Shitara Kohei, Van Cutsem Eric, Gümüş Mahmut, Lonardi Sara, de la Fouchardière Christelle, Coutzac Clélia, Dekervel Jeroen, Hochhauser Daniel, Shen Lin, Mansoor Wasat, Liu Bo, Fornaro Lorenzo, Ryu Min-Hee, Lee Jeeyun, Faustino Cátia, Metges Jean-Philippe, Tabernero Josep, Franke Fábio, Janjigian Yelena Y, Souza Fabricio, Jukofsky Lori, Zhao Yumin, Kamio Takahiro, Zaanan Aziz, Pietrantonio Filippo
National Cancer Center Hospital East, Kashiwa, Japan.
University Hospitals Gasthuisberg, Leuven, Belgium.
N Engl J Med. 2025 Jul 24;393(4):336-348. doi: 10.1056/NEJMoa2503119. Epub 2025 May 31.
On the basis of phase 2 studies, trastuzumab deruxtecan was approved for patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic gastric cancer or gastroesophageal junction adenocarcinoma who had previously received trastuzumab-based therapy. Ramucirumab plus paclitaxel is also a standard second-line treatment option regardless of HER2 status.
We conducted an international, randomized, phase 3 trial comparing second-line trastuzumab deruxtecan at a dose of 6.4 mg per kilogram of body weight with ramucirumab plus paclitaxel in patients with HER2-positive metastatic gastric cancer or gastroesophageal junction adenocarcinoma confirmed on tumor biopsy conducted after the patient had progression while receiving trastuzumab-based therapy. The primary end point was overall survival. Secondary end points included progression-free survival, confirmed objective response (complete or partial response lasting ≥4 weeks), disease control, duration of response, and safety.
Among 494 patients who had undergone randomization, overall survival was significantly longer with trastuzumab deruxtecan than with ramucirumab plus paclitaxel (median, 14.7 vs. 11.4 months; hazard ratio for death, 0.70; 95% confidence interval, 0.55 to 0.90; P = 0.004). Significant results were also seen with regard to progression-free survival (hazard ratio for disease progression or death, 0.74; 95% CI, 0.59 to 0.92) and confirmed objective response (in 44.3% of the patients in the trastuzumab deruxtecan group vs. 29.1% of those in the ramucirumab-paclitaxel group). The incidence of drug-related adverse events of any grade was 93.0% with trastuzumab deruxtecan and 91.4% with ramucirumab plus paclitaxel; the incidence of drug-related adverse events of grade 3 or higher was 50.0% and 54.1%, respectively. Adjudicated drug-related interstitial lung disease or pneumonitis occurred in 13.9% of the patients who received trastuzumab deruxtecan (grade 1 or 2 in 33 patients and grade 3 in 1) and in 1.3% of those who received ramucirumab plus paclitaxel (grade 3 in 2 patients and grade 5 in 1).
Trastuzumab deruxtecan led to significantly longer overall survival than ramucirumab plus paclitaxel among patients with HER2-positive metastatic gastric cancer or gastroesophageal junction adenocarcinoma. Adverse events were common in both groups. Events of interstitial lung disease or pneumonitis with trastuzumab deruxtecan, a known risk, were mainly low-grade. (Funded by Daiichi Sankyo and AstraZeneca; DESTINY-Gastric04 ClinicalTrials.gov number, NCT04704934.).
基于2期研究结果，曲妥珠单抗德鲁昔单抗被批准用于接受过曲妥珠单抗为基础治疗的人表皮生长因子受体2（HER2）阳性转移性胃癌或胃食管交界腺癌患者。无论HER2状态如何，雷莫西尤单抗联合紫杉醇也是一种标准的二线治疗选择。
我们进行了一项国际、随机、3期试验，比较在接受曲妥珠单抗为基础治疗病情进展后经肿瘤活检确诊为HER2阳性转移性胃癌或胃食管交界腺癌的患者中，每公斤体重剂量为6.4毫克的二线曲妥珠单抗德鲁昔单抗与雷莫西尤单抗联合紫杉醇的疗效。主要终点为总生存期。次要终点包括无进展生存期、确认的客观缓解（完全或部分缓解持续≥4周）、疾病控制、缓解持续时间和安全性。
在494例随机分组的患者中，曲妥珠单抗德鲁昔单抗组的总生存期显著长于雷莫西尤单抗联合紫杉醇组（中位数分别为14.7个月和11.4个月；死亡风险比为0.70；95%置信区间为0.55至0.90；P = 0.004）。在无进展生存期（疾病进展或死亡风险比为0.74；95%CI为0.59至0.92）和确认的客观缓解方面（曲妥珠单抗德鲁昔单抗组44.3%的患者有缓解，而雷莫西尤单抗-紫杉醇组为29.1%）也观察到显著结果。任何级别的药物相关不良事件发生率在曲妥珠单抗德鲁昔单抗组为93.0%，在雷莫西尤单抗联合紫杉醇组为91.4%；3级或更高等级的药物相关不良事件发生率分别为50.0%和54.1%。经判定的药物相关间质性肺病或肺炎在接受曲妥珠单抗德鲁昔单抗治疗的患者中发生率为13.9%（33例为1级或2级，1例为3级），在接受雷莫西尤单抗联合紫杉醇治疗的患者中发生率为1.3%（2例为3级，1例为5级）。
在HER2阳性转移性胃癌或胃食管交界腺癌患者中，曲妥珠单抗德鲁昔单抗的总生存期显著长于雷莫西尤单抗联合紫杉醇。两组不良事件均常见。曲妥珠单抗德鲁昔单抗引发的间质性肺病或肺炎事件，这是已知风险，主要为低级别。（由第一三共株式会社和阿斯利康资助；DESTINY-Gastric04临床试验注册号，NCT04704934。）
