Brain metastases are a common and severe complication of metastatic breast cancer (MBC), with approximately 20% to 30% of patients experiencing brain metastases[1]. Among these, the incidence of brain metastases in HER2-positive MBC patients can reach 30% to 55%[2]; the incidence is also high in HER2-negative patients[3]. This makes MBC the second leading cause of brain metastases after lung cancer[4].
Currently, traditional treatments for breast cancer brain metastases primarily involve local methods such as whole-brain radiotherapy, stereotactic radiotherapy, and surgery[5]. In terms of systemic treatment, targeted HER2 small molecule tyrosine kinase inhibitors have also shown good intracranial activity[6]. Unfortunately, due to the generally poor prognosis of patients with brain metastases[7], developing more novel and effective treatment strategies can provide patients with more treatment options. In this context, antibody-drug conjugates (ADCs) have emerged.
Current Research Status of Trastuzumab Deruxtecan in Treating Brain Metastases from Breast Cancer
In recent years, the emergence of novel ADCs has brought significant progress in the treatment of MBC, among which the novel ADC drug Trastuzumab Deruxtecan (T-DXd) has shown therapeutic potential in the treatment of brain metastases from breast cancer. T-DXd consists of a humanized anti-HER2 monoclonal antibody, a highly stable cleavable linker, and a highly effective and membrane-permeable topoisomerase I inhibitor, with a high drug-to-antibody ratio of 8:1[8], which helps penetrate the blood-brain barrier, and multiple clinical studies have preliminarily verified its good efficacy.
The subgroup analysis of the DESTINY-Breast01 study showed[9] that among 24 HER2-positive brain metastasis patients, the objective response rate (ORR) of T-DXd reached 58%. The DESTINY-Breast02 study[10] further confirmed the efficacy of T-DXd in patients with HER2-positive metastatic breast cancer who were resistant or refractory to Trastuzumab Emtansine. The results showed that the median progression-free survival (mPFS) in the T-DXd group was 13.9 months (95% CI: 11.1–18.0) compared to 5.6 months (95% CI: 3.3–8.1) in the physician’s choice treatment group. The DESTINY–Breast03 study[11] showed that in patients with stable brain metastases, the mPFS in the T-DXd group was 15.0 months (95% CI: 12.6–22.2) compared to 5.7 months (95% CI: 2.9–7.1) in the Trastuzumab Emtansine (T-DM1) group. However, these studies mostly included patients with stable brain metastases and did not consider intracranial efficacy as a primary endpoint, leading to insufficient treatment evidence for patients with active brain metastases[7-9].
Subsequent studies further explored the efficacy of T-DXd in patients with active brain metastases: the DESTINY-Breast12 study[12] showed that the intracranial objective response rate (iORR) of T-DXd in HER2-positive patients with active brain metastases reached 62.3%. The TUXEDO-1[13] and DEBBRAH[14] two phase II studies also preliminarily showed that the iORR of T-DXd in patients with active brain metastases was 73.3% and 46.2%, respectively, and exhibited a trend of sustained response. However, due to the small sample size and single-arm design, the strength of the evidence is limited[12-14]. Currently, the efficacy of T-DXd in this population still requires more high-quality research support, making real-world study data particularly important.
Real-World Data on Trastuzumab Deruxtecan for HER2-Positive/Low-Expressing Breast Cancer with Active Brain Metastases
Study Design[15]
This study is a multicenter, retrospective real-world study conducted from June 2022 to May 2024 in three hospitals in China, aiming to evaluate the efficacy and safety of Trastuzumab Deruxtecan in patients with HER2-positive or HER2-low expressing MBC with active brain metastases[15].
A total of 38 patients were included in the study, with a median age of 48.0 years (range 31.0–84.0 years). The proportion of patients with an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 was 84.2%, and the proportion of hormone receptor-negative patients was 78.9%. Additionally, 76.3% (29/38) of patients were HER2-positive, while 23.7% (9/38) were HER2-low expressing.
