Bacillus Calmette–Guérin (BCG) induction and maintenance (I+M) after transurethral resection of bladder tumor is standard of care (SOC) in high-risk non-muscle invasive bladder cancer (NMIBC). However, disease recurrence/progression occurs in approximately 40% of patients at 2 years, with unfavorable prognosis. Limited bladder-sparing therapeutic options exist, and no improvements to response durability have been observed in decades. CREST is a global, phase 3, randomized trial evaluating subcutaneous sasanlimab in combination with BCG-I+M (Arm A), sasanlimab in combination with BCG-I (Arm B) or BCG-I+M (Arm C) in BCG-naive high-risk NMIBC. The primary endpoint was investigator-assessed event-free survival (EFS) for Arm A versus Arm C; key secondary endpoints were EFS (Arm B versus Arm C) and overall survival. Patients were randomized 1:1:1 to Arm A (N = 352), Arm B (N = 352) and Arm C (N = 351). The trial met its primary endpoint with a statistically significant and clinically meaningful prolongation of EFS (Arm A versus Arm C); hazard ratio, 0.68 (95% confidence interval: 0.49–0.94); one-sided P = 0.0095. The 36-month estimated EFS rates were 82.1% (Arm A) and 74.8% (Arm C). EFS benefit for Arm A versus Arm C was observed across prespecified subgroups, including carcinoma in situ (CIS) and T1. The safety profile of the combination was consistent with the known profiles. To our knowledge, sasanlimab is the first anti-PD-1 antibody to show a clinically meaningful prolongation of EFS when combined with BCG-I+M versus SOC in patients with BCG-naive high-risk NMIBC. Sasanlimab combined with BCG-I+M has the potential to redefine the treatment paradigm and clinical decision-making for patients with BCG-naive high-risk NMIBC. ClinicalTrials.gov identifier: NCT04165317.

经尿道膀胱肿瘤切除术后卡介苗 （BCG） 诱导和维持 （I+M） 是高危非肌层浸润性膀胱癌 （NMIBC） 的标准治疗 （SOC）。然而，大约 40% 的患者在 2 年时出现疾病复发/进展，预后不良。保留膀胱的治疗选择有限，几十年来未观察到反应持久性的改善。CREST 是一项全球性的 3 期随机试验，评估皮下注射 sasanlimab 联合 BCG-I+M（A 组）、sasanlimab 联合 BCG-I（B 组）或 BCG-I+M（C 组）治疗 BCG 初治高危 NMIBC。主要终点是研究者评估的 A 组与 C 组的无事件生存期 （EFS）;关键次要终点是 EFS （B 组与 C 组） 和总生存期。患者以 1：1：1 的比例随机分配到 A 组 （n = 352） 、 B 组 （n = 352） 和 C 组 （n = 351）。该试验达到其主要终点，EFS 延长具有统计学意义和临床意义（A 组与 C 组）;风险比，0.68 （95% 置信区间：0.49-0.94）;单侧 P = 0.0095。36 个月估计的 EFS 发生率为 82.1%（A 组）和 74.8%（C 组）。在预先指定的亚组中观察到 A 组与 C 组的 EFS 获益，包括原位癌 （CIS） 和 T1。该组合的安全性特征与已知的特征一致。据我们所知，sasanlimab 是第一个在 BCG 初治高危 NMIBC 患者中与 BCG-I+M 与 SOC 联合使用时显示 EFS 具有临床意义延长的抗 PD-1 抗体。Sasanlimab 联合 BCG-I+M 有可能重新定义 BCG 初治高危 NMIBC 患者的治疗范式和临床决策。ClinicalTrials.gov 标识符：NCT04165317。