Patritumab Deruxtecan (HER3-DXd) Shows Promising Activity in Breast Cancer Patients with Active Brain Metastases: Insights from the TUXEDO-3 Phase 2 Trial

Highlight

Patritumab deruxtecan (HER3-DXd), a novel HER3-directed antibody-drug conjugate, demonstrated intracranial response in 24% of heavily pretreated metastatic breast cancer patients with active brain metastases in the multicentre phase 2 TUXEDO-3 trial. The treatment was generally well tolerated with manageable adverse events.

Study Background

Brain metastases are a frequent and devastating complication in metastatic breast cancer, presenting a significant clinical challenge due to limited effective systemic therapies with central nervous system (CNS) activity. HER3, a member of the human epidermal growth factor receptor family, is often overexpressed in CNS metastases from breast cancer, representing a potential therapeutic target. Patritumab deruxtecan (HER3-DXd) is an investigational antibody-drug conjugate that selectively targets HER3, delivering cytotoxic payloads to tumor cells while potentially sparing normal tissue. This study aimed to evaluate the efficacy and safety of HER3-DXd in patients with newly diagnosed or progressing brain metastases of breast cancer, a population for whom treatment options remain limited.

Study Design

The TUXEDO-3 trial is a multicentre, single-arm, open-label, phase 2 clinical study conducted across six sites in Spain and Austria. This cohort enrolled adults aged 18 years or older with histologically confirmed breast cancer and radiologically confirmed metastatic disease, including newly diagnosed or progressive brain metastases after local therapy. Eligibility required at least one measurable brain lesion ≥10 mm and an Eastern Cooperative Oncology Group (ECOG) performance status ranging from 0 to 2. Patients received intravenous HER3-DXd at a dose of 5.6 mg/kg every three weeks. The primary endpoint was intracranial response rate assessed by the Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria, with a prespecified threshold of ≥15% to demonstrate clinical activity. Secondary endpoints included safety and tolerability. The trial is registered under ClinicalTrials.gov (NCT05865990) and the European Union Clinical Trials Register (2023-503251-10-00).

Key Findings

Between December 12, 2023, and July 8, 2024, 21 evaluable female patients were recruited, representing diverse breast cancer subtypes: luminal (n=5), HER2-positive (n=9), and triple-negative (n=7). Among these, 71% were White, while race data were unavailable for six patients. The median number of prior systemic therapy lines was four, indicating a heavily pretreated population. Median treatment duration was three months, and median follow-up was approximately five months.

The primary endpoint was met with an overall intracranial response rate of 23.8% (5 of 21 patients; 95% CI, 8.2–47.1), exceeding the prespecified activity threshold and observed across breast cancer subtypes. This response rate is notable given the enrollment of patients with progressive or untreated brain metastases after local interventions.

Adverse events were generally manageable. The most frequent grade 3 or higher toxicities were neutropenia (14%), diarrhea (10%), asthenia (5%), and vomiting (5%). Serious adverse events were reported in 29% of patients, including one case of grade 2 pneumonitis deemed related to the study drug. Importantly, no treatment-related mortality occurred.

Expert Commentary

The TUXEDO-3 trial provides encouraging evidence that targeting HER3 with a potent antibody-drug conjugate can achieve meaningful intracranial tumor control in a challenging patient population with limited therapeutic options. The inclusion of multiple breast cancer subtypes underscores HER3-DXd’s potential broad applicability. While the single-arm design limits direct comparisons, the observed response rate surpasses historical outcomes in similar settings.

Notably, the manageable safety profile, particularly the low incidence of severe pneumonitis and absence of treatment-related deaths, suggests a favorable risk-benefit balance. Future randomized trials could further clarify HER3-DXd’s role and its use in combination with other systemic or local therapies.

Mechanistically, by delivering cytotoxic agents directly to HER3-expressing cells within brain metastases, HER3-DXd may overcome blood-brain barrier limitations that constrain many systemic agents. This supports its rationale in CNS-active treatment strategies.

Conclusion

Patritumab deruxtecan (HER3-DXd) holds promise as a novel therapeutic option for metastatic breast cancer patients with active brain metastases, demonstrating intracranial activity across subtypes and a manageable safety profile in the phase 2 TUXEDO-3 trial. These findings address a significant unmet need for effective CNS-directed systemic therapies in breast cancer. Further evaluation in larger, controlled studies will be key to establishing its clinical utility and optimizing integration into treatment paradigms.

Funding and Trial Registration

This study was funded by Daiichi-Sankyo and Merck Sharp & Dohme. Clinical trial registration identifiers: ClinicalTrials.gov NCT05865990, European Union Clinical Trials Register 2023-503251-10-00.

References

Bartsch R, Marhold M, Garde-Noguera J, et al. Patritumab deruxtecan (HER3-DXd) in patients with active brain metastases of breast cancer (TUXEDO-3): a multicentre, single-arm, phase 2 trial. Lancet Oncol. 2025 Nov;26(11):1467-1478. doi:10.1016/S1470-2045(25)00470-X IF: 35.9 Q1 B1. PMID: 41167215 IF: 35.9 Q1 B1

IF: 35.9 Q1 B1.

Fuereder T, Garde-Noguera J, García-Mosquera JJ, Ruiz-Borrego M, Valero M, Llombart-Cussac A, Gion M, Greil R, Arumi M, Campolier M, Guerrero JA, Raimondi G, Mancino M, Jiménez-Cortegana C, Vaz-Batista M, Oberndorfer F, Marhold M, Berghoff AS, Furtner J, Bartsch R, Preusser M. Patritumab deruxtecan (HER3-DXd) in patients with active brain metastases of non-small-cell lung cancer (TUXEDO-3): a multicentre, single-arm, phase 2 trial. Lancet Oncol. 2025 Nov;26(11):1454-1466. doi: 10.1016/S1470-2045(25)00465-6. PMID: 41167214.