Published OnlineFirst June 10, 2021; DOI: 10.1158/1078-0432.CCR-21-0474 CLINICAL CANCER RESEARCH | CLINICAL TRIALS: TARGETED THERAPY Pyrotinib Treatment in Patients With HER2-positive Metastatic Breast Cancer and Brain Metastasis: Exploratory Final Analysis of Real-World, Multicenter Data Munawar Anwar1, Qitong Chen1, Dengjie Ouyang1,2, Shouman Wang3, Ning Xie4, Quchang Ouyang4, Peizhi Fan5, Liyuan Qian6, Gannong Chen1, Enxiang Zhou1, Lei Guo3, Xiaowen Gu5, Boning Ding6, Xiaohong Yang7, Liping Liu7, Chao Deng8, Zhi Xiao3, Jing Li9, Yunqi Wang10, Shan Zeng11, Jinhui Hu12, Wei Zhou13, Bo Qiu14, Zhongming Wang15, Jie Weng16, Mingwen Liu17,YiLi18, Tiegang Tang19, Jianguo Wang20, Hui Zhang21, Bin Dai22, Wuping Tang23, Tao Wu24, Maoliang Xiao25, Xiantao Li26, Hailong Liu27, Lai Li28, and Wenjun Yi1 ABSTRACT ◥ þ Purpose: Patients with HER2-positive (HER2 ) metastatic PFS (P ¼ 0.0028). In the 39 patients with BM, the median PFS and breast cancer (MBC) have poor prognoses. Pyrotinib has shown OS were 8.67 and 13.93 months, respectively. The surgery/radiation promising antitumor activity in MBC to improve progression-free (S/R) group of patients with BM had prolonged survival (PFS: survival (PFS). However, findings based on real-world data to 9.97 vs. 7.73 months P ¼ 0.19; OS: 20.67 vs. 12.43 months P ¼ 0.021) analyze whether pyrotinib affects overall survival (OS) remain compared with the no surgery/no radiation group (NS/NR). The scarce. CBR was 58.6% (S/R) vs. 41.4% (NS/NR), while the ORR was 24.1% Experimental Design: This real-world study is an exploratory (S/R) vs. 31.0% (NS/NR). analysis of brain metastasis (BM) and the final update of our Conclusions: Pyrotinib shows promise as a novel pan-HER2 þ preceding study of 168 patients with HER2 MBC. PFS, OS, tumor tyrosine kinase inhibitor (TKI) for the treatment of BM and mutation burden (TMB), clinical benefit rate (CBR), and overall should be evaluated further. Surgical or radiotherapy in combi- response rate (ORR) were analyzed. nation with pyrotinib was found to statistically improve OS in Results: Pyrotinib treatment led to a median PFS time of our cohort. TMB could be an exploratory biomarker for pre- 8.00 months and a median OS of 19.07 months in the 168 parti- dicting PFS and OS, but its clinical application still needs further cipants. High TMB was associated with poor OS (P ¼ 0.0072) and verification. 1Department of General Surgery, The Second Xiangya Hospital, Central South Central Hospital, Xiangtan, China. 20Department of General Surgery, Xiangtan University, Changsha, China. 2Department of General Surgery, Xiangya Hospital Central Hospital, Xiangtan, China. 21Department of Oncology, Central Hospital of Central South University, Changsha, China. 3Department of Breast Surgery, Shaoyang, Shaoyang, China. 22Department of Breast and Thyroid Surgery, Xiangya Hospital Central South University, Changsha, China. 4Department of Central Hospital of Shaoyang, Shaoyang, China. 23Department of Breast Breast Internal Medicine, The Affiliated Cancer Hospital of Xiangya School of Surgery, Shaoyang Hospital of Traditional Chinese Medicine, Shaoyang, Medicine, Central South University, Changsha, China. 5Department of Breast and China. 24Department of Oncology, The First People’s Hospital of Changde, Thyroid Surgery, Hunan Provincial People’s Hospital, Changsha, China. 6Depart- Changde, China. 25Department of Oncology, The Third Hospital of Hunan ment of Breast and Thyroid Surgery, Central South University Third Xiangya University of Chinese Medicine, Zhuzhou, China. 26Department of Oncology, Hospital, Changsha, China. 7Department of Oncology, The Affiliated Cancer The Central Hospital of Yiyang, Yiyang, China. 27Department of Internal Hospital of Xiangya School of Medicine, Central South University, Changsha, Medicine – Oncology, The First People’s Hospital of Chenzhou, Chenzhou, China. 8Department of Oncology, The Second Xiangya Hospital, Central South China. 28Department of Breast and Thyroid Surgery, The People’sHospitalof University, Changsha, China. 9Department of Breast Medical Oncology, The Xiangtan County, Xiangtan, China. Affiliated Cancer Hospital of Xiangya School of Medicine, Central South Uni- Note: Supplementary data for this article are available at Clinical Cancer versity, Changsha, China. 10Department of Traditional Chinese Medicine, The Research Online (http://clincancerres.aacrjournals.org/). Affiliated Cancer Hospital of Xiangya School of Medicine, Central South Uni- fi versity, Changsha, China. 11Department of Internal Medicine – Oncology, Xiangya M. Anwar and Q. Chen contributed equally as co- rst authors of this article. 