Preclinical and early clinical data of ZN-1041, a best-in-class BBB penetrable HER2 inhibitor to treat breast cancer with CNS metastases.

person Fei Ma National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences, Beijing, China info_outline Fei Ma, Yiqun Li, Herui Yao, Jingfen Wang, Quchang Ouyang, Jing Cheng, Xiaoyan Li, Xiao-Xiao Dinglin, Gongsheng Jin, Huan Zhou, Xinshuai Wang, Yuee Teng, Yongsheng Wang, Qi Dang, Jin Yang, Hui Hua Xiong, Weihong Zhao, Li Cai, Tingting Fu, Di Zhu

Authors person Fei Ma National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences, Beijing, China info_outline Fei Ma, Yiqun Li, Herui Yao, Jingfen Wang, Quchang Ouyang, Jing Cheng, Xiaoyan Li, Xiao-Xiao Dinglin, Gongsheng Jin, Huan Zhou, Xinshuai Wang, Yuee Teng, Yongsheng Wang, Qi Dang, Jin Yang, Hui Hua Xiong, Weihong Zhao, Li Cai, Tingting Fu, Di Zhu Organizations National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences, Beijing, China, Cancer Institute and Hospital, Chinese Academy of Medical Sciences, Beijing, China, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China, Department II of breast, Linyi Cancer Hospital, Linyi, China, Hunan Cancer Hospital, Changsha, China, Department of Breast Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science &Technology, Wuhan, China, Beijing Tiantan Hospital, Capital Medical University, Beijing, China, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China, The First Affiliated Hospital of Henan University of Science and Technology, Luoyang, China, Department of Medical Oncology, The First Affiliated Hospital of China Medical University, Shenyang, China, Department of Breast Surgery, Shandong Provincial Cancer Hospital, Jinan, China, Shandong Provincial Institute of Cancer Prevention and Treatment, Jinan, China, Department of Oncology, The First Affiliated Hospital of Xi 'an Jiaotong University, Xi 'an, China, Tongji Hospital,Tongji Medical College,Huazhong University of Science & Technology, Wuhan, China, Medical oncology，Chinese PLA General Hospital, Beijing, China, Departments of Medical Oncology, The Affiliated Tumour Hospital of Harbin Medical University, Harbin, China, Suzhou Zanrong Pharma Limited, Shanghai, China Abstract Disclosures Research Funding Pharmaceutical/Biotech Company Suzhou Zanrong Pharma Limited Background: HER2+ breast cancer brain metastases (BCBM) is an aggressive malignancy with high prevalence and limited treatment options. ZN-1041 is a best-in-class HER2 inhibitor designed to be delivered across the blood-brain barrier (BBB) with high selectivity and broader safety margin to treat HER2+ BCBM. Methods: Brain penetration of ZN-1041 and other approved HER2 tyrosine kinase inhibitors (TKI) were evaluated. Anti-tumor activity of ZN-1041 alone or in combination were evaluated in xenograft models. ZN-A-1041-101 (NCT04487236) is an on-going phase 1, multicenter, open-label study. The study comprises first-in-human dose escalation of ZN-1041 monotherapy (phase 1a) in HER2+ solid tumor patients (pts) with or without BM, dose escalation (phase 1b) and expansion (phase 1c) of ZN-1041 in combination with capecitabine and trastuzumab in pts with HER2+ BCBM (including active BM). The primary objective was safety and tolerability. The secondary objective includes pharmacokinetics and anti-tumor response including ORR per RECIST 1.1 and intracranial ORR (iORR) per RANO-BM. Results: Unlike currently approved HER2 TKIs which are strong human efflux transporter P-gp and BCRP substrates, ZN-1041 is not a substrate of either and has high BBB permeability, therefore predicted to have good BBB penetration. ZN-1041 alone demonstrated dose-dependent and significant anti-tumor activity when compared to tucatinib in BM model. ZN-1041 could synergize with capecitabine and trastuzumab to demonstrate significantly improved intracranial efficacy in BM models, while maintaining good tolerability. In total, 21 HER2+ mBC pts were enrolled to complete phase 1a and 1b. No dose-limiting toxicities or treatment-related SAE were observed across all dose levels. PK exposure was increased with dose escalation and K puu,CSF of ZN-1041 was 4.9. In ZN-1041 monotherapy, the overall ORR and iORR were 50% in TKI naïve, unequivocal HER2+ pts. The longest treatment duration was 15 months. As of data cutoff (Dec 02, 2022), totally 35 TKI naïve, HER2+ BCBM pts with median 2L treatments were enrolled for phase 1c and all pts were well tolerated to date. Adverse reactions of grade 3 or higher (≥5%) were hepatic function impairment (8.7%), headache (8.7%), hyperbilirubinemia (5.7%), ALT increased (5.7%), AST increased (5.7%), GGT increased (5.7%) and WBC decreased (5.7%). Among 19 BCBM pts with at least twice tumor assessment, the overall ORR was 78.9% (95% CI: 54.4–93.9) and iORR was 73.7% (95% CI: 48.8–90.9), DCR was 100%. In addition, 6 pts completed first tumor assessment and 5 achieved PR and 1 had SD per RECISIT 1.1. Conclusions: Encouraging efficacy and tolerability was observed for ZN-1041 monotherapy or combined with capecitabine and trastuzumab in TKI naïve, HER2+ BCBM patients. A Phase 2 pivotal trial for HER2+ BCBM with ZN-1041, capecitabine and trastuzumab combination therapy is planned. Clinical trial information: NCT04487236.

Clinical