本文由小咖机器人翻译整理

期刊来源：Nat Med

原文链接：https://doi.org/10.1038/s41591-024-03025-3

摘要内容如下：

Cretostimogene Grenadenorepvec是一种血清5型溶瘤腺病毒，设计用于在视网膜母细胞瘤通路改变的癌细胞中选择性复制，先前在卡介苗（BCG）经历的非肌层浸润性膀胱癌中作为单一疗法进行测试。在这项2期研究中，我们评估了膀胱内注射Cretostimogene和全身性pembrolizumab对卡介苗（BCG）无反应的非肌层浸润性膀胱癌原位癌（CIS）患者的潜在协同疗效。35名患者接受了膀胱内Cretostimogene和全身pembrolizumab治疗。在维持完全缓解（Cr）的患者中，诱导Cretostimogene每周给药一次，持续6周，然后在第3、6、9、12和18个月进行每周三次的维持输注。在3个月的评估中，持续性CIS/高级别TA的患者符合再次诱导的条件。Pembrolizumab给药长达24个月。主要终点是12个月时的Cr，通过膀胱镜检查、尿细胞学检查、横断面成像和强制性膀胱定位活检进行评估。次要终点包括任何时间的Cr、缓解持续时间、无进展生存期和安全性。在12个月时，意向治疗人群的CR率为57.1%（35人中有20人，95%可信区间（CI）为40.7-73.5%），达到了主要终点。35例患者中共有29例（82.9%，95%CI 70.4-95.3%）在3个月时获得Cr。中位随访时间为26.5个月，中位缓解持续时间尚未达到（95%CI 15.7至未达到）。24个月时的CR率为51.4%（18/35）（95%CI 34.9-68.0%）。在该试验中，没有患者进展为肌层浸润性膀胱癌。可归因于Cretostimogene的不良事件为低度、自限性且主要限于膀胱相关症状。免疫相关不良反应仅与pembrolizumab有关。35例患者中共有5例（14.3%）出现3级治疗相关不良反应，均与pembrolizumab有关。没有重叠或协同毒性的证据。联合膀胱内注射Cretostimogene和全身性pembrolizumab显示出持久的疗效。由于其毒性特征与其单药治疗成分相似，这种联合治疗可能会改变卡介苗无反应CIS患者的获益风险比。ClinicalTrials.gov标识符：NCT04387461。

英文原文如下：

Abstracts

Cretostimogene grenadenorepvec is a serotype-5 oncolytic adenovirus designed to selectively replicate in cancer cells with retinoblastoma pathway alterations, previously tested as monotherapy in bacillus Calmette-Guérin (BCG)-experienced non-muscle-invasive bladder cancer. In this phase 2 study, we assessed the potential synergistic efficacy between intravesical cretostimogene and systemic pembrolizumab in patients with BCG-unresponsive non-muscle-invasive bladder cancer with carcinoma in situ (CIS). Thirty-five patients were treated with intravesical cretostimogene with systemic pembrolizumab. Induction cretostimogene was administered weekly for 6 weeks followed by three weekly maintenance infusions at months 3, 6, 9, 12 and 18 in patients maintaining complete response (CR). Patients with persistent CIS/high-grade Ta at the 3-month assessment were eligible for re-induction. Pembrolizumab was administered for up to 24 months. The primary endpoint was CR at 12 months as assessed by cystoscopy, urine cytology, cross-sectional imaging and mandatory bladder mapping biopsies. Secondary endpoints included CR at any time, duration of response, progression-free survival and safety. The CR rate in the intention-to-treat population at 12 months was 57.1% (20 out of 35, 95% confidence interval (CI) 40.7-73.5%), meeting the primary endpoint. A total of 29 out of 35 patients (82.9%, 95% CI 70.4-95.3%) derived a CR at 3 months. With a median follow-up of 26.5 months, the median duration of response has not been reached (95% CI 15.7 to not reached). The CR rate at 24 months was 51.4% (18 out of 35) (95% CI 34.9-68.0%). No patient progressed to muscle-invasive bladder cancer in this trial. Adverse events attributed to cretostimogene were low grade, self-limiting and predominantly limited to bladder-related symptoms. Immune-related adverse effects were exclusively associated with pembrolizumab. A total of 5 out of 35 patients (14.3%) developed grade 3 treatment-related adverse effects, all related to pembrolizumab. There was no evidence of overlapping or synergistic toxicities. Combination intravesical cretostimogene and systemic pembrolizumab demonstrated enduring efficacy. With a toxicity profile similar to its monotherapy components, this combination may shift the benefit-to-risk ratio for patients with BCG-unresponsive CIS. ClinicalTrials.gov Identifier: NCT04387461 .

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