Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer

Author(s): Shanu Modi, M.D., Cristina Saura, M.D., Ph.D., Toshinari Yamashita, M.D., Yeon Hee Park, M.D., Sung-Bae Kim, M.D., Ph.D., Kenji Tamura, M.D., Ph.D., Fabrice Andre, M.D., Ph.D., Hiroji Iwata, M.D., Ph.D., Yoshinori Ito, M.D., Junji Tsurutani, M.D., Ph.D., Joohyuk Sohn, M.D., Ph.D., Neelima Denduluri, M.D., et al., for the DESTINY-Breast01 Investigators*
Source: DOI: 10.1056/NEJMoa2203690
Lucio Gordan MD

This study is as exciting as it gets in terms of innovation and impact in a large population of metastatic breast cancer, low HER2 expressors. Rapid identification of such patients is of critical importance given the superiority to standard chemotherapy agents.

Among 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.


We 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.


Of 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.


In 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 number, NCT03734029. opens in new tab.)

Author Affiliations

From Memorial Sloan Kettering Cancer Center, New York (S.M.); Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology, Barcelona (C.S., J.C.), and IOB Institute of Oncology, Quiron Group, Barcelona and Madrid (J.C.); Kanagawa Cancer Center, Yokohama (T.Y.), National Cancer Center Hospital (K.T.), the Cancer Institute Hospital of the Japanese Foundation for Cancer Research (Y.I.), and the Advanced Cancer Translational Research Institute, Showa University (J.T.), Tokyo, Aichi Cancer Center Hospital, Nagoya (H.I.), Kindai University Faculty of Medicine, Osaka (J.T.), Shikoku Cancer Center, Matsuyama (K.A.), and the National Hospital Organization Kyushu Cancer Center, Fukuoka (E.T.) — all in Japan; Samsung Medical Center (Y.H.P.), Asan Medical Center, University of Ulsan College of Medicine (S.-B.K.), Yonsei Cancer Center, Yonsei University Health System (J. Sohn), and Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine (S.-A.I.), Seoul, and the National Cancer Center, Gyeonggi (K.S.L.) — all in South Korea; Institut Gustave Roussy, Université Paris-Sud, Villejuif (F.A.), and Centre Eugène Marquis, Rennes (C.P.) — both in France; the US Oncology Network, Virginia Cancer Specialists, Arlington (N.D.); the University of California, Los Angeles–Jonsson Comprehensive Cancer Center, Los Angeles (S.A.H.); Daiichi Sankyo, Basking Ridge, NJ (C.L., S.C., L.Z., J. Shahidi, A.Y.); and the Dana–Farber Cancer Institute, Boston (I.K.).

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