TOPLINE:

A single-arm phase 2 trial showed that patritumab deruxtecan (HER3-DXd) demonstrated meaningful clinical activity in pretreated patients with metastatic breast cancer and active brain metastases, achieving intracranial responses across all breast cancer subtypes.

METHODOLOGY:

• Researchers conducted an international, multicentre, single-arm phase 2 trial across six sites (four in Spain and two in Austria) and evaluated the activity and safety of HER3-DXd in 21 women with metastatic breast cancer and active brain metastases.
• Among those included, five had luminal breast cancer, nine had HER2-positive breast cancer, and seven had triple-negative breast cancer. Progressive brain metastases were seen in 15 patients, and newly diagnosed untreated brain metastases were seen in six patients.
• Patients received HER3-DXd 5.6 mg/kg intravenously on day 1 of each 21-day cycle until disease progression, unacceptable toxicity, death, withdrawal, loss to follow-up, or the investigator's decision, whichever occurred first.
• The primary outcome was the intracranial overall response rate, and secondary outcomes included extracranial and bicompartmental overall response rates, clinical benefit rate, disease control rate, progression-free survival, overall survival, and treatment-emergent adverse events.

TAKEAWAY:

• The primary endpoint was met, with 5 of 21 patients achieving a locally assessed intracranial overall response rate of 23.8%, including responses across all breast cancer subtypes regardless of previous antibody-drug conjugate treatment.
• For bicompartmental lesions, the overall response rate was 14.3%, the clinical benefit rate was 28.6%, and the disease control rate was 66.7%, and for extracranial lesions, the rates were 11.8%, 29.4%, and 64.7%, respectively.
• The median progression-free survival was 4.7 months among patients with extracranial lesions and 4.3 months among patients with bicompartmental lesions; the median overall survival was not reached.
• Treatment-emergent adverse events occurred in 18 patients; the most common adverse events of grade 3 or higher were neutropenia, diarrhoea, asthenia, and vomiting. Serious adverse events were reported in six patients.

IN PRACTICE:

The authors mentioned that "the findings indicate antitumour activity of HER3-targeted therapy in heavily pretreated patients with active brain metastases of HER2-negative breast cancer" and added "HER3-DXd showed activity after previous ADCs [antibody-drug conjugates] and irrespective of the breast cancer subtype."

SOURCE:

This study was led by Rupert Bartsch, MD, Division of Oncology, Department of Medicine 1, Medical University of Vienna, Vienna, Austria. It was published online in November 2025 in The Lancet Oncology.

LIMITATIONS:

This study was limited by its single-arm phase 2 design, its small sample size, and the inclusion of participants with heterogeneous breast cancer subtypes and varied pretreatment histories. Additionally, although both local investigators and central radiology reviews were planned, this analysis included only investigator assessments, which could have introduced variability and bias in the evaluation of radiologic findings.

DISCLOSURES:

This study was funded by Daiichi-Sankyo and Merck Sharp & Dohme. Several authors reported serving in consulting or advisory roles and receiving research funding, honoraria, and travel support from Daiichi-Sankyo, Merck, AstraZeneca, Bristol-Myers Squibb, Eisai, Eli Lilly, Pfizer, and various other sources. Additional disclosures are noted in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.