Prior treatment history: 21.1% (8/38) had received ≥ 5 lines of treatment, 73.7% (28/38) had been treated with Trastuzumab, 31.6% (12/38) had been treated with T-DM1, and 60.5% (23/38) had been treated with TKIs (Lapatinib or Pyrotinib).
Characteristics of brain metastases: 52.6% (20/38) were newly diagnosed untreated brain metastases, and 47.4% (18/38) had progressed after prior local treatment; 23.7% (9/38) had a single lesion, while 76.3% (29/38) had multiple lesions. There were a total of 24 cases of visceral metastases (65.5% in the HER2-positive group, 55.6% in the HER2-low expressing group).
History of prior local treatment for brain metastases: 2 patients had received whole-brain radiotherapy (WBRT), and 11 patients had undergone stereotactic radiotherapy/radiosurgery (SRS/SRT). The median interval from the last local treatment to receiving T-DXd was 3.87 months (range: 0.03–17.7).
The primary endpoint of this study was the best intracranial objective response rate (iORR), defined as the sum of complete response (CR) and partial response (PR) rates assessed according to the Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria. Secondary endpoints included intracranial progression-free survival (iPFS), overall progression-free survival (PFS), overall survival (OS), and safety.
Study Results
Intracranial Efficacy:
In patients with active brain metastases, the iORR in the HER2-positive group was 65.5% (1 CR, 18 PR), while the iORR in the HER2-low expressing group was 66.7% (1 CR, 5 PR).
Further analysis based on the status of brain metastases revealed that, regardless of HER2 status, the iORR in untreated brain metastases patients was superior to that in patients who had progressed after prior local treatment: in the HER2-positive group, the iORR in untreated brain metastases patients was 78.6%, while it was 53.3% in those with a history of prior local treatment; in the HER2-low expressing group, the iORR in untreated brain metastases patients was 83.3%, while it was 33.3% in those who had progressed after prior treatment.
Survival Analysis:
iPFS and PFS:
The 12-month iPFS rate in the HER2-positive group was 79.8% (95% CI: 65.2–97.7%), with a median PFS of 12.8 months (95% CI: 10.2–not reached); the 12-month iPFS rate in the HER2-low expressing group was 51.9% (95% CI: 26.7–100.0%), with a median PFS of 6.33 months (95% CI: 3.93–not reached);
OS:
The median follow-up time was 10.3 months (range: 1.53–24.4 months), and the median OS was not reached in both groups; in the HER2-positive group, the 12-month OS rate was 86.5% (95% CI: 69.4–100.0%); in the HER2-low expressing group, the 12-month OS rate was 85.7% (95% CI: 63.3–100.0%).
Safety:
The treatment-related adverse events of T-DXd were mostly mild to moderate, with no treatment-related deaths. The most common were fatigue (60.5% grade 1-2, 5.3% grade 3) and nausea (28.9%, all grade 1-2), with only 1 HER2-positive patient experiencing grade 4 interstitial lung disease (ILD), and all adverse events have resolved or improved.
Conclusion
This study indicates that Trastuzumab Deruxtecan demonstrates clinically meaningful intracranial efficacy in patients with HER2-positive and HER2-low expressing metastatic breast cancer with active brain metastases, improving patient survival outcomes with good safety. This conclusion is consistent with previous studies such as DESTINY-Breast12, further confirming the clinical value of Trastuzumab Deruxtecan as a treatment option for these difficult-to-treat patients. However, this study is retrospective in design, which carries certain selection and information biases, and the sample size is limited with a short follow-up time, making the assessment of long-term efficacy and safety insufficient. Additionally, since all HER2-low expressing patients included were hormone receptor-positive and patients with leptomeningeal metastases were excluded, the conclusions of this study should not be directly generalized to all breast cancer patients with brain metastases. Future prospective, large-sample studies are still needed to further validate the efficacy of Trastuzumab Deruxtecan in different subgroups, providing more robust evidence for clinical practice.
This material is supported by AstraZeneca and is intended for healthcare professionals only.
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Content Planning: Cony
Content Review: Liu Ruizi
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