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期刊来源：Nat Med

原文链接：https://doi.org/10.1038/s41591-024-02877-z

摘要内容如下：

胃食管癌动力学和免疫检查点抑制剂（ICI）临床反应的驱动因素仍然知之甚少。双重程序性细胞死亡蛋白1（PD-1）和淋巴细胞活化基因3（LAG-3）抑制的潜在协同活性可能有助于改善这些肿瘤的免疫治疗反应。我们报道了一项Ib期试验，该试验评估了32例可切除的II期/III期胃食管癌患者的新辅助化疗Nivolumab（A组，n=16）或Nivolumab-Relatlimab（B组，n=16）联合放化疗，并对病理、分子和功能性免疫应答进行了深入评估。主要终点是安全性；次要终点是可行性；探索性终点包括病理完全缓解（PCR）和主要病理缓解（MPR）、无复发生存率（RFS）和总生存率（OS）。该研究在A组中达到了其主要安全终点，尽管B组需要修改以减轻毒性。A组的PCR和MPR率分别为40%和53.5%，B组的PCR和MPR率分别为21.4%和57.1%。最常见的不良事件是疲劳、恶心、血小板减少和皮炎。总体而言，2年RFS和OS率分别为72.5%和82.6%。较高的基线程序性细胞死亡配体1（PD-L1）和LAG-3表达与较深的病理反应相关。循环肿瘤DNA（ctDNA）的探索性分析显示，在ICI诱导后、术前和术后检测不到ctDNA的患者的RFS和OS显著延长；ctDNA清除率反映了新抗原特异性T细胞应答。我们的研究结果为PD-1和LAG-3联合阻断剂在胃食管癌中的安全性提供了见解，并强调了ctDNA分析在新辅助ICI期间动态评估全身肿瘤负荷的潜力，这可能为未来的干预打开一个治疗窗口。ClinicalTrials.gov注册：NCT03044613。

英文原文如下：

Abstracts

Gastroesophageal cancer dynamics and drivers of clinical responses with immune checkpoint inhibitors (ICI) remain poorly understood. Potential synergistic activity of dual programmed cell death protein 1 (PD-1) and lymphocyte-activation gene 3 (LAG-3) inhibition may help improve immunotherapy responses for these tumors. We report a phase Ib trial that evaluated neoadjuvant nivolumab (Arm A, n = 16) or nivolumab-relatlimab (Arm B, n = 16) in combination with chemoradiotherapy in 32 patients with resectable stage II/stage III gastroesophageal cancer together with an in-depth evaluation of pathological, molecular and functional immune responses. Primary endpoint was safety; the secondary endpoint was feasibility; exploratory endpoints included pathological complete (pCR) and major pathological response (MPR), recurrence-free survival (RFS) and overall survival (OS). The study met its primary safety endpoint in Arm A, although Arm B required modification to mitigate toxicity. pCR and MPR rates were 40% and 53.5% for Arm A and 21.4% and 57.1% for Arm B. Most common adverse events were fatigue, nausea, thrombocytopenia and dermatitis. Overall, 2-year RFS and OS rates were 72.5% and 82.6%, respectively. Higher baseline programmed cell death ligand 1 (PD-L1) and LAG-3 expression were associated with deeper pathological responses. Exploratory analyses of circulating tumor DNA (ctDNA) showed that patients with undetectable ctDNA post-ICI induction, preoperatively and postoperatively had a significantly longer RFS and OS; ctDNA clearance was reflective of neoantigen-specific T cell responses. Our findings provide insights into the safety profile of combined PD-1 and LAG-3 blockade in gastroesophageal cancer and highlight the potential of ctDNA analysis to dynamically assess systemic tumor burden during neoadjuvant ICI that may open a therapeutic window for future intervention. ClinicalTrials.gov registration: NCT03044613 .

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