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Phase 1 Study of Chemoradiotherapy Combined with Nivolumab ± Ipilimumab for the Curative Treatment of Muscle-invasive Bladder Cancer
European Urology ( IF 23.4 ) Pub Date : 2022-08-03 , DOI: 10.1016/j.eururo.2022.07.009
Ben-Max de Ruiter 1 , Jons W van Hattum 1 , Djoeri Lipman 2 , Theo M de Reijke 1 , R Jeroen A van Moorselaar 3 , Erik J van Gennep 4 , A H Maartje Piet 3 , Mila Donker 5 , Tom van der Hulle 6 , Jens Voortman 7 , Jorg R Oddens 1 , Maarten C C M Hulshof 8 , Adriaan D Bins 9
Affiliation  

Background

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.

Objective

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.

Intervention

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).

Outcome measurements and statistical analysis

The primary endpoint was safety. Secondary objectives were response rate, disease-free survival, metastatic-free survival (MFS), and overall survival (OS).

Results and limitations

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.

Conclusions

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.

Patient summary

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.



中文翻译:

放化疗联合 Nivolumab ± Ipilimumab 治疗肌层浸润性膀胱癌的 1 期研究

背景

肌层浸润性膀胱癌 (MIBC) 的预后较差。对选定患者进行放化疗 (CRT) 的结果与根治性膀胱切除术相当。根治性膀胱切除术前新辅助免疫检查点抑制剂 (ICI) 的结果很有希望。我们假设 ICI 同步进行 CRT (iCRT) 是安全的,并且可以改善治疗结果。

客观的

确定 iCRT 对 MIBC 的安全性。

设计、设置和参与者

这项多中心、1b 期、开放标签、剂量递增研究确定了 CRT 与三种 ICI 方案在非转移性 (T2-4aN0-1) MIBC 患者中的安全性。26 名患者接受了丝裂霉素 C/卡培他滨和 20 × 2.75 Gy 的膀胱照射。在多达 10 名患者的队列中评估了耐受性。如果前 6 名患者中有 2 名或更少患者或 10 名患者中有 3 名或更少患者出现剂量限制性毒性 (DLT),则在下一个队列中继续增加。

干涉

患者接受 nivolumab 480 mg (NIVO480)、nivolumab 3 mg/kg 和 ipilimumab 1 mg/kg (NIVO3 + IPI1),或 nivolumab 1 mg/kg 和 ipilimumab 3 mg/kg (IPI3 + NIVO1)。

结果测量和统计分析

主要终点是安全性。次要目标是反应率、无病生存期、无转移生存期 (MFS) 和总生存期 (OS)。

结果和局限性

在 NIVO480 队列中,没有患者经历 DLT。NIVO3 + IPI1 2 名患者经历了 DLT、血小板减少症(4 级)和心搏停止(5 级)。IPI3 + NIVO1 在六分之三的患者经历 DLT 后停用。在 NIVO480、NIVO3 + IPI1 和 IPI3 + NIVO1 组中,分别有 0 名、3 名和 5 名患者发生了≥3 级的临床显着不良事件 (AE)。最常见的 AE 是免疫相关的和胃肠道的。NIVO480 的 MFS 和 OS 在 2 年时为 90%,而 NIVO3 + IPI1 在 1 年时为 90%。局限性包括缺乏集中的病理学和放射学审查,以及缺乏生物标志物分析。

结论

在这项 iCRT 剂量探索研究中,nivolumab 单一疗法和 nivolumab 3 mg/kg 联合 ipilimumab 1 mg/kg 的方案具有可接受的毒性。

患者总结

我们针对肌肉浸润性膀胱癌患者测试了一种新的保留膀胱治疗方式的安全性,该方式将免疫检查点抑制剂与放化疗同时进行。我们报告说,纳武单抗单一疗法和纳武单抗 3 mg/kg 加易普利姆玛 1 mg/kg 两种方案是安全的,可用于 3 期试验。

更新日期:2022-08-03
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