Kohei Shitara1, Yung-Jue Bang1, Satoru Iwasa1, Naotoshi Sugimoto1, Min-Hee Ryu1, Daisuke Sakai1, Hyun-Cheol Chung1, Hisato Kawakami1, Hiroshi Yabusaki1, Jeeyun Lee1, Kaku Saito1, Yoshinori Kawaguchi1, Takahiro Kamio1, Akihito Kojima1, Masahiro Sugihara1, Kensei Yamaguchi1. 1. From the National Cancer Center Hospital East, Kashiwa (K. Shitara), the National Cancer Center Hospital (S.I.), Daiichi Sankyo (T.K., A.K., M.S.), and the Cancer Institute Hospital of JFCR (K.Y.), Tokyo, the Osaka International Cancer Institute (N.S.), Osaka University Hospital (D.S.), and Kindai University Hospital (H.K.), Osaka, and Niigata Cancer Center Hospital, Niigata (H.Y.) - all in Japan; Seoul National University College of Medicine (Y.-J.B.), the Asan Medical Center, University of Ulsan College of Medicine (M.-H.R.), the Yonsei Cancer Center, Yonsei University College of Medicine (H.-C.C.), and the Samsung Medical Center, Sungkyunkwan University School of Medicine (J.L.) - all in Seoul, South Korea; and Daiichi Sankyo, Basking Ridge, NJ (K. Saito, Y.K.).
Abstract
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, includingtrastuzumab, 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 receivedtrastuzumab 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.).
RCT Entities:
BACKGROUND:Trastuzumabderuxtecan (DS-8201) is an antibody-drug conjugate consisting of an anti-HER2 (humanepidermal 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 trastuzumabderuxtecan 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 trastuzumabderuxtecan (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 trastuzumabderuxtecan and 62 chemotherapy (55 received irinotecan and 7 paclitaxel). An objective response was reported in 51% of the patients in the trastuzumabderuxtecan group, as compared with 14% of those in the physician's choice group (P<0.001). Overall survival was longer with trastuzumabderuxtecan 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 trastuzumabderuxtecan 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 trastuzumabderuxtecan-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 trastuzumabderuxtecan group; no drug-related deaths occurred in the physician's choice group. CONCLUSIONS: Therapy with trastuzumabderuxtecan 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.).
Authors: Daniel V T Catenacci; Stephanie Moya; Samantha Lomnicki; Leah M Chase; Bryan F Peterson; Natalie Reizine; Lindsay Alpert; Namrata Setia; Shu-Yuan Xiao; John Hart; Uzma D Siddiqui; D Kyle Hogarth; Oliver S Eng; Kiran Turaga; Kevin Roggin; Mitchell C Posner; Paul Chang; Sunil Narula; Murtuza Rampurwala; Yuan Ji; Theodore Karrison; Chih-Yi Liao; Blase N Polite; Hedy L Kindler Journal: Cancer Discov Date: 2020-11-24 Impact factor: 39.397
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