Trastuzumab deruxtecan in HER2-positive advanced breast cancer with or without brain metastases: a phase 3b/4 trial
Authors: Harbeck Nadia , Ciruelos Eva , Jerusalem Guy , Müller Volkmar , Niikura Naoki , Viale Giuseppe , Bartsch Rupert , Kurzeder Christian , Higgins Michaela J. , Connolly Roisin M. , Baron-Hay Sally , Gión María , Guarneri Valentina , Bianchini Giampaolo , Wildiers Hans , Escrivá-de-Romaní Santiago , Prahladan Manoj , Bridge Helen , Kuptsova-Clarkson Nataliya , Scotto Nana , Verma Sunil , Lin Nancy U. ,   the DESTINY-Breast12 study group, Yeo Belinda , McCarthy Nicole , McCartney Amelia , Clay Timothy , Murray Nicholas , Gombos Andrea , Collignon Joëlle , De Cuypere Eveline , Jerzak Katarzyna , Chia Stephen , Maraldo Maja , Rønlev Jeanette , Brix Eva , Tanner Minna , Mattson Johanna , Huovinen Riikka , Wimberger Pauline , Reinisch Mattea , Tesch Hans , Untch Michael , Fasching Peter , Park-Simon Tjoung-Won , Tio Joke , Braun Michael , Grischke Eva Maria , Marmé Frederik , van Mackelenbergh Marion , McCaffrey John , De Laurentiis Michelino , Caruso Michele , Berardi Rossana , Biganzoli Laura , Fotia Vittoria , Yamashita Toshinari , Tsurutani Junji , Tsugawa Koichiro , Tomioka Nobumoto , de Boer Maaike , Houtsma Daniel , Pilskog Martin , Engebråten Olav , Sætersdal Anna , Wysocki Piotr , Nowecki Zbigniew , Radecka Barbara , Jassem Jacek , Duchnowska Renata , Simões Joana , Cardoso Fatima , Sousa Ana Rita , Losada María Jesús Vidal , Manich Cristina Saura , Gregori Joaquin Gavilá , Marti Maria Pilar Lopez , Borrego Manuel Ruiz , Castán Javier Cortés , López Rafael López , Sanchez César Rodríguez , Flores Encarnación González , González Carmen Hinojo , del Prado Purificación Martínez , Schiza Aglaia , Killander Fredrika , Klint Leif , Rossi Lorenzo , Aebi Stefan , Zaman Khalil , Hall Peter , Anders Carey 
Published: September 2024

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.