Trastuzumab Deruxtecan Induces Responses in Patients With HER2+ Breast Cancer and Brain Metastases

Investigators continue to explore possible systemic treatment options that could improve disease control for patients with brain metastases derived from breast cancer.

Fam-trastuzumab deruxtecan-nxki (Enhertu) demonstrated significant responses and prolonged disease control among patients with HER2-positive breast cancers and brain metastases, according to primary results of the phase 2 TUXEDO-1 trial (NCT04752059).1

In the intention-to-treat (ITT) population (n = 15), the objective response rate (ORR) per Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria was 73.3% (95% CI, 48.1%-89.1%). In the per protocol (PP) population (n = 14), the ORR was 78.6%.

“TUXEDO-1 therefore adds to the growing body of evidence that systemic treatment is feasible in patients with active brain metastasis, and more generally supports further investigation of [antibody-drug conjugates] in the context of secondary CNS malignancies,” said Rupert Bartsch, MD, an associate professor of medicine at the Medical University of Vienna in Austria, in a presentation during the 2022 European Society for Medical Oncology Breast Cancer Congress.

Investigators continue to explore possible systemic treatment options that could improve disease control for patients with brain metastases derived from breast cancer.

In a cohort of the phase 2 DEBBRAH trial (NCT04420598) of patients with HER2-positive advanced breast cancer and brain metastases that were progressing following surgery, stereotactic surgery, and/or whole brain radiotherapy, 4 of 9 patients (44.4%) responded to treatment with trastuzumab deruxtecan.2

TUXEDO-1 is an ongoing open-label, study of trastuzumab deruxtecan in adult patients with HER2-positive breast cancer with newly diagnosed or progressing brain metastases after prior local therapy. The Simon 2-stage design for the trial assumed at least 7 responses among 15 patients.

Patient eligibility required radiologically documented metastatic disease, no leptomeningeal disease, no indication for immediate local treatment, and an ECOG performance status below 2. Prior exposure to trastuzumab (Herceptin) and pertuzumab (Perjeta) was expected, and prior exposure to adotrastuzumab emtansine (Kadcyla) was allowed. Additionally, patients were required to have a life expectancy of at least 3 months and a left ventricular ejection fraction of at least 50%.

All patients received 5.4 mg/kg of intravenous trastuzumab deruxtecan every 3 weeks until disease progression, unacceptable toxicity or patient withdrawal.

The primary end point was ORR for central nervous system (CNS) response per RANOBM criteria. Secondary end points included clinical benefit rate, extracranial response rate, progression-free survival, overall survival, safety, and quality of life.

One patient was excluded from the PP population due to the absence of brain metastases; this patient had dural metastasis. As of the study cutoff, 9 patients had discontinued treatment, 3 due to progression and 6 due to other reasons.

All but 1 patient was female and the median age at baseline was 69 years (range, 30-76). Sixty percent of patients had an ECOG performance status of 0 and no neurologic symptoms at baseline. Eighty percent of patients had luminal B disease and visceral metastases. The median brain metastases–free survival from diagnosis to the time of metastatic disease was 17 months (range, 0-48).

Prior HER2-targeted therapy included trastuzumab and pertuzumab in all patients, trastuzumab emtansine in 60%, lapatinib (Tykerb) in 26.7%, and other treatment in 6.7%. Brain metastases were untreated in 40% of patients and progressive after prior local therapy in 60%. The median number of prior lines of therapy for metastatic disease was 2 (range, 1-5).

The clinical benefit rate was 86.7% in the ITT group and 92.9% in the PP group. “Nearly all the patients benefited, to a degree, from systemic therapy,” Bartsch said.

At a median follow-up of 11 months (range, 3-17), the median progression-free survival was 14 months (95% CI, 11.0-not reached) and the median overall survival was not reached.

Thirteen patients had extracranial metastases at baseline; the extracranial response rate among these patients was 27.8%. The response rate among patients with measurable extracranial disease (n = 8) was 62.5%.

All patients experienced at least 1 adverse event (AE). Hematologic AEs consisted of anemia (53.3%) and neutropenia (46.6%). Common nonhematologic AEs included fatigue (80%), nausea (46.7%), constipation (40%), hypokalemia (40%), diarrhea (40%), and dyspnea (33.4%). Bartsch said no new safety signals were observed.

One case of grade 3 ejection fraction decrease was reported and one case of grade 2 interstitial lung disease. Investigators observed 6 serious AEs in 4 patients, including 1 patient with grade 5 urosepsis.

Quality-of-life metrics, including global health status, physical functioning, emotional functioning, and cognitive functioning were maintained over the treatment period following initial dips in the first weeks of treatment. “Importantly in a trial conducted in patients with active brain metastasis, cognitive function was maintained over the entire treatment period,” Bartsch stated.


1. Bartsch R, Berghoff AS, Furtner J, et al. Trastuzumab-deruxtecan (T-DXd) in HER2-positive breast cancer patients (pts) with active brain metastases: primary outcome analysis from the TUXEDO-1 trial. Ann Oncol. 2022;33(suppl 3):S194-S223. doi:10.1016/annonc/annonc894

2. Vaz Batista M, Cortez P, Ruiz M, et al. Trastuzumab deruxtecan (T-DXd; DS-8201) in patients with HER2-positive or HER2-low-expressing advanced breast cancer and central nervous system involvement: preliminary results from the DEBBRAH phase 2 study. Presented at: 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021; San Antonio, TX.