Limited treatment options exist for the management of HER2-positive breast cancer with brain metastases. 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 breast cancer with brain metastases. Preclinical and first-in-human studies were conducted to evaluate the safety and antitumor activity of ZN-1041, the results of which were presented at the 2023 ASCO annual meeting.
Preclinical evaluations included the evaluation of the brain penetration of ZN-1041 and other TKIs, and the 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 is evaluating the safety and antitumor activity of ZN-1041 in 3 phases, including ZN-1041 monotherapy (dose escalation; phase 1a) in HER2-positive patients with solid tumor with or without brain metastasis, dose escalation (phase 1b), and dose expansion (phase 1c) of ZN-1041 in combination with capecitabine and trastuzumab in patients with HER2-positive breast cancer with brain metastases. The primary objective of this clinical study was safety and tolerability; the secondary objective included pharmacokinetics and antitumor response, including overall response rate (ORR) per RECIST version 1.1, intracranial ORR per RANO-BM criteria, and disease control rate.
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 breast cancer with brain metastases were enrolled. Across all dose levels tested in the phase 1a trial, there were no dose-limiting adverse events or treatment-related serious adverse events; pharmacokinetic exposure increased with dose escalation. In the phase 1b portion of the trial, ZN-1041 monotherapy yielded an ORR and intracranial ORR of 50% in patients with TKI-naïve HER2-positive tumors.
In phase 1c of the trial (data cutoff of December 2, 2022), a total of 35 patients with TKI-naïve, HER2-positive breast cancer and brain metastases were enrolled. These patients had received a median of 2 previous lines of therapy. In terms of safety, the 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), the ORR was 78.9%, the intracranial ORR was 73.7%, and the disease control rate was 100%. Of the 6 patients who completed the first tumor assessment, 5 patients achieved a partial response and 1 had stable disease. A total of 3 patients achieved a complete response in brain lesions.
The investigators 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 breast cancer and brain metastases. 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 breast cancer and brain metastases.
Source: 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.