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

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • the DESTINY-Breast12 study group - (Author)
  • Department of Gynecology and Obstetrics
  • Ludwig Maximilian University of Munich
  • Hospital Universitario 12 de Octubre
  • University of Liege
  • University of Hamburg
  • Tokai University
  • IRCCS Istituto Europeo di Oncologia - Milano
  • Medical University of Vienna
  • University of Basel
  • St Vincent's University Hospital
  • University College Cork
  • Royal North Shore Hospital
  • Beata María Ana Hospital
  • Hospital Ramon y Cajal
  • University of Padua
  • IRCCS Istituto Oncologico Veneto - Padova
  • IRCCS Hospital San Raffaele - Milano
  • Vita-Salute San Raffaele University
  • KU Leuven
  • Vall d'Hebron Institute of Oncology (VHIO)
  • AstraZeneca
  • Dana-Farber Cancer Institute
  • Duke University
  • University of Edinburgh
  • University of Lausanne
  • Cantonal Hospital Luzern
  • Ente Ospedaliero Cantonale (EOC)
  • Sahlgrenska University Hospital
  • Lund University
  • Uppsala University
  • Hospital de Basurto
  • Hospital Universitario Marques de Valdecilla
  • Hospital Universitario Virgen de las Nieves
  • Hospital Clínico Universitario de Salamanca
  • University of Santiago de Compostela
  • Hospital Ruber Internacional
  • Hospital Universitario Virgen del Rocio
  • Hospital Universitario de la Princesa
  • Instituto Valenciano de Oncologia
  • University Hospital of Bellvitge
  • Hospital Clinic of Barcelona
  • Saint Mary's Hospital
  • Champalimaud Foundation
  • University of Porto
  • Centralny Szpital Kliniczny Wojskowej Akademii Medycznej z Poliklinika
  • University Clinical Center Gdansk
  • Opolskie Centrum Onkologii im. prof. T. Koszarowskiego
  • Maria Sklodowska-Curie Institute of Oncology
  • Krakow University Hospital
  • University Hospital Carl Gustav Carus Dresden

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.

Details

Original languageEnglish
Article number967
Pages (from-to)3717-3727
Number of pages11
JournalNature medicine
Volume30
Issue number12
Publication statusPublished - Dec 2024
Peer-reviewedYes

External IDs

PubMed 39271844

Keywords