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

Harbeck N, Ciruelos E, Jerusalem G, Müller V, Niikura N, Viale G, Bartsch R, Kurzeder C, Higgins MJ, Connolly RM, Baron-Hay S, Gión M, Guarneri V, Bianchini G, Wildiers H, Escrivá-de-Romaní S, Prahladan M, Bridge H, Kuptsova-Clarkson N, Scotto N, Verma S, Lin NU, Anders C, Hall P, Zaman K, Aebi S, Rossi L, Klint L, Killander F, Schiza A, del Prado PM, González CH, Flores EG, Sanchez CR, López RL, Castán JC, Borrego MR, Marti MPL, Gregori JG, Manich CS, Losada MJV, Sousa AR, Cardoso F, Simões J, Duchnowska R, Jassem J, Radecka B, Nowecki Z, Wysocki P, Sætersdal A, Engebråten O, Pilskog M, Houtsma D, de Boer M, Tomioka N, Tsugawa K, Tsurutani J, Yamashita T, Fotia V, Biganzoli L, Berardi R, Caruso M, De Laurentiis M, McCaffrey J, van Mackelenbergh M, Marmé F, Grischke EM, Braun M, Tio J, Park-Simon TW, Fasching P, Untch M, Tesch H, Reinisch M, Wimberger P, Huovinen R, Mattson J, Tanner M, Brix E, Rønlev J, Maraldo M, Chia S, Jerzak K, De Cuypere E, Collignon J, Gombos A, Murray N, Clay T, McCartney A, McCarthy N, Yeo B (2024)

Publication Language: English

Publication Type: Journal article

Publication year: 2024

Journal

Book Volume: 30

Pages Range: 3717-3727

Article Number: 967

Journal Issue: 12

DOI: 10.1038/s41591-024-03261-7

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⁺) 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⁺ 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⁺ mBC irrespective of stable/active baseline BMs. ClinicalTrials.gov identifier: NCT04739761.

