In an investigator-initiated prospective, open-label, single-arm phase II TUXEDO-1 study conducted among patients with newly diagnosed or progressive brain metastases from HER2-positive breast cancer, antibody drug conjugate trastuzumab deruxtecan yielded responses by response assessment in neuro-oncology brain metastases (RANO-BM) criteria in 11 of 15 patients with a response rate by central review of 73.3% in the intention-to-treat (ITT) population. Median progression-free survival (PFS) was 14 months, and median overall survival (OS) was not reached at a median follow-up of 12 months. The study team led by Prof. Matthias Preusser and Prof. Rupert Bartsch of the Department of Medicine I, Division of Oncology, Medical University of Vienna in Vienna, Austria who published the findings on 8 August 2022 in the Nature Medicine, upon reporting findings earlier this year during the ESMO Breast Cancer Congress 2022, wrote that their results indicate clinically relevant intracranial activity of trastuzumab deruxtecan and should be discussed in the light of experimental and clinical data on systemic treatment options for brain metastases.

Highest incidences of brain metastases are reported in patients with triple-negative breast cancer and HER2-positive disease. Overall, incidence of brain metastases has been rising over the last two decades, commonly attributed to improved OS due to the progress in systemic treatment options, and a hypothetical shift to a more aggressive phenotype in patients recurring after primary adjuvant treatment. Local treatment such as whole-brain radiotherapy (WBRT), stereotactic radiotherapy, radiosurgery and neurosurgery has been the mainstay of brain metastases treatment, but patients’ prognosis remains poor. Systemic treatment has become an attractive alternative approach to WBRT when stereotactic radiotherapy or radiosurgery are not possible or indicated, aiming at the prevention of WBRT-associated neurocognitive decline.

The authors wrote in the study background that research in the field of systemic treatment for brain metastases has initially focused on small molecule tyrosine-kinase inhibitors due to their low molecular weight. Larger molecules such as antibodies and antibody-drug conjugates were considered ineffective due to the blood-brain-barrier. However, as the blood-brain-barrier is disrupted at the site of metastases and replaced by a blood-tumour barrier with higher endothelial fenestration, larger molecules may also penetrate the brain parenchyma. The drug-to-antibody ratio in trastuzumab deruxtecan is 8:1 which is higher compared with earlier generation of antibody-drug conjugates. Data regarding the potential activity of trastuzumab deruxtecan in active brain metastases is limited.

TUXEDO-1 study was specifically designed to evaluate efficacy and safety of trastuzumab deruxtecan in patients with HER2-positive breast cancer with active brain metastases (e.g. newly diagnosed brain metastases or brain metastases progressing after prior local treatment) and also as proof-of-principle for the intracranial activity of antibody drug conjugates. TUXEDO-1 investigators enroled patients aged 18 years and older with HER2-positive breast cancer and newly diagnosed untreated brain metastases or brain metastases progressing after prior local treatment, prior exposure to trastuzumab and pertuzumab, and no indication for immediate local treatment. Patients received trastuzumab deruxtecan intravenously at the standard dose of 5.4 mg/kg body weight once every three weeks. The primary endpoint was intracranial response rate measured according to RANO-BM criteria. A Simon two-stage design was used to compare a null hypothesis of <26% response rate against an alternative of 61%.

The ITT population of patients who received at least one dose of study drug comprised 15 patients. Two patients (13.3%) had a complete intracranial response, 9 (60%) had a partial intracranial response, and 3 patients (20%) had stable disease as the best intracranial response, with a best overall intracranial response rate of 73.3% (95% confidence interval 48.1-89.1), thus meeting the predefined primary outcome.

In the biomarker substudy, serum NSE and S100 levels were compared between responders and non-responders. The study team observed significantly lower serum NSE levels in patients responding to trastuzumab deruxtecan than in non-responders at 4 weeks after treatment initiation, despite similar baseline levels. This finding may relate to reduced brain parenchyma destruction due to the inhibition of metastatic growth as a direct result of systemic treatment. The authors commented while this is an exploratory analysis, it could suggest a potential use of serum NSE as biomarker for monitoring of brain metastases in the clinical setting, which needs to be validated in further studies.

No new safety signals were observed, and side-effects were consistent with the toxicity profile expected from the pivotal studies. One patient was diagnosed with grade II interstitial lung disease and had to permanently discontinue treatment but recovered fully with systemic administration of corticosteroids. Global quality-of-life (QoL) and cognitive functioning was maintained over the duration of treatment.

The authors commented that despite the strong biological rational, the stringent response evaluation by RANO-BM criteria with central response assessment, the availability of biomarkers, and extensive QoL evaluation, the study is limited by the non-randomised phase II design and the small sample size. However, it is a prospective study indicating clinically relevant activity of the trastuzumab deruxtecan in active brain metastases from HER2-positive breast cancer with comparable intra- and extracranial response rates in a pretreated population. Furthermore, PFS results indicate prolonged disease control despite the presence of brain metastases. Therefore, the results suggest that trastuzumab deruxtecan could be safely used for the treatment of these patients when immediate local intervention is not indicated and more generally support the notion that antibody drug conjugates may be of interest in CNS malignancies.

Commenting for the ESMO oncology news, Prof. Giuseppe Curigliano of the Department of Oncology and Hemato-Oncology, University of Milan, European Institute of Oncology, IRCCS in Milan, Italy said: “In the TUXEDO-1 trial an intracranial response was reported in 73.3% of the ITT population of 15 patients and 78.6% of the per-protocol population of 14 patients. The clinical benefit rate (≥ 6 months) was 86.7% and 92.9%, respectively. Data are of interest but need a robust, randomised methodologically well designed clinical trial to confirm potential PFS and OS benefit in the population of patients with active brain metastases.”

The Department of Medicine I, Division of Oncology, Medical University of Vienna as an academic, non-profit organisation was the regulatory sponsor, designed and conducted this study. Daiichi-Sankyo provided financial funding and trastuzumab deruxtecan.


Bartsch R, Berghoff AS, Furtner J, et al. Trastuzumab 1 deruxtecan in HER2-positive breast cancer with brain metastases: a single-arm, phase 2 trial. Nature Medicine; Published online 8 August 2022. DOI: