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. 2025 Feb 28;21(9):1065–1073. doi: 10.1080/14796694.2025.2470604

TUXEDO-4: phase II study of trastuzumab-deruxtecan in HER2-low breast cancer with new or progressing brain metastases

Maximilian Marhold a, Marta Vaz Batista b,c, Isabel Blancas d,e,f, Cristina Morales g, Cristina Saura-Manich h, Cristina Saavedra i,j, Manuel Ruíz-Borrego k, Patricia Cortez j, Felipe Slebe c, Marta Campolier c, Juliana Carvalho Santos c, José Antonio Guerrero-Martínez c, Carlos Jiménez-Cortegana c, Beate Rottenmanner a, Heidrun Forstner a, Rupert Bartsch a, Matthias Preusser a,✉
PMCID: PMC11988270  PMID: 40018758

ABSTRACT

Breast cancer (BC) is the most common cause of leptomeningeal disease (LMD) and the second most common cause of brain metastases (BMs) among all solid malignancies. Both BMs and LMD are associated with high morbidity and mortality and treatment options are limited. Trastuzumab deruxtecan (T-DXd), an antibody drug conjugate combining a HER2-targeting antibody with a topoisomerase I inhibitor, has shown activity in HER2-positive (HER2[+]) and HER2-low tumors in both preclinical and clinical settings. Similarly, T-DXd has shown efficacy in HER2[+] BC patients with central nervous system (CNS) involvement. However, data on activity in HER2-low BC patients with BMs and/or LMD using T-DXd are limited. TUXEDO-4 is an international, multicenter, single-arm, two-stage optimal Simon’s design, phase II trial (NCT06048718) that will recruit a total of 27 adult patients (13 in the first stage, and 14 in second stage depending on responses in the first stage) to evaluate T-DXd in the HER2-low metastatic BC population presenting with newly diagnosed or progressing BM with or without type II LMD.

Clinical trial registration

NCT06048718 (clinicaltrials.gov); 2023 -506,702-39–00 (EudraCT number).

KEYWORDS: Breast, brain/neurologic, metastasis, clinical trials, novel therapy

Plain Language Summary

Breast cancer cells often spread to the brain (brain metastases) or the membranes surrounding the brain and spinal cord (leptomeningeal disease). Therapies to treat these serious conditions are limited. Trastuzumab deruxtecan (T-DXd), which targets a protein called HER2 (found on the surface of breast cells to control their growth) and includes a powerful anti-cancer component to kill the tumor cells, has shown clinically meaningful results in both HER2-positive (high concentration of HER2 proteins) and HER2-low (low concentration of HER2 proteins) breast cancers. Interestingly, T-DXd has successfully worked in HER2-positive breast cancer patients with brain metastases and/or leptomeningeal disease, but results in their HER2-low counterparts are limited. TUXEDO-4 is a medical study to evaluate the effectiveness of T-DXd in HER2-low breast cancer patients with recently diagnosed or worsening brain metastases, with or without aggressive leptomeningeal disease. The study is taking place in Austria and Spain, and will recruit 27 adult patients. TUXEDO-4 trial TUXEDO-4 is an international, multicenter, single-arm, two-stage optimal Simon’s design, phase II clinical trial evaluating the efficacy of trastuzumab-deruxtecan (T-DXd) in human epidermal growth factor receptor 2 (HER2)-low breast cancer (BC) patients presenting with newly diagnosed or progressing brain metastases (BMs), with or without type II leptomeningeal disease (LMD).

TUXEDO-4 TRIAL

TUXEDO-4 is an international, multicenter, single-arm, two-stage optimal Simon’s design, phase II clinical trial evaluating the efficacy of trastuzumab-deruxtecan (T-DXd) in human epidermal growth factor receptor 2 (HER2)-low breast cancer (BC) patients presenting with newly diagnosed or progressing brain metastases (BMs), with or without type II leptomeningeal disease (LMD).

