日本国立癌症研究中心东医院Kohei Shitara团队探讨了曲妥珠单抗德鲁替康治疗HER2阳性胃癌患者的疗效。2020年5月29日，相关论文发表在《新英格兰医学杂志》上。

曲妥珠单抗德鲁替康（DS-8201）是一种抗体-药物偶联物，由抗HER2（人类表皮生长因子受体2）抗体、可裂解四肽基连接剂和细胞毒性拓扑异构酶I抑制剂组成。该药物可能对HER2阳性晚期胃癌患者有效。

在这项开放标签、随机、2期临床试验中，研究组比较了曲妥珠单抗德鲁替康与化疗治疗HER2阳性晚期胃癌患者的效果。研究组招募了187例确诊为HER2阳性的胃或胃食管交界处腺癌患者，在先前接受至少两种药物治疗（包括曲妥珠单抗）后仍疾病进展。将其按2:1随机分组，其中125例接受曲妥珠单抗德鲁替康治疗，62例接受医生选择的化疗。根据独立中央评估，主要终点是客观缓解。

曲妥珠单抗德鲁替康组中51％的患者客观缓解，显著高于化疗组的14％；中位总生存期为12.5个月，显著长于化疗组的8.4个月。最常见的3级及以上不良事件是嗜中性白血球数量减少（曲妥珠单抗德鲁替康组为51％，化疗组为24％），贫血（分别为38％和23％）和白细胞计数减少（21％和11％）。由独立委员会判定，共有12例患者患有曲妥珠单抗德鲁替康相关的间质性肺疾病或肺炎（9例患者为1-2级，3例为3-4级）。曲妥珠单抗德鲁替康组中发生1例药物相关死亡，化疗组中未发生。

总之，与标准疗法相比，曲妥珠单抗德鲁替康治疗HER2阳性胃癌患者中可显著改善缓解率和总体生存率。骨髓抑制和间质性肺疾病是明显的毒副作用。

附：英文原文

Title: Trastuzumab Deruxtecan in Previously Treated HER2-Positive Gastric Cancer | NEJM

Author: Kohei Shitara, M.D.,, Yung-Jue Bang, M.D., Ph.D.,, Satoru Iwasa, M.D., Ph.D.,, Naotoshi Sugimoto, M.D., Ph.D.,, Min-Hee Ryu, M.D., Ph.D.,, Daisuke Sakai, M.D., Ph.D.,, Hyun-Cheol Chung, M.D., Ph.D.,, Hisato Kawakami, M.D., Ph.D.,, Hiroshi Yabusaki, M.D., Ph.D.,, Jeeyun Lee, M.D., Ph.D.,, Kaku Saito, M.Sc.,, Yoshinori Kawaguchi, M.Sc.,, Takahiro Kamio, M.D.,, Akihito Kojima, M.Sc.,, Masahiro Sugihara, Ph.D.,, and Kensei Yamaguchi, M.D.

Issue&Volume: 2020-05-29

Abstract: 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, 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.

DOI: 10.1056/NEJMoa2004413

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa2004413