Novel HER2 TKI Shows Preliminary Activity in Breast Cancer Brain Metastases

“Encouraging preliminary efficacy and tolerability were observed for ZN-1041 either as monotherapy or combined with capecitabine and trastuzumab in [patients with HER2-positive breast cancer brain metastases who were naïve to tyrosine kinase inhibitors],” according to the study authors.

The investigational blood-brain barrier (BBB)–penetrant tyrosine kinase inhibitor (TKI) ZN-1041, administered alone or in combination with trastuzumab (Herceptin) and capecitabine, demonstrated encouraging preliminary efficacy and tolerability among patients with HER2-positive breast cancer with brain metastases and extracranial disease, according to findings from a Chinese phase 1 study (NCT04487236).¹

Data from the phase 1c portion of the trial included 40 patients—with 37 being evaluated for efficacy—and showed a confirmed objective response rate (ORR) of 73.0% (95% CI, 55.88%-86.21%), with a median duration of response (DOR) of 12.6 months (95% CI, 6.70-16.59). Additionally, treatment yielded a disease control rate (DCR) of 100% (95% CI, 90.51%-100.0%), which included complete responses (CRs) in 5.4% and partial responses (PRs) in 67.5%.

Intracranial objective responses were confirmed in 64.9% (95% CI, 47.46%-79.79%) of patients, and the median DOR was 14.7 months (95% CI, 6.51-not reached [NR]). The intracranial DCR was 91.9% (95% CI, 78.09%-98.30%), with intracranial CRs reported in 24% and PRs occurring in 40.5%.

Based on Kaplan-Meier analysis, the study treatment produced a median progression-free survival (PFS) of 14 months (95% CI, 9.13-17.94) and a 12-month PFS rate of 56.4% (95% CI, 37.76%-71.45%). Subgroup analysis revealed that the median intracranial PFS was 17.4 months (95% CI, 8.74-19.61).

“Encouraging preliminary efficacy and tolerability were observed for ZN-1041 either as monotherapy or combined with capecitabine and trastuzumab in [patients with HER2-positive breast cancer brain metastases who were naïve to tyrosine kinase inhibitors],” Fei Ma, of National Cancer Center/Cancer Hospital at the Chinese Academy of Medical Sciences in Beijing, China, and coauthors wrote.¹ “Further development of ZN-1041 combination therapies in a larger population is warranted, including the ongoing phase 1 ZN-1041-101-US study [NCT05593094], which is evaluating the safety and efficacy of ZN-1041 in combination with trastuzumab deruxtecan [Enhertu] and with trastuzumab and pertuzumab [Perjeta] in a larger population across the US, France, Spain, UK, Australia, and New Zealand.”

In this multicenter, open-label study, investigators first assessed dose escalation of ZN-1041 monotherapy among those with HER2-positive solid tumors with or without brain metastases in the phase 1a portion of the trial. Phase 1b and phase 1c were the dose-escalation and dose-expansion portions, respectively, in which patients with HER2-positive breast cancer and brain metastases received ZN-1041 with capecitabine at 1000 mg/m² twice daily for 14 days followed by a 7-day break plus trastuzumab at 8 mg/kg loading dose and a 6 mg/kg maintenance dose intravenously every 3 weeks.

The trial’s primary end points were the safety, tolerability, and recommended phase 2 dose. Secondary end points included pharmacokinetics and antitumor responses per RECIST v1.1 criteria and Response Assessment in Neuro-Oncology Brain Metastases guidelines.

Patients with unresectable locally advanced or metastatic HER2-positive brain cancer with brain metastases were eligible for enrollment on the phase 1c portion of the study.² Exclusion criteria included having evidence of other primary tumors at the time of enrollment and a prior cumulative dose of doxorubicin (Adriamycin) exceeding 360 mg/m².

Of 40 evaluable patients in the phase 1c portion, the median age was 52 years (range, 27-68), and most patients had an ECOG performance status of 1 (85%). Additionally, most patients received prior therapy with trastuzumab (87.5%) and had HER2 expression of immunohistochemistry 3+ (87.5%). Patients received a median of 1 (range, 0-7) prior line of therapy and had a median of 3 (range, 1-6) metastatic lesions.

Investigators reported no grade 5 adverse effects (AEs) associated with the study treatment. The most common grade 3 or higher treatment-related AEs included hyperbilirubinemia (20%), gamma-glutamyl transferase increases (17.5%), white blood cell count decreases (15%), alanine aminotransferase increases (5.7%), aspartate aminotransferase increases (7.5%), weight decreases (7.5%), and headaches (7.5%).

Data showed that 77.5% of patients required dose interruptions due to treatment-emergent AEs (TEAEs). Additionally, 5.0% discontinued treatment following TEAEs, while 2.5% required a dose reduction. Any-grade diarrhea affected 37.5% of patients; no grade 3 or higher events occurred.

Investigators presented these findings in a poster session at the 2024 San Antonio Breast Cancer Symposium (SABCS).

References

1. Ma F, Li Y, Yao H, et al. ZN-1041, a potential best-in-class BBB penetrable HER2 inhibitor, has high antitumor activity in patients with breast cancer with CNS metastases. Presented at the 2024 San Antonio Breast Cancer Symposium; San Antonio, TX; December 10-13, 2024. PS8-01.
2. Trial of ZN-A-1041 enteric capsules in patients with HER2-positive advanced solid tumors. ClinicalTrials.gov. Updated August 1, 2023. Accessed January 6, 2025. https://tinyurl.com/223tsyj5