1. Background and rationale

1.1. Treatment approaches in MBC, BMs, and LMD

BC was the most common-diagnosed type of cancer and the second-leading cause of cancer-related death among women during 2023 [1]. HER2-low BC accounts for more than 50% of all BC cases [2,3] and is defined by immunohistochemistry (IHC) score 1+ or IHC 2+/in-situ hybridization (ISH)– [2]. Metastatic BC (MBC) is one of the main causes of BMs and LMD among all solid malignancies [4,5]. BMs occur in approximately one-third of MBC patients [6]. Prognosis remains poor and survival rate after one year of diagnosis is approximately 20% [7]. Interestingly, prior studies have indicated that HER2-low BMs represent a high proportion among hormone receptor-positive and triple-negative BC BMs [8–10]. LMD is a debilitating condition that comprises 10–20% of all central nervous system (CNS) metastases and is developed in 5% of BC patients [11–13]. According to the EANO – ESMO Clinical Practice Guideline, type I LMD requires positive cerebrospinal fluid cytology or positive leptomeningeal biopsy, whereas type II LMD diagnosis only requires clinical findings and neuroimaging [14,15]. It has been demonstrated that patients with type I LMD have significantly poorer outcomes compared with their type II LMD counterparts [16,17]. Of note, patients with CNS involvement are usually excluded from clinical trials due to poor condition and short-term outcomes [18]. Therefore, data regarding potential CNS activity are usually not available from pivotal trials making CNS specific studies necessary.

Treatment strategies in the MBC setting substantially differ depending on the BC subtype. The development of anti-HER2 therapies (e.g., trastuzumab) remarkably improved survival in HER2-positive (HER2[+]) BC patients [19]. However, those treatments have not improved clinical outcomes in their HER2-low BC counterparts [20]. Combinations of endocrine therapy and targeted agents are effective for patients with hormone receptor – positive, HER2[–] MBC, but endocrine resistance may eventually occur, and alternative treatment approaches are needed [21,22]. In metastatic triple-negative BC, limited treatment options are currently available but recent years have seen the introduction of checkpoint-inhibitors, PARPi, and antibody-drug conjugates (ADCs) [23–25].

First-line therapies for metastases to the CNS include a variety of treatments such as local treatment with surgery, radiation therapy, stereotactic radiosurgery, chemotherapy, targeted therapy, or immunotherapy [26,27]. Stereotactic radiosurgery provides high local control rates [28] but may produce radionecrosis and dose spreading to a significant proportion of healthy brain tissues [29]. In addition, systemic therapy has demonstrated improved intracranial (IC) response rates and overall survival in HER2[+] BC patients with BMs [30] but has shown little improvement in other BC subtypes [31]. Also, the blood-brain barrier (BBB) plays a key role because it can limit the penetration of systemic drugs to treat metastatic lesions and treatments may not reach therapeutic levels in the CNS [32].

The development of ADCs, which are targeted therapies combining monoclonal antibodies with a cytotoxic payload through a chemical linker, has brought promising clinical activity in different solid tumor types [33] and holds promise for diseases with CNS involvement [34]. Different ADCs have shown favorable preclinical and clinical outcomes on BMs of HER2[+] BC, including trastuzumab-emtansine (T-DM1) or T-DXd [35]. Specifically, T-DXd has also shown clinically meaningful efficacy in previously treated HER2-low advanced BC patients [36].

1.2. T-DXd as a promising therapeutic option in HER2-low BC patients with BMs and/or LMD

T-DXd is an ADC consisting of a humanized anti-HER2 monoclonal antibody (trastuzumab) linked to a topoisomerase I inhibitor payload (deruxtecan) through a chemical tetrapeptide-based cleavable linker [37]. Once trastuzumab binds HER2 and T-DXd undergoes endocytosis, the linker is cleaved by lysosomal cathepsins, and deruxtecan is released inside the cell to inhibit DNA replication and induce apoptosis by binding the topoisomerase I-DNA complex [38]. During BMs, T-DXd could not penetrate the BBB easily due to its large size, but tumor invasion may cause CNS damage and neovascularization, which would increase drug permeability [39].

