z Phase II Feasibility and Biomarker Study of Neoadjuvant Trastuzumab and Pertuzumab With Chemoradiotherapy for Resectable Human Epidermal Growth Factor Receptor 2-Positive Esophageal Adenocarcinoma: TRAP Study
z Phase II Feasibility and Biomarker Study of Neoadjuvant Trastuzumab and Pertuzumab With Chemoradiotherapy for Resectable Human Epidermal Growth Factor Receptor 2-Positive Esophageal Adenocarcinoma: TRAP Study
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DOI：
10.1200/jco.19.01814
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发表时间：
2020-02-10
影响因子：
45.3
通讯作者：
van Laarhoven, Hanneke W. M.
中科院分区：
文献类型：
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作者：
Stroes, Charlotte, I;Schokker, Sandor;van Laarhoven, Hanneke W. M.
目的 大约 15% 至 43% 的食管腺癌 (EAC) 呈人表皮生长因子受体 2 (HER2) 阳性。由于双药 HER2 阻断已证明对乳腺癌有生存益处，因此我们对 EAC 患者在新辅助放化疗 (nCRT) 中添加曲妥珠单抗和帕妥珠单抗进行了 II 期可行性研究。 患者和方法 可切除 HER2 阳性 EAC 患者接受标准 nCRT 卡铂和紫杉醇以及 41.4 Gy 放疗，剂量为 4 mg/kg第 1 天给予曲妥珠单抗，第 2 至 6 周每周 2 mg/kg，第 7、10 和 13 周每周 6 mg/kg，每 3 周给予 840 mg 帕妥珠单抗。主要终点是可行性，定义为曲妥珠单抗和帕妥珠单抗的治疗完成率≥80%。对接受标准 nCRT 的倾向评分匹配队列的生存率进行了探索性比较，并进行了探索性药代动力学和生物标志物分析。 结果 在 40 名入组患者（78% 男性；中位年龄 63 岁）中，33 名 (83%) 完成了曲妥珠单抗和帕妥珠单抗的治疗。未观察到意外安全事件。所有接受手术的患者均实现 R0 切除，其中 13 名患者（34%）获得病理完全缓解。三年无进展生存率和总生存率 (OS) 分别为 57% 和 71%（中位随访时间为 32.1 个月）。与倾向评分匹配队列相比，HER2 阻断的 OS 显着延长（风险比，0.58；95% CI，0.34 至 0.97）。 [F-18]氟脱氧葡萄糖正电子发射断层扫描的药代动力学分析结果和活性与生存或病理反应不相关。基线时 HER2 3+ 过表达或生长因子受体结合蛋白 7 (Grb7) 阳性肿瘤的患者分别表现出明显更好的生存 (P = .007) 或治疗反应 (P = .016)。 结论 在 HER2 阳性 EAC 患者的 nCRT 中添加曲妥珠单抗和帕妥珠单抗是可行的，并且与历史对照相比显示出潜在的有希望的活性。 HER2 3+ 过度表达和 Grb7 阳性分别可能预测生存和治疗反应。 (C) 2019 年美国临床肿瘤学会
PURPOSE Approximately 15% to 43% of esophageal adenocarcinomas (EACs) are human epidermal growth factor receptor 2 (HER2) positive. Because dual-agent HER2 blockade demonstrated a survival benefit in breast cancer, we conducted a phase II feasibility study of trastuzumab and pertuzumab added to neoadjuvant chemoradiotherapy (nCRT) in patients with EAC.PATIENTS AND METHODS Patients with resectable HER2-positive EAC received standard nCRT with carboplatin and paclitaxel and 41.4 Gy of radiotherapy, with 4 mg/kg of trastuzumab on day 1, 2 mg/kg per week during weeks 2 to 6, and 6 mg/kg per week during weeks 7, 10, and 13 and 840 mg of pertuzumab every 3 weeks. The primary end point was feasibility, defined as >= 80% completion of treatment with both trastuzumab and pertuzumab. An exploratory comparison of survival with a propensity score-matched cohort receiving standard nCRT was performed, as were exploratory pharmacokinetic and biomarker analyses.RESULTS Of the 40 enrolled patients (78% men; median age, 63 years), 33 (83%) completed treatment with trastuzumab and pertuzumab. No unexpected safety events were observed. R0 resection was achieved in all patients undergoing surgery, with pathologic complete response in 13 patients (34%). Three-year progression-free and overall survival (OS) were 57% and 71%, respectively (median follow-up, 32.1 months). Compared with the propensity score-matched cohort, a significantly longer OS was observed with HER2 blockade (hazard ratio, 0.58; 95% CI, 0.34 to 0.97). Results of pharmacokinetic analysis and activity on [F-18]fluorodeoxyglucose positron emission tomography scans did not correlate with survival or pathologic response. Patients with HER2 3+ overexpression or growth factor receptor-bound protein 7 (Grb7) -positive tumors at baseline demonstrated significantly better survival (P = .007) or treatment response (P = .016), respectively.CONCLUSION Addition of trastuzumab and pertuzumab to nCRT in patients with HER2-positive EAC is feasible and demonstrates potentially promising activity compared with historical controls. HER2 3+ overexpression and Grb7 positivity are potentially predictive for survival and treatment response, respectively. (C) 2019 by American Society of Clinical Oncology