Binghe Xu1, Min Yan2, Fei Ma3, Xichun Hu4, Jifeng Feng5, Quchang Ouyang6, Zhongsheng Tong7, Huiping Li8, Qingyuan Zhang9, Tao Sun10, Xian Wang11, Yongmei Yin12, Ying Cheng13, Wei Li14, Yuanting Gu15, Qianjun Chen16, Jinping Liu17, Jing Cheng18, Cuizhi Geng19, Shukui Qin20, Shusen Wang21, Jinsong Lu22, Kunwei Shen23, Qiang Liu24, Xiaojia Wang25, Hong Wang26, Ting Luo27, Jin Yang28, Yudong Wu29, Zhiyong Yu30, Xiaoyu Zhu31, Chunxia Chen31, Jianjun Zou31. 1. National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. Electronic address: xubinghe@medmail.com.cn. 2. The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China. 3. National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. 4. Fudan University Cancer Hospital, Shanghai, China. 5. Jiangsu Cancer Hospital, Nanjing, China. 6. Hunan Cancer Hospital, Changsha, China. 7. Tianjin Medical University Cancer Institute and Hospital, Tianjin, China. 8. Beijing Cancer Hospital, Beijing, China. 9. Harbin Medical University Cancer Hospital, Harbin, China. 10. Liaoning Cancer Hospital & Institute, Shenyang, China. 11. Zhejiang University School of Medicine Sir Run Run Shaw Hospital, Hangzhou, China. 12. The First Affiliated Hospital of Nanjing Medical University, Nanjing, China. 13. Jilin Cancer Hospital, Changchun, China. 14. The First Bethune Hospital of Jilin University, Changchun, China. 15. The First Bethune Hospital of Jilin University, Changchun, China; The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China. 16. Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou, China. 17. Sichuan Academy of Medical Sciences, Sichuan Provincial People's Hospital, Chengdu, China. 18. Wuhan Union Hospital, Wuhan, China. 19. The Fourth Hospital of Hebei Medical University, Shijiazhuang, China. 20. Cancer Centre of Jinling Hospital, Nanjing, China. 21. Sun Yat-Sen University Cancer Center, Guangzhou, China. 22. Renji Hospital Shanghai Jiaotong University School of Medicine, Shanghai, China. 23. Ruijin Hospital Shanghai Jiaotong University School of Medicine, Shanghai, China. 24. Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China. 25. Zhejiang Cancer Hospital, Hangzhou, China. 26. The Third Hospital of Nanchang, Nanchang, China. 27. West China Hospital, Sichuan University, Chengdu, China. 28. The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China. 29. Jiangxi Cancer Hospital, Nanchang, China. 30. Shandong Tumor Hospital, Jinan, China. 31. Jiangsu Hengrui Medicine, Shanghai, China.
Abstract
BACKGROUND: Despite therapeutic advances in HER2-positive metastatic breast cancer, resistance to trastuzumab inevitably develops. In the PHOEBE study, we aimed to assess the efficacy and safety of pyrotinib (an irreversible pan-HER inhibitor) plus capecitabine after previous trastuzumab. METHODS: This is an open-label, randomised, controlled, phase 3 trial done at 29 hospitals in China. Patients with pathologically confirmed HER2-positive metastatic breast cancer, aged 18-70 years, who had an Eastern Cooperative Oncology Group performance status of 0 or 1, and had been previously treated withtrastuzumab and taxanes were randomly assigned (1:1) to receive oral pyrotinib 400 mg or lapatinib 1250 mg once daily plus oral capecitabine 1000 mg/m2 twice daily on days 1-14 of each 21-day cycle. Randomisation was done via a centralised interactive web-response system with a block size of four or six and stratified by hormone receptor status and previous lines of chemotherapy for metastatic disease. The primary endpoint was progression-free survival according to masked independent central review. Efficacy and safety were assessed in all patients who received at least one dose of the study drugs. Results presented here are from a prespecified interim analysis. This study is registered with ClinicalTrials.gov, NCT03080805. FINDINGS:Between July 31, 2017, and Oct 30, 2018, 267 patients were enrolled and randomly assigned. 