Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Clin Transl Oncol. 2020 Oct;22(10):1750-1761. doi: 10.1007/s12094-020-02316-8. Epub 2020 Feb 21.
Urothelial carcinoma (UC) is an aggressive malignancy and has a poor prognosis in the metastatic state. Treatment of UC remains a challenge, and as a first-line regimen for advanced UC, standard platinum-based chemotherapy is unfit for many patients due to numerous comorbidities and poor performance status. Recently, five immune checkpoint inhibitors have been approved for the treatment of patients with advanced UC who were ineligible for platinum-based regimens or suffered tumor progression in post-platinum setting. However, not long ago, the U.S. Food and Drug Administration restricted the use of two common immune checkpoint blockades, atezolizumab and pembrolizumab, due to uncertain survival benefit as mono-therapy. In this scenario, we reviewed rapidly surfacing clinical trials to assess the efficacy and safety of immunotherapy targeting the PD-1 pathway for advanced UC.
A comprehensive search was conducted in PubMed, EMBASE and Cochrane Library for all clinical trials where the efficacy and safety were reported. Our primary outcome was efficacy evaluated by objective response rate (ORR), 1-year overall survival (OS) rate and 1-year progression-free survival (PFS) rate, and second outcome was safety assessed by any grade and grade 3-4 treatment-related adverse events (TRAEs). We chose percentages with 95% confidence intervals (CI) as the evaluation indexes and used a random-effects model to account for heterogeneity.
We included 14 clinical trials with 2674 total patients in this meta-analysis. After removing unqualified studies on the basis of sensitivity analyses, 13 studies were pooled to evaluate the overall ORR, 8 studies for the 1-year OS rate and 6 studies for the 1-year PFS rate. The pooled data of ORR, 1-year OS rate, and 1-year PFS rate were 0.20 (95% CI 0.18-0.22, I = 38.4%, P = 0.078), 0.50 (95% CI 0.46-0.53, I = 30.3%, P = 0.186), and 0.17 (95% CI 0.14-0.20, I = 0.0%, P = 0.668), respectively. Similarly, 13 trials were utilized to compute the pooled rate of any-grade TRAEs. The pooled estimation of any-grade was 0.65 (95% CI 0.63-0.67, I = 1.7%, P = 0.429). The pooled rate of grade 3-4 TRAEs subgroups with Atezolizumab, Pembrolizumab, Durvalumab, Nivolumab and Avelumab were 0.11 (95% CI 0.06-0.15, I = 83.5%, P = 0.000), 0.15 (95% CI 0.13-0.18, I = 0.0%, P = 0.971), 0.06 (95% CI 0.03-0.09, I = 0.0%, P = 0.566), 0.19 (95% CI 0.15-0.23, I = 0.0%, P = 0.480) and 0.08 (95% CI 0.05-0.11, I = 0.0%, P = 0.702), respectively.
This study showed that the immunotherapy targeting the PD-1 pathway had durable efficacy and acceptable safety in patients with advanced UC. The comprehensive role of immune checkpoint inhibitors in comparison to other treatments needs further confirmation basing on RCTs.
尿路上皮癌（UC）是一种侵袭性恶性肿瘤，转移性疾病预后不良。UC 的治疗仍然是一个挑战，作为晚期 UC 的一线方案，标准铂类化疗由于许多合并症和较差的表现状态，不适合许多患者。最近，五种免疫检查点抑制剂已被批准用于不符合铂类方案条件或在铂类治疗后肿瘤进展的晚期 UC 患者的治疗。然而，不久前，美国食品和药物管理局由于单药治疗的生存获益不确定而限制了两种常见的免疫检查点阻断剂阿替利珠单抗和帕博利珠单抗的使用。在这种情况下，我们回顾了迅速出现的临床试验，以评估 PD-1 通路免疫疗法治疗晚期 UC 的疗效和安全性。
在 PubMed、EMBASE 和 Cochrane Library 中进行了全面检索，以查找报告疗效和安全性的所有临床试验。我们的主要结局是客观缓解率（ORR）、1 年总生存率（OS）率和 1 年无进展生存率（PFS）率评估的疗效，次要结局是任何等级和 3-4 级治疗相关不良事件（TRAEs）评估的安全性。我们选择了具有 95%置信区间（CI）的百分比作为评估指标，并使用随机效应模型来解释异质性。
我们纳入了这项荟萃分析中的 14 项临床试验，共 2674 名患者。根据敏感性分析排除不合格的研究后，共有 13 项研究被纳入以评估总 ORR，8 项研究评估 1 年 OS 率，6 项研究评估 1 年 PFS 率。ORR、1 年 OS 率和 1 年 PFS 率的合并数据分别为 0.20（95%CI 0.18-0.22，I=38.4%，P=0.078）、0.50（95%CI 0.46-0.53，I=30.3%，P=0.186）和 0.17（95%CI 0.14-0.20，I=0.0%，P=0.668）。同样，我们利用 13 项试验计算了任何等级 TRAEs 的合并发生率。任何等级的合并估计值为 0.65（95%CI 0.63-0.67，I=1.7%，P=0.429）。阿替利珠单抗、帕博利珠单抗、度伐单抗、纳武利尤单抗和avelumab 的 3-4 级 TRAEs 亚组的合并发生率分别为 0.11（95%CI 0.06-0.15，I=83.5%，P=0.000）、0.15（95%CI 0.13-0.18，I=0.0%，P=0.971）、0.06（95%CI 0.03-0.09，I=0.0%，P=0.566）、0.19（95%CI 0.15-0.23，I=0.0%，P=0.480）和 0.08（95%CI 0.05-0.11，I=0.0%，P=0.702）。
这项研究表明，针对 PD-1 通路的免疫疗法在晚期 UC 患者中具有持久的疗效和可接受的安全性。免疫检查点抑制剂与其他治疗方法的综合作用需要进一步基于 RCT 进行证实。
