Fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) demonstrated durable systemic and intracranial activity in patients with breast cancer brain metastases (BCBM), including those with HER2-positive, HER2-low, and HER2-zero disease, according to findings from a retrospective real-world analysis.1
At a median follow-up of 13 months (95% CI, 9.1-16.9), patients with HER2-positive disease (n = 58) achieved a median progression-free survival (PFS) of 11.0 months (95% CI, 7.0-14.9) and a median overall survival (OS) of 46.0 months (95% CI, 21.8-70.2). The 12-month PFS and OS rates were 42.9% (95% CI, 29.4%-62.7%) and 88.7% (95% CI, 79.7%-98.8%), respectively. The median intracranial PFS (IC-PFS) was 13.0 months (95% CI, 10.0%-16.0%), and the 12-month IC-PFS rate was 52.6% (95% CI, 38.2%-72.3%).
At a median follow-up of 10 months (95% CI, 4.5-15.5) in the HER2-low/zero cohort (n = 30), the median PFS and OS were 4.0 months (95% CI, 2.5-5.5) and 26.0 months (95% CI, 13.7-not evaluable), respectively. The respective 12-month PFS and OS rates were 26.0% (95% CI, 12.9%-52.3%) and 55.6% (95% CI, 39.5%-78.2%). The median CNS PFS was 5 months (95% CI, 3.2–6.8), and the 12-month IC-PFS rate was 44.6 (95% CI, 26.4%-75.4%)
“The present study showed a substantial and durable intracranial efficacy of T-DXd in breast cancer brain metastases with both HER2-positive and low/zero expression, stable and active disease, and patients with significant symptoms and leptomeningeal disease, thus providing valuable insights for routine practice,” lead study author Qingru Zhou, MD, of the Department of Medical Oncology at Sun Yat-Sen University Cancer Center in Guangzhou, China, and colleagues wrote in a publication of the data.
Real-World Study Design and Enrollment Criteria
In the United States, T-DXd has been approved by the FDA in the following breast cancer indications:2
- For adult patients with unresectable or metastatic HER2-positive (immunohistochemistry [IHC] 3+ or in situ hybridization [ISH]+) breast cancer who have received a prior anti-HER2-based regimen either in the metastatic setting, or in the neoadjuvant or adjuvant setting and have developed disease recurrence during or within six months of completing therapy.
- For adult patients with unresectable or metastatic hormone receptor (HR)–positive, HER2-low (IHC 1+ or IHC 2+/ISH–) or HER2-ultralow (IHC 0 with membrane staining) breast cancer, as determined by an FDA-approved test, that has progressed on one or more endocrine therapies in the metastatic setting.
- For adult patients with HER2-low (IHC 1+ or IHC 2+/ISH–) breast cancer, as determined by an FDA-approved test, who have received a prior chemotherapy in the metastatic setting; or developed disease recurrence during or within 6 months of completing adjuvant chemotherapy.
This multicenter, retrospective, real-world study was conducted to evaluate the efficacy and safety of T-DXd in patients with breast cancer brain metastases, including those with HER2-positive, HER2-low, and HER2-zero disease, as well as patients with stable or active brain metastases, neurological symptoms, or leptomeningeal disease.1 Eligible patients were treated between January 2020 and July 2024.
Inclusion criteria required patients to have histologically confirmed breast cancer; brain metastases confirmed by MRI; and either HER2-positive disease (IHC 3+ or IHC 2+/ISH+) or HER2-low/zero disease (IHC 0, 1+, or 2+/ISH–). Patients needed to receive at least one cycle of T-DXd, either as monotherapy or in combination with other agents, and have available clinical data.
Data were collected retrospectively from hospital information systems, including demographics, clinical symptoms, tumor characteristics, prior therapies, laboratory testing, and imaging studies. Patients with active brain metastases were defined as those with newly diagnosed, untreated brain metastases or central nervous system disease progression following local or systemic therapy.
