With median seven lines of prior systemic therapy, the best antitumor efficacy in intracranial, extracranial and overall lesions was stable disease. The mean K p,uu,CSF was 2.1 for DZD1516 and 0.76 for its active metabolite DZ2678. No diarrhea or skin rash was observed at ≤ 250 mg. The most common adverse events included headache, vomiting, and hemoglobin decreased. Dose-limiting toxicities were reported at 300 mg, and thus 250 mg was defined as the maximum tolerated dose. Twenty-three patients were enrolled and received DZD1516 monotherapy treatment across six dose levels (25–300 mg, twice daily). ResultsĭZD1516 showed good selectivity against HER2 over wild-type EGFR in vitro and potent antitumor activity in vivo. A phase 1 first-in-human study evaluated the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of DZD1516 in patients with HER2+ MBC who relapsed from standard of care. The antitumor activity of DZD1516 monotherapy or in combination with HER2 antibody–drug conjugate was assessed in CNS and subcutaneous xenograft mouse models. The potency and selectivity of DZD1516 were determined by enzymatic and cellular assays. The design and structure–activity relationship of DZD1516 was described. A potent and selective HER2 inhibitor with good blood–brain barrier (BBB) penetration is highly desirable. Patients with HER2-positive metastatic breast cancer (MBC) are at high risk of developing central nervous system (CNS) metastases.
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