• Shanu Modi, William Jacot, Toshinari Yamashita, Joohyuk Sohn, Maria Vidal, Eriko Tokunaga, Junji Tsurutani, Naoto T Ueno, Aleix Prat, Yee Soo Chae, Keun Seok Lee, Naoki Niikura, Yeon Hee Park, Binghe Xu, Xiaojia Wang, Miguel Gil-Gil, Wei Li, Jean-Yves Pierga, Seock-Ah Im, MooreHalle C FHCFFrom the Memorial Sloan Kettering Cancer Center, New York (S.M.); Institut du Cancer de Montpellier, Université Montpellier, INSERM Unité 1194, Montpellier (W.J.), and Institut Curie, Université Paris Cité, Paris (J.-Y.P.) - both in Franc, Hope S Rugo, Rinat Yerushalmi, Flora Zagouri, Andrea Gombos, Sung-Bae Kim, Qiang Liu, Ting Luo, Cristina Saura, Peter Schmid, Tao Sun, Dhiraj Gambhire, Lotus Yung, Yibin Wang, Jasmeet Singh, Patrik Vitazka, Gerold Meinhardt, Nadia Harbeck, David A Cameron, and DESTINY-Breast04 Trial Investigators.
• From the Memorial Sloan Kettering Cancer Center, New York (S.M.); Institut du Cancer de Montpellier, Université Montpellier, INSERM Unité 1194, Montpellier (W.J.), and Institut Curie, Université Paris Cité, Paris (J.-Y.P.) - both in France; Kanagawa Cancer Center, Yokohama (T.Y.), Kyushu Cancer Center, National Hospital Organization, Fukuoka (E.T.), Showa University Hospital, Tokyo (J.T.), and Tokai University School of Medicine, Isehara-shi (N.N.) - all in Japan; Yonsei Cancer Center, Yonsei University Health System (J. Sohn), Samsung Medical Center (Y.H.P.), Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul National University (S.-A.I.), and Asan Medical Center, University of Ulsan College of Medicine (S.-B.K.), Seoul, Kyungpook National University Chilgok Hospital, Daegu (Y.S.C.), and the National Cancer Center, Goyang-si (K.S.L.) - all in South Korea; the Department of Medical Oncology, Hospital Clínic de Barcelona (M.V., A.P.), Translational Genomics and Targeted Therapies in Solid Tumors, Institut d'Investigacions Biomèdiques August Pi i Sunyer (A.P.), the Department of Medicine, University of Barcelona (A.P.), the Breast Cancer Unit, Institute of Oncology (IOB)-Quirón Salud (A.P.), Institut Catala d'Oncologia l'Hospitalet-Hospital Duran i Reynals (M.G.-G.), and Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (C.S.) - all in Barcelona; the University of Texas M.D. Anderson Cancer Center, Houston (N.T.U.); Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing (B.X.), Zhejiang Cancer Hospital, Hangzhou (X.W.), the First Hospital of Jilin University, Changchun (W.L.), Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou (Q.L.), West China Hospital, Sichuan University, Chengdu (T.L.), and Liaoning Cancer Hospital and Institute, Shenyang (T.S.) - all in China; the Cleveland Clinic Foundation, Cleveland (H.C.F.M.); the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center, San Francisco (H.S.R.); Rabin Medical Center, Petah Tikva, Tel Aviv University, Tel Aviv, Israel (R.Y.); Alexandra Regional General Hospital, Athens (F.Z.); Institut Jules Bordet, Brussels (A.G.); Queen Mary University of London, London (P.S.), and Edinburgh Cancer Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh (D.A.C.) - both in the United Kingdom; Daiichi Sankyo, Basking Ridge, NJ (D.G., L.Y., Y.W., J. Singh, P.V., G.M.); and the Breast Center, Department of Obstetrics and Gynecology, and Comprehensive Cancer Center Munich, Ludwig Maximilian University Hospital, Munich, Germany (N.H.).
• N. Engl. J. Med. 2022 Jul 7; 387 (1): 9209-20.

BackgroundAmong breast cancers without human epidermal growth factor receptor 2 (HER2) amplification, overexpression, or both, a large proportion express low levels of HER2 that may be targetable. Currently available HER2-directed therapies have been ineffective in patients with these "HER2-low" cancers.MethodsWe conducted a phase 3 trial involving patients with HER2-low metastatic breast cancer who had received one or two previous lines of chemotherapy. (Low expression of HER2 was defined as a score of 1+ on immunohistochemical [IHC] analysis or as an IHC score of 2+ and negative results on in situ hybridization.) Patients were randomly assigned in a 2:1 ratio to receive trastuzumab deruxtecan or the physician's choice of chemotherapy. The primary end point was progression-free survival in the hormone receptor-positive cohort. The key secondary end points were progression-free survival among all patients and overall survival in the hormone receptor-positive cohort and among all patients.ResultsOf 557 patients who underwent randomization, 494 (88.7%) had hormone receptor-positive disease and 63 (11.3%) had hormone receptor-negative disease. In the hormone receptor-positive cohort, the median progression-free survival was 10.1 months in the trastuzumab deruxtecan group and 5.4 months in the physician's choice group (hazard ratio for disease progression or death, 0.51; P<0.001), and overall survival was 23.9 months and 17.5 months, respectively (hazard ratio for death, 0.64; P = 0.003). Among all patients, the median progression-free survival was 9.9 months in the trastuzumab deruxtecan group and 5.1 months in the physician's choice group (hazard ratio for disease progression or death, 0.50; P<0.001), and overall survival was 23.4 months and 16.8 months, respectively (hazard ratio for death, 0.64; P = 0.001). Adverse events of grade 3 or higher occurred in 52.6% of the patients who received trastuzumab deruxtecan and 67.4% of those who received the physician's choice of chemotherapy. Adjudicated, drug-related interstitial lung disease or pneumonitis occurred in 12.1% of the patients who received trastuzumab deruxtecan; 0.8% had grade 5 events.ConclusionsIn this trial involving patients with HER2-low metastatic breast cancer, trastuzumab deruxtecan resulted in significantly longer progression-free and overall survival than the physician's choice of chemotherapy. (Funded by Daiichi Sankyo and AstraZeneca; DESTINY-Breast04 ClinicalTrials.gov number, NCT03734029.).Copyright © 2022 Massachusetts Medical Society.

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