• Min Yan, Quchang Ouyang, Tao Sun, Limin Niu, Jin Yang, Li Li, Yuhua Song, Chunfang Hao, Zhanhong Chen, Armando Orlandi, Naohiro Ishii, Kazuaki Takabe, Gianluca Franceschini, Francesco Ricci, Claire Verschraegen, Zhenzhen Liu, Mengwei Zhang, Huimin Lv, Liping Liu, Xiaohong Yang, Huawu Xiao, Zhichao Gao, Xiaorui Li, Fangyuan Dong, Xiuchun Chen, Jianghua Qiao, and Guifang Zhang.
• Henan Breast Cancer Centre, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China. Electronic address: ym200678@126.com.
• Lancet Oncol. 2022 Mar 1; 23 (3): 353361353-361.

BackgroundPatients with HER2-positive metastatic breast cancer have a high risk of developing brain metastases. Efficacious treatment options are scarce. We investigated the activity and safety of pyrotinib plus capecitabine in patients with HER2-positive metastatic breast cancer and brain metastases.MethodsWe did a multicentre, single-arm, two-cohort, phase 2 trial in eight tertiary hospitals in China. Patients aged 18 years or older who had radiotherapy-naive HER2-positive brain metastases (cohort A) or progressive disease after radiotherapy (cohort B), with an Eastern Cooperative Oncology Group performance status of 0-2, received pyrotinib 400 mg orally once daily, and capecitabine 1000 mg/m2 orally twice daily for 14 days, followed by 7 days off every 3 weeks until disease progression or unacceptable toxicity. The primary endpoint was confirmed intracranial objective response rate by investigator assessment according to the Response Evaluation Criteria In Solid Tumours (version 1.1). Activity and safety were analysed in patients with at least one dose of study drug. The study is ongoing, but recruitment is complete. The study is registered with ClinicalTrials.gov, NCT03691051.FindingsBetween Jan 29, 2019, and July 10, 2020, we enrolled 78 women: 51 (86%) of 59 patients in cohort A and 18 (95%) of 19 patients in cohort B had previous exposure to trastuzumab. Median follow-up duration was 15·7 months (IQR 9·7-19·0). The intracranial objective response rate was 74·6% (95% CI 61·6-85·0; 44 of 59 patients) in cohort A and 42·1% (20·3-66·5; eight of 19 patients) in cohort B. The most common grade 3 or worse treatment-emergent adverse event was diarrhoea (14 [24%] in cohort A and four [21%] in cohort B). Two (3%) patients in cohort A and three (16%) in cohort B had treatment-related serious adverse events. No treatment-related deaths occurred.InterpretationTo our knowledge, this is the first prospective study showing the activity and safety of pyrotinib plus capecitabine in patients with HER2-positive breast cancer and brain metastases, especially in radiotherapy-naive population. This combination deserves further validation in a randomised, controlled trial.FundingNational Cancer Centre Climbing Foundation Key Project of China, Jiangsu Hengrui Pharmaceuticals.TranslationFor the Chinese translation of the abstract see Supplementary Materials section.Copyright © 2022 Elsevier Ltd. All rights reserved.

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