
==== Front
ESMO Open
ESMO Open
ESMO Open
2059-7029
Elsevier

S2059-7029(24)01468-6
10.1016/j.esmoop.2024.103699
103699
Original Research
Trastuzumab deruxtecan in patients with previously treated HER2-low advanced breast cancer and active brain metastases: the DEBBRAH trial
Vaz Batista M. 12†
Pérez-García J.M. 23†
Cortez P. 4
Garrigós L. 35
Fernández-Abad M. 67
Gion M. 6
Martínez-Bueno A. 5
Saavedra C. 6
Teruel I. 8
Fernandez-Ortega A. 9
Servitja S. 10
Ruiz-Borrego M. 11
de la Haba-Rodríguez J. 12
Martrat G. 2
Pérez-Escuredo J. 2
Alcalá-López D. 2
Sampayo-Cordero M. 2
Braga S. 1
Cortés J. javier.cortes@maj3.health
2313∗
Llombart-Cussac A. antoniollombart@medsir.org
21415∗
1 Hospital Professor Doutor Fernando Fonseca EPE, Lisbon, Portugal
2 Medica Scientia Innovation Research (MEDSIR) – Oncoclínicas & Co, Jersey City, USA, Sao Paulo, Brazil
3 International Breast Cancer Center (IBCC), Pangaea Oncology, Quiron Group, Barcelona
4 IOB Institute of Oncology, Hospital Ruber Internacional, Quiron Group, Madrid
5 Hospital Universitari Dexeus, Barcelona
6 Medical Oncology Department, Hospital Ramon y Cajal, Madrid
7 Alcalá de Henares University, Faculty of Medicine, Madrid
8 Institut Català d'Oncologia Badalona (ICO), Badalona, Barcelona
9 Institut Català d'Oncologia L'Hospitalet (ICO), L'Hospitalet de Llobregat, Barcelona
10 Hospital del Mar, Barcelona
11 Hospital Universitario Virgen del Rocío, Seville
12 Instituto Maimonides de Investigacion Biomedica, Hospital Reina Sofia, Universidad de Córdoba, Córdoba
13 Universidad Europea de Madrid, Faculty of Biomedical and Health Sciences, Department of Medicine, Madrid
14 Hospital Arnau de Vilanova, FISABIO, Valencia
15 Universidad Católica de Valencia, Valencia, Spain
∗ Correspondence to: Dr Antonio Llombart-Cussac, Hospital Arnau de Vilanova, FISABIO, Calle de Sant Clement, 12, 46015, Valencia, Spain. Tel: +34-932-214-135; Fax: +34-932-214-135 antoniollombart@medsir.org
∗ Dr Javier Cortés, International Breast Cancer Center (IBCC), Quironsalud Group, Carrer de Vilana 12, 08022 Barcelona, Spain. Tel: +34-935-504-848 javier.cortes@maj3.health
† Both authors contributed equally.

09 9 2024
9 2024
09 9 2024
9 9 103699© 2024 The Author(s)
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Background

Trastuzumab deruxtecan (T-DXd) is approved for human epidermal growth factor receptor 2 (HER2)-positive and HER2-low advanced breast cancer (ABC). T-DXd has shown encouraging intracranial activity in HER2-positive ABC patients with stable or active brain metastases (BMs); however, its efficacy in patients with HER2-low ABC with BMs is not well established yet.

Methods

DEBBRAH is a single-arm, five-cohort, phase II study evaluating T-DXd in patients with central nervous system involvement from HER2-positive and HER2-low ABC. Here, we report results from patients with heavily pretreated HER2-low ABC and active BMs, enrolled in cohorts 2 (n = 6, asymptomatic untreated BMs) and 4 (n = 6, progressing BMs after local therapy). Patients received 5.4 mg/kg T-DXd intravenously once every 21 days. The primary endpoint was intracranial objective response rate per Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) for both cohorts.

Results

Intracranial objective response rate per RANO-BM was 50.0% [3/6 patients; 95% confidence interval (CI) 11.8% to 88.2%] and 33.3% [2/6 patients; 95% CI 4.3% to 77.7%; P = 0.033 (one-sided)] in cohorts 2 and 4, respectively. All responders had partial responses. Median time to intracranial response was 2.3 months (range, 1.5-4.0 months) and median duration of intracranial response was 7.2 months (range, 2.8-16.8 months). Median progression-free survival per RECIST v.1.1. was 5.4 months (95% CI 4.1-10.0 months). Treatment-emergent adverse events occurred in all patients included (16.7% grade 3). Three patients (25.0%) had grade 1 interstitial lung disease/pneumonitis.

Conclusions

T-DXd demonstrated promising intracranial activity in pretreated HER2-low ABC patients with active BMs. Further studies are needed to validate these results in larger cohorts. This trial is registered with ClinicalTrials.gov, NCT04420598.

Highlights

• T-DXd showed encouraging preliminary intra- and extracranial activity in pretreated HER2-low ABC patients with active BMs.

• ORR-IC per RANO-BM was 50.0% and 33.3% in patients with asymptomatic untreated and progressing BMs, respectively.

• Median time to intracranial response and duration of intracranial response were 2.3 and 7.2 months, respectively.

• Median PFS per RECIST v.1.1. was 5.4 months in HER2-low ABC pts with BMs.

Key words

advanced breast cancer
active brain metastases
HER2-low
T-DXd
trastuzumab deruxtecan
==== Body
pmcIntroduction

Brain metastases (BMs) represent a major challenge in advanced breast cancer (ABC) and are associated with poor prognosis. Overall, ∼30% of patients with ABC will develop BMs during the course of their disease.1

Recent evidence has recognized human epidermal growth factor receptor 2 (HER2)-low expression as a new targetable biomarker with major clinical implications for patients with ABC. HER2-low breast cancer, defined as either HER2 immunohistochemistry (IHC) 2+ and in situ hybridization (ISH)-negative, or IHC 1+, accounts for ∼50% of all breast cancers and appears to occur more frequently in hormone receptor-positive disease.2, 3, 4

Incidence of BMs can vary widely according to breast cancer subtype. Patients with HER2-positive or triple-negative ABC are particularly susceptible to developing BMs, with nearly one in three patients affected.1 Its specific occurrence in luminal and triple-negative ABC with HER2-low expression, however, is not well described in literature.5

Trastuzumab deruxtecan (T-DXd) is an antibody–drug conjugate consisting of a humanized anti-HER2 monoclonal antibody linked to a topoisomerase I inhibitor payload through a tetrapeptide-based cleavable linker. T-DXd has demonstrated unprecedented antitumor activity in patients with HER2-positive ABC.6, 7, 8 Recently, clinical practice-changing results from the DESTINY-Breast04 study also showed superior progression-free survival (PFS) and overall survival (OS) with T-DXd in patients with HER2-low ABC compared with single-agent chemotherapy.9 On the basis of these results, T-DXd is currently approved for treating both HER2-positive and HER2-low ABC.9,10

T-DXd has also shown important intracranial efficacy in HER2-positive ABC, mainly in patients with stable BMs (those who have received prior therapy and are clinically and radiographically stable), but also in patients with active BMs (defined as untreated or progressing BMs after prior local therapy), in different studies.6, 7, 8,11, 12, 13, 14 Nevertheless, data regarding the intracranial efficacy of T-DXd in patients with HER2-low ABC and BMs are limited. In the DESTINY-Breast04 and DAISY trials, only a small number of patients with HER2-low ABC and stable BMs were included9,15; therefore, the intracranial activity of T-DXd in patients with HER2-low ABC and active BMs has not been assessed.

To bridge this knowledge gap, we conducted the DEBBRAH study as a proof of concept to evaluate the efficacy and safety of T-DXd in patients with HER2-positive and HER2-low ABC with a history of BMs and/or leptomeningeal carcinomatosis. Here, we present the final results from HER2-low ABC patients with active BMs.

Patients and methods

Study design and patients

DEBBRAH is a single-arm, open-label, five-cohort, phase II study conducted across 21 sites in Spain and Portugal. This trial is registered with ClinicalTrials.gov, NCT04420598. The study design has been previously described.14 Patients were enrolled into one of five cohorts based on HER2 expression and type of central nervous system (CNS) involvement. Cohort 2 included patients with either HER2-positive or HER2-low ABC with asymptomatic untreated BMs, and cohort 4 enrolled patients with HER2-low ABC with progressing BMs after local therapy with radiation therapy and/or surgery (Figure 1). HER2-low breast cancer was defined as HER2 IHC 2+ and ISH-negative, or IHC 1+, according to local laboratory results on the most recently analyzed biopsy. In cohort 2, HER2-low status was evaluated in the primary tumor (four out of six patients) and in a metastatic site (two out of six patients). In cohort 4, HER2-low status was assessed in a metastatic site in all patients.Figure 1 Patient enrollment and disposition at data cut-off. ABC, advanced breast cancer; BMs, brain metastases; HER2, human epidermal growth factor receptor 2; SRS, stereotactic radiosurgery; SRT, stereotactic radiotherapy; WBRT, whole-brain radiotherapy. ∗Patient died as result of a pulmonary embolism and deep vein thrombosis unrelated to the study treatment.

Additional inclusion criteria for patients with HER2-low breast cancer included in cohorts 2 and 4 were: age ≥18 years old; at least one measurable brain lesion [≥10 mm on T1-weighted, gadolinium-enhanced magnetic resonance imaging (MRI)]; Eastern Cooperative Oncology Group (ECOG) performance status of 0-1; normal liver and renal function; prior treatment with at least one chemotherapy regimen for advanced disease; and previous treatment with one endocrine therapy-based regimen for ABC for patients whose tumors were hormone receptor-positive.14 Full eligibility criteria are listed in Supplementary Table S1, available at https://doi.org/10.1016/j.esmoop.2024.103699.

This study was conducted in compliance with the Declaration of Helsinki. It was approved by the competent regulatory authorities of Spain (AEMPS) and Portugal (INFARMED), the Ethics Committee of Fundación Instituto Valenciano de Oncología (Valencia, Spain), as well as the institutional review boards at each site. All patients provided written informed consent.

Procedures

Patients received 5.4 mg/kg of T-DXd as an intravenous infusion on day 1 of each 21-day cycle until progressive disease (intracranial and/or extracranial), unacceptable toxicity, withdrawal from study, or study completion. Premedication for study drug administration was determined at the investigator’s discretion.

MRI of the brain and computed tomography or MRI of the chest, abdomen, and pelvis were conducted at baseline, every 6 weeks up to week 24, and every 9 weeks thereafter. Bone scans were conducted at baseline and repeated during the study only if bone involvement was found at baseline. Patient-reported outcomes (PROs) were assessed using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30 and the breast cancer module QLQ-BR23 questionnaires at baseline, on day 1 of cycles 2 and 8, and at the end-of-treatment visit.

Outcome

The primary endpoint for cohorts 2 and 4 was intracranial objective response rate (ORR-IC) sustained for at least 4 weeks based on local investigator’s assessment according to Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria for intracranial lesions. Radiological confirmation of objective response had to be confirmed in the next tumor evaluation. Secondary endpoints were PFS, clinical benefit rate (CBR), time to response (TTR), duration of response (DoR), best percentage of change from baseline in the size of tumor lesions using RANO-BM for intracranial lesions and Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v.1.1) for extracranial and overall lesions, and time from T-DXd initiation to intracranial disease progression that requires local treatment (only cohort 2) using RANO-BM and RECIST v.1.1, OS, and safety according to Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v.5.0). Exploratory endpoints were patient-reported global health status/quality of life through the use of the EORTC QLQ-C30 and QLQ-BR23 questionnaires and the relationship between tissue-, blood-, and cerebrospinal fluid-based biomarkers with patient clinical characteristics and outcomes.14 Some secondary endpoints are currently under study and not reported here. The definition of all endpoints is provided in Supplementary Table S2, available at https://doi.org/10.1016/j.esmoop.2024.103699.

Statistical analysis

All treated patients who met the selection criteria were included in the efficacy and safety analysis. This study followed a one-stage A’Hern design for cohorts 2 and 4 based on a one-sided binomial exact test. The primary analysis for cohorts 2 and 4 was designed to test the null and alternative hypotheses that the true ORR-IC rates were ≤5% and ≥40% (based on previous well-known designs to assess antitumor activity16), respectively. We estimated that 10 patients in cohort 2 (with HER2-low or HER2-positive disease) and seven patients in cohort 4 (HER2-low disease) would be needed to attain 80% power at the nominal level of one-sided α of 0.05 in each cohort. Expected sample size in cohort 2 was increased to 10 patients (30% increase) to ensure that a minimum number of participants were included in both subtypes, HER2-positive and HER2-low disease.

A positive finding in cohorts 2 and 4 was defined as at least three or two patients attaining an intracranial objective response, respectively. For the subgroup of patients with HER2-low in cohort 2 presented in this study results are only descriptive.

Clopper–Pearson methodology was used to calculate the two-sided 95% confidence interval (CI) for response rates. PFS (from treatment initiation to disease progression in all patients) was estimated using the Kaplan–Meier method, reporting the median with 95% CIs with the log-log method. The TTR and DoR (from treatment response to disease progression in responder patients) were described with median and range. R software v.4.2.2 was used to conduct the statistical analyses.

The R code for the calculation of sample size and the analysis of primary endpoint is reported in Supplementary Methods, available at https://doi.org/10.1016/j.esmoop.2024.103699.

Results

Patients disposition and baseline characteristics

Between 23 October 2020, and 15 February 2022, a total of 69 patients underwent eligibility screening. Among them, 17 patients diagnosed with ABC and active BMs were enrolled in cohorts 2 (n = 10, asymptomatic untreated BMs) and 4 (n = 7, progressing BMs after local therapy). Subsequently, one patient with concomitant leptomeningeal disease was excluded from cohort 4. The data presented in this study correspond to HER2-low patients (n = 6 in cohort 2; n = 6 in cohort 4) (Figure 1). Results regarding the HER2-positive subgroup of patients enrolled in cohort 2 have been previously reported.14

The median age was 54.0 years (range, 40.0-73.0 years). All patients were female, had at least three metastatic organ sites, and presented intracranial measurable disease at baseline. Of the 12 patients, 9 (75.0%) had hormone receptor-positive tumors and 10 (83.3%) had HER2 IHC 1+ tumors. The median number of previous lines of therapy for advanced disease was 4 (range, 2-8) (Table 1).Table 1 Baseline characteristics of patients with HER2-low disease

Baseline characteristics	Cohort 2, n (%), N = 6	Cohort 4, n (%), N = 6	All patients, n (%), N = 12	
Age; median (min; max) (years)	49.5 (40.0; 72.0)	61.5 (48.0; 73.0)	54.0 (40.0; 73.0)	
Female sex	6 (100)	6 (100)	12 (100)	
ECOG performance statusa				
 0	5 (83.3)	1 (16.7)	6 (50.0)	
 1	1 (16.7)	5 (83.3%)	6 (50.0)	
HER2 statusb				
 1+	5 (83.3)	5 (83.3)	10 (83.3)	
 2+/ISH non-amplified	1 (16.7)	1 (16.7)	2 (16.7)	
Hormone receptor status				
 ER+ and/or PgR+	5 (83.3)	4 (66.7)	9 (75.0)	
 ER− and PgR−	1 (16.7)	2 (33.3)	3 (25.0)	
Measurable disease at baseline				
 Intracranial	6 (100)	6 (100)	12 (100)	
 Extracranial	5 (83.3)	6 (100)	11 (91.7)	
Number of metastatic organ sites				
 3	3 (50.0)	2 (33.3)	5 (41.7)	
 >3	3 (50.0)	4 (66.7)	7 (58.3)	
Metastatic organ sites				
 Brain	6 (100)	6 (100)	12 (100)	
 Bone	6 (100)	6 (100)	12 (100)	
 Liver	4 (66.7)	4 (66.7)	8 (66.7)	
 Lung	4 (66.7)	3 (50.0)	7 (58.3)	
 Lymph nodes	1 (16.7)	1 (16.7)	2 (16.7)	
 Other	2 (33.3)	4 (66.7)	6 (50.0)	
Number of previous lines of therapy for advanced diseasec; median (min; max)	6.5 (4.0; 8.0)	3.0 (2.0; 4.0)	4.0 (2.0; 8.0)	
Duration of last prior therapy; median (min; max) (months)	4.6 (0.7; 12.6)	3.3 (1.4; 11.2)	4.2 (0.7; 12.6)	
Prior systemic therapy				
 Trastuzumab	0 (0)	1 (16.7)	1 (8.3)	
 Chemotherapy	6 (100)	6 (100)	12 (100)	
 Endocrine therapy	5 (83.3)	4 (66.7)	9 (75.0)	
Prior local therapy for brain metastases				
 WBRT	0 (0)	5 (83.3)	5 (41.7)	
 SRS/SRT	0 (0)	3 (50.0)	3 (25.0)	
 Surgery	0 (0)	1 (16.7)	1 (8.3)	
All values are n (%) unless otherwise specified (percentage based on N). ECOG, Eastern Cooperative Oncology Group; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; ISH, in situ hybridization; PgR, progesterone receptor; SRS, stereotactic radiosurgery; SRT, stereotactic radiotherapy; WBRT, whole-brain radiotherapy.

a ECOG performance status scores range from 0 to 5, with higher score indicating greater disability.

b HER2-low was defined as immunohistochemistry 1+ or 2+ and ISH-negative.

c Prior therapies for advanced breast cancer do not include endocrine therapy.

At data cut-off (5 January 2023), the median duration of follow-up in HER2-low patients was 13.1 months [interquartile range (IQR), 4.6-19.0 months]: 13.4 months (IQR, 4.7-18.4 months) in cohort 2, and 12.9 months (IQR, 4.6-19.0 months) in cohort 4. A total of 6 (50.0%) out of the 12 patients were alive. All six (100.0%) patients in cohort 2 discontinued treatment due to progressive disease. In cohort 4, four (66.7%) out of six patients discontinued treatment because of disease progression, one (16.7%) patient died due to an adverse event unrelated to the study treatment, and one (16.7%) patient remained on treatment (27 cycles) (Figure 1 and Supplementary Table S3, available at https://doi.org/10.1016/j.esmoop.2024.103699).

Clinical activity

In HER2-low patients in cohort 2, ORR-IC per RANO-BM criteria was 50% (95% CI 11.8% to 88.2%), with three of six patients having an intracranial partial response (Figure 2). The primary endpoint ORR-IC was met in the analysis of the entire cohort 2, including both HER2-low and HER2-positive patients [50.0% (95% CI 18.7% to 81.3%; P < 0.0001)] (Supplementary Table S4, available at https://doi.org/10.1016/j.esmoop.2024.103699). In cohort 4, ORR-IC per RANO-BM criteria was 33.3% [95% CI 4.3% to 77.7%; P = 0.033 (one-sided)], meeting the primary endpoint (Figure 2). Intracranial partial responses were observed in two of six patients. Overall, the ORR-IC in patients with HER2-low and active BMs (cohorts 2 and 4) was 41.7% (95% CI 15.2% to 72.3%) (Supplementary Table S5, available at https://doi.org/10.1016/j.esmoop.2024.103699).Figure 2 Waterfall plots of best response in patients with HER2-low disease and measurable lesions in cohorts 2 and 4. (A) Intracranial best response by RANO-BM; (B) extracranial best response by RECIST v.1.1; (C) overall (intracranial + extracranial) best response by RECIST v.1.1. Data cut-off for this analysis is 5 January 2023. One patient for cohort 2 did not have extracranial measurable lesions and is not shown in panel (B). Dotted lines indicate a 30% reduction and 20% increase from baseline, which are the cut-off values used to determine partial response and progressive disease, respectively. HER2 protein expression by immunohistochemistry and hormone receptor status is reported at the bottom of the figures (positive versus negative). 24w, 24 weeks; HER2, human epidermal growth factor receptor 2; HR, hormone receptors; PD, progressive disease; PR, partial response; RANO-BM, Response Assessment in Neuro-Oncology Brain Metastases; SD, stable disease.

For HER2-low patients, intracranial CBR per RANO-BM criteria was 66.7% (95% CI 22.3% to 95.7%) in cohort 2 and 50.0% (95% CI 11.8% to 88.2%) in cohort 4. Overall, the intracranial CBR in patients with active BMs (cohorts 2 and 4) was 58.3% (95% CI 27.7% to 84.8%). Among HER2-low patients in cohorts 2 and 4, median time to intracranial response was 2.3 months (range, 1.5-4.0 months) and median intracranial DoR was 7.2 months (range, 2.8-16.8 months) (Supplementary Table S5, available at https://doi.org/10.1016/j.esmoop.2024.103699).

Moreover, most of the enrolled patients had a reduction in tumor size in both intracranial and extracranial lesions with an overall (intracranial + extracranial) ORR of 50.0% (95% CI 21.1% to 78.9%), an overall CBR of 50.0% (95% CI 21.1% to 78.9%), and a median PFS of 5.4 months (95% CI 4.1-10.0 months) per RECIST v.1.1 (Figure 2; Supplementary Tables S5-S7; Supplementary Figure S1, available at https://doi.org/10.1016/j.esmoop.2024.103699). At the time of this analysis, OS data were still immature with 41.7% of events recorded.

Safety

The median relative dose intensity of T-DXd was 96.2% (IQR, 72.4% to 100.0%) and the median duration of treatment was 4.6 months (IQR, 3.3-9.5 months).

HER2-low patients experienced at least one treatment-emergent adverse event (TEAE) and grade 3 TEAEs occurred in 2 (16.7%) of the 12 patients (Table 2). There were no grade 4 TEAEs registered. The most common TEAEs of any grade were fatigue (75.0%), nausea (58.3%), vomiting (33.3%), increased gamma-glutamyltransferase (33.3%), and anemia (33.3%). The reported grade 3 TEAEs were thrombocytopenia (8.3%) and fatigue (8.3%). TEAEs related to study drug occurred in 10 (83.3%) of the 12 patients, and the most frequent of any grade were fatigue (66.7%) and nausea (50.0%). All grade 3 TEAEs were associated with T-DXd (Table 2).Table 2 Treatment-emergent adverse events occurring in ≥15% of patients with HER2-low disease or grade 5

	Cohort 2 (n = 6)	Cohort 4 (n = 6)	All patients (n = 12)	
TEAEs, n (%)	Any grade	Grade 3a	Any grade	Grade 3a	Grade 5a	Any grade	Grade 3a	Grade 5a	
All TEAEs	6 (100)	2 (33.3)	6 (100)	0 (0)	1 (16.7)	12 (100)	2 (16.7)	0 (0)	
Hematologic	4 (66.7)	1 (16.7)	1 (16.7)	0 (0)	0 (0)	5 (41.7)	1 (8.3)	0 (0)	
 Anemia	3 (50.0)	0 (0)	1 (16.7)	0 (0)	0 (0)	4 (33.3)	0 (0)	0 (0)	
 Neutropenia	3 (50.0)	0 (0)	0 (0)	0 (0)	0 (0)	3 (25.0)	0 (0)	0 (0)	
 Thrombocytopenia	2 (33.3)	1 (16.7)	0 (0)	0 (0)	0 (0)	2 (16.7)	1 (8.3)	0 (0)	
Non-hematologic	6 (100)	1 (16.7)	6 (100)	0 (0)	1 (16.7)	12 (100)	1 (8.3)	1 (16.7)	
 Fatigue	4 (66.7)	1 (16.7)	5 (83.3)	0 (0)	0 (0)	9 (75.0)	1 (8.3)	0 (0)	
 Nausea	4 (66.7)	0 (0)	3 (50.0)	0 (0)	0 (0)	7 (58.3)	0 (0)	0 (0)	
 Vomiting	3 (50.0)	0 (0)	1 (16.7)	0 (0)	0 (0)	4 (33.3)	0 (0)	0 (0)	
 Increased gamma- glutamyltransferase	2 (33.3)	0 (0)	2 (3.3)	0 (0)	0 (0)	4 (33.3)	0 (0)	0 (0)	
 Stomatitis	1 (16.7)	0 (0)	2 (33.3)	0 (0)	0 (0)	3 (25.0)	0 (0)	0 (0)	
 Alanine aminotransferase increased	2 (33.3)	0 (0)	1 (16.6)	0 (0)	0 (0)	3 (25.0)	0 (0)	0 (0)	
 Aspartate aminotransferase increased	3 (50.0)	0 (0)	0 (0)	0 (0)	0 (0)	3 (25.0)	0 (0)	0 (0)	
 Constipation	1 (16.7)	0 (0)	2 (3.3)	0 (0)	0 (0)	3 (25.0)	0 (0)	0 (0)	
 Diarrhea	2 (33.3)	0 (0)	1 (16.7)	0 (0)	0 (0)	3 (25.0)	0 (0)	0 (0)	
 Interstitial lung disease/pneumonitis	2 (33.3)	0 (0)	1 (16.7)	0 (0)	0 (0)	3 (25.0)	0 (0)	0 (0)	
 Dyspnea	1 (16.7)	0 (0)	1 (16.7)	0 (0)	0 (0)	2 (16.7)	0 (0)	0 (0)	
 Arthralgia	1 (16.7)	0 (0)	1 (16.7)	0 (0)	0 (0)	2 (16.7)	0 (0)	0 (0)	
 Back pain	0 (0)	0 (0)	2 (33.3)	0 (0)	0 (0)	2 (16.7)	0 (0)	0 (0)	
 Blood lactate dehydrogenase increased	2 (33.3)	0 (0)	0 (0)	0 (0)	0 (0)	2 (16.7)	0 (0)	0 (0)	
 Cough	1 (16.7)	0 (0)	1 (16.7)	0 (0)	0 (0)	2 (16.7)	0 (0)	0 (0)	
 Headache	2 (33.3)	0 (0)	0 (0)	0 (0)	0 (0)	2 (16.7)	0 (0)	0 (0)	
 Hyperglycemia	1 (16.7)	0 (0)	1 (16.7)	0 (0)	0 (0)	2 (16.7)	0 (0)	0 (0)	
 Pulmonary embolism	0 (0)	0 (0)	1 (16.7)	0 (0)	1 (16.7)	1 (8.3)	0 (0)	1 (8.3)	
All values are n (%) unless otherwise specified (percentage based on N).

TEAEs, treatment-emergent adverse events.

a There were no TEAEs of grade 4 reported. There were no TEAEs of grade 5 related to study drug. One patient died in cohort 4 as result of a pulmonary embolism and deep vein thrombosis unrelated to study drug

TEAEs led to a dose interruption in 6 (50.0%) and a dose reduction in 1 (8.3%) of the 12 patients. A total of 2 (16.7%) of the 12 patients discontinued treatment because of a TEAE, including abdominal pain and hepatic failure; in both cases, TEAEs were related to disease progression. Three (25.0%) grade 1 events of interstitial lung disease/pneumonitis were reported, resulting in temporary discontinuation of T-DXd. These patients had normal renal function at baseline with no relevant clinical changes during the study (Supplementary Table S8, available at https://doi.org/10.1016/j.esmoop.2024.103699). Only 1 (8.3%) of the 12 patients experienced a serious TEAE, a simultaneous pulmonary embolism and deep vein thrombosis unrelated to T-DXd that led to death. There were no treatment-related deaths.

PROs

Across all HER2-low patients, no significant decline in the global health status at 24 weeks was registered by the EORTC QLQ-C30 questionnaire [mean score 48.6 ± 24.6 (baseline) versus 53.5 ± 21.7 (24 weeks); P = 0.892]. Similarly, at 24 weeks, no other parameter was significantly affected within the QLQ-C30 and the QLQ-BR23 scales (Supplementary Tables S9 and S10, available at https://doi.org/10.1016/j.esmoop.2024.103699).

Discussion

The poor prognosis faced by ABC patients with untreated or progressing BMs following prior local therapy often results in their exclusion from clinical trials, leaving a shortage of treatment options available for this patient population. T-DXd is approved for HER2-positive and HER2-low ABC, but limited data exist on its effectiveness in HER2-low ABC patients with active BMs. In this study, T-DXd showed promising intracranial activity, as well as extracranial activity, in patients with HER2-low ABC and active BMs, with generally manageable toxicity and preserved quality of life. To our knowledge, this is the first published study that has evaluated the intracranial efficacy of T-DXd in this patient population.

In the DEBBRAH study, treatment with T-DXd in HER2-low patients resulted in an ORR-IC per RANO-BM of 50.0% in cohort 2 and 33.3% in cohort 4. Likewise, we observed promising CBR and DoR with T-DXd. These findings, along with previous results from HER2-positive patients included in cohorts 1, 2, and 3 of this study,14 reinforce that T-DXd can lead to activity in the brain in patients with ABC and BMs. Differently from the HER2-positive breast cancer BMs scenario that, apart from T-DXd, can also benefit from other anti-HER2 therapies,17, 18, 19 however, the management of HER2-low breast cancer BMs still largely relies on chemotherapy and/or radiotherapy.20 Therefore, these results provide relevant data for the use of T-DXd in an important subgroup of patients with an unmet medical need.

The overall ORR-IC (41.7%) in patients with active BMs reached in our study is numerically similar to the ORR (around 50.0%) reported in the DESTINY-Breast04 trial;9 however, direct comparison is limited by the differences in study designs and patient cohort sizes. The DESTINY-Breast04 trial revealed a consistent efficacy benefit of T-DXd over single-agent chemotherapy across all analyzed subgroups, including a small subgroup of patients with stable BMs. Among these 32 (5.7%) patients with stable BMs, T-DXd improved median PFS in comparison with single-agent chemotherapy (8.1 versus 4.8 months, hazard ratio 0.71).21 Similarly, T-DXd has also showed meaningful antitumor activity in a limited subgroup of HER2-low ABC patients with stable BMs at baseline (n = 10) included in the DAISY trial with a median PFS of 4.1 months.15 Median PFS achieved in the DEBBRAH study is inferior to that reported in the DESTINY-Breast04 trial for patients with BMs, but slightly better than median PFS observed in the DAISY study. These differences could be related to the limited number of patients with BMs included in these studies, but also it is important to highlight that patients in our study have active BMs, who commonly have worse outcomes compared with those with stable BMs.22

Currently, three ongoing studies are evaluating T-DXd alone (DESTINY-Breast0623) or in combination with other treatments (DESTINY-Breast0824 and DESTINY-Breast1525) in patients with HER2-low ABC, but all of them exclude patients with active BMs. Therefore, DEBBRAH is the only study that has assessed the efficacy of T-DXd in patients with HER2-low ABC with active BMs.

The toxicity profile of T-DXd in our study was consistent with prior reports.6,7,9,26 Concerning the safety profile, however, we report a 25.0% rate (3/12 patients) of interstitial lung disease/pneumonitis, all grade 1, which is numerically higher than the reported rate in phase III trials.7, 8, 9 Therefore, despite the fact that this finding might be attributed to chance due to the small sample size of our analysis, it is important to alert physicians on this potential risk for patients receiving T-DXd. Indeed, among the 21 patients with HER2-positive ABC receiving T-DXd within the DEBBRAH cohorts 1-3, the rate of interstitial lung disease/pneumonitis was 9.5% (2/21 patients), all grade 1,14 in line with phase III trials.6,8,26

Breast cancer patients with CNS involvement commonly experience poorer outcomes and treatment-related TEAEs that significantly affect their physical, emotional, social, and cognitive quality of life. Despite the challenge of accurately measuring these aspects due to their inherent subjectivity, they are increasingly regarded as crucial endpoints in the domain of cancer care. In our study we found that, over a 6-month period, the T-DXd regimen did not deteriorate global health status/quality of life of pretreated HER2-low ABC patients with active BMs. Despite the limited number of patients included, these results highlight a potential positive impact in managing this condition.

We have previously reported the main strength of DEBBRAH14 being the enrolment of patients with active BMs, as recommended by the Food and Drug Administration,27 the American Society of Clinical Oncology and Friends of Cancer Research,28 and the RANO-BM working group.29 Another strength is the use of RANO-BM to assess intracranial response, as well as RECIST v.1.1 to assess extracranial response, in contrast to the use of RECIST v.1.1 only, as in most studies that have proven the efficacy of T-DXd in ABC.6, 7, 8, 9,26 Main limitations of this study include its non-randomized single-arm design and the small sample size. Additionally, because cohort 2 included patients with both HER2-positive and HER2-low disease, the results presented here for the HER2-low subgroup in this cohort lack a complete formal statistical analysis and are purely descriptive.

In conclusion, T-DXd showed promising intracranial activity in patients with heavily pretreated HER2-low ABC and active BMs with no new safety signals identified. Although these findings are hypothesis generating and warrant further exploration in larger cohorts, they strengthen the need to include patients with active BMs in clinical trials evaluating HER2-targeted agents in HER2-low ABC.

Supplementary data

Supplementary data

Acknowledgements

This study was funded by 10.13039/501100022274 Daiichi Sankyo /AstraZeneca, who did not participate in data collection, data analysis, data interpretation, or writing of this report. MEDSIR funded medical writing support, provided by Angela Rynne Vidal, PhD, and Valeria Di Giacomo, PhD, from ThePaperMill. This study was presented at the 2022 San Antonio Breast Cancer Symposium, December 5-9, as a Poster presentation entitle ‘Trastuzumab Deruxtecan in patients with Active Central Nervous System Involvement from HER2-Low Advanced Breast Cancer: The DEBBRAH Trial’. We thank the patients and their caregivers for participating in this study, as well as the medical team at each participating site.

Funding

This work was supported by the 10.13039/501100022274 Daiichi Sankyo /AstraZeneca, which had no role in data collection, data analysis, data interpretation, or writing of this report.

Disclosure

MVB reports participating in a consulting/advisory board for AstraZeneca; has participated as invited speaker for Daiichi Sankyo, Nutricia; and receiving travel fees from AstraZeneca, Daiichi Sankyo, Pfizer, GSK. JMPG reports having a consulting or advisory role for Lilly, Roche, Eisai, Daichii Sankyo, AstraZeneca, Seattle Genetics; travel compensation from Roche; and employment at MEDSIR. MFA reports participating in an advisory board for Seagen, Daiichi Sankyo–AstraZeneca; and speakers’ bureau from Novartis, Lilly. MG reports receiving honoraria from Roche, Novartis, Gilead, Daiichi Sankyo; and travel compensation from Roche, Pfizer, Daiichi Sankyo. AMB reports receiving travel expenses, accommodation and registration fees from GSK, Roche; has participated as invited speaker for Seagen, GSK; has personal financial interests in GSK, Roche; has other financial interest in GSK, Roche. CS reports receiving honoraria from Novartis, Fundación ECO, Roche; and travel support from Lilly. SS reports participating in and advisory board for Seagen, Genomic Health, Merck Sharp & Dohme, Daiichi Sankyo; and speakers’ bureau from Daiichi Sankyo, AstraZeneca, Roche, Novartis. MRB reports participating in an advisory board for Seagen, Genomic Health, Daiichi Sankyo, Pierre-Fabre; and speakers’ bureau from Daiichi Sankyo, AstraZeneca, Novartis, Pierre Fabre. GM is a full-time employee at MEDSIR. JPE is a full-time employee at MEDSIR. DAL is a full-time employee at MEDSIR. MSC reports participating in an advisory board for Optimapharm, Ability Pharma, and MD Anderson; and is a full-time employee at MEDSIR. SB reports participating in a consulting/advisory board for Daiichi Sankyo, AstraZeneca, Novartis, Roche; has participated as invited speaker for Daiichi Sankyo, AstraZeneca, Novartis, Roche; and receiving travel fees from Daiichi Sankyo, AstraZeneca, Novartis, Roche. JC reports serving as a consultant/advisor to Roche, Celgene, Cellestia, AstraZeneca, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex, Polyphor, Lilly, Merck Sharp & Dohme, GSK, Leuko, Bioasis, Clovis Oncology, Boehringer Ingelheim, Ellipses, HiberCell, BioInvent, GEMoaB, Gilead, Menarini, Zymeworks, Reveal Genomics, Expres2ion Biotechnologies; receiving honoraria from Roche, Novartis, Celgene, Eisai, Pfizer, Samsung Bioepis, Lilly, Merck Sharp & Dohme, Daiichi Sankyo; research funding to the Institution from Roche, Ariad Pharmaceuticals, AstraZeneca, Baxalta GMBH/Servier Affaires, Bayer Healthcare, Eisai, F. Hoffman-La Roche, Guardant Health, Merck Sharp & Dohme, Pfizer, Piqur Therapeutics, Puma C, Queen Mary University of London; stock of MEDSIR, Nektar Pharmaceuticals, Leuko (relative); travel, accommodation, expenses from Roche, Novartis, Eisai, Pfizer, Daiichi Sankyo, AstraZeneca, Gilead; and patents: (1) Pharmaceutical combinations of a Pi3k inhibitor and a microtubule destabilizing agent. Javier Cortés Castán, Alejandro Piris Giménez, Violeta Serra Elizalde. WO 2014/199294 A. ISSUED. (2) Her2 as a predictor of response to dual HER2 blockade in the absence of cytotoxic therapy. Aleix Prat, Antonio Llombart, Javier Cortés. US 2019/0338368 A1. LICENSED. ALC reports receiving research support from Roche, Agendia, Lilly, Pfizer, Novartis, Merck Sharp & Dohme, Gilead, and Daichii Sankyo; consulting or advisory role for Lilly, Roche, Pfizer, and Novartis; speakers’ bureaus from Lilly, AstraZeneca, Merck Sharp & Dohme; travel support from Roche, Pfizer, AstraZeneca; and stock or other ownership of MEDSIR and Initia-Research. All other authors have declared no conflicts of interest.

Data sharing

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 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. All data provided are anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. Estimate timeframe for response will be within 30 days.
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