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