T-DXd 5.4 mg/kg administered by intravenous (IV) infusion every 3 weeks was suggested as an effective dose for HER2[+] BC patients [40]. T-DXd has shown pharmacological efficacy in this BC population [41–43], including objective response rates (ORR) of more than 60% in the DESTINY-Breast01 trial [42] and 79.7% in the DESTINY-Breast03 trial [41]. In HER2-low BC patients, T-DXd provided a significantly improved median progression-free survival (PFS) versus physician’s treatment choice in both the DESTINY-Breast04 (10.1 vs. 5.4 months, respectively) and DESTINY-Breast06 (13.2 vs. 8.1 months, respectively) [36,44]. Due to the beneficial results with T-DXd, the Food and Drug Administration (FDA) approved the use of this therapy to treat HER2[+] and HER2-low BC patients.

Importantly, T-DXd has also shown encouraging IC efficacy in HER2[+] BC patients with BMs [45–49] and/or LMD [50,51]. The TUXEDO-1 trial reported IC responses of 73.3% and 78.6% in the intention-to-treat and per protocol populations, respectively, as well as a clinical benefit rate of 92.9% in patients with newly diagnosed untreated or progressing BMs [45]. The DEBBRAH study achieved a 16-week PFS rate of 87.5% in patients with non-progressing BMs after local therapy, and IC-ORR of 50.0% and 44.4% in those with asymptomatic untreated BMs and progressing BMs after local therapy, respectively [52]. In the DESTINY-Breast03 trial, the first interim analysis provided an investigator-assessed median PFS of 25.1 months with T-DXd versus 7.2 months with T-DM1 in patients with clinically stable, previously treated BMs [41]. In the second interim analysis, T-DXd demonstrated a significant, clinically meaningful median PFS by blinded independent central review of 28.8 months compared to 6.8 months with T-DM1 [53]. Long-term survival analyses from this trial showed median PFS by investigator assessment of 29.0 versus 7.2 months, 36-month PFS rate of 45.7% versus 12.4%, and median OS of 52.6 versus 42.7 months using T-DXd versus T-DM1, respectively [53]. The pooled analysis of the DESTINY-Breast01, 02, and 03 showed robust IC responses compared to the comparator drug, reporting similar ORR and PFS between those patients with treated/stable BMs (45.2% and 12.3 months) and those with untreated/active BMs (45.5% and 18.5 months) [48]. The DESTINY-Breast12 trial exhibited overall PFS at 12 months of 61.6%, being 62.9% in those with stable BMs and 59.6% in those with active BMs, as well as an ORR of 49.7% and 54.7%, respectively [49].

Some analyses have further suggested that T-DXd may have activity in HER2-low BC patients with CNS involvement [47,54–56]. Updated results from the DEBBRAH trial reported that HER2-low advanced BC patients with untreated BMs achieved an IC-ORR of 50% and IC clinical benefit rate (CBR) of 66.7%, whereas those with progressing BMs obtained IC-ORR of 33.3% and IC-CBR of 50.0% [57]. The small size (n = 6) of patients with progressing HER2-low BMs in DEBBRAH, however, hinders reliable estimation of response rates. Of note, studies have reported that the outcome of HER2-low BC patients with BMs may be dismal compared to their HER2[+] BC counterparts [58,59]. Based on the current scenario, the TUXEDO-4 trial was designed to assess the efficacy and safety of T-DXd in patients with HER2-low BC who have either newly diagnosed or progressing BM, with or without the presence of type II LMD. This study will address a critical need by aiming to enhance clinical outcomes and quality in this patient cohort.

2. Study design

TUXEDO-4 is an international, multicenter, single-arm, two-stage optimal Simon’s design, phase II clinical trial (NCT06048718) to evaluate the efficacy of T-DXd in HER2-low BC patients presenting with newly diagnosed or progressing BMs (Figure 1). Twenty-seven patients (13 in stage one plus 14 in stage two if there are more than 2 responder patients in stage one) will be enrolled from 13 sites in Austria and Spain (Figure 2). Enrollment began in June 2024, and the study is estimated to be completed in July 2026. Key inclusion and exclusion criteria are shown in Table 1.

Figure 1.

Figure 1.

