• Aditya Bardia, Xichun Hu, Rebecca Dent, Kan Yonemori, Carlos H Barrios, Joyce A O'Shaughnessy, Hans Wildiers, Jean-Yves Pierga, Qingyuan Zhang, Cristina Saura, Laura Biganzoli, Joohyuk Sohn, Seock-Ah Im, Christelle Lévy, William Jacot, Natasha Begbie, Jun Ke, Gargi Patel, Giuseppe Curigliano, and DESTINY-Breast06 Trial Investigators.
• From Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, and Massachusetts General Hospital, Boston, MA (A.B.); the Department of Medical Oncology, Fudan University Shanghai Cancer Center, and the Department of Oncology, Shanghai Medical College, Fudan University, Shanghai (X.H.), and Harbin Medical University Cancer Hospital, Harbin (Q.Z.) - all in China; the Division of Medical Oncology, National Cancer Center Singapore, Singapore (R.D.); National Cancer Center Hospital, Tokyo (K.Y.); the Latin American Cooperative Oncology Group, Porto Alegre, Brazil (C.H.B.); Texas Oncology and US Oncology, Baylor University Medical Center, Dallas (J.A.O.); the Department of General Medical Oncology, University Hospitals Leuven, Leuven, Belgium (H.W.); the Department of Medical Oncology, Institut Curie and Université Paris Cité, Paris (J.-Y.P.), Centre François Baclesse, Caen (C.L.), and the Department of Medical Oncology, Institut du Cancer de Montpellier, Université de Montpellier, INSERM Unité 1194, Montpellier (W.J.) - all in France; Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology, Barcelona (C.S.); the Department of Oncology, Santo Stefano Hospital, Azienda Unità Sanitaria Locale Toscana Centro, Prato (L.B.), and the European Institute of Oncology, IRCCS, and the Department of Oncology and Hematology-Oncology, University of Milan, Milan (G.C.) - all in Italy; the Division of Medical Oncology, Yonsei Cancer Center (J.S.), and the Department of Internal Medicine, Seoul National University Hospital (S.-A.I.) - both in Seoul, South Korea; Clinical Development, Late-Stage Development, Oncology Research and Development, AstraZeneca, Cambridge, United Kingdom (N.B., G.P.); and Biometrics Oncology, Late-Stage Development, Oncology Research and Development, AstraZeneca, Waltham, MA (J.K.).
• N. Engl. J. Med. 2024 Sep 15.

BackgroundOutcomes in patients with hormone receptor-positive metastatic breast cancer worsen after one or more lines of endocrine-based therapy. Trastuzumab deruxtecan has shown efficacy in patients with metastatic breast cancer with low expression of human epidermal growth factor receptor 2 (HER2) after previous chemotherapy.MethodsWe conducted a phase 3, multicenter, open-label trial involving patients with hormone receptor-positive metastatic breast cancer with low HER2 expression (a score of 1+ or 2+ on immunohistochemical [IHC] analysis and negative results on in situ hybridization) or ultralow HER2 expression (IHC 0 with membrane staining) who had received one or more lines of endocrine-based therapy and no previous chemotherapy for metastatic breast cancer. Patients were randomly assigned in a 1:1 ratio to receive trastuzumab deruxtecan or the physician's choice of chemotherapy. The primary end point was progression-free survival (according to blinded independent central review) among the patients with HER2-low disease. Secondary end points included progression-free survival among all the patients who had undergone randomization, overall survival, and safety.ResultsOf the 866 patients who underwent randomization, 713 had HER2-low disease, and 153 had HER2-ultralow disease. Among the patients with HER2-low disease, the median progression-free survival was 13.2 months (95% confidence interval [CI], 11.4 to 15.2) in the trastuzumab deruxtecan group and 8.1 months (95% CI, 7.0 to 9.0) in the chemotherapy group (hazard ratio for disease progression or death, 0.62; 95% CI, 0.51 to 0.74; P<0.001); the results were consistent in the exploratory HER2-ultralow population. Data for overall survival were immature. Adverse events of grade 3 or higher occurred in 52.8% of the patients in the trastuzumab deruxtecan group and in 44.4% of those in the chemotherapy group. Adjudicated interstitial lung disease or pneumonitis occurred in 49 patients (11.3%; three events were grade 5 in severity) and in 1 patient (0.2%; grade 2), respectively.ConclusionsAmong patients with hormone receptor-positive, HER2-low or HER2-ultralow metastatic breast cancer who had received one or more lines of endocrine-based therapy, treatment with trastuzumab deruxtecan resulted in longer progression-free survival than chemotherapy. No new safety signals were identified. (Funded by AstraZeneca and Daiichi Sankyo; DESTINY-Breast06 ClinicalTrials.gov number, NCT04494425.).Copyright © 2024 Massachusetts Medical Society.

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