12 Hospital Central South University, Changsha, China. Department of Breast Corresponding Author: Wenjun Yi, Department of General Surgery, The Second Surgery, The First Hospital Hunan University of Chinese Medicine, Changsha, Xiangya Hospital, Central South University, No. 139, Renmin Central Road, 13 China. Department of Breast and Thyroid Surgery, The Affiliated ZhuZhou Changsha 410011, P.R. China. Phone: 8618-6084-03318; E-mail: Hospital of Xiangya School of Medicine Central South University, Zhuzhou, [email protected] China. 14Department of Oncology, The Affiliated ZhuZhou Hospital of Xiangya – School of Medicine Central South University, Zhuzhou, China. 15Department of Clin Cancer Res 2021;XX:XX XX Breast Surgery, The Third People’s Hospital of Yongzhou, Yongzhou, China. doi: 10.1158/1078-0432.CCR-21-0474 16Department of Oncology, The First People’s Hospital of Yueyang, Yueyang, This open access article is distributed under Creative Commons Attribution- China. 17Department of Breast and Thyroid Surgery, The First People’s Hospital NonCommercial-NoDerivatives License 4.0 International (CC BY-NC-ND). of Xiangtan City, Xiangtan, China. 18Department of Oncology, The Third People’s Hospital of Changde, Changde, China. 19Department of Oncology, Xiangtan Ó2021 The Authors; Published by the American Association for Cancer Research AACRJournals.org | OF1 Downloaded from clincancerres.aacrjournals.org on October 1, 2021. © 2021 American Association for Cancer Research. Published OnlineFirst June 10, 2021; DOI: 10.1158/1078-0432.CCR-21-0474 Anwar et al. In our previous multicenter real-world study, pyrotinib was found Translational Relevance þ to be effective against HER2 MBC with tolerable side effects. A total of þ Patients with HER2-positive (HER2 ) metastatic breast cancer 168 patients were enrolled, and the median PFS time was 8.07 months (MBC) have a poor prognosis and tend to develop brain metastases [95% confidence interval (CI), 7.041–9.099 months] in the entire (BMs). Pyrotinib, a pan-HER2 receptor tyrosine kinase inhibitor cohort (17). For patients with BM (n ¼ 39, 23.21%) at baseline the (TKI), has encouraging antitumor effects on progression-free median PFS time was 8.80 months (17). After ongoing follow-up for þ survival (PFS) in patients with HER2 MBC. However, overall 1 more year, 99 patients reached OS events. Here, we report the final þ survival (OS) data from HER2 patients with BM remain scarce. In analysis results from all cohorts, with a focus on the results from this multicenter real-world study, pyrotinib shows promise as a patients with baseline BM. novel pan-HER2 TKI for the treatment of BM. Surgical or radio- therapy in combination with pyrotinib was found to improve OS in our BM cohort statistically. Our results could be a crucial com- Materials and Methods plement to current clinical trials. This work also demonstrates Data collection and study design tumor mutation burden (TMB) could be an exploratory biomarker This real-world study is an exploratory analysis of BM and the final for predicting PFS and OS in patients treated with pyrotinib, which update of our preceding study (17), with an extended follow-up warrants further prospective clinical studies. through December 2020. Between June 2018 and August 2019, 168 þ patients with HER2 MBC treated with pyrotinib were enrolled in our real-world analysis. The enrollment inclusion criteria were as follows: þ (i) confirmed pathologic diagnosis of HER2 MBC (IHC category 3þ or positive results of FISH; ref. 18); (ii) a measurable lesion as defined Introduction by the revised Response Evaluation Criteria in Solid Tumors 1.1 Human epidermal growth factor receptor 2 (HER2) (also referred to (ref. 19; RECIST 1.1); and (iii) adequate hematologic, hepatic, and as ERBB2) is amplified and/or overexpressed in approximately 15% to renal functions. The enrollment exclusion criteria were as follows: (i) 20% of primary breast cancers (1). Patients with HER2-positive discontinued pyrotinib treatment; (ii) pyrotinib medication use as þ (HER2 ) breast cancer have a poor prognosis and tend to develop neoadjuvant therapy; (iii) severe adverse side effects could not be metastatic disease in the central nervous system (CNS), and these controlled by dose reductions according to drug instructions; and (iv) patients have an especially high risk of brain metastasis (BM; refs. 2, 3). loss to follow-up for other unknown reasons. CNS metastases have been reported in 15%–25% of patients with Most enrolled patients received 400 mg pyrotinib at baseline, and 15 breast cancer (4), and BM occurs in 30%–55% of patients with patients (15/168, 8.9%) had a dose reduction to 320-mg pyrotinib once metastatic breast cancer (MBC; ref. 5), highlighting the need for safe daily in a 21-day meditation cycle because of grade 3 and 4 diarrhea. and effective BM-targeted treatments. Moreover, the survival of these Informed consent was