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TUXEDO-4 study design. ABM: active (newly diagnosed or progressing after prior local therapy) brain Metastases; HER2: human epidermal growth factor receptor 2; LMD: leptomeningeal Disease; MRI: magnetic resonance imaging; PD: progression of disease; T-DXd: Trastuzumab Deruxtecan.

Figure 2.

Figure 2.

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Map of the participating countries in the TUXEDO-4 trial. created in BioRender. Jiménez-Cortegana, C. (2025) https://biorender.com/i68m714.

Table 1.

Key eligibility criteria in the TUXEDO-4 study.

Inclusion criteria*

  • Female or male patients ≥18 years.

  • Radiologically documented metastatic breast cancer with locally documented HER2-low status according to the 2018 ASCO/CAP guidelines.

  • Life expectancy ≥12 weeks.

  • KPS ≥70% and ECOG PS 0–2.

  • Newly diagnosed or progressive BM without indication for immediate local therapy.

  • ≥1 brain lesion (≥10 mm per local radiological assessment), measurable by RANO-BM criteria.

  • Must have undergone ≥1 line of systemic treatment in the advanced setting.

  • LVEF ≥50% by either ECHO or MUGA scan within 28 days before enrollment.

  • Adequate bone marrow, liver, renal, and coagulation function.

Exclusion criteria**

  • Treatment with approved or investigational cancer therapy within 4 weeks or targeted agents within 3 weeks prior to initiation of study drug.

  • Prior treatment with T-DXd and allergy or hypersensitivity to T-DXd or any of its components.

  • Myocardial infarction within 6 months before enrollment.

  • LVEF <50% by either ECHO or MUGA scan within 28 days before treatment.

  • Lung-specific intercurrent clinically significant illnesses; autoimmune, connective tissue or inflammatory disorders; or prior pneumonectomy.

  • Pregnant or lactating women.

  • Abnormal clinical laboratory tests; infection with hepatitis B virus or hepatitis C virus; or non-controlled human immunodeficiency virus infection.

  • Major surgical procedure (requiring general anesthesia) or significant traumatic injury within 21 days prior to enrollment, or patients who have not recovered from the side effects.

  • Uncontrolled seizures, central nervous system disorders, or serious and/or unstable preexisting psychiatric disability.
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ASCO/CAP: American Society of Clinical Oncology/College of American Pathologists; BM: Brain metastases; ECHO: Echocardiogram; ECOG PS: Eastern Cooperative Oncology Group performance status; HER2: Human epidermal growth factor receptor 2; KPS: Karnofsky Performance Status; LVEF: Left ventricular ejection fraction; MUGA: Multigated acquisition; RANO: Response Assessment in Neuro-Oncology; T-DXd: Trastuzumab-deruxtecan.

*Patients must meet all inclusion criteria.

**Patients meeting any exclusion criteria must be excluded.

3. Intervention

Eligible patients will receive T-DXd at 5.4 mg/kg administered as IV infusion every 3 weeks, on day 1 of each 21-day cycle. Patients will receive T-DXd until disease progression, unacceptable toxicity, death, or discontinuation from the study treatment for any other reason or as per physician’s choice.

T-DXd dose will be reduced to 4.4 mg/kg (first reduction) and 3.2 mg/kg (second reduction) in case of toxicity. More than two dose reductions or dose re-escalation are not allowed. The doses of T-DXd to be administered must be recalculated if the patient’s body weight has changed by 10% from baseline.

4. Patient population

Patients will be women or men ≥18 years of age, with HER2-low expression presenting with newly diagnosed or progressing BMs, with or without type II LMD, one or more brain lesions (≥10 mm per local radiological assessment), KPS ≥ 70%, and ECOG PS 0–2 (further eligibility criteria are shown in Table 1). A total of 27 patients will be recruited.

