Phase 2 study of pembrolizumab and circulating biomarkers to predict anticancer response in advanced, unresectable hepatocellular carcinoma.
Phase 2 study of pembrolizumab and circulating biomarkers to predict anticancer response in advanced, unresectable hepatocellular carcinoma.
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DOI：
10.1002/cncr.32339
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发表时间：
2019-10-15
期刊：
影响因子：
6.2
通讯作者：
Savaraj N
中科院分区：
文献类型：
--
作者：
Feun LG;Li YY;Wu C;Wangpaichitr M;Jones PD;Richman SP;Madrazo B;Kwon D;Garcia-Buitrago M;Martin P;Hosein PJ;Savaraj N
检查点抑制剂在晚期肝细胞癌（HCC）患者中显示出适度的活性。在本文中，作者报告了一项前瞻性单机构临床/翻译2期研究，在晚期HCC患者中进行pembrolizumab，循环生物标志物与缓解密切相关。在接受索拉非尼治疗期间可能发生疾病进展、不耐受或拒绝接受索拉非尼治疗的患者中，每3周一次静脉注射200 mg Pembrolizumab。细胞因子、趋化因子、程序性细胞死亡蛋白1（PD-1）、程序性死亡配体1（PD-L1）和PD-L2的循环水平与缓解、肿瘤PD-L1表达和其他临床病理学特征相关。共29例患者接受治疗，28例患者可评价缓解。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升高，大部分是可逆的。在疗效方面，1例患者达到完全缓解，8例患者达到部分缓解，总缓解率为32%。其他4名患者病情稳定。中位无进展生存期为4.5个月，中位总生存期为13个月。缓解与既往索拉非尼治疗、PD-L1肿瘤染色或既往肝炎史无关。相关研究显示，高基线血浆TGF-β水平（≥200 pg/mL）与帕博利珠单抗治疗后的不良治疗结局显著相关。肿瘤PD-L1和血浆PD-L1/PD-1水平与血浆IFN-γ或IL-10相关。发现Pembrolizumab在晚期HCC患者中表现出活性。毒性通常是可耐受和可逆的。血浆中的一组免疫学标志物以及PD-L1染色表明，基线TGF-β可能是派姆单抗应答的预测性生物标志物。
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. 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. 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. 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.
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影响因子：
5.7
作者：
Yamazaki N;Kiyohara Y;Uhara H;Iizuka H;Uehara J;Otsuka F;Fujisawa Y;Takenouchi T;Isei T;Iwatsuki K;Uchi H;Ihn H;Minami H;Tahara H
通讯作者：
Tahara H
影响因子：
7.3
作者：
Gibbons Johnson RM;Dong H
通讯作者：
Dong H
影响因子：
7.2
作者：
Knudson KM;Hicks KC;Luo X;Chen JQ;Schlom J;Gameiro SR
通讯作者：
Gameiro SR
影响因子：
64.8
作者：
Mariathasan S;Turley SJ;Nickles D;Castiglioni A;Yuen K;Wang Y;Kadel EE III;Koeppen H;Astarita JL;Cubas R;Jhunjhunwala S;Banchereau R;Yang Y;Guan Y;Chalouni C;Ziai J;Şenbabaoğlu Y;Santoro S;Sheinson D;Hung J;Giltnane JM;Pierce AA;Mesh K;Lianoglou S;Riegler J;Carano RAD;Eriksson P;Höglund M;Somarriba L;Halligan DL;van der Heijden MS;Loriot Y;Rosenberg JE;Fong L;Mellman I;Chen DS;Green M;Derleth C;Fine GD;Hegde PS;Bourgon R;Powles T
通讯作者：
Powles T
影响因子：
7.2
作者：
Guirnalda P;Wood L;Goenka R;Crespo J;Paterson Y
通讯作者：
Paterson Y