The primary efficacy end points included PFS, IC-PFS, OS, objective response rate (ORR), disease control rate (DCR), and intracranial ORR (IC-ORR).
Additional Data
Among evaluable patients with HER2-positive disease (n = 46), the confirmed ORR was 65.2% (95% CI, 49.7%-78.2%), and the disease control rate (DCR) was 91.3% (95% CI, 78.3%-97.2%); complete response (CR) was observed in 6.7% of patients. The IC-ORR and IC-DCR were 61.0% (95% CI, 44.5%-75.4%) and 90.2% (95% CI, 75.9%-96.8%) per RECIST 1.1 criteria, respectively; these respective rates were 59.5% (95% CI, 43.4%-74.0%) and 88.1% (95% CI, 73.6%-95.5%) by RANO-BM criteria.
For patients with HER2-low/zero disease evaluable for response (overall, n = 21; intracranial, n = 18), the ORR was 33.3% (95% CI, 15.5%-56.9%), and the DCR was 66.7% (95% CI, 43.1%-84.5%), with no CRs observed. The IC-ORR was 44.4% (95% CI, 22.4%-68.7%), and the IC-DCR was 88.9% (95% CI, 64.0%-98.1%) by both RECIST 1.1 and RANO-BM criteria. Notably, among 3 patients with HER2-zero disease, 1 achieved a partial response, 1 achieved stable disease, and 1 patient experienced progressive intracranial disease.
HR status further influenced outcomes within this subgroup. Patients with HR-positive/HER2-low or zero disease (n = 19) had longer PFS and IC-PFS compared with those with HR-negative/HER2-low or zero disease (n = 11), with a median PFS of 10.0 vs 3.0 months (P < .001). The median IC-PFS was not reached vs 4.0 months, respectively (P = .06).
LMD Cohort Findings
In the leptomeningeal disease subgroup (n = 16), efficacy outcomes differed by HER2expression. Among the 10 patients with HER2-positive disease, the median IC-PFS was 16.0 months (95% CI, 8.4-23.7), with a 12-month IC-PFS rate of 72.0% (95% CI, 44.4%-100%). In contrast, the 6 patients with HER2-low/zero disease had a median IC-PFS of 5 months (95% CI, 3.4-6.6), and a 12-month IC-PFS rate of 27.8% (95% CI, 5.4-%-100%). One patient with HR-negative/HER2-low disease experienced a PFS of 4 months. Median OS had not been reached for either HER2-positive or HER2-low/zero subgroups at the time of data cutoff.
Additionally, 7 of the 16 patients in this subgroup received T-DXd in combination with bevacizumab (Avastin). However, no statistically significant improvement in IC-PFS was observed with combination therapy compared with T-DXd monotherapy (P = .58).
Safety Findings
In this real-world cohort, treatment discontinuation due to adverse effects (AEs) occurred in 7 patients (8.0%), with financial toxicity representing the leading cause (n = 4; 4.6%). The most frequently reported treatment-emergent AEs (TEAEs) were fatigue (45.9%), loss of appetite (25.2%), and nausea (11.4%).
Grade 3 or higher TEAEs were primarily hematologic, including neutropenia in 6 patients (6.9%) and thrombocytopenia in 4 patients (4.6%). Interstitial lung disease (ILD) was observed in 7 patients (8.0%); of these, 2 patients (2.3%) experienced grade 3 ILD requiring treatment discontinuation.
No new safety signals were identified, and the overall safety profile of T-DXd in this real-world population was consistent with prior clinical experience.
References
- Zhou Q, Li Y, He N, et al. Efficacy and safety of T-DXd in HER2-positive and low/zero metastatic breast cancer brain metastases: a retrospective multicenter real-world study. Cancer Sci. Published online September 11, 2025. doi:10.1111/cas.70181
- Enhertu. Prescribing information. Daiichi Sankyo. Updated January 2025. Accessed September 15, 2025. https://daiichisankyo.us/prescribing-information-portlet/getPIContent?productName=Enhertu&inline=true