Preclinical and Early Clinical Data of the HER2 Inhibitor ZN-1041 in Patients With BC With Brain Metastases

Limited treatment options exist for management of HER2-positive breast cancer with brain metastases (BCBM). The tyrosine kinase inhibitor (TKI) ZN-1041 is a highly selective HER2 inhibitor that is specifically designed to cross the blood-brain barrier for the treatment of HER2-positive BCBM. Preclinical and first-in-human studies were conducted to evaluate the safety and antitumor activity of ZN-1041. These results were presented at the 2023 ASCO annual meeting.

Preclinical evaluations included evaluation of the brain penetration of ZN-1041 and other TKIs, and antitumor activity of ZN-1041 alone or in combination with trastuzumab plus capecitabine in animal xenograft models. In addition, a phase 1, multicenter, open-label study (NCT04487236) is evaluating the safety and antitumor activity of ZN-1041 in 3 phases: 1) ZN-1041 monotherapy (dose escalation; phase 1a) in HER2-positive patients with solid tumor with or without brain metastasis; 2) dose escalation (phase 1b); and 3) dose expansion (phase 1c) of ZN-1041 in combination with capecitabine and trastuzumab in patients with HER2-positive BCBM. The primary objective of this clinical study was safety and tolerability; secondary objective included pharmacokinetics and antitumor response, including overall response rate (ORR) per RECIST 1.1, intracranial ORR (iORR) per RANO-BM criteria, and disease control rate (DCR).

In preclinical brain orthotopic metastasis xenograft animal models, improvement in intracranial antitumor activity was demonstrated with ZN-1041 monotherapy or combined with capecitabine and trastuzumab compared with tucatinib alone.

In the phase 1a and 1b portions of the clinical study, a total of 21 patients with HER2-positive BCBM were enrolled. Across all dose levels tested in phase 1a, no dose-limiting toxicities or treatment-related serious adverse events were noted; pharmacokinetic exposure increased with dose escalation. In the phase 1b portion, ZN-1041 monotherapy yielded ORR and iORR of 50% in patients with TKI-naïve HER2-positive tumors.

In phase 1c (at data cutoff of December 2, 2022), a total of 35 patients with TKI-naïve HER2-positive BCBM were enrolled, and these patients had received a median of 2 prior lines of therapy. In terms of safety, grade ≥3 adverse events that occurred in ≥5% of patients included hepatic function impairment (8.7%), headache (8.7%), hyperbilirubinemia (5.7%), increased alanine transaminase (5.7%), increased aspartate aminotransferase (5.7%), increased gamma-glutamyl transferase (5.7%), and decreased white blood count (5.7%). Overall, of the 19 evaluable patients (with ≥2 tumor assessments), ORR was 78.9%, iORR was 73.7%, and DCR was 100%. Of the 6 patients who completed the first tumor assessment, 5 patients achieved partial response and 1 had stable disease. A total of 3 patients achieved complete response in brain lesions.

The authors concluded that ZN-1041 as monotherapy or in combination with capecitabine and trastuzumab showed promising tolerability and antitumor activity in patients with TKI-naïve HER2-positive BCBM. Based on these encouraging results, a phase 2 pivotal trial is planned, which will evaluate ZN-1041 and capecitabine plus trastuzumab therapy in patients with HER2-positive BCBM.


Ma F, Li Y, Yao H, et al. Preclinical and early clinical data of ZN-1041, a best-in-class BBB penetrable HER2 inhibitor to treat breast cancer with CNS metastases. Abstract presented at: ASCO Annual Meeting, June 2-6, 2023; Chicago, IL. Abstract 1040.

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