5. Objectives and endpoints

The primary objective of the TUXEDO-4 study is to assess the efficacy of T-DXd, defined as objective response rate (ORR) at any timepoint as judged by best CNS response according to RANO-BM criteria. Key secondary objectives are (i) to assess ORR as judged by best response determined locally by the investigator using the RECIST v.1.1 criteria for extracranial (EC) and overall lesions, (ii) to assess the bicompartmental CBR (Bi-CBR), defined as the sum of complete response (CR) rate, partial response (PR) rate and stable disease (SD) rate ≥24 weeks, and determined locally by the investigator using the RANO-BM criteria for IC lesions and RECIST v.1.1 criteria for EC and overall lesions, and (iii) to assess the bicompartmental disease control rate (Bi-DCR), defined as the sum of CR rate, PR rate, and SD rate, and determined locally by the investigator using the RANO-BM criteria for IC lesions and RECIST v.1.1 criteria for EC and overall lesions. Of note, bicompartmental assessments were carried out to provide more comprehensive insights on how T-DXd affects both IC and EC diseases. All endpoints, including additional secondary endpoints and exploratory endpoints, are summarized in Table 2.

Table 2.

TUXEDO-4 endpoints.

Primary endpoint ORR at any timepoint determined by best central nervous system response per RANO-BM criteria.
Secondary endpoints

  • ORR for EC and overall lesions, defined by rate of CR or PR, locally determined by the investigator per RECIST v.1.1 criteria.

  • Bi-CBR*, defined as CR+PR+SD ≥24 weeks, locally determined by the investigator.

  • Bi-DCR*, defined as CR+PR+SD, locally determined by the investigator.

  • Time to response*, defined from treatment initiation to first objective tumor response (tumor shrinkage ≥30%) in patients with CR or PR.

  • Duration of response*, defined from the first occurrence of a documented objective response to disease progression or death from any cause, in patients with CR or PR.

  • Best percentage of change in tumor burden*.

  • Progression-free survival, defined from treatment initiation to the first occurrence of disease progression or death from any cause.

  • Overall survival, defined from treatment initiation to death from any cause, determined locally by the investigator.

  • Safety and tolerability as per NCI-CTCAE v.5.0.

  • Assessment of quality of life with EORTC QLQ-c30, the brain- specific tool (BN20), and the breast-specific tool BR45.

  • Neurologic function as per NANO scale.
Exploratory endpoints

  • Evaluation of biomarkers associated with brain damage.

  • Evaluation of response to T-DXd.

  • Assessment of HER2 gene copy number changes throughout the treatment
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Bi-CBR: Bicompartmental clinical benefit rate; Bi-DCR: Bicompartmental disease control rate; CR: Complete response; EC: Extracranial; EORTC QLQ: European Organisation For Research And Treatment Of Cancer Core – Quality of Life questionnaire; HER2: Human epidermal growth factor receptor 2; IC: Intracranial; NANO: Neurologic Assessment in Neuro-Oncology; NCI-CTCAE: National Cancer Institute – Common Terminology Criteria for Adverse Events; ORR: Overall response rate; PR: Partial response; RANO-BM: Response Assessment in Neuro-Oncology for Brain Metastasis; RECIST: Response evaluation criteria in solid tumors; SD: Stabilization of disease; T-DXd: Trastuzumab-deruxtecan

*These secondary endpoints were assessed as per RANO-BM criteria for IC and RECIST v.1.1 for EC and overall lesions.

6. Study procedures

Participants will be enrolled into the study after signing the ICF. Different evaluations will be performed and reviewed during the screening phase to confirm that patients meet all eligibility criteria before enrollment. Those evaluations will include (but will not be limited to) cranial MRI and computed tomography (CT) scan of chest, abdomen, and pelvis, bone scan, and blood tests. A tumor tissue sample will be collected for determination of HER2 status. Demographic data, such as age, sex, or self-reported ethnicity, and clinical information such as significant diseases, history of cancer, or surgical interventions will be recorded.

The initial T-DXd dose will be administered as a 90-minute IV infusion, and subsequent doses as 30-minute infusions if there is no infusion-related reaction. IC tumor response will be assessed by local investigator using RANO-BM criteria, extracranial and overall responses by local investigator using RECIST v.1.1 criteria. Response to T-DXd will be assessed within ten days before the third administration, within ten days before the fifth administration, and every nine weeks thereafter.

