新辅助吉西他滨-顺铂联合替莫唑单抗用于可切除肌层浸润性膀胱癌的多中心单臂第2期试验

Neoadjuvant gemcitabine-cisplatin plus tislelizumab in persons with resectable muscle-invasive bladder cancer: a multicenter, single-arm, phase 2 trial

Nature Cancer

影响因子:28.5

分区:医学1区 Top / 肿瘤学1区

发表日期:2024 Oct

作者: Kaiwen Li, Wenlong Zhong, Jinhai Fan, Shaogang Wang, Dexin Yu, Tao Xu, Jiaju Lyu, Shaoxu Wu, Tao Qin, Zhuo Wu, Longhao Xu, Kaijie Wu, Zheng Liu, Zhiquan Hu, Fan Li, Jinyou Wang, Qi Wang, Jie Min, Zhiqiang Zhang, Luping Yu, Sentai Ding, Longfei Huang, Tingting Zhao, Jian Huang, Tianxin Lin

DOI: 10.1038/s43018-024-00822-0

摘要

程序性死亡1（PD-1）抑制剂（替莫唑单抗）已获批用于转移性尿路上皮癌，但尚未作为肌层浸润性膀胱癌（MIBC）的新辅助治疗方案。在这项多中心单臂试验（ChiCTR2000037670）中，65名患有cT2-4aN0M0 MIBC的患者接受了吉西他滨-顺铂联合替莫唑单抗的新辅助治疗；其中57例患者接受了根治性膀胱切除术（RC）。主要终点为病理完全缓解（pCR）率，达50.9%（29/57，95%置信区间[CI] 37.3-64.4%）；次要终点为病理分期下降率，为75.4%（43/57，95% CI 62.2-85.9%）。基因组和转录组分析揭示了三种MIBC分子亚型（S）：S1（免疫沙漠型）激活细胞周期通路，S2（免疫排除型）激活转化生长因子-β通路，S3（免疫炎症型）上调干扰素-α和干扰素-γ反应。事后分析显示，pCR率在S1为16%（3/19），S2为77%（10/13），S3为80%（12/15）（P=0.006）。总结而言，吉西他滨-顺铂联合替莫唑单抗作为新辅助治疗在MIBC中显示出提高pCR的潜力。

Abstract

Programmed death 1 blockade (tislelizumab) has been approved for metastatic urothelial carcinoma but not as part of neoadjuvant therapy for muscle-invasive bladder cancer (MIBC). In this multicenter single-arm trial (ChiCTR2000037670), 65 participants with cT2-4aN0M0 MIBC received neoadjuvant gemcitabine-cisplatin plus tislelizumab; 57 of them underwent radical cystectomy (RC). The primary endpoint of pathologic complete response (pCR) rate was 50.9% (29/57, 95% confidence interval (CI) 37.3-64.4%) and the pathologic downstaging (secondary endpoint) rate was 75.4% (43/57, 95% CI 62.2-85.9%) in participants undergoing RC. Genomic and transcriptomic analyses revealed three MIBC molecular subtypes (S): S1 (immune-desert) with activated cell-cycle pathway, S2 (immune-excluded) with activated transforming growth factor-β pathway and S3 (immune-inflamed) with upregulated interferon-α and interferon-γ response. Post hoc analysis showed pCR rates of 16% (3/19, S1), 77% (10/13, S2) and 80% (12/15, S3) (P = 0.006). In conclusion, neoadjuvant gemcitabine-cisplatin plus tislelizumab for MIBC was compatible with an enhanced pCR rate.