This study evaluated the efficacy and safety of pembrolizumab, trastuzumab combined with FLOT in patients with HER2-positive locally advanced esophagogastric adenocarcinoma, demonstrating a high pathological complete response rate and promising antitumor activity, providing critical evidence for future randomized controlled trials.
Literature Overview
This study, titled 'Perioperative pembrolizumab, trastuzumab and FLOT in HER2-positive localized esophagogastric adenocarcinoma: a phase 2 trial', published in Nature Medicine, reviewed and summarized the safety and effectiveness of combining PD-1 inhibitor pembrolizumab, HER2-targeted agent trastuzumab, and the FLOT chemotherapy regimen in patients with HER2-positive locally advanced esophagogastric adenocarcinoma. The primary endpoints were pathological complete response (pCR) rate and 2-year disease-free survival (DFS).
Background Knowledge
Esophagogastric adenocarcinoma (EGA) is one of the most commonly diagnosed malignancies globally. Although the FLOT regimen has become the standard treatment for resectable patients, its efficacy remains limited. HER2-positive EGA patients can benefit from trastuzumab in terms of survival, and PD-1/PD-L1 inhibitors combined with HER2-targeted therapy have also demonstrated survival benefits in metastatic EGA. However, the application of perioperative immunotherapy in HER2-positive locally advanced patients remains unclear. The PHERFLOT study aimed to address this gap. Based on a triplet regimen combining FLOT chemotherapy, trastuzumab, and pembrolizumab, this study assessed the efficacy and safety in locally advanced HER2-positive EGA patients, providing a foundation for future randomized trials.
Research Methods and Experiments
This was an open-label, single-arm, phase 2 clinical trial conducted across 11 centers in Germany, enrolling 31 HER2-positive, resectable esophagogastric adenocarcinoma patients. Preoperatively, patients received three cycles of pembrolizumab (200 mg) and trastuzumab (loading dose 8 mg/kg, subsequent doses 6 mg/kg) every 3 weeks, along with FLOT chemotherapy (four cycles every 2 weeks). Surgery was performed 4 weeks after completion of preoperative therapy. Postoperatively, patients continued with four cycles of FLOT combination therapy, followed by up to 11 cycles of pembrolizumab and trastuzumab maintenance treatment, with a total treatment duration of approximately 1 year. The primary endpoints were pCR rate and 2-year DFS rate; this interim analysis reported only the pCR rate and selected secondary endpoints including R0 resection rate, feasibility, and safety.
Key Conclusions and Perspectives
Research Significance and Prospects
This study supports the feasibility and high efficacy of combining PD-1 inhibitors and HER2-targeted therapy in perioperative treatment for HER2-positive EGA. Despite higher rates of postoperative complications and reoperations, overall safety was manageable. Future phase III randomized controlled trials are needed to further validate the potential of this regimen in improving DFS and enabling organ-preserving strategies. Additionally, this study provides evidence for personalized treatment, suggesting that biomarker-guided therapy selection may enhance treatment outcomes.
Conclusion
This study is the first to evaluate the efficacy of pembrolizumab and trastuzumab combined with the FLOT regimen in HER2-positive locally advanced esophagogastric adenocarcinoma. The results show that this triplet regimen demonstrates strong antitumor activity, achieving a pCR rate exceeding 48%, with significant responses observed across multiple molecular subgroups. Although the incidence of treatment-related adverse events is relatively high, no treatment-related deaths were recorded, and safety profiles were manageable. These findings support the potential adoption of this regimen as a standard approach in perioperative treatment for HER2-positive EGA patients and provide key data for future randomized trials. Moreover, the study highlights the importance of biomarkers such as PD-L1 CPS, HER2 expression, and MMR/MSI status in guiding treatment decisions, suggesting that personalized strategies may further optimize clinical outcomes. In summary, the PHERFLOT trial offers novel clinical evidence and research directions for immunotherapy combined with targeted therapy in HER2-positive EGA.
