Department of Urology, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands; Cancer Center Amsterdam, Amsterdam, The Netherlands.
Department of Radiation Oncology, Isala Hospital Zwolle, Zwolle, The Netherlands.
Eur Urol. 2022 Nov;82(5):518-526. doi: 10.1016/j.eururo.2022.07.009. Epub 2022 Aug 3.
Muscle-invasive bladder cancer (MIBC) has a poor prognosis. Chemoradiotherapy (CRT) in selected patients has comparable results to radical cystectomy. Results of neoadjuvant immune checkpoint inhibitors (ICIs) before radical cystectomy are promising. We hypothesize that ICI concurrent to CRT (iCRT) is safe and may improve treatment outcomes.
To determine the safety of iCRT for MIBC.
DESIGN, SETTING, AND PARTICIPANTS: This multicenter, phase 1b, open-label, dose-escalation study determined the safety of CRT with three ICI regimens in patients with nonmetastatic (T2-4aN0-1) MIBC. Twenty-six patients received mitomycin C/capecitabine and 20 × 2.75 Gy to the bladder. Tolerability was evaluated in a cohort of up to ten patients. If two or fewer out of the first six patients or three or fewer of ten patients experienced dose-limiting toxicity (DLT), accrual continued in the next cohort.
Patients received nivolumab 480 mg (NIVO480), nivolumab 3 mg/kg and ipilimumab 1 mg/kg (NIVO3 + IPI1), or nivolumab 1 mg/kg and ipilimumab 3 mg/kg (IPI3 + NIVO1).
The primary endpoint was safety. Secondary objectives were response rate, disease-free survival, metastatic-free survival (MFS), and overall survival (OS).
In the NIVO480 cohort, no patients experienced DLT. The NIVO3 + IPI1 2 patients experienced DLT, thrombocytopenia (grade 4), and asystole (grade 5). IPI3 + NIVO1 was discontinued after three out of six patients experienced DLT. Clinically significant adverse events (AEs) of grade ≥3 occurred in zero, three, and five patients in the NIVO480, NIVO3 + IPI1, and IPI3 + NIVO1 groups, respectively. The most common AEs were immune related and gastrointestinal. MFS and OS were 90% at 2 yr for NIVO480 and 90% at 1 yr for NIVO3 + IPI1. Limitations include the absence of a centralized pathology and radiology review, and a lack of biomarker analysis.
In this dose-finding study of iCRT, the regimens of nivolumab monotherapy and nivolumab 3 mg/kg with ipilimumab 1 mg/kg have acceptable toxicity.
We tested the safety of a new bladder-sparing treatment modality for muscle-invasive bladder cancer patients, combining immune checkpoint inhibitors simultaneously with chemoradiotherapy. We report that two regimens, nivolumab monotherapy and nivolumab 3 mg/kg with ipilimumab 1 mg/kg, are safe and can be used in phase 3 trials.
肌层浸润性膀胱癌（MIBC）预后较差。在选定的患者中，放化疗（CRT）与根治性膀胱切除术的结果相当。新辅助免疫检查点抑制剂（ICI）在根治性膀胱切除术前的疗效令人鼓舞。我们假设 CRT 时联合使用 ICI（iCRT）是安全的，并可能改善治疗结果。
确定 MIBC 患者接受 iCRT 的安全性。
设计、地点和参与者：这是一项多中心、1b 期、开放标签、剂量递增研究，旨在确定三种 ICI 方案联合 CRT 治疗非转移性（T2-4aN0-1）MIBC 患者的安全性。26 例患者接受丝裂霉素 C/卡培他滨和 20×2.75 Gy 膀胱照射。在前 10 例患者中最多有 10 例患者评估耐受性。如果前 6 例患者中只有 2 例或更少或 10 例患者中有 3 例或更少发生剂量限制毒性（DLT），则在下一个队列中继续入组。
患者接受纳武单抗 480 mg（NIVO480）、纳武单抗 3 mg/kg 联合伊匹单抗 1 mg/kg（NIVO3+IPI1）或纳武单抗 1 mg/kg 联合伊匹单抗 3 mg/kg（IPI3+NIVO1）。
主要终点是安全性。次要目标是反应率、无病生存率、无转移生存率（MFS）和总生存率（OS）。
在 NIVO480 队列中，没有患者发生 DLT。NIVO3+IPI1 队列中有 2 例患者发生 DLT，血小板减少症（4 级）和心搏停止（5 级）。由于 6 例患者中有 3 例发生 DLT，IPI3+NIVO1 被停用。NIVO480、NIVO3+IPI1 和 IPI3+NIVO1 组分别有 0、3 和 5 例患者发生≥3 级的临床显著不良事件（AE）。最常见的 AE 是免疫相关和胃肠道。NIVO480 的 2 年 MFS 和 OS 均为 90%，NIVO3+IPI1 的 1 年 MFS 和 OS 均为 90%。局限性包括缺乏中央病理学和放射学审查，以及缺乏生物标志物分析。
在这项 iCRT 的剂量探索研究中，纳武单抗单药和纳武单抗 3 mg/kg 联合伊匹单抗 1 mg/kg 的方案具有可接受的毒性。
我们测试了一种新的膀胱保留治疗方法治疗肌层浸润性膀胱癌患者的安全性，同时联合使用免疫检查点抑制剂和放化疗。我们报告，纳武单抗单药和纳武单抗 3 mg/kg 联合伊匹单抗 1 mg/kg 两种方案是安全的，可以在 3 期试验中使用。
