T-DXd Demonstrates Safety, Efficacy After Pyrotinib Therapy Failure in Patients With HER2+ Breast Cancer

Trastuzumab deruxtecan (T-DXd, Enhertu; Daiichi Sankyo) demonstrated clinical promise as a treatment for patients with human epidermal growth factor receptor 2-positive (HER2+) breast cancer (BC) with brain metastases (BMs) who progressed following treatment with pyrotinib (Irene; Jiangsu Hengrui Medicine). The study findings, which were published in Scientific Reports, showed improved rates of progression-free survival (PFS) and overall survival (OS).¹

Blood sample for HER2 testing | Image Credit: © MdBabul - stock.adobe.com

HER2+ BC is the most common subtype of BC that is characterized by the overexpression of HER2 proteins, leading to more aggressive tumor biology. Approximately 50% of patients with HER2+ BC develop BMs, which significantly impact survival times. Although local therapy or radiotherapy is an important approach, anti-HER2 agents, such as antibody drug conjugates (ADCs), Tyrosine kinase inhibitors (TKIs), and monoclonal antibodies, show promising therapeutic potential and capabilities in penetrating the blood-brain barrier.^1,2

Pyrotinib is a TKI that received conditional approval in China in 2018 for treatment of patients with HER2+ metastatic BC (mBC) and has since been integrated into national clinical guidelines. Pyrotinib has demonstrated efficacy for various HER2-mutated metastatic cancers, such as HER2+ BC with liver metastases, but many patients still progress following treatment.¹

T-DXd is a HER2-targeting ADC that has promising anticancer efficacy, as observed in the DESTINY-Breast trials. According to clinical trial and real-world data, treatment with T-DXd yields favorable objective response rates (ORR) and duration of response in patients with HER2+ mBC with BMs. However, in Chinese clinical practice, there is little data on the efficacy and safety of T-DXd following pyrotinib treatment failure. This led the study authors to conduct a single-center, retrospective cohort study evaluating T-DXd treatment in this patient population.¹

The study included data from the electronic medical records of patients with HER2+ mBC with BMs who received T-DXd after failing pyrotinib therapy. There were a total of 15 patients (≥ 18 years of age) who were treated between April 2021 and July 2023 with T-DXd at the recommended dosage of 5.4 mg per kg every 21 days. The primary end point was central nervous system PFS (CNS-PFS), with key secondary end points ORR for intracranial, extracranial and overall lesions; the clinical benefit rate (CBR) for intracranial, extracranial and overall lesions; OS; and safety.¹

The data showed that treatment with T-DXd following pyrotinib treatment failure yielded a median CNS-PFS of about 7.4 months (95% confidence interval (CI) 6.1–8.8 months) with a median PFS of 6.4 months for patients with extracranial/total lesions (95% CI 4.4–8.3 months). The authors reported an OS of 9.8 months (95% CI 5.9–13.8 months). For intracranial, extracranial, and overall lesions, the ORRs were 33.3%, 71.4%, and 73.3%, respectively.¹

The safety profile was favorable, with an incidence rate of greater than or equal to 5% of grade 3 adverse events, of which leukopenia (20.0%), neutropenia (13.3%), thrombocytopenia (6.7%), and nausea (6.7%) were the most common. The authors also reported instances of grade 1 interstitial lung disease or pneumonitis, which occurred in 2 patients.¹

Continued study in a larger population is critical to validate the safety and efficacy of T-DXd following pyrotinib therapy for this patient population. However, these initial findings help inform real-world clinical practice approaches for patients with progressive disease.

REFERENCES

1. Zhou J, Xiao J, Wu X, et al. Efficacy and safety of trastuzumab deruxtecan in HER2-positive breast cancer patients with brain metastases after failure of pyrotinib-based therapy. Scientific Reports. May 22, 2025. doi:10.1038/s41598-025-02550-6

2. Pyrotinib-based therapy may improve survival in patients with HER2+ breast cancer and liver metastases. Pharmacy Times. April 25, 2025. Accessed May 22, 2025. https://www.pharmacytimes.com/view/pyrotinib-based-therapy-may-improve-survival-in-patients-with-her2-breast-cancer-and-liver-metastases