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Preclinical and clinical activity of DZD1516, a full blood-brain barrier-penetrant, highly selective HER2 inhibitor
Jian Zhang1,2, Nicholas P McAndrew3, Xiaojia Wang4
1Phase I Clinical Trial Center, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China.
Background:
Patients with HER2-positive metastatic breast cancer (MBC) are at high risk of developing central nervous system (CNS) metastases. A potent and selective HER2 inhibitor with good blood-brain barrier (BBB) penetration is highly desirable.
Methods:
The design and structure-activity relationship of DZD1516 was described. The potency and selectivity of DZD1516 were determined by enzymatic and cellular assays. The antitumor activity of DZD1516 monotherapy or in combination with HER2 antibody-drug conjugate was assessed in CNS and subcutaneous xenograft mouse models. 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.
Results:
DZD1516 showed good selectivity against HER2 over wild-type EGFR in vitro and potent antitumor activity in vivo. Twenty-three patients were enrolled and received DZD1516 monotherapy treatment across six dose levels (25-300 mg, twice daily). Dose-limiting toxicities were reported at 300 mg, and thus 250 mg was defined as the maximum tolerated dose. The most common adverse events included headache, vomiting, and hemoglobin decreased. No diarrhea or skin rash was observed at ≤ 250 mg. The mean Kp,uu,CSF was 2.1 for DZD1516 and 0.76 for its active metabolite DZ2678. With median seven lines of prior systemic therapy, the best antitumor efficacy in intracranial, extracranial and overall lesions was stable disease.
Conclusions:
DZD1516 provides positive proof of concept for an optimal HER2 inhibitor with high BBB penetration and HER2 selectivity. Further clinical evaluation of DZD1516 is warranted, with the RP2D being 250 mg BID.
Clinicaltrials:
gov identifier NCT04509596. Registered on August 12, 2020; Chinadrugtrial: CTR20202424 Registered on December 18, 2020.
Insights
DZD1516, a HER2 inhibitor, shows promise for treating HER2-positive metastatic breast cancer with brain metastases. The phase 1 study established a maximum tolerated dose and demonstrated preliminary efficacy, warranting further clinical investigation.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- HER2-positive metastatic breast cancer (MBC) frequently involves central nervous system (CNS) metastases.
- A need exists for potent, selective HER2 inhibitors with effective blood-brain barrier (BBB) penetration.
Purpose of the Study:
- To describe the design and structure-activity relationship of DZD1516.
- To evaluate the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of DZD1516 in patients with HER2+ MBC.
Main Methods:
- DZD1516's potency and selectivity were assessed via enzymatic and cellular assays.
- Antitumor activity was evaluated in CNS and subcutaneous xenograft mouse models.
- A Phase 1 first-in-human study enrolled patients with relapsed HER2+ MBC.
Main Results:
- DZD1516 demonstrated good HER2 selectivity and potent in vitro/in vivo antitumor activity.
- The maximum tolerated dose (MTD) was determined to be 250 mg twice daily (BID).
- Preliminary efficacy showed stable disease in intracranial, extracranial, and overall lesions, with common adverse events including headache and vomiting.
Conclusions:
- DZD1516 shows proof of concept as an optimal HER2 inhibitor with high BBB penetration and selectivity.
- Further clinical evaluation of DZD1516 at 250 mg BID is warranted.