Authors with CRIS profile

Involved external institutions

European Institute of Oncology / Istituto Europeo di Oncologia (IEO) Italy (IT) Tokai University / 東海大学 (Tōkai Daigaku) Japan (JP) Centre Hospitalier Universitaire de Liège (CHU Liège) Belgium (BE) Klinikum der Universität München (LMU Klinikum) Germany (DE) Hospital Universitario 12 de Octubre Spain (ES) Medizinische Universität Wien Austria (AT) Odense Universitetshospital (OUH) Denmark (DK) Turku University Hospital / Turun yliopistollinen keskussairaala (TYKS) Finland (FI) British Columbia Cancer Agency Canada (CA) Tampere University Hospital / Tampereen yliopistollinen sairaala (TAYS) Finland (FI) Agaplesion Markus Krankenhaus Germany (DE) AZ Sint-Jan Belgium (BE) Universitätsklinikum Carl Gustav Carus Dresden Germany (DE) Gentofte Hospital Denmark (DK) Rigshospitalet Denmark (DK) HELIOS Kliniken Germany (DE) Kliniken Essen-Mitte Germany (DE) HUSLAB Finland (FI) Sunnybrook Health Sciences Centre Canada (CA) Austin Health Australia (AU) GenesisCare Australia (AU) MonashHeart (formerly: Cardiology, Monash Medical Centre) Australia (AU) St John of God Subiaco Hospital Australia (AU) Icon Group Australia (AU) Institut Jules Bordet Belgium (BE) Rotkreuzklinikum München Germany (DE) Wojskowy Instytut Medyczny Poland (PL) Royal North Shore Hospital (RNSH) Australia (AU) Complejo Hospitalario de Salamanca / Complejo Asistencial Universitario de Salamanca Spain (ES) Bellvitge University Hospital / Hospital Universitari de Bellvitge Spain (ES) Skåne University Hospital / Skånes universitetssjukhus Sweden (SE) Ruber International Hospital Spain (ES) Azienda Ospedaliera Papa Giovanni XXIII Italy (IT) AstraZeneca UK Limited United Kingdom (GB) Western General Hospital United Kingdom (GB) Complejo Hospitalario Universitario de Santiago de Compostela Spain (ES) Hospital Universitario de La Princesa Spain (ES) Hospital Beata María Ana Spain (ES) Oslo University Hospital / Oslo Universitetssykehus Rikshospitalet Norway (NO) Szpital Uniwersytecki w Krakowie Poland (PL) University College Cork (UCC) Ireland (IE) Hospitales Universitarios Virgen Macarena y Virgen del Rocío Spain (ES) Lausanne University Hospital / Centre hospitalier universitaire vaudois (CHUV) Switzerland (CH) Universitätsklinikum Tübingen Germany (DE) Vall d'Hebron University Hospital / Hospital Universitari Vall d'Hebron Spain (ES) Uppsala University Hospital / Akademiska sjukhuset Sweden (SE) Humanitas Istituto Clinico Catanese Italy (IT) Complejo Hospitalario Universitario de Granada Spain (ES) HagaZiekenhuis Netherlands (NL) Valencia Oncology Institute Foundation / Fundación Instituto Valenciano de Oncología / Fundació Institut Valencià d’Oncologia (IVO) Spain (ES) Universitätsklinikum Münster Germany (DE) Dana-Farber Cancer Institute United States (USA) (US) Duke University Medical Center United States (USA) (US) Ospedale San Raffaele (früher: Centro San Raffaele del Monte Tabor Foundation) Italy (IT) Kanagawa Prefectural Hospital / Kanagawa Cancer Center / 神奈川県立がんセンター Japan (JP) Ente Ospedaliero Cantonale Switzerland (CH) Hospital Clínic de Barcelona Spain (ES) Marqués de Valdecilla University Hospital / Hospital Universitario de Marqués de Valdecilla (HUMV) Spain (ES) Azienda Ospedaliero Universitaria Ospedali Riuniti Ancona Italy (IT) Medizinische Hochschule Hannover (MHH) / Hannover Medical School Germany (DE) Luzerner Kantonsspital (LUKS) Switzerland (CH) Haukeland University Hospital / Haukeland universitetssykehus Norway (NO) Maria Skłodowska-Curie Institute of Oncology / Centrum Onkologii–Instytut im. Marii Skłodowskiej-Curie w Warszawie Poland (PL) Showa University Hospitals Japan (JP) Ospedale Misericordia e Dolce Italy (IT) Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale" Italy (IT) Ruprecht-Karls-Universität Heidelberg Germany (DE) Champalimaud Foundation / Fundação Champalimaud Portugal (PT) Universitätsklinikum Schleswig-Holstein (UKSH) Germany (DE) Mater Misericordiae University Hospital (MMUH) / Ospidéal an Mater Misercordiae Ireland (IE) Centro Hospitalar de Lisboa Central Portugal (PT) Opolskie Centrum Onkologii im. prof. Tadeusza Koszarowskiego w Opolu Poland (PL) Maastricht University Netherlands (NL) National Hospital Organization Hokkaido Medical Center / 独立行政法人 国立病院機構 北海道医療センター Japan (JP) Hospital de Basurto Spain (ES) University Hospital Leuven (UZ) / Universitaire ziekenhuizen Leuven Belgium (BE) Universitätsspital Basel Switzerland (CH) University of Padua / Universita degli Studi di Padova Italy (IT) Universidade do Porto Portugal (PT) St Vincent's University Hospital Ireland (IE) Universitätsklinikum Hamburg-Eppendorf (UKE) Germany (DE) St. Marianna University School of Medicine / 聖マリアンナ医科大学 Japan (JP) Sahlgrenska University Hospital / Sahlgrenska Universitetssjukhuset Sweden (SE)

How to cite

APA:

Harbeck, N., Ciruelos, E., Jerusalem, G., Müller, V., Niikura, N., Viale, G.,... Yeo, B. (2024). Trastuzumab deruxtecan in HER2-positive advanced breast cancer with or without brain metastases: a phase 3b/4 trial. Nature Medicine, 30(12), 3717-3727. https://doi.org/10.1038/s41591-024-03261-7

MLA:

Harbeck, Nadia, et al. "Trastuzumab deruxtecan in HER2-positive advanced breast cancer with or without brain metastases: a phase 3b/4 trial." Nature Medicine 30.12 (2024): 3717-3727.

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