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Trastuzumab Deruxtecan in Previously Treated HER2-Positive Gastric Cancer

 Kohei Shitara  ;  Yung-Jue Bang  ;  Satoru Iwasa  ;  Naotoshi Sugimoto  ;  Min-Hee Ryu  ;  Daisuke Sakai  ;  Hyun-Cheol Chung  ;  Hisato Kawakami  ;  Hiroshi Yabusaki  ;  Jeeyun Lee  ;  Kaku Saito  ;  Yoshinori Kawaguchi  ;  Takahiro Kamio  ;  Akihito Kojima  ;  Masahiro Sugihara  ;  Kensei Yamaguchi  ;  DESTINY-Gastric01 Investigators 
 NEW ENGLAND JOURNAL OF MEDICINE, Vol.382(25) : 2419-2430, 2020-06 
Journal Title
Issue Date
Adenocarcinoma / drug therapy* ; Adult ; Aged ; Aged, 80 and over ; Antibodies, Monoclonal, Humanized / adverse effects ; Antibodies, Monoclonal, Humanized / therapeutic use* ; Antineoplastic Agents / adverse effects ; Antineoplastic Agents / therapeutic use* ; Bone Marrow / drug effects ; Camptothecin / adverse effects ; Camptothecin / analogs & derivatives* ; Camptothecin / therapeutic use ; Esophageal Neoplasms / drug therapy ; Female ; Humans ; Immunoconjugates / adverse effects ; Immunoconjugates / therapeutic use* ; Irinotecan / therapeutic use ; Lung Diseases, Interstitial / chemically induced ; Male ; Middle Aged ; Paclitaxel / therapeutic use ; Receptor, ErbB-2 / analysis ; Stomach Neoplasms / drug therapy* ; Survival Analysis
Background: Trastuzumab deruxtecan (DS-8201) is an antibody-drug conjugate consisting of an anti-HER2 (human epidermal growth factor receptor 2) antibody, a cleavable tetrapeptide-based linker, and a cytotoxic topoisomerase I inhibitor. The drug may have efficacy in patients with HER2-positive advanced gastric cancer. Methods: In an open-label, randomized, phase 2 trial, we evaluated trastuzumab deruxtecan as compared with chemotherapy in patients with HER2-positive advanced gastric cancer. Patients with centrally confirmed HER2-positive gastric or gastroesophageal junction adenocarcinoma that had progressed while they were receiving at least two previous therapies, including trastuzumab, were randomly assigned in a 2:1 ratio to receive trastuzumab deruxtecan (6.4 mg per kilogram of body weight every 3 weeks) or physician's choice of chemotherapy. The primary end point was the objective response, according to independent central review. Secondary end points included overall survival, response duration, progression-free survival, confirmed response (response persisting ≥4 weeks), and safety. Results: Of 187 treated patients, 125 received trastuzumab deruxtecan and 62 chemotherapy (55 received irinotecan and 7 paclitaxel). An objective response was reported in 51% of the patients in the trastuzumab deruxtecan group, as compared with 14% of those in the physician's choice group (P<0.001). Overall survival was longer with trastuzumab deruxtecan than with chemotherapy (median, 12.5 vs. 8.4 months; hazard ratio for death, 0.59; 95% confidence interval, 0.39 to 0.88; P = 0.01, which crossed the prespecified O'Brien-Fleming boundary [0.0202 on the basis of number of deaths]). The most common adverse events of grade 3 or higher were a decreased neutrophil count (in 51% of the trastuzumab deruxtecan group and 24% of the physician's choice group), anemia (38% and 23%, respectively), and decreased white-cell count (21% and 11%). A total of 12 patients had trastuzumab deruxtecan-related interstitial lung disease or pneumonitis (grade 1 or 2 in 9 patients and grade 3 or 4 in 3), as adjudicated by an independent committee. One drug-related death (due to pneumonia) was noted in the trastuzumab deruxtecan group; no drug-related deaths occurred in the physician's choice group. Conclusions: Therapy with trastuzumab deruxtecan led to significant improvements in response and overall survival, as compared with standard therapies, among patients with HER2-positive gastric cancer. Myelosuppression and interstitial lung disease were the notable toxic effects. (Funded by Daiichi Sankyo; DESTINY-Gastric01 ClinicalTrials.gov number, NCT03329690.).
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1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Chung, Hyun Cheol(정현철) ORCID logo https://orcid.org/0000-0002-0920-9471
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