Trastuzumab with trimodality treatment for oesophageal adenocarcinoma with HER2 overexpression (NRG Oncology/RTOG 1010): a multicentre, randomised, phase 3 trial.
Trastuzumab with trimodality treatment for oesophageal adenocarcinoma with HER2 overexpression (NRG Oncology/RTOG 1010): a multicentre, randomised, phase 3 trial.
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DOI：
10.1016/s1470-2045(21)00718-x
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发表时间：
2022-03
期刊：
影响因子：
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通讯作者：
Crane CH
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作者：
Safran HP;Winter K;Ilson DH;Wigle D;DiPetrillo T;Haddock MG;Hong TS;Leichman LP;Rajdev L;Resnick M;Kachnic LA;Seaward S;Mamon H;Diaz Pardo DA;Anderson CM;Shen X;Sharma AK;Katz AW;Salo J;Leonard KL;Moughan J;Crane CH
曲妥珠单抗是一种针对 HER2（也称为 ERBB2）的单克隆抗体。 NRG Oncology/RTOG-1010 试验的主要目的是确定对于未经治疗的 HER2 过表达食管腺癌患者，曲妥珠单抗与三联治疗（紫杉醇加卡铂和放疗，然后手术）相结合是否可以改善无病生存期。 NRG Oncology/RTOG-1010 是一项开放标签、随机、3 期试验，患者来自美国 111 家 NRG 附属机构。符合资格的患者是新诊断的经病理证实的食管腺癌的成年人（年龄≥18岁），美国癌症联合委员会第7版T1N1-2或T2-3N0-2阶段疾病，且Zubrod表现状态为0-2。根据腺病对患者进行分层（无、有[腹腔缺失]与有[腹腔存在≤2 cm]），并随机分配（1:1）接受每周静脉注射紫杉醇（50 mg/m2，静脉注射超过1小时）和卡铂（曲线2下面积，静脉注射超过30-60分钟），持续6周，分28次进行50·4 Gy放射治疗（化放疗），然后进行手术，联合或不联合静脉曲妥珠单抗（第一周 4 mg/kg，放化疗期间每周 2 mg/kg，持续 5 周，术前一次 6 mg/kg，术后 21-56 天开始，每 3 周 6 mg/kg，共 13 次治疗）。主要终点无病生存期定义为从随机分组到死亡或第一次局部疾病持续或复发、远处转移或第二原发恶性肿瘤的时间。通过修改意向治疗进行分析。本研究已在 ClinicalTrials.gov 注册，NCT01196390；目前已关闭并正在跟进中。 2010年12月30日至2015年11月10日期间，共有606名患者接受HER2评估，其中203名符合条件的HER2阳性患者被纳入并随机分配接受放化疗加曲妥珠单抗（n=102）或单独放化疗（n=101）。中位随访时间为 2·8 年 (IQR 1·4–5·7)。放化疗联合曲妥珠单抗的中位无病生存期为 19·6 个月 (95% CI 13·5–26·2)，而单独放化疗的中位无病生存期为 14·2 个月 (10·5–23·0)（风险比 0·99 [95% CI 0·71–1·39]，对数秩 p=0·97）。放化疗加曲妥珠单抗组的 95 名患者中，有 41 名患者 (43%) 发生了 3 级治疗相关不良事件，而放化疗组的 96 名患者中有 52 名患者 (54%) 发生了 4 级事件，分别为 20 名患者 (21%) 和 21 名患者 (22%)。两组中最常见的 3 级或更严重的治疗相关不良事件是血液学（放化疗联合曲妥珠单抗组 95 名患者中的 53 名 [56%]，化疗组 96 名患者中 55 名 [57%]）或胃肠道疾病（28 名 [29%] 比 20 名 [21%]）。放化疗加曲妥珠单抗组的 95 名患者中有 34 名患者 (36%) 和仅放化疗组的 96 名患者中有 27 名患者 (28%) 出现了治疗相关的严重不良事件。共有 8 例与治疗相关的死亡：放化疗加曲妥珠单抗组 95 例患者中有 5 例 (5%)（支气管胸膜瘘、食管吻合口漏、肺部感染、猝死和未另行说明的死亡），放化疗组 96 例患者中有 3 例 (3%)（2 例多器官衰竭和 1 例脓毒症）。在新辅助放化疗中添加曲妥珠单抗治疗 HER2 过表达的食管癌效果不佳。曲妥珠单抗不会导致毒性增加，这表明未来将其与其他靶向 HER2 的药物联合或使用治疗食管癌的研究是有必要的。
Trastuzumab is a monoclonal antibody against HER2 (also known as ERBB2). The primary objective of the NRG Oncology/RTOG-1010 trial was to establish whether trastuzumab improves disease-free survival when combined with trimodality treatment (paclitaxel plus carboplatin and radiotherapy, followed by surgery) for patients with untreated HER2-overexpressing oesophageal adenocarcinoma. NRG Oncology/RTOG-1010 was an open label, randomised, phase 3 trial for which patients were accrued from 111 NRG-affiliated institutions in the USA. Eligible patients were adults (aged ≥18 years) with newly diagnosed pathologically confirmed oesophageal adenocarcinoma, American Joint