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.).
N Engl J Med. 2020 Jun 18;382(25):2419-2430. doi: 10.1056/NEJMoa2004413. Epub 2020 May 29.
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.
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.
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.
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.).
曲妥珠单抗-德鲁替康（DS-8201）是一种抗体药物偶联物，由抗 HER2（人表皮生长因子受体 2）抗体、可裂解的四肽基连接子和细胞毒性拓扑异构酶 I 抑制剂组成。该药可能对 HER2 阳性晚期胃癌患者有效。
在一项开放标签、随机、2 期临床试验中，我们评估了曲妥珠单抗-德鲁替康与化疗在 HER2 阳性晚期胃癌患者中的疗效。接受至少两种包括曲妥珠单抗在内的既往治疗后进展的经中心确认的 HER2 阳性胃或胃食管交界处腺癌患者，以 2:1 的比例随机分配接受曲妥珠单抗-德鲁替康（每公斤体重 6.4 毫克，每 3 周一次）或医生选择的化疗。主要终点为独立中心评估的客观缓解。次要终点包括总生存期、缓解持续时间、无进展生存期、确认缓解（持续缓解≥4 周）和安全性。
在 187 名接受治疗的患者中，125 名接受了曲妥珠单抗-德鲁替康治疗，62 名接受了化疗（55 名接受伊立替康治疗，7 名接受紫杉醇治疗）。曲妥珠单抗-德鲁替康组的客观缓解率为 51%，而医生选择组为 14%（P<0.001）。与化疗相比，曲妥珠单抗-德鲁替康的总生存期更长（中位 12.5 个月 vs. 8.4 个月；死亡风险比为 0.59；95%置信区间为 0.39 至 0.88；P=0.01，超过了预设的 O'Brien-Fleming 边界[基于死亡人数为 0.0202]）。最常见的 3 级或更高级别的不良事件是中性粒细胞计数下降（曲妥珠单抗-德鲁替康组为 51%，医生选择组为 24%）、贫血（分别为 38%和 23%）和白细胞计数下降（分别为 21%和 11%）。共有 12 名患者发生曲妥珠单抗-德鲁替康相关的间质性肺病或肺炎（9 名患者为 1 级或 2 级，3 名患者为 3 级或 4 级），由独立委员会裁定。曲妥珠单抗-德鲁替康组有 1 例与药物相关的死亡（因肺炎），医生选择组无药物相关死亡。
与标准疗法相比，曲妥珠单抗-德鲁替康治疗可显著改善 HER2 阳性胃癌患者的缓解率和总生存期。骨髓抑制和间质性肺病是显著的毒性作用。（由 Daiichi Sankyo 资助；DESTINY-Gastric01 ClinicalTrials.gov 编号，NCT03329690。）
