Intravesical cretostimogene grenadenorepvec oncolytic immunotherapy in high-risk, BCG-unresponsive, non-muscle-invasive bladder cancer with carcinoma in situ (BOND-003 Cohort C): a single-arm, phase 3 trial.

Cretostimogene grenadenorepvec (hereafter, cretostimogene) is an oncolytic immunotherapy with dual mechanisms of action-it replicates in and lyses cancer cells with retinoblastoma-E2F pathway alterations and amplifies the immune response.

Cretostimogene grenadenorepvec（以下简称cretostimogene）是一种具有双重作用机制的溶瘤免疫疗法——它在具有视网膜母细胞瘤-E2F通路改变的癌细胞中复制并裂解癌细胞，并放大免疫反应。

We evaluated the response and safety/tolerability of cretostimogene in patients with high-risk, BCG-unresponsive, non-muscle-invasive bladder cancer.

我们评估了cretostimogene在高风险、BCG无应答、非肌层浸润性膀胱癌患者中的疗效和安全性/耐受性。

Methods

BOND-003 Cohort C is a single-arm, international, phase 3 study done in 41 centres (community practices and academic centres) located in North America, Asia, and Australia.

BOND-003队列C是一项单臂、国际、3期研究，研究在北美、亚洲和澳大利亚的41个中心（社区实践和学术中心）进行。

Sites were selected through a study team-led qualification process that evaluated feasibility, protocol alignment, operational capabilities, and regulatory readiness, as applicable.

通过研究团队主导的资格评估过程选择研究地点，评估了可行性、协议一致性、运营能力和监管准备情况，适用的情况下。

We enrolled patients aged at least 18 years with Eastern Cooperative Oncology Group performance status of 0-2 and pathologically confirmed, high-risk, BCG-unresponsive, non-muscle-invasive bladder cancer with carcinoma in situ, with or without resected high-grade Ta or T1 disease.

我们招募了至少18岁的患者，东部肿瘤协作组（ECOG）表现状态为0-2，且病理证实为高风险、BCG无应答、非肌层浸润性膀胱癌，伴有或不伴有切除的高级别Ta或T1疾病。

Patients received intravesical cretostimogene (1 × 1012 viral particles per 0·8 mL per week) as 6-week induction followed by maintenance; re-induction was permitted for persistent disease at 3 months.

患者接受了膀胱内注射cretostimogene（每周0·8毫升，1 × 1012病毒颗粒），为期6周的诱导治疗后进行维持治疗；对于3个月时仍持续存在的疾病，允许重新诱导。

The primary endpoint was centrally confirmed complete response at any time in patients who received at least one dose of cretostimogene and completed the 3-month assessment; safety was assessed in those who received at least one dose of cretostimogene.

主要终点是接受至少一次cretostimogene治疗并完成3个月评估的患者在任何时间点的中心确认的完全缓解；安全性评估在那些接受至少一次cretostimogene治疗的患者中进行。

This trial is registered with ClinicalTrials.gov (NCT04452591) and is ongoing.

该试验已在ClinicalTrials.gov注册（NCT04452591），目前正在进行中。

Results

Between Oct 9, 2020, and Aug 3, 2023, 165 patients were assessed for eligibility; 115 patients were enrolled in the study and 112 received cretostimogene. 83 (74%) were male and 29 (26%) were female; median age was 74·0 years (IQR 68·5-79·5).

在2020年10月9日至2023年8月3日期间，共有165名患者进行了资格评估；115名患者被纳入研究，其中112名接受了cretostimogene治疗。其中83名（74%）为男性，29名（26%）为女性；中位年龄为74·0岁（四分位数间距68·5-79·5）。

As of June 23, 2025, after a median follow-up of 25·8 months (IQR 22·1-33·1), complete response at any time was observed in 83 (75% [95% CI 66·3-83·2]) of 110 patients. 71 (63%) of 112 patients had at least one treatment-related adverse event, the most common being bladder spasm in 28 (25%) patients, pollakiuria in 25 (22%) patients, and micturition urgency in 23 (21%) patients; there were no grade 3 or 4 treatment-related adverse events and no treatment-related discontinuations or deaths.

截至2025年6月23日，经过中位随访时间25·8个月（四分位数间距22·1-33·1），在110名患者中有83名（75% [95% CI 66·3-83·2]）观察到任何时间点的完全缓解。在112名患者中有71名（63%）至少出现一次与治疗相关的不良事件，最常见的为膀胱痉挛在28名（25%）患者中，频尿在25名（22%）患者中，排尿急迫在23名（21%）患者中；没有出现3级或4级的与治疗相关的不良事件，也没有因治疗相关的中断治疗或死亡。

Two (2%) patients had serious treatment-related adverse events (one non-infective cystitis and one urinary bladder haemorrhage, both grade 2).

有两名（2%）患者出现了严重的与治疗相关的不良事件（一名为非感染性膀胱炎，一名为尿路膀胱出血，均为2级）。

interpretation

Cretostimogene showed clinically meaningful anti-tumour response, with an adverse eventprofile characterised predominantly by low-grade, transient events.

Cretostimogene显示出具有临床意义的抗肿瘤反应，其不良事件特征主要为低级别、短暂性事件。

Cretostimogene shows promise as an innovative bladder-sparing treatment for high-risk, BCG-unresponsive, non-muscle-invasive bladder cancer with carcinoma in situ.

Cretostimogene作为一种创新的膀胱保护治疗手段，对于高风险、BCG无反应、非肌层浸润性膀胱癌伴原位癌显示出巨大潜力。

funding

CG Oncology.

CG肿瘤学。