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

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

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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