Abstract P4-01-23: Updated data from the phase 1 trial of DZD1516, a BBB-penetrant selective HER2 inhibitor, in patients with HER2 positive metastatic breast cancer
Authors: McAndrew Nicholas P. , Hu Xichun , Zhang Jian , Wang Xiaojia , Yu Wenlei , Pan Xiaomei 
Published: March 2023

Abstract
Background: Patients with HER2 positive (+) breast cancer and central nervous system (CNS) metastases often have poor prognoses. DZD1516 is designed as a reversible and selective HER2 tyrosine kinase inhibitor (TKI) with full blood-brain barrier (BBB) penetration. Methods: DZD1516 is being developed in a phase 1 study (NCT04509596) in patients with HER2+ advanced or metastatic breast cancer relapsed from the standard of care. Key overall eligibility criteria were previously presented. DZD1516 was given orally twice daily (BID) in a continuous 21-day cycle (except Cycle 0). The primary objective is to evaluate the safety and tolerability of DZD1516 monotherapy and define the maximum tolerated dose (MTD). Results: As of June 23, 2022, twenty-three patients with HER2+ MBC from the USA and China were enrolled and dosed with DZD1516 monotherapy (25 mg ~ 300 mg, BID). Fifteen patients (65.2%) had baseline CNS metastases. Patients were heavily pre-treated, with a median of 7 lines of prior systemic treatment. All patients had been treated with HER2 large molecules, and 82.6% of patients also received prior HER2 TKI treatment. DZD1516 was well tolerated at doses up to 250 mg BID. Two dose-limiting toxicities were reported in the 300 mg cohort. As a result, 250 mg was defined as the MTD. Treatment-emergent adverse events (TEAEs) were reported in 91.3% of patients. Grade 3 drug-related TEAEs were reported in two patients. No grade 4 or 5 TEAEs were reported. The most common TEAEs included headache, vomiting, and hemoglobin decreased. The majority of the TEAEs could be managed and were reversible. The longest treatment duration was &gt; 3 months. Following single oral dosing, DZD1516 was eliminated with a mean half-life of 13.4 – 22.5 hrs. After twice-daily dosing for 15 days, moderate accumulation of DZD1516 systemic exposure was observed at doses ≤ 200 mg BID and negligible accumulation at 250 mg BID. The combined molar exposure of DZD1516 and its active metabolite DZ2678 increased with dose between 50 mg to 250 mg dose range. In patients (n = 6), mean Kpuu,CSF was 2.1 for DZD1516 and 0.76 for DZ2678 across the dose range, indicating full penetration of DZD1516 and DZ2678 into human CNS. Nineteen patients (82.6%) had at least one post-treatment RECIST assessment. With a median of 7 lines of prior systemic treatment, the best antitumor efficacy in intracranial, extracranial, and overall lesions was stable disease. Conclusion: DZD1516 is a full BBB-penetrant HER2 inhibitor. Consistent with its high selectivity, no wild-type EGFR-related AEs have been reported. The updated data will be presented at the meeting.
Citation Format: Nicholas P. McAndrew, Xichun Hu, Jian Zhang, Xiaojia Wang, Wenlei Yu, Xiaomei Pan. Updated data from the phase 1 trial of DZD1516, a BBB-penetrant selective HER2 inhibitor, in patients with HER2 positive metastatic breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-01-23.