英国伦敦玛丽女王大学Thomas Powles等研究人员的临床试验报道了，新佐剂atezolizumab治疗可手术尿路上皮癌的临床疗效和生物标志物分析。《自然—医学》杂志于2019年11月4日在线发表了该研究成果。

研究人员进行了一项单臂2期研究，研究了95例肌肉浸润性尿路上皮癌患者在膀胱切除术前atezolizumab的两个周期（ClinicalTrials.gov编号：NCT02662309）。病理完全缓解是主要终点。次要研究重点是安全性，无复发生存和生物标志物分析。病理完全缓解率为31％（95％置信区间：21–41％），达到了主要疗效终点。基线生物标志物显示，预先存在的活化T细胞比预期的更为突出，并且与结果相关。其他已建立的生物标志物，例如肿瘤突变负荷，不能预测结果，这与转移情况有所不同。基因表达特征和蛋白质生物标志物的动态变化随治疗发生，而DNA随治疗变化的变化并不常见。响应的肿瘤在治疗后显示出与组织修复相关的基因的主要表达，这使得该组中对肿瘤生物标志物的解释具有挑战性。诸如转化生长因子-β和成纤维细胞活化蛋白之类的基质因子与抗药性有关，处理后细胞周期基因标记的高表达也与抗药性相关。

据介绍，靶向PD-1或其配体PD-L1的抗体（例如atezolizumab）在一定比例的转移性尿路上皮癌中具有巨大的功效。生物标志物可能有助于鉴定这些反应性肿瘤。这些药物的新辅助使用与包括尿路上皮癌在内的一系列肿瘤的病理完全应答有关。这些研究的顺序组织采样允许进行详细的治疗中生物标志物分析。

附：英文原文

Title: Clinical efficacy and biomarker analysis of neoadjuvant atezolizumab in operable urothelial carcinoma in the ABACUS trial

Author: Thomas Powles, Mark Kockx, Alejo Rodriguez-Vida, Ignacio Duran, Simon J. Crabb, Michiel S. Van Der Heijden, Bernadett Szabados, Albert Font Pous, Gwenaelle Gravis, Urbano Anido Herranz, Andrew Protheroe, Alain Ravaud, Denis Maillet, Maria Jose Mendez, Cristina Suarez, Mark Linch, Aaron Prendergast, Pieter-Jan van Dam, Diana Stanoeva, Sofie Daelemans, Sanjeev Mariathasan, Joy S. Tea, Kelly Mousa, Romain Banchereau, Daniel Castellano

Issue&Volume: 2019-11-04

Abstract: Antibodies targeting PD-1 or its ligand 1 PD-L1 such as atezolizumab, have great efficacy in a proportion of metastatic urothelial cancers1,2. Biomarkers may facilitate identification of these responding tumors3. Neoadjuvant use of these agents is associated with pathological complete response in a spectrum of tumors, including urothelial cancer4,5,6,7. Sequential tissue sampling from these studies allowed for detailed on-treatment biomarker analysis. Here, we present a single-arm phase 2 study, investigating two cycles of atezolizumab before cystectomy in 95 patients with muscle-invasive urothelial cancer (ClinicalTrials.gov identifier: NCT02662309). Pathological complete response was the primary endpoint. Secondary endpoints focused on safety, relapse-free survival and biomarker analysis. The pathological complete response rate was 31% (95% confidence interval: 21–41%), achieving the primary efficacy endpoint. Baseline biomarkers showed that the presence of preexisting activated T cells was more prominent than expected and correlated with outcome. Other established biomarkers, such as tumor mutational burden, did not predict outcome, differentiating this from the metastatic setting. Dynamic changes to gene expression signatures and protein biomarkers occurred with therapy, whereas changes in DNA alterations with treatment were uncommon. Responding tumors showed predominant expression of genes related to tissue repair after treatment, making tumor biomarker interpretation challenging in this group. Stromal factors such as transforming growth factor-β and fibroblast activation protein were linked to resistance, as was high expression of cell cycle gene signatures after treatment.

DOI: 10.1038/s41591-019-0628-7

Source: https://www.nature.com/articles/s41591-019-0628-7