background：checkpoint inhibitors have shown modest activity in patients with advanced hepatocellular carcinoma (hcc). herein, the authors report a prospective single-institution clinical/translational phase 2 study of pembrolizumab in patients with advanced hcc and circulating biomarkers closely related to response.
methods：pembrolizumab was administered at a dose of 200 mg intravenously every 3 weeks among patients who may have developed disease progression while receiving, were intolerant of, or refused sorafenib. the circulating levels of cytokines, chemokines, programmed cell death protein 1 (pd-1), programmed death-ligand 1 (pd-l1), and pd-l2 were correlated with response, tumor pd-l1 expression, and other clinicopathological features.
方法：在接受索拉非尼治疗时可能出现疾病进展，以及不耐受或拒绝使用索拉非尼的患者中，每3周静脉注射200mg pembrolizumab。检查与治疗反应、肿瘤组织pd-l1表达及其他临床病理特征相关的细胞因子、趋化因子、程序性死亡受体-1 (pd-1)、程序性死亡受体-配体1 (pd-l1)、pd-l2的循环水平。
results：a total of 29 patients were treated and 28 patients were evaluable for response. the most common laboratory grade 3/4 adverse events were increases in aspartate aminotransferase and/or alanine aminotransferase and serum bilirubin, which for the most part were reversible. in terms of efficacy, one patient achieved a complete response and 8 patients achieved partial responses for an overall response rate of 32%.four other patients had stable disease. the median progression-free survival was 4.5 months and the median overall survival was 13 months. response did not correlate with prior sorafenib therapy, pd-l1 tumor staining, or a prior history of hepatitis. correlative studies revealed that high baseline plasma tgf-β levels (≥200 pg/ml) significantly correlated with poor treatment outcomes after pembrolizumab. tumor pd-l1 and plasma pd-l1/pd-1 levels were associated with plasma ifn-γ or il-10.
结果：共有29例患者接受治疗，28例患者可进行治疗反应评价。最常见的实验室3/4级不良事件是天冬氨酸转氨酶和/或丙氨酸转氨酶和血清胆红素的增加，这些情况大多是可逆的。在疗效方面，1例患者完全缓解，8例患者部分缓解，总缓解率为32%。另外4例患者病情稳定。中位无进展生存期为4.5个月，中位总生存期为13个月。治疗反应与先前索拉非尼治疗、pd-l1肿瘤染色或肝炎病史无关。相关研究显示，基线血浆tgf-β水平高(≥200 pg / ml)与pembrolizumab治疗结果差显著相关。肿瘤组织pd-l1和血浆pd-l1 / pd-1水平与血浆ifn-γ 或 il-10相关。
conclusions:pembrolizumab was found to demonstrate activity in patients with advanced hcc. toxicity generally was tolerable and reversible. a set of immunological markers in blood plasma as well as pd-l1 staining indicated that baseline tgf-β could be a predictive biomarker for response to pembrolizumab.