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.

BACKGROUND

There are few bladder-sparing treatment options for high-risk, BCG-unresponsive, non-muscle-invasive bladder cancer that are effective and have a manageable adverse event profile. 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. We evaluated the response and safety/tolerability of cretostimogene in patients with high-risk, BCG-unresponsive, non-muscle-invasive bladder cancer.

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. Sites were selected through a study team-led qualification process that evaluated feasibility, protocol alignment, operational capabilities, and regulatory readiness, as applicable. 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. 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. 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. This trial is registered with ClinicalTrials.gov (NCT04452591) and is ongoing.

FINDINGS

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

INTERPRETATION

Cretostimogene showed clinically meaningful anti-tumour response, with an adverse event profile characterised predominantly by low-grade, transient events. Cretostimogene shows promise as an innovative bladder-sparing treatment for high-risk, BCG-unresponsive, non-muscle-invasive bladder cancer with carcinoma in situ.

FUNDING

CG Oncology.

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