Tintelnot Joseph, Stein Alexander, Al-Batran Salah-Eddin, Ettrich Thomas, Götze Thorsten, Grün Barbara, Haag Georg Martin, Heuer Vera, Hofheinz Ralf-Dieter, Homann Nils, Bröring Tobias Sebastian, Cruz Mariana Santos, Kurreck Annika, Lorenzen Sylvie, Moosmann Nicolas, Müller Christian, Schuler Markus, Siegler Gabriele, Binder Mascha, Gökkurt Eray
ll. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Hematology-Oncology Practice Eppendorf (HOPE), Hamburg, Germany.
Front Oncol. 2023 Oct 16;13:1272175. doi: 10.3389/fonc.2023.1272175. eCollection 2023.
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.
食管胃腺癌（EGA）的病例数持续上升，给全球健康带来了重大挑战。目前治疗局限性EGA的标准方法是三联化疗联合手术，三联化疗由铂类化合物、氟嘧啶和紫杉烷组成（称为FLOT方案）。在HER2阳性的转移性EGA病例或某些局限性EGA的研究中，使用曲妥珠单抗等HER2靶向抗体已显示出更好的反应。最近，在与5-氟尿嘧啶、铂类化疗和曲妥珠单抗联合使用时，添加程序性细胞死亡蛋白1（PD-1）抑制剂，如帕博利珠单抗，已证明可显著提高HER2阳性转移性EGA的缓解率。然而，目前关于这种治疗方法在局限性HER2阳性疾病中的证据不足。
PHERFLOT研究是一项开放标签、单臂、多中心的探索性II期试验，旨在评估围手术期帕博利珠单抗、FLOT方案和曲妥珠单抗在先前未治疗的局限性HER2阳性EGA患者中的疗效、安全性和耐受性。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年后的无病生存率。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疗效以及转化标志物，如基于血液的特征（如免疫库变化或抗HER2耐药变体的出现）或可能与免疫激活和治疗反应相关的微生物群特征。
II期临床试验的最新证据表明，围手术期FLOT方案中添加曲妥珠单抗可提高疗效。此外，在晚期或转移性EGA中，曲妥珠单抗、FLOT方案和PD-1抑制剂帕博利珠单抗的联合使用显著改善了治疗反应。PHERFLOT研究旨在评估这种治疗方法在HER2阳性局限性EGA中的疗效和安全性，有可能为局限性EGA确定一种有前景的新围手术期方案，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，并为未来临床试验确定潜在的转化靶点。
https://clinicaltrials.gov（标识符NCT0********） （译者注：此处原文NCT编号不全，翻译时保留原文形式）
