Preclinical and early clinical data of ZN-1041 in combination with trastuzumab deruxtecan to treat breast cancer with or without CNS metastases.
Authors: Anders Carey K. , Lin Nancy U. , Chand Aarti , Fu Tingting , Zhu Di , Wang Zheng , Zhou Ding , Cheng Ziqiang (Zack) 
Published: June 2023

1041 Background: While treatment options for advanced HER2+ breast cancer have improved, HER2+ breast cancer brain metastases (BCBM) remain a clinical challenge warranting the development of additional, brain permeable HER2-targeted therapies. ZN-1041 is a brain permeable, selective HER2-targeted oral tyrosine kinase inhibitor. Preclinical studies have demonstrated efficacy and safety of ZN-1041 warranting clinical development alone and in combination with approved monoclonal antibodies or antibody drug conjugates for patients (pts) with HER2+ BCBM. Methods: Anti-tumor activity of ZN-1041 alone or in combination with trastuzumab emtansine (TDM1), trastuzumab deruxtecan (TDXd), or trastuzumab (H) plus pertuzumab (P) was evaluated in BT474 BM orthotopic xenograft models. ZN-A-1041-101-US (NCT05593094) is an on-going phase 1, multicenter, open-label study. The study comprises dose escalation of ZN-1041 monotherapy (Phase 1a) in pts with HER2+ solid tumors with or without BM, dose escalation (Phase 1b) and expansion (phase 1c) of ZN-1041 in combination with TDM1 (Arm 1), TDXd (Arm 2), or HP as maintenance therapy (Arm 3) in pts with HER2+ mBC with or without BM. The primary objectives were safety, tolerability and recommended phase 2 dose. The secondary objective includes pharmacokinetics (PK) and preliminary efficacy per RECIST 1.1. Results: Preclinically, ZN-1041 alone or combined with TDM1, TDXd or HP demonstrated significant improvement in intracranial tumor growth inhibition compared to TDM1, TDXd, or HP alone. As of data cutoff, Phase 1a (n = 7 pts) and Arm 2 of Phase 1b (n = 3 pts) were completed. Among 10 pts enrolled, 8 pts had received prior HER2 TKI. In Phase 1a, ZN-1041 was well tolerated with no dose-limiting toxicities (DLTs) or drug discontinuation due to toxicity up to a dose of 800 mg BID. Adverse reactions were mainly grade 1. The most common treatment related adverse reactions (TRAEs≥15%) were grade 1 nausea (43%) and vomiting (29%), with no ≥ grade 2 diarrhea reported. PK exposure was increased with dose escalation. In Phase 1a, one pt with mBC (without BM) achieved a confirmed partial response (PR) at 400 mg BID dose for > 15 months; one with gastric cancer achieved stable disease at the first dose level of 50mg BID for nearly 1 year. In Phase 1b, pts who had previously progressed on TDXd and/or TKI were enrolled and received ZN-1041 at a dose of 800 mg BID in combination with TDXd. Combination therapy was well tolerated with no DLTs reported. One pt with BCBM who was previously on tucatinib and TDXd had a confirmed PR. Conclusions: Safety and tolerability was observed for ZN-1041 with maximum tolerated dose 800 mg BID as monotherapy and combined with TDXd in pts with advanced HER2+ malignancies. Encouraging efficacy was observed in treatment-refractory settings. Additional safety and efficacy data of ZN-1041 in combination with TDM1, TDXd or HP are warranted. Clinical trial information: NCT05593094 .