New York-Presbyterian/Columbia University Medical Center, Hematology/Oncology, 177 Fort Washington Avenue, 6GN-435, New York, NY, 10032, USA.
J Immunother Cancer. 2017 Nov 21;5(1):94. doi: 10.1186/s40425-017-0299-1.
Treatment options for metastatic urothelial carcinoma (mUC) remained relative unchanged over the last 30 years with combination chemotherapy as the mainstay of treatment. Within the last year the landscape for mUC has seismically shifted following the approval of five therapies targeting the programmed cell death protein (PD-1)/programmed cell death ligand 1 (PD-L1) axis. Notably, the anti-PD-1 antibody pembrolizumab demonstrated improved OS relative to chemotherapy in a randomized phase III study for second line treatment of mUC; this level 1 evidence led to approval from the U.S. Food and Drug Administration (FDA). The PD-1 antibody nivolumab also demonstrated an overall survival benefit, in this case in comparison to historical controls. Similarly, antibodies targeting PD-L1 including atezolizumab, durvalumab, and avelumab have now received accelerated approval from the FDA as second line treatments for mUC, with durable response lasting more than 1 year in some patients. Some of these agents are approved in the first line setting as well - based on single-arm phase II studies atezolizumab and pembrolizumab received accelerated approval for first-line treatment of cisplatin ineligible patients. Despite these multiple approvals, the development of clinically useful biomarkers to determine the optimal treatment for patients remains somewhat elusive. In this review, we examine key clinical trial results with anti-PD1/PD-L1 antibodies and discuss progress towards developing novel biomarkers beyond PD-L1 expression.
在过去的 30 年中，转移性尿路上皮癌（mUC）的治疗选择相对没有改变，联合化疗仍然是治疗的主要方法。在过去的一年中，随着五种针对程序性细胞死亡蛋白（PD-1）/程序性细胞死亡配体 1（PD-L1）轴的治疗方法的批准，mUC 的治疗格局发生了重大变化。值得注意的是，抗 PD-1 抗体 pembrolizumab 在 mUC 的二线治疗的随机 III 期研究中，与化疗相比，改善了 OS；这一 1 级证据导致美国食品和药物管理局（FDA）批准。PD-1 抗体 nivolumab 也显示出总生存获益，在这种情况下，与历史对照相比。同样，针对 PD-L1 的抗体包括 atezolizumab、durvalumab 和 avelumab，现在也已获得 FDA 的加速批准，作为 mUC 的二线治疗药物，一些患者的持久反应持续超过 1 年。其中一些药物也在一线治疗中得到批准——基于单臂 II 期研究，atezolizumab 和 pembrolizumab 获得了加速批准，用于不符合顺铂治疗条件的患者的一线治疗。尽管有这些多种批准，但确定患者最佳治疗方法的临床有用生物标志物的开发仍然有些难以捉摸。在这篇综述中，我们检查了抗 PD-1/PD-L1 抗体的关键临床试验结果，并讨论了在 PD-L1 表达之外开发新型生物标志物的进展。
