Abstract 238P
Background
Patients with HER2-positive (+) metastatic breast cancer (MBC) are at high risk of developing central nervous system (CNS) metastases. DZD1516 is designed as a reversible and selective HER2 tyrosine kinase inhibitor (TKI) with full blood-brain barrier (BBB) penetration.
Methods
The phase I study (NCT04509596) is enrolling patients with HER2+ MBC who relapsed from standard of care. The primary objective is to evaluate the safety of DZD1516 and to define maximum tolerated dose (MTD).
Results
As of February 20, 2022, twenty-two HER2+ MBC patients from the USA and China were enrolled and dosed with DZD1516 monotherapy (25 mg ∼ 300 mg BID). Fifteen patients had CNS metastases at baseline. All patients had been treated with HER2 large molecules. Nineteen patients also received prior HER2 TKI treatment. DZD1516 was well tolerated at doses ≤ 250 mg BID. Two dose limiting toxicities (DLTs) were reported in the 300 mg cohort. Thus, 250 mg was defined as MTD. Treatment emergent adverse events (TEAEs) were reported in twenty patients. ≥ grade 3 drug-related TEAEs were reported in two patients. The most common TEAEs included hemoglobin decreased, headache and vomiting. Majority of the TEAEs were grade 1 and were reversible. The longest treatment duration was > 3 months. Following single oral dosing, DZD1516 was eliminated with 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 ∼ 250 mg dose range. In patients, 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. Eighteen patients had completed ≥ 1 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.
Conclusions
DZD1516 is a full BBB-penetrant HER2 TKI. Consistent with its high selectivity, no wild-type EGFR related AEs have been reported. Further clinical evaluation of DZD1516 is warranted.
Clinical trial identification
NCT04509596.
Editorial acknowledgement
Legal entity responsible for the study
Dizal Pharmaceutical Co., Ltd.
Funding
Dizal Pharmaceutical Co., Ltd.
Disclosure
W. Yu, X. Pan: Financial Interests, Personal, Full or part-time Employment: Dizal Pharmaceutical. All other authors have declared no conflicts of interest.