Committee on Cancer 7th edition T1N1–2 or T2–3N0–2 stage disease, and a Zubrod performance status of 0–2. Patients were stratified by adenopathy (no vs yes [coeliac absent] vs yes [coeliac present ≤2 cm] ) and randomly assigned (1:1) to receive weekly intravenous paclitaxel (50 mg/m2 intravenously over 1 h) and carboplatin (area under the curve 2, intravenously over 30–60 min) for 6 weeks with radiotherapy 50·4 Gy in 28 fractions (chemoradiotherapy) followed by surgery, with or without intravenous trastuzumab (4 mg/kg in week one, 2 mg/kg per week for 5 weeks during chemoradiotherapy, 6 mg/kg once presurgery, and 6 mg/kg every 3 weeks for 13 treatments starting 21–56 days after surgery). The primary endpoint, disease-free survival, was defined as the time from randomisation to death or first of locoregional disease persistence or recurrence, distant metastases, or second primary malignancy. Analyses were done by modified intention to treat. This study is registered with Clinicaltrials.gov, NCT01196390; it is now closed and in follow-up. 606 patients were entered for HER2 assessment from Dec 30, 2010 to Nov 10, 2015, and 203 eligible patients who were HER2-positive were enrolled and randomly assigned to chemoradiotherapy plus trastuzumab (n=102) or chemoradiotherapy alone (n=101). Median duration of follow-up was 2·8 years (IQR 1·4–5·7). Median disease-free survival was 19·6 months (95% CI 13·5–26·2) with chemoradiotherapy plus trastuzumab compared with 14·2 months (10·5–23·0) for chemoradiotherapy alone (hazard ratio 0·99 [95% CI 0·71–1·39], log-rank p=0·97). Grade 3 treatment-related adverse events occurred in 41 (43%) of 95 patients in the chemoradiotherapy plus trastuzumab group versus 52 (54%) of 96 in the chemoradiotherapy group and grade 4 events occurred in 20 (21%) versus 21 (22%). The most common grade 3 or worse treatment-related adverse events for both groups were haematological (53 [56%] of 95 patients in the chemoradiotherapy plus trastuzumab group vs 55 [57%] of 96 patients in the chemotherapy group) or gastrointestinal disorders (28 [29%] vs 20 [21 %]). 34 (36%) of 95 patients in the chemoradiotherapy plus trastuzumab group and 27 (28%) of 96 patients in the chemoradiotherapy only group had treatment-related serious adverse events. There were eight treatment-related deaths: five (5%) of 95 patients in the chemoradiotherapy plus trastuzumab group (bronchopleural fistula, oesophageal anastomotic leak, lung infection, sudden death, and death not otherwise specified), and three (3%) of 96 in the chemoradiotherapy group (two multiorgan failure and one sepsis). The addition of trastuzumab to neoadjuvant chemoradiotherapy for HER2-overexpressing oesophageal cancer was not effective. Trastuzumab did not lead to increased toxicities, suggesting that future studies combining it with or using other agents targeting HER2 in oesophageal cancer are warranted.