DZD1516 With CSF Penetration Has Antitumor Activity in Heavily Pretreated HER2+ Metastatic Breast Cancer

DZD1516, a reversible and selective HER2 TKI with full blood–brain barrier (BBB) penetration led to tumor responses, including in patients with baseline central nervous system (CNS) metastases, in a phase 1 study of patients with metastatic HER2-positive breast cancer.¹

Findings from the first in-human phase 1 study of DZD1516 were presented by lead study author Nicholas P. McAndrew, MD, at the 2022 San Antonio Breast Cancer Symposium. Nineteen (82.6%) patients had at least 1 posttreatment tumor assessment. The best response in intracranial, extracranial, and overall lesions was stable disease.

“Preclinically, DZD1516 was designed to have full BBB penetration,” McAndrew, assistant professor, University of California, Los Angeles, said during the presentation. “Importantly, in the methods of the phase 1 study, cerebrospinal fluid [CSF] samples were collected so that we could measure the degree to which it penetrated BBB. This was a monotherapy dose-escalation portion of the trial.”

“This was in heavily pretreated patients, which is why we didn’t see a lot of responses,” he said. “Importantly, the pharmacokinetic [PK] data from the CSF exactly matched the preclinical models, so it does get into the brain and the CSF quite well.”

The study was conducted in the United States and China in 23 patients with HER2-positive metastatic breast cancer who relapsed from standard of care.

Across the dose range, CSF levels measured in 6 patients showed that mean Kpuu,CSF was 2.1 for DZD1516 and 0.76 for DZ2678, indicating full penetration of DZD1516 and DZ2678 into human CNS.

Patients were treated with either 25 mg (n = 1), 50 mg (n = 4), 100 mg (n = 4), 200 mg (n = 5), 250 mg (n = 5), or 300 mg (n = 4) twice daily. Fifteen patients had CNS metastases. Patients had a median of 7 lines of prior systemic treatment; all had been treated with HER2 large molecules, and 82.6% also received a prior HER2 TKI.

In a HER2-positive brain metastasis xenograft model, DZD1516 in combination with DS-8201a, an anti-HER2 antibody-drug conjugate with a novel topoisomerase I inhibitor, showed synergistic antitumor activity. In a brain metastasis xenograft model, tumor volume decreased with DS8201-a monotherapy and the combination of DZD1516 and DS8201-a.

DZD1516 was well tolerated at 25 to 250 mg twice daily (dose-limiting toxicities were reported only in the 300-mg twice daily cohort). Therefore, 250 mg was defined as the maximum-tolerated dose. With the longest treatment duration of greater than 3 months, the most common treatment-emergent adverse events (TEAEs) were headache (n = 10) vomiting (n = 8), and a decrease in hemoglobin level (n = 7). Most TEAEs were manageable and reversible; there were 4 grade 3 TEAEs, the most common being vomiting, nausea, fatigue, malaise, an increase in bilirubin conjugate, and musculoskeletal pain. There were no grade 4/5 TEAEs.

“In part, the goal of designing this drug was to try to maximize central nervous system penetration. It’s possible that it may not be a good drug after progression on a TKI. It would depend on how patients responded previously,” McAndrew said. “The next steps are combining it with other agents and moving it to earlier lines so we can see how efficacious it is in patients who have progressed on a TKI.”

After twice daily dosing for 15 days, an approximate 2-fold accumulation of DZD1516 was observed systemically at doses 200 mg or lower. The combined exposure of DZD1516 and its active metabolite (DZ2678) generally increased with an increase in the dosage.

Additionally, in a HER2-positive brain metastasis xenograft model, DZD1516 in combination with DS-8201a, an anti-HER2 antibody-drug conjugate with a novel topoisomerase I inhibitor, showed synergistic antitumor activity. In a brain metastasis xenograft model, tumor volume decreased with DS8201-a monotherapy and the combination of DZD1516 and DS8201-a.

Reference

1. McAndrew NP, Hu X, Zhang J, et al. Updated data from the phase 1 trial of DZD1516, a BBB-penetrant selective HER2 inhibitor, in patients with HER2 positive metastatic breast cancer. Presented at: 2022 San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, TX; Abstract P4-01-23.