Key safety assessments will include evaluations of vital signs, peripheral oxygen saturation, laboratory tests, physical examinations, ECOG PS, LVEF, quality of life and neurocognitive function using the EORTC QLQ-c30, the QLQ-BN20, the QLQ-BR45, and the NANO scale.

Post-treatment follow-ups will be carried out in patients to collect survival and subsequent anti-cancer therapy information every 3 months until death, lost to follow-up, elective withdrawal from the study, or the end of study.

7. Statistical analysis

7.1. Sample size determination

The sample size was calculated based on Simon’s two-stage design, which was used to minimize patient exposure to ineffective treatments and reduce costs by allowing for early termination if initial results are unpromising. This method was previously used in the TUXEDO-1 trial [45] and is being used in the TUXEDO-2 and TUXEDO-3 trials [60,61] because it balances ethical considerations and statistical rigor, providing a clear framework for deciding whether to proceed with further development based on predefined success thresholds.

A total of 27 patients will be enrolled. Of them, thirteen patients will be recruited in the first stage. The study will be stopped for futility if there are ≤2 (15.4%) IC responses in this stage. If not, 14 additional patients will be recruited in the second stage.

7.2. Primary endpoint analysis

The hypothesis is that T-DXd may exhibit clinical activity among HER2-low BC patients with BM, and with or without type II LMD. Based on the EC response rate reported in the DESTINY-Breast04 and preliminary data from cohort 3 of the DEBBRAH trial [36,52], a CNS ORR of ≥42% will be considered as indicating clinically relevant activity (alternative hypothesis). Similarly, since we expected a poor drug response based on the Destiny-Breast04 physician’s choice arm [42], a CNS ORR of ≤16% will be considered clinically unmeaningful (null hypothesis). This design yields a one-sided type I error rate of 5% and a power of 90% to reject the null hypothesis.

Primary endpoint will be analyzed on the full analysis and per protocol sets, which will involve all patients who meet selection criteria and receive at least one dose of T-DXd. Koyama T and Chen H methods for Simon’s two-stage design, and 95% Pearson-Clopper and Wilson confidence intervals (CI) will be also used. The primary endpoint will be met with ≥8 out of 27 (29.6%) patients exhibiting IC response.

7.3. Secondary endpoint analysis

Secondary endpoint analyses will be carried out in the full population. The proportion of responders will be calculated with the uniformly minimum variance unbiased estimator (UMVUE), to ensure precise estimates, and p-value and 95% CI with Koyama and Chen method, to better analyze censoring and survival data [62]. These methods will provide more confident and accurate conclusions about treatment efficacy. ORR, CBR, and DCR will be given by the number and the rate of patients with response, clinical benefit, and disease control, respectively. 95% Clopper-Pearson CI will be calculated.

The following key secondary endpoint analyses will be performed: TTR and DoR (median in months, range, interquartile range and Kaplan–Meier estimations), PFS and OS (Kaplan–Meier plots, number and percentage of events, median survival, and CI based on “log-log” method), adverse events (AEs), treatment emergent adverse events (TEAEs), serious AEs, grade ≥3 TEAEs, TEAEs leading to dose interruption, reduction, or permanent discontinuation based on MedDRA System Organ Classes (SOCs) and Preferred Terms (PTs). Descriptive analyses will involve physical examination, ECOG status, vital signs, physical examination, ophthalmologic assessment, ECG, ECHO, MUGA scan, pregnancy test, and laboratory parameters (at each cycle), as well as duration of treatment (months), duration of follow-up (months), number of cycles, number of patients with dose interruptions, reductions, and permanent discontinuations, and relative dose intensity for study drugs. Demographic data and other baseline characteristics will be presented for all patients who receive at least one dose of study treatment.

8. Conclusions

If the results of the TUXEDO-4 trial are positive, T-DXd could be introduced as a promising treatment option for HER2-low metastatic BC patients with newly diagnosed or progressing BMs with or without type II LMD. The results of this trial may influence future clinical guidelines. Larger, randomized trials comparing T-DXd with other treatments of active BMs – especially whole-brain radiotherapy – are worth considering.

