{ "abstract": "Abstract Objective To report updated results of the phase 3 PHILA trial, which evaluated the efficacy and safety of pyrotinib or placebo in combination with trastuzumab and docetaxel in patients with untreated human epidermal growth factor receptor 2 (HER2) positive metastatic breast cancer.Design Multicentre, double blind, randomised, placebo controlled phase 3 trial.Setting 40 centres in China, 6 May 2019 to 17 January 2022.Participants 590 female patients with untreated HER2 positive metastatic breast cancer.Interventions Eligible patients were randomly assigned in a 1:1 ratio to receive either the irreversible pan-HER inhibitor pyrotinib (400 mg orally once daily) or placebo, both in combination with intravenous trastuzumab (8 mg/kg for the first cycle, then 6 mg/kg in subsequent cycles) and docetaxel (75 mg/m 2) on day 1 of each 21 day treatment cycle.Main outcome measure The primary endpoint was investigator assessed progression-free survival.Results 590 patients were randomised and received treatment (297 in the pyrotinib group and 293 in the placebo group). As of 30 April 2024, during a median follow-up of 35.7 months in the pyrotinib group and 34.3 months in the placebo group, 59 (20%) and 87 (30%) patients died, respectively. Overall survival was longer in the pyrotinib group (hazard ratio 0.64 (95% confidence interval (CI) 0.46 to 0.89); nominal one-sided P=0.004). At end of follow-up, neither group had reached the median overall survival. Improvement in progression-free survival in the pyrotinib group was maintained (22.1 months (95% CI 19.3 to 27.8) v 10.5 months (9.5 to 12.4), hazard ratio 0.44 (95% CI 0.36 to 0.53); nominal one sided P<0.001). Adverse event profiles remained consistent with the interim analysis for type, frequency, and severity. After discontinuation of docetaxel, the overall incidence of adverse events decreased substantially. As of 30 May 2025, with a median follow-up of 45.5 months, the pyrotinib based regimen showed consistent and prolonged survival benefit.Conclusions The updated analysis of the phase 3 PHILA trial confirmed the superiority of pyrotinib in combination with trastuzumab and docetaxel over placebo in combination with trastuzumab and docetaxel in sustaining longer progression-free survival and improving overall survival for initial treatment of HER2 positive metastatic breast cancer. The safety profile remained consistent with interim findings, with no new safety signals identified during extended follow-up. This analysis reinforces the efficacy of this dual anti-HER2 (pyrotinib plus trastuzumab) regimen as an effective treatment strategy for this patient population.Trial registration ClinicalTrials.gov NCT03863223.", "authors": [ { "affiliations": [ "Department of Medical Oncology, Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College, Chaoyang District, Beijing, 100021, China" ], "name": "Fei Ma" }, { "affiliations": [ "Department of Breast Disease, Henan Breast Cancer Center, The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, China" ], "name": "Min Yan" }, { "affiliations": [ "Department of Oncology, The First Hospital of Jilin University, Changchun, China" ], "name": "Wei Li" }, { "affiliations": [ "Breast Internal Medicine Department, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China" ], "name": "Quchang Ouyang" }, { "affiliations": [ "Department of Breast Oncology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China" ], "name": "Zhongsheng Tong" }, { "affiliations": [ "Department of Breast Internal Medicine, The First Hospital of China Medical University, Shenyang, China" ], "name": "Yuee Teng" }, { "affiliations": [ "Breast Surgery, Shandong Cancer Hospital and Institute, Jinan, China" ], "name": "Yongsheng Wang" }, { "affiliations": [ "Department of Internal Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China" ], "name": "Shusen Wang" }, { "affiliations": [ "Breast Center, The Fourth Hospital of Hebei Medical University and Hebei Tumor Hospital, Shijiazhuang, China" ], "name": "Cuizhi Geng" }, { "affiliations": [ "Department of Medical Oncology of Cancer Center, West China Hospital, Sichuan University, Chengdu, China" ], "name": "Ting Luo" }, { "affiliations": [ "Medical Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China" ], "name": "Jincai Zhong" }, { "affiliations": [ "Ward One of Mammary Department, Harbin Medical University Cancer Hospital, Harbin, China" ], "name": "Qingyuan Zhang" }, { "affiliations": [ "Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China" ], "name": "Qiang Liu" }, { "affiliations": [ "Breast Cancer Center, Affiliated Cancer Hospital of Chongqing University, Chongqing, China" ], "name": "Xiaohua Zeng" }, { "affiliations": [ "Department of Breast Medicine 1, Cancer Hospital of Dalian University of Technology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, China" ], "name": "Tao Sun" }, { "affiliations": [ "Breast Surgery, Guangxi Medical University Affiliated Tumor Hospital, Nanning, China" ], "name": "Qinguo Mo" }, { "affiliations": [ "Department of Breast Oncology, The First Affiliated Hospital of USTC West District, Hefei, China" ], "name": "Shoubing Zhou" }, { "affiliations": [ "Department of Thoracic Oncology, Jilin Cancer Hospital, Changchun, China" ], "name": "Peidong Li" }, { "affiliations": [ "Oncology Center Breast Department, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China" ], "name": "Jing Cheng" }, { "affiliations": [ "Breast Medicine, Zhejiang Cancer Hospital, Hangzhou, China" ], "name": "Xiaojia Wang" }, { "affiliations": [ "Breast Surgery, Yunnan Cancer Hospital, Kunming, China" ], "name": "Jianyun Nie" }, { "affiliations": [ "Department of Medical Oncology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China" ], "name": "Jin Yang" }, { "affiliations": [ "Department of Breast Oncology, Hubei Cancer Hospital, Wuhan, China" ], "name": "Xinhong Wu" }, { "affiliations": [ "Department of Medical Oncology, Henan Key Laboratory of Cancer Epigenetics, Cancer Hospital, The First Affiliated Hospital, College of Clinical Medicine, Medical College of Henan University of Science and Technology, Luoyang, China" ], "name": "Xinshuai Wang" }, { "affiliations": [ "Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Breast Oncology, Peking University Cancer Hospital and Institute, Beijing, China" ], "name": "Huiping Li" }, { "affiliations": [ "Department of Breast, Southern Medical University Nanfang Hospital, Guangzhou, China" ], "name": "Guangyu Yao" }, { "affiliations": [ "Jiangsu Hengrui Pharmaceuticals, Shanghai, China" ], "name": "Yang Fan" }, { "affiliations": [ "Jiangsu Hengrui Pharmaceuticals, Shanghai, China" ], "name": "Jiaman Lin" }, { "affiliations": [ "Jiangsu Hengrui Pharmaceuticals, Shanghai, China" ], "name": "Xiaoyu Zhu" }, { "affiliations": [ "Department of Medical Oncology, Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College, Chaoyang District, Beijing, 100021, China" ], "name": "Binghe Xu" } ], "title": "Pyrotinib or placebo in combination with trastuzumab and docetaxel for HER2 positive metastatic breast cancer: long term survival results from randomised phase 3 PHILA trial", "uid": "d162fa1f-7249-591b-af04-70aa178d4702" }