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期刊来源：Nat Med

原文链接：https://doi.org/10.1038/s41591-023-02758-x

摘要内容如下：

胃癌和胃食管结合部（G/GEJ）癌预后不良，尽管最近取得了进展，但大多数患者死于他们的疾病。尽管免疫检查点阻断已成为转移性G/GEJ癌症患者治疗标准的一部分，但其在早期疾病中的疗效和对肿瘤微环境（TME）的影响在很大程度上仍是未知的。我们假设新辅助免疫治疗联合化疗在非转移性G/GEJ癌患者中具有更高的疗效。在2期PANDA试验中，既往未经治疗的可切除G/GEJ肿瘤患者（n=21）接受了新辅助治疗，即1个周期的atezolizumab单药治疗，随后4个周期的atezolizumab联合多西他赛、奥沙利铂和卡培他滨治疗。治疗耐受性良好。20例患者中有2例（10%）发生了3级免疫相关不良事件，但没有发生4级或5级免疫相关不良事件，所有患者均接受了手术切除，无治疗相关延迟，达到了安全性和可行性的主要终点。在多个时间点获得组织，分析单药抗程序性细胞死亡配体1（PD-L1）和随后联合化疗对TME的影响。21例患者中有20例接受了手术，并可评价继发性病理反应和生存终点，19例可评价探索性转化分析。20例患者中有14例（70%，95%可信区间46-88%）出现主要病理反应（≤10%残留肿瘤），其中9例（45%，95%可信区间23-68%）出现病理完全反应。中位随访时间为47个月，14名应答者中有13名存活且无病，6名无应答者中有5名因复发而死亡。值得注意的是，基线抗程序性细胞死亡蛋白1（PD-1）+CD8+T细胞浸润在应答者中显著高于无应答者，并且抗PD-L1单药治疗与随后联合化疗后TME改变的比较显示，单药PD-1/L1轴阻断后免疫激活增加。在这些数据的基础上，在联合化疗之前，单药治疗抗PD-L1值得在更大的非转移性G/GEJ癌症患者队列中进行进一步的探索和验证。ClinicalTrials.gov注册：NCT03448835。

英文原文如下：

Abstracts

Gastric and gastroesophageal junction (G/GEJ) cancers carry a poor prognosis, and despite recent advancements, most patients die of their disease. Although immune checkpoint blockade became part of the standard-of-care for patients with metastatic G/GEJ cancers, its efficacy and impact on the tumor microenvironment (TME) in early disease remain largely unknown. We hypothesized higher efficacy of neoadjuvant immunotherapy plus chemotherapy in patients with nonmetastatic G/GEJ cancer. In the phase 2 PANDA trial, patients with previously untreated resectable G/GEJ tumors (n = 21) received neoadjuvant treatment with one cycle of atezolizumab monotherapy followed by four cycles of atezolizumab plus docetaxel, oxaliplatin and capecitabine. Treatment was well tolerated. There were grade 3 immune-related adverse events in two of 20 patients (10%) but no grade 4 or 5 immune-related adverse events, and all patients underwent resection without treatment-related delays, meeting the primary endpoint of safety and feasibility. Tissue was obtained at multiple time points, allowing analysis of the effects of single-agent anti-programmed cell death ligand 1 (PD-L1) and the subsequent combination with chemotherapy on the TME. Twenty of 21 patients underwent surgery and were evaluable for secondary pathologic response and survival endpoints, and 19 were evaluable for exploratory translational analyses. A major pathologic response (≤10% residual viable tumor) was observed in 14 of 20 (70%, 95% confidence interval 46-88%) patients, including 9 (45%, 95% confidence interval 23-68%) pathologic complete responses. At a median follow-up of 47 months, 13 of 14 responders were alive and disease-free, and five of six nonresponders had died as a result of recurrence. Notably, baseline anti-programmed cell death protein 1 (PD-1)+CD8+ T cell infiltration was significantly higher in responders versus nonresponders, and comparison of TME alterations following anti-PD-L1 monotherapy versus the subsequent combination with chemotherapy showed an increased immune activation on single-agent PD-1/L1 axis blockade. On the basis of these data, monotherapy anti-PD-L1 before its combination with chemotherapy warrants further exploration and validation in a larger cohort of patients with nonmetastatic G/GEJ cancer. ClinicalTrials.gov registration: NCT03448835 .

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