared camrelizumab plus gemcitabine and cisplatin with placebo plus gemcitabine and cisplatin in a randomised phase 3 trial. METHODS: In this randomised, double-blind, phase 3 trial done at 28 hospitals in China, patients were eligible if they were aged 18-75 years, had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, and had previously untreated recurrent or metastatic nasopharyngeal carcinoma. Patients were randomly assigned (1:1; using an interactive web-response system with a block size of four) to receive either camrelizumab (200 mg on day 1) or matching placebo intravenously, plus gemcitabine and cisplatin (gemcitabine 1000 mg/m2 on days 1 and 8; cisplatin 80 mg/m2 on day 1) intravenously every 3 weeks for four to six cycles, followed by maintenance therapy with camrelizumab or placebo, until radiographic progression, unacceptable toxicity, start of new anticancer treatment, investigator decision, or withdrawal of consent. Stratification factors used in randomisation were liver metastases, previous radical concurrent chemoradiotherapy, and ECOG performance status. The allocation sequence was generated by an independent randomisation group. The primary endpoint was progression-free survival per independent review committee. The significance threshold for independent review committee-assessed progression-free survival was p=0·0086 (one-sided) at the interim analysis. Efficacy and safety analyses included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT03707509, and is closed for enrolment but is ongoing. FINDINGS:Between Nov 13, 2018, and Nov 29, 2019, 343 patients were screened and 263 were eligible and were randomly assigned to the camrelizumab group (n=134) or placebo group (n=129). At the prespecified interim analysis (June 15, 2020), independent review committee-assessed progression-free survival was significantly longer in the camrelizumab group (median 9·7 months [95% CI 8·3-11·4]) than in the placebo group (median 6·9 months [5·9-7·3]; hazard ratio 0·54 [95% CI 0·39-0·76]; one-sided p=0·0002). As of Dec 31, 2020, the most common grade 3 or worse adverse events of any cause were decreased white blood cell count (89 [66%] of 134 patients in the camrelizumab group vs 90 [70%] of 129 patients in the placebo group), decreased neutrophil count (86 [64%] vs 85 [66%]), anaemia (53 [40%] vs 57 [44%]), and decreased platelet count (53 [40%] vs 52 [40%]). Serious adverse events were reported in 59 (44%) of 134 patients in the camrelizumab group and 48 (37%) of 129 patients in the placebo group. Treatment-related deaths occurred in five (4%) patients in the camrelizumab group (two unknown cause of death, one multiple organ dysfunction syndrome, one pharyngeal haemorrhage, and one arrhythmia) and one (<1%) patient in the placebo group (unknown cause of death). INTERPRETATION: Our findings suggest that camrelizumab plus gemcitabine and cisplatin could be a new standard of care for patients with recurrent or metastatic nasopharyngeal carcinoma in the first-line setting. Longer follow-up is needed to confirm this conclusion. FUNDING: Jiangsu Hengrui Pharmaceuticals (formerly Jiangsu Hengrui Medicine). TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.
RCT Entities:
BACKGROUND: The addition of camrelizumab to gemcitabine and cisplatin showed promising activity as first-line therapy in patients with recurrent or metastatic nasopharyngeal carcinoma in a phase 1 trial. We therefore compared camrelizumab plus gemcitabine and cisplatin with placebo plus gemcitabine and cisplatin in a randomised phase 3 trial. METHODS: In this randomised, double-blind, phase 3 trial done at 28 hospitals in China, patients were eligible if they were aged 18-75 years, had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, and had previously untreated recurrent or metastatic nasopharyngeal carcinoma. Patients were randomly assigned (1:1; using an interactive web-response system with a block size of four) to receive either camrelizumab (200 mg on day 1) or matching placebo intravenously, plus gemcitabine and cisplatin (gemcitabine 1000 mg/m2 on days 1 and 8; cisplatin 80 mg/m2 on day 1) intravenously every 3 weeks for four to six cycles, followed by maintenance therapy with camrelizumab or placebo, until radiographic progression, unacceptable toxicity, start of new anticancer treatment, investigator decision, or withdrawal of consent. Stratification factors used in randomisation were liver metastases, previous radical concurrent chemoradiotherapy, and ECOG performance status. The allocation sequence was generated by an independent randomisation group. The primary endpoint was progression-free survival per independent review committee. The significance threshold for independent review committee-assessed progression-free survival was p=0·0086 (one-sided) at the interim analysis. Efficacy and safety analyses included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT03707509, and is closed for enrolment but is ongoing. FINDINGS: Between Nov 13, 2018, and Nov 29, 2019, 343 patients were screened and 263 were eligible and were randomly assigned to the camrelizumab group (n=134) or placebo group (n=129). At the prespecified interim analysis (June 15, 2020), independent review committee-assessed progression-free survival was significantly longer in the camrelizumab group (median 9·7 months [95% CI 8·3-11·4]) than in the placebo group (median 6·9 months [5·9-7·3]; hazard ratio 0·54 [95% CI 0·39-0·76]; one-sided p=0·0002). As of Dec 31, 2020, the most common grade 3 or worse adverse events of any cause were decreased white blood cell count (89 [66%] of 134 patients in the camrelizumab group vs 90 [70%] of 129 patients in the placebo group), decreased neutrophil count (86 [64%] vs 85 [66%]), anaemia (53 [40%] vs 57 [44%]), and decreased platelet count (53 [40%] vs 52 [40%]). Serious adverse events were reported in 59 (44%) of 134 patients in the camrelizumab group and 48 (37%) of 129 patients in the placebo group. Treatment-related deaths occurred in five (4%) patients in the camrelizumab group (two unknown cause of death, one multiple organ dysfunction syndrome, one pharyngeal haemorrhage, and one arrhythmia) and one (<1%) patient in the placebo group (unknown cause of death). INTERPRETATION: Our findings suggest that camrelizumab plus gemcitabine and cisplatin could be a new standard of care for patients with recurrent or metastatic nasopharyngeal carcinoma in the first-line setting. Longer follow-up is needed to confirm this conclusion. FUNDING: Jiangsu Hengrui Pharmaceuticals (formerly Jiangsu Hengrui Medicine). TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.
Authors: Pierre Blanchard; Anne W M Lee; Alexandra Carmel; Ng Wai Tong; Jun Ma; Anthony T C Chan; Ruey Long Hong; Ming-Yuan Chen; Lei Chen; Wen-Fei Li; Pei-Yu Huang; Dora L W Kwong; Sharon S X Poh; Roger Ngan; Hai-Qiang Mai; Camille Ollivier; George Fountzilas; Li Zhang; Jean Bourhis; Anne Aupérin; Benjamin Lacas; Jean-Pierre Pignon Journal: Clin Transl Radiat Oncol Date: 2021-11-26