Clinical studies support the efficacy of programmed cell death 1 (PD-1) targeted therapy in a subset of patients with metastatic gastric cancer (mGC). With the goal of identifying determinants of response, we performed molecular characterization of tissues and circulating tumor DNA (ctDNA) from 61 patients with mGC who were treated with pembrolizumab as salvage treatment in a prospective phase 2 clinical trial. In patients with microsatellite instability-high and Epstein-Barr virus-positive tumors, which are mutually exclusive, dramatic responses to pembrolizumab were observed (overall response rate (ORR) 85.7% in microsatellite instability-high mGC and ORR 100% in Epstein-Barr virus-positive mGC). For the 55 patients for whom programmed death-ligand 1 (PD-L1) combined positive score positivity was available (combined positive score cut-off value ≥1%), ORR was significantly higher in PD-L1(+) gastric cancer when compared to PD-L1(-) tumors (50.0% versus 0.0%, P value <0.001). Changes in ctDNA levels at six weeks post-treatment predicted response and progression-free survival, and decreased ctDNA was associated with improved outcomes. Our findings provide insight into the molecular features associated with response to pembrolizumab in patients with mGC and provide biomarkers potentially relevant for the selection of patients who may derive greater benefit from PD-1 inhibition.

中文翻译：

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转移性胃癌中对PD-1抑制的临床反应的全面分子表征。

临床研究支持在部分转移性胃癌（mGC）患者中进行程序性细胞死亡1（PD-1）靶向治疗的功效。为了确定反应的决定因素，我们在一项前瞻性2期临床试验中对61例接受了派姆单抗治疗的mGC患者进行了组织分子表征和循环肿瘤DNA（ctDNA）的研究。在微卫星不稳定性高和爱泼斯坦-巴尔病毒阳性的肿瘤相互排斥的患者中，观察到了对pembrolizumab的剧烈反应（微卫星不稳定性高mGC的总体缓解率（ORR）为85.7％，爱泼斯坦-巴尔的ORC为100％病毒阳性mGC）。对于55例程序性死亡配体1（PD-L1）联合阳性评分阳性（合并阳性评分截止值≥1％）可用的患者，PD-L1（+）胃癌的ORR显着高于对PD-L1（-）肿瘤有效（50.0％对0.0％，P值<0.001）。治疗后六周ctDNA水平的变化可预测疗效和无进展生存期，而ctDNA降低与预后改善相关。我们的发现提供了对mGC患者对pembrolizumab应答相关分子特性的见解，并提供了与可能从PD-1抑制中获益更大的患者选择相关的生物标记物。治疗后六周ctDNA水平的变化可预测疗效和无进展生存期，而ctDNA降低与预后改善相关。我们的发现提供了对mGC患者对pembrolizumab应答相关分子特性的见解，并提供了与可能从PD-1抑制中获益更大的患者选择相关的生物标记物。治疗后六周ctDNA水平的变化可预测疗效和无进展生存期，而ctDNA降低与预后改善相关。我们的发现提供了对mGC患者对pembrolizumab应答相关分子特性的见解，并提供了与可能从PD-1抑制中获益更大的患者选择相关的生物标记物。