• Shanu Modi, Cristina Saura, Toshinari Yamashita, Yeon Hee Park, Sung-Bae Kim, Kenji Tamura, Fabrice Andre, Hiroji Iwata, Yoshinori Ito, Junji Tsurutani, Joohyuk Sohn, Neelima Denduluri, Christophe Perrin, Kenjiro Aogi, Eriko Tokunaga, Seock-Ah Im, Keun Seok Lee, Sara A Hurvitz, Javier Cortes, Caleb Lee, Shuquan Chen, Lin Zhang, Javad Shahidi, Antoine Yver, Ian Krop, and DESTINY-Breast01 Investigators.
• 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.).
• N. Engl. J. Med. 2020 Feb 13; 382 (7): 610-621.

BackgroundTrastuzumab deruxtecan (DS-8201) is an antibody-drug conjugate composed of an anti-HER2 (human epidermal growth factor receptor 2) antibody, a cleavable tetrapeptide-based linker, and a cytotoxic topoisomerase I inhibitor. In a phase 1 dose-finding study, a majority of the patients with advanced HER2-positive breast cancer had a response to trastuzumab deruxtecan (median response duration, 20.7 months). The efficacy of trastuzumab deruxtecan in patients with HER2-positive metastatic breast cancer previously treated with trastuzumab emtansine requires confirmation.MethodsIn this two-part, open-label, single-group, multicenter, phase 2 study, we evaluated trastuzumab deruxtecan in adults with pathologically documented HER2-positive metastatic breast cancer who had received previous treatment with trastuzumab emtansine. In the first part of the study, we evaluated three different doses of trastuzumab deruxtecan to establish a recommended dose; in the second part, we evaluated the efficacy and safety of the recommended dose. The primary end point was the objective response, according to independent central review. Key secondary end points were the disease-control rate, clinical-benefit rate, duration of response and progression-free survival, and safety.ResultsOverall, 184 patients who had undergone a median of six previous treatments received the recommended dose of trastuzumab deruxtecan (5.4 mg per kilogram of body weight). In the intention-to-treat analysis, a response to therapy was reported in 112 patients (60.9%; 95% confidence interval [CI], 53.4 to 68.0). The median duration of follow-up was 11.1 months (range, 0.7 to 19.9). The median response duration was 14.8 months (95% CI, 13.8 to 16.9), and the median duration of progression-free survival was 16.4 months (95% CI, 12.7 to not reached). During the study, the most common adverse events of grade 3 or higher were a decreased neutrophil count (in 20.7% of the patients), anemia (in 8.7%), and nausea (in 7.6%). On independent adjudication, the trial drug was associated with interstitial lung disease in 13.6% of the patients (grade 1 or 2, 10.9%; grade 3 or 4, 0.5%; and grade 5, 2.2%).ConclusionsTrastuzumab deruxtecan showed durable antitumor activity in a pretreated patient population with HER2-positive metastatic breast cancer. In addition to nausea and myelosuppression, interstitial lung disease was observed in a subgroup of patients and requires attention to pulmonary symptoms and careful monitoring. (Funded by Daiichi Sankyo and AstraZeneca; DESTINY-Breast01 ClinicalTrials.gov number, NCT03248492.).Copyright © 2019 Massachusetts Medical Society.

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