[en] 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 .
Disciplines :
Oncology
Author, co-author :
Harbeck, Nadia ; Breast Center, Department of Gynecology and Obstetrics, Comprehensive Cancer Center Munich, LMU University Hospital, Munich, Germany. nadia.harbeck@med.uni-muenchen.de
Ciruelos, Eva ; Hospital Universitario 12 de Octubre, Madrid, Spain
Jerusalem, Guy ; Université de Liège - ULiège > Département des sciences cliniques > Oncologie
Müller, Volkmar; University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Niikura, Naoki; Tokai University School of Medicine, Kanagawa, Japan
Viale, Giuseppe; Department of Pathology and Laboratory Medicine, IEO European Institute of Oncology IRCCS, Milan, Italy
Bartsch, Rupert; Division of Oncology, Department of Medicine 1, Medical University of Vienna, Vienna, Austria
Kurzeder, Christian; Breast Center, University Hospital Basel, Basel, Switzerland
Higgins, Michaela J; St. Vincent's University Hospital, UCD Cancer Trials Cluster, Dublin, Ireland
Connolly, Roisin M ; Cancer Research @UCC, College of Medicine and Health, University College Cork, Cork, Ireland ; Cancer Trials Cork, CUH/UCC Cancer Center, Cork University Hospital, Cork, Ireland
Baron-Hay, Sally ; Department of Medical Oncology, Royal North Shore Hospital, St Leonards, NSW, Australia
Gión, María; IOB-Madrid, Beata María Ana Hospital, Madrid, Spain ; Department of Medical Oncology, Ramón y Cajal University Hospital, Madrid, Spain
Guarneri, Valentina; Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy ; Medical Oncology 2, Istituto Oncologico Veneto IRCCS, Padova, Italy
Bianchini, Giampaolo ; Department of Medical Oncology, IRCCS Ospedale San Raffaele, Milan, Italy ; School of Medicine and Surgery, Vita-Salute San Raffaele University, Milan, Italy
Wildiers, Hans ; Department of General Medical Oncology, University Hospitals Leuven, KU Leuven, Leuven, Belgium
Escrivá-de-Romaní, Santiago; Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology, Barcelona, Spain
Prahladan, Manoj; Global Medical Affairs, Oncology R&D, AstraZeneca, Cambridge, UK
Bridge, Helen; Oncology Global Medical Affairs / Payer Biometrics, AstraZeneca, Macclesfield, UK
Kuptsova-Clarkson, Nataliya; Patient Safety, Oncology R&D, AstraZeneca, Gaithersburg, MD, USA
Scotto, Nana; Oncology Global Medical Affairs, AstraZeneca, Baar, Switzerland
Verma, Sunil; Oncology Franchise, AstraZeneca, Gaithersburg, MD, USA
Lin, Nancy U ; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
This study was sponsored by AstraZeneca and Daiichi Sankyo. In March 2019, AstraZeneca entered into a global development and commercialization collaboration agreement with Daiichi Sankyo for T-DXd (DS-8201). This study was designed by AstraZeneca and Daiichi Sankyo. The authors prepared and approved the paper and made the decision to submit the paper for publication. Medical writing support, under the direction of the authors, was provided by K. Rimmer of Helios Medical Communications, part of Helios Global Group, and was funded by AstraZeneca in accordance with Good Publication Practice guidelines (http://www.ismpp.org/gpp-2022). We thank the patients who participated in this study as well as their families and caregivers, the staff and investigators at all the study sites and members of the ILD advisory committee. We also thank the following AstraZeneca employees: M. Haughton for publication leadership, interpretation of the data and scientific review of the paper; R. Antony for clinical leadership of the study, interpretation of the data and scientific review of the paper; M. Leroux for overseeing the operational functions of the study; and S. Anand for statistical analysis. We would like to acknowledge G. James of Medical Statistics Consultancy, Ltd. for assistance with statistical analysis.
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