Supplementary Material

Supplemental Material
IFON_A_2470604_SM9749.zip (1.9MB, zip)

Acknowledgments

The TUXEDO-4 team is grateful to all patients and their families. We acknowledge the trial teams of the participating sites and Daiichi Sankyo, which is the funder of the TUXEDO-4 study. The design of this clinical trial was communicated as a poster presentation at the San Antonio Breast Cancer Symposium (SABCS) 2024, held on December 10–13, 2024.

Funding Statement

The TUXEDO-4 trial has been funded by Daiichi Sankyo, who has been involved in the decision to publish, and the preparation of the manuscript.

Article highlights

Background

  • Metastatic breast cancer (BC) is one of the main causes of brain metastases (BMs) and leptomeningeal disease (LMD) among all solid malignancies.

  • Patients with BMs and/or LMD are usually excluded form clinical trials due to their poor outcomes, and treatment options are limited.

  • Antibody-drug conjugates (ADCs) have emerged as a promising therapeutic option in tumors with central nervous system (CNS) involvement.

Trastuzumab deruxtecan (T-DXd)

  • T-DXd is an ADC consisting of an anti-HER2 monoclonal antibody linked to a topoisomerase I inhibitor payload through a chemical linker.

  • This drug has shown clinical efficacy in human epidermal growth factor receptor 2-positive (HER2[+]) and HER2-low breast cancers. The Food and Drug Administration approved T-DXd for HER2[+] and HER2-low BC patients based upon the results of the DESTINY-Breast01, DESTINY-Breast03, and DESTINY-Breast04 trials, respectively.

  • T-DXd has shown great efficacy in HER2[+] and some efficacy in HER2-low BC patients with CNS involvement. Of note, the DEBBRAH trial reported limited data of 3 IC responses in 6 patients (50% IC-ORR) in HER2-low advanced BC patients with untreated/asymptomatic BMs, and 2 IC responses in 6 patients (33.3% IC-ORR) in their progressing BMs counterparts.

  • Results in HER2-low tumor involving BMs and/or LMD are limited.

TUXEDO-4

  • TUXEDO-4 is an international, multicenter, single-arm, two-stage optimal Simon’s design, phase II clinical trial (NCT06048718).

  • The primary endpoint is to assess the objective response rate (ORR) at any timepoint as by best CNS response according to RANO-BM criteria. Key secondary objectives are ORR as by best response determined locally by the investigator using the RECIST v.1.1 for extracranial (EC) and overall lesions, and bicompartmental clinical benefit and bicompartmental disease control rates determined locally by the investigator using the RANO-BM criteria for intracranial (IC) lesions and RECIST v.1.1 criteria for EC and overall lesions.

  • Twenty-seven patients (13 in stage one, plus 14 in stage two if there are more than 2 responder patients in stage one) will be enrolled from 13 sites in Austria and Spain.

Conclusions

  • If results are positive, this clinical trial could introduce T-DXd as a promising treatment option for HER2-low metastatic BC patients with newly diagnosed or progressing BMs with or without type II LMD.

Author contributions

Study idea: Maximilian Marhold.

Study concept: Maximilian Marhold, Matthias Preusser, and Rupert Bartsch.

Protocol writing: Maximilian Marhold, Marta Vaz-Batista, Felipe Slebe, Marta Campolier, Juliana Carvalho-Santos, José Antonio Guerrero-Martínez, Carlos Jiménez-Cortegana, Matthias Preusser, and Rupert Bartsch.

Study participation, patient accrual, data entry: Maximilian Marhold, Marta Vaz-Batista, Isabel Blancas, Cristina Morales, Cristina Saura-Manich, Cristina Saavedra, Manuel Ruíz-Borrego, Patricia Cortez, Rupert Bartsch, and Matthias Preusser.

Writing and approval of manuscript: All authors.

Disclosure statement

Maximilian Marhold has received honoraria for lectures, advisory board participation and consultation from Roche, Eli Lilly, Novartis, AstraZeneca, Daiichi Sankyo, Pfizer, MSD, Gilead, and Medmedia; and travel support from Amgen, Gilead, Roche, Novartis, Pierre Fabre, Daiichi Sankyo, and Eisai.

