In the phase III BOND-003 Cohort C trial, intravesical cretostimogene grenadenorepvec, an oncolytic immunotherapy, produced complete responses in three-quarters of patients with high-risk, bacillus Calmette-Guérin (BCG)-unresponsive, non–muscle-invasive bladder cancer (NMIBC) with carcinoma in situ. Among responders, