Trastuzumab deruxtecan in HER2-positive advanced breast cancer with or without brain metastases: a phase 3b/4 trial

Trastuzumab deruxtecan (T-DXd) intracranial activity has been observed in small or retrospective patient cohorts with human epidermal growth factor receptor 2-positive (HER2<sup>+</sup>) advanced/metastatic breast cancer (mBC) and stable or active (untreated/previously treated and progressing) brain metastases (BMs). The phase 3b/4 DESTINY-Breast12 study investigated T-DXd in patients with HER2<sup>+</sup> mBC and is, to our knowledge, the largest prospective study of T-DXd in patients with BMs in this setting. Patients (stable/active BMs (n = 263) and no BMs (n = 241)) treated with one or more prior anti-HER2-based regimens received T-DXd (5.4 mg per kg). Primary endpoints were progression-free survival (PFS; BMs cohort) and objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 (non-BMs cohort). Additional endpoints included central nervous system (CNS) PFS, ORR, time to second progression, CNS ORR (BMs cohort), incidence of new symptomatic CNS metastases (non-BMs cohort), time to progression, duration of response, overall survival and safety (both cohorts). No formal hypothesis testing was conducted for this single-arm, open-label study. In the BMs cohort, 12-month PFS was 61.6% (95% confidence interval (CI): 54.9-67.6), and 12-month CNS PFS was 58.9% (95% CI: 51.9-65.3). In the non-BMs cohort, ORR was 62.7% (95% CI: 56.5-68.8). Grade 3 or higher adverse events occurred in 51% (BMs cohort) and 49% (non-BMs cohort) of patients. Investigator-reported interstitial lung disease/pneumonitis occurred in 16% (grade ≥3: 3%) of patients with BMs and 13% (grade ≥3: 1%) of patients without BMs. These data show substantial and durable overall and intracranial activity for T-DXd, supporting its use in previously treated patients with HER2<sup>+</sup> mBC irrespective of stable/active baseline BMs. ClinicalTrials.gov identifier: NCT04739761 .

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Journal
Nature Medicine
Published
2024-09-13
DOI
https://doi.org/10.1038/s41591-024-03261-7
Citations
153
Primary Topic
Brain Metastases and Treatment
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article
Field-Weighted Citation Impact
63.26

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article

Trastuzumab deruxtecan in HER2-positive advanced breast cancer with or without brain metastases: a phase 3b/4 trial

Sally E. Baron-Hay, Roisín M. Connolly, Naoki Niikura, Nana Scotto et al.
153 citations
Nature Medicine
Brain Metastases and Treatment
63.26
article

Trastuzumab deruxtecan in HER2-positive advanced breast cancer with or without brain metastases: a phase 3b/4 trial

Sally E. Baron-Hay, Roisín M. Connolly, Naoki Niikura, Nana Scotto, Manoj Prahladan, Nadia Harbeck, Michaela J. Higgins, María Gión, Valentina Guarneri, Rupert Bartsch, Nancy U. Lin, Giampaolo Bianchini, Hans Wildiers, Nataliya Kuptsova‐Clarkson, Guy Jérusalem, Santiago Escrivá-de-Romaní, Eva Ciruelos, Giuseppe Viale, Sunil Verma, Christian Kurzeder, Volkmar Müller, Helen Bridge
article en
153 citations

Abstract

Trastuzumab deruxtecan (T-DXd) intracranial activity has been observed in small or retrospective patient cohorts with human epidermal growth factor receptor 2-positive (HER2<sup>+</sup>) advanced/metastatic breast cancer (mBC) and stable or active (untreated/previously treated and progressing) brain metastases (BMs). The phase 3b/4 DESTINY-Breast12 study investigated T-DXd in patients with HER2<sup>+</sup> mBC and is, to our knowledge, the largest prospective study of T-DXd in patients with BMs in this setting. Patients (stable/active BMs (n = 263) and no BMs (n = 241)) treated with one or more prior anti-HER2-based regimens received T-DXd (5.4 mg per kg). Primary endpoints were progression-free survival (PFS; BMs cohort) and objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 (non-BMs cohort). Additional endpoints included central nervous system (CNS) PFS, ORR, time to second progression, CNS ORR (BMs cohort), incidence of new symptomatic CNS metastases (non-BMs cohort), time to progression, duration of response, overall survival and safety (both cohorts). No formal hypothesis testing was conducted for this single-arm, open-label study. In the BMs cohort, 12-month PFS was 61.6% (95% confidence interval (CI): 54.9-67.6), and 12-month CNS PFS was 58.9% (95% CI: 51.9-65.3). In the non-BMs cohort, ORR was 62.7% (95% CI: 56.5-68.8). Grade 3 or higher adverse events occurred in 51% (BMs cohort) and 49% (non-BMs cohort) of patients. Investigator-reported interstitial lung disease/pneumonitis occurred in 16% (grade ≥3: 3%) of patients with BMs and 13% (grade ≥3: 1%) of patients without BMs. These data show substantial and durable overall and intracranial activity for T-DXd, supporting its use in previously treated patients with HER2<sup>+</sup> mBC irrespective of stable/active baseline BMs. ClinicalTrials.gov identifier: NCT04739761 .

Nature MedicineVol. 30(12)
AstraZeneca (United Kingdom) (GB), Champalimaud Foundation (PT), Oslo University Hospital (NO), BC Cancer Agency (CA), St John of God Subiaco Hospital (AU), Tokai University (JP), Sunnybrook Health Science Centre (CA), Uppsala University Hospital (SE), University of Padua (IT), Vita-Salute San Raffaele University (IT), University of Liège (BE), Universität Hamburg (DE), St. Marianna University School of Medicine (JP), Instituto Cajal (ES), Heidelberg University (DE), University College Cork (IE), Royal North Shore Hospital (AU), Western General Hospital (GB), Haukeland University Hospital (NO), Sahlgrenska University Hospital (SE), Monash Medical Centre (AU), Odense University Hospital (DK), Institut Jules Bordet (BE), Turku University Hospital (FI), Centre Hospitalier Universitaire Vaudois (CH), Health Sciences Centre (CA), Cork University Hospital (IE), Gentofte Hospital (DK), Rigshospitalet (DK), Mater Misericordiae University Hospital (IE), Kanagawa Prefectural Hospital Organization (JP), Maastricht University (NL), Medizinische Hochschule Hannover (DE), Universitätsklinikum Erlangen (DE), Australian and New Zealand Intensive Care Society (AU), Cardiovascular Center Bethanien (DE), Hospital de Basurto (ES), Universitätsklinikum Tübingen (DE), Ente Ospedaliero Cantonale (CH), Complejo Hospitalario Universitario de Santiago (ES), Complejo Hospitalario de Salamanca (ES), Marqués de Valdecilla University Hospital (ES), Hospital Universitario 12 De Octubre (ES), Fundación Instituto Valenciano de Oncología (ES), National Hospital Organization Hokkaido Medical Center (JP), University Hospital Münster (DE), Ospedale Papa Giovanni XXIII (IT), University Medical Center Hamburg-Eppendorf (DE), Istituto Oncologico Veneto (IT), University Hospital Schleswig-Holstein (DE), Centro Hospitalar Lisboa Norte (PT), Hospital Clínic de Barcelona (ES), St. Vincent's University Hospital (IE), Universitäts Hautklinik Kiel (DE), Hospital Universitario Virgen de las Nieves (ES), Dana-Farber Cancer Institute (US), Luzerner Kantonsspital (CH), Breast Center (CH), AZ Sint-Jan (BE), Duke Medical Center (US), Vall d'Hebron Hospital Universitari (ES), AstraZeneca (Switzerland) (CH), Humanitas Mater Domini (IT), Hospital Universitario de La Princesa (ES), University Clinical Centre (PL), IRCCS Ospedale San Raffaele (IT), Centre Hospitalier Universitaire de Liège (BE), Skåne University Hospital (SE), Centrum Onkologii (PL), Helios Kliniken (DE), Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale" (IT), Haga Hospital (NL), Kliniken Essen-Mitte (DE), Wojskowy Instytut Medyczny (PL), Rotkreuzklinikum München (DE), AstraZeneca (United States) (US), Hospital Ruber Internacional (ES), The Maria Sklodowska-Curie National Research Institute of Oncology (PL), Istituti di Ricovero e Cura a Carattere Scientifico (IT), Hospital Universitario Virgen del Rocío (ES), Centro Hospitalar do Porto (PT), Helios Hospital Berlin-Buch (DE), Ospedale di Prato Santo Stefano (IT), SHOWA Medical University Hospital (JP), University Hospital Carl Gustav Carus (DE), Austin Health (AU), Sapporo National Hospital (JP), Ospedali Riuniti Umberto I (IT), Hospital District of Helsinki and Uusimaa (FI), Szpital Uniwersytecki w Krakowie (PL), Kanagawa Cancer Center, Medizinische Fakultät Mannheim, Vall d'Hebron Institute of Oncology (ES), European Institute of Oncology (IT), Medical University of Vienna (AT), Technische Universität Dresden (DE), Ludwig-Maximilians-Universität München (DE), National Patient Safety Foundation (US), University of Lübeck (DE), KU Leuven (BE)
Amgen, Eli Lilly and Company, Pfizer, AstraZeneca, GlaxoSmithKline, Sanofi, Gilead Sciences, Helsinn, Jazz Pharmaceuticals, Les Laboratories Pierre Fabre, Seagen, Eisai, Chugai Pharmaceutical, Daiichi Sankyo Europe
Good health and well-being
Openalex Percentile: Top 0%
Brain Metastases and Treatment
63.26
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