Marta Vaz-Batista has received honoraria from Daichii Sankyo, GSK, and AstraZeneca; consulting or advisory role from Daichii Sankyo and AstraZeneca; speakers’ bureau from Novartis; and travel, accomodation, and expenses from AstraZeneca.

Isabel Blancas has received grants and research support to the Institution from AstraZeneca, Lilly, Pfizer and Roche; honoraria and advisor collaboration from AstraZeneca, Roche, Novartis, Eisai, Celgene, Pfizer, Lilly, Pierre–Fabre, Bristol–Myers Squibb, Daiichi Sankyo, Grünenthal, Seagen, and Veracyte; and support for attending meetings and/or travel from AstraZeneca, Roche, Novartis, Pfizer, Lilly, Pierre-Fabre, Bristol-Myers Squibb, and Daiichi Sankyo.

Cristina Saura-Manich has received research support and consulting or advisory role from Genentech, AstraZeneca, Aragon Pharmaceuticals, Bayer Pharma, Byondis, Boehringer Ingelheim, Bristol-Myers Squibb, Cytomx Therapeutics, Daiichi Sankyo, F. Hoffmann-La Roche, Eisai, Genomic Health, GlaxoSmithKline, Innoup Farma, Eli Lilly, Macrogenics, Menarini Ricerche, Merck Sharp & Dohme, Merus, Millennium Pharmaceuticals, Novartis, Pfizer, Pierre Fabre, PintPharma, Puma Biotechnology, Sanofi, Seattle Genetics, and Zymeworks.

Manuel Ruíz-Borrego has received consulting fees from Roche and Puma, and honoraria expenses from Roche/Genentech, Pfizer, and Novartis.

Felipe Slebe, Marta Campolier, Juliana Carvalho-Santos, José Antonio Guerrero-Martínez, and Carlos Jiménez-Cortegana declare to be full-time employees at MEDSIR.

Rupert Bartsch has received honoraria from AstraZeneca, BMS, Daiichi-Sankyo, Eisai, and Eli-Lilly; consulting or advisory role from AstraZeneca, Daichi, Eisai, and Eli-Lilly; research funding from Daiichi-Sankyo; and travel, accommodations, and expenses from MSD, Daiichi-Sankyo, Novartis, and Pfizer.

Matthias Preusser has received honoraria for lectures, consultation and advisory board participation from the following for-profit companies: Bayer, Bristol-Myers Squibb, Novartis, Gerson Lehrman Group (GLG), CMC Contrast, GlaxoSmithKline, Mundipharma, Roche, BMJ Journals, MedMedia, Astra Zeneca, AbbVie, Lilly, Medahead, Daiichi Sankyo, Sanofi, Merck Sharp & Dome, Tocagen, Adastra, Gan & Lee Pharmaceuticals, Janssen, Servier, Miltenyi, Böhringer-Ingelheim, Telix, Medscape, OncLive.

Cristina Morales, Cristina Saavedra, Patricia Cortez, Beate Rottenmanner, and Heidrun Forstner have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Ethical conduct of research

The investigators have obtained appropriate institutional review board approval (Comité de Ética de la Investigación con Medicamentos. Hospital Arnau de Vilanova-Llíria, Valencia, Spain; and the Federal Office for Safety in Healthcare, Austria) to carry out the TUXEDO-4 trial (approval number 2023 -506,702-39-00_9622). The investigators have also followed the principles outlined in the Declaration of Helsinki for all human experimental investigations. Written informed consent is required and has been obtained from the participants involved.

Data sharing statement

Data collected within this study will be made available to researchers after contacting the corresponding author and upon revision and approval based on scientific merit by the TUXEDO-4 trial management group (which includes a qualified statistician) of a detailed proposal for their use. The data required for the approved, specified purposes and the trial protocol will be provided after the completion of a data sharing agreement that will be set up by the study sponsor (MEDSIR). All data provided are anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. The estimated timeframe for response will be within 30 days. Please address requests for data to the corresponding author.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/14796694.2025.2470604

References

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