随着病例数量持续增加，食管胃腺癌（EGA）对全球健康构成了重大挑战。目前治疗局部 EGA 的标准方法包括三联化疗的组合，其中包括铂化合物、氟嘧啶和紫杉烷（称为 FLOT），然后进行手术。在 HER2 阳性的转移性 EGA 病例或局部 EGA 的某些研究中，使用 HER2 靶向抗体（例如曲妥珠单抗）已显示出改善的反应。最近，添加程序性细胞死亡蛋白 1 (PD-1) 抑制剂（例如派姆单抗）与 5-FU、铂类化疗和曲妥珠单抗联合使用，已证明 HER2 阳性转移性 EGA 的缓解率显着提高。然而，目前关于这种治疗方法治疗局部 HER2 阳性疾病的证据不足。 PHERFLOT 研究是一项开放标签、单臂、多中心、探索性 II 期试验，旨在评估围手术期派姆单抗的有效性、安全性和耐受性、FLOT 和曲妥珠单抗用于先前未经治疗的局部 HER2 阳性 EGA 患者。总共将招募30名患者。共同主要终点是病理完全缓解率和2年后无病生存率。次要目标包括安全性和耐受性、无进展生存期和客观缓解率方面的功效以及转化标记，例如基于血液的特征（例如，免疫库变化或抗 HER2 耐药变体的出现）或可能相关的微生物群特征II 期临床试验的最新证据表明，通过在围手术期 FLOT 中添加曲妥珠单抗可改善疗效。此外，在晚期或转移性 EGA 中，曲妥珠单抗、FLOT 和 PD1 抑制剂派姆单抗的组合显着改善了治疗反应。 PHERFLOT 研究旨在评估这种治疗方法在 HER2 阳性局部 EGA 中的有效性和安全性，有可能确定一种有前景的局部 EGA 围手术期新方案，然后需要在随机试验中进行确认。此外，该研究附带的转化计划可能有助于改善合适患者的分层，并确定未来临床试验的潜在转化目标。https://clinicaltrials.gov，标识符 NCT05504720。版权所有 © 2023 Tintelnot, Stein, Al-Batran 、Ettrich、Götze、Grün、Haag、Heuer、Hofheinz、Homann、Bröring、Cruz、Kurreck、Lorenzen、Moosmann、Müller、Schuler、Siegler、Binder 和 Gökkurt。

Esophagogastric adenocarcinoma (EGA) presents a substantial global health challenge as the number of cases continues to rise. The current standard approach for treating localized EGA involves a combination of triplet chemotherapy, which consists of a platinum compound, a fluoropyrimidine, and a taxane (known as FLOT), followed by surgery. In cases of metastatic EGA with HER2-positive status or in certain studies with localized EGA, the use of HER2-targeted antibodies such as trastuzumab has shown improved responses. Recently, the addition of programmed cell death protein 1 (PD-1) inhibitors, such as pembrolizumab, when combined with 5-FU, platinum-based chemotherapy, and trastuzumab, has demonstrated significant enhancements in response rates for HER2-positive metastatic EGA. However, there is currently insufficient evidence regarding this treatment approach in localized HER2-positive disease.The PHERFLOT study is an open-label, single-arm, multicenter, exploratory phase II trial designed to assess the efficacy, safety, and tolerability of perioperative pembrolizumab, FLOT, and trastuzumab in patients with previously untreated localized HER2-positive EGA. In total, 30 patients will be recruited. The co-primary end points are pathological complete response rate and disease-free survival rate after 2 years. Secondary objectives include safety and tolerability, efficacy in terms of progression-free survival and objective response rate and translational markers, such as blood-based signatures (e.g., immune repertoire changes or emergence of anti-HER2 resistance variants) or microbiota signatures that may correlate with immune activation and therapy response.Recent evidence from phase II clinical trials demonstrated improved efficacy through the addition of trastuzumab to perioperative FLOT. Furthermore, in advanced or metastatic EGA, the combination of trastuzumab, FLOT, and the PD1-inhibitor pembrolizumab significantly improved treatment response. The PHERFLOT study aims to assess the efficacy and safety of this treatment approach in HER2-positive-localized EGA, potentially identifying a promising new perioperative regimen for localized EGA, which then needs to be confirmed within a randomized trial. Furthermore, the accompanying translational program of the study might help to improve the stratification of suitable patients and to identify potential translational targets for future clinical trials.https://clinicaltrials.gov, identifier NCT05504720.Copyright © 2023 Tintelnot, Stein, Al-Batran, Ettrich, Götze, Grün, Haag, Heuer, Hofheinz, Homann, Bröring, Cruz, Kurreck, Lorenzen, Moosmann, Müller, Schuler, Siegler, Binder and Gökkurt.