134 patients receivedpyrotinib plus capecitabine and 132 received lapatinib plus capecitabine. At data cutoff of the interim analysis on March 31, 2019, median progression-free survival was significantly longer with pyrotinib plus capecitabine (12·5 months [95% CI 9·7-not reached]) than with lapatinib plus capecitabine (6·8 months [5·4-8·1]; hazard ratio 0·39 [95% CI 0·27-0·56]; one-sided p<0·0001). The most common grade 3 or worse adverse events were diarrhoea (41 [31%] in the pyrotinib group vs 11 [8%] in the lapatinib group) and hand-foot syndrome (22 [16%] vs 20 [15%]). Serious adverse events were reported for 14 (10%) patients in the pyrotinib group and 11 (8%) patients in the lapatinib group. No treatment-related deaths were reported in the pyrotinib group and one sudden death in the lapatinib group was considered treatment related. INTERPRETATION:Pyrotinib plus capecitabine significantly improved progression-free survival compared with that for lapatinib plus capecitabine, with manageable toxicity, and can be considered an alternative treatment option for patients with HER2-positive metastatic breast cancer after trastuzumab and chemotherapy. FUNDING: Jiangsu Hengrui Medicine and National Key R&D Program of China. TRANSLATIONS: For the Chinese translation of the abstract see Supplementary Materials section.
RCT Entities:
BACKGROUND: Despite therapeutic advances in HER2-positive metastatic breast cancer, resistance to trastuzumab inevitably develops. In the PHOEBE study, we aimed to assess the efficacy and safety of pyrotinib (an irreversible pan-HER inhibitor) plus capecitabine after previous trastuzumab. METHODS: This is an open-label, randomised, controlled, phase 3 trial done at 29 hospitals in China. Patients with pathologically confirmed HER2-positive metastatic breast cancer, aged 18-70 years, who had an Eastern Cooperative Oncology Group performance status of 0 or 1, and had been previously treated with trastuzumab and taxanes were randomly assigned (1:1) to receive oral pyrotinib 400 mg or lapatinib 1250 mg once daily plus oral capecitabine 1000 mg/m2 twice daily on days 1-14 of each 21-day cycle. Randomisation was done via a centralised interactive web-response system with a block size of four or six and stratified by hormone receptor status and previous lines of chemotherapy for metastatic disease. The primary endpoint was progression-free survival according to masked independent central review. Efficacy and safety were assessed in all patients who received at least one dose of the study drugs. Results presented here are from a prespecified interim analysis. This study is registered with ClinicalTrials.gov, NCT03080805. FINDINGS: Between July 31, 2017, and Oct 30, 2018, 267 patients were enrolled and randomly assigned. 134 patients received pyrotinib plus capecitabine and 132 received lapatinib plus capecitabine. At data cutoff of the interim analysis on March 31, 2019, median progression-free survival was significantly longer with pyrotinib plus capecitabine (12·5 months [95% CI 9·7-not reached]) than with lapatinib plus capecitabine (6·8 months [5·4-8·1]; hazard ratio 0·39 [95% CI 0·27-0·56]; one-sided p<0·0001). The most common grade 3 or worse adverse events were diarrhoea (41 [31%] in the pyrotinib group vs 11 [8%] in the lapatinib group) and hand-foot syndrome (22 [16%] vs 20 [15%]). Serious adverse events were reported for 14 (10%) patients in the pyrotinib group and 11 (8%) patients in the lapatinib group. No treatment-related deaths were reported in the pyrotinib group and one sudden death in the lapatinib group was considered treatment related. INTERPRETATION:Pyrotinib plus capecitabine significantly improved progression-free survival compared with that for lapatinib plus capecitabine, with manageable toxicity, and can be considered an alternative treatment option for patients with HER2-positive metastatic breast cancer after trastuzumab and chemotherapy. FUNDING: Jiangsu Hengrui Medicine and National Key R&D Program of China. TRANSLATIONS: For the Chinese translation of the abstract see Supplementary Materials section.
Authors: G Nader-Marta; D Martins-Branco; E Agostinetto; M Bruzzone; M Ceppi; L Danielli; M Lambertini; N Kotecki; A Awada; E de Azambuja Journal: ESMO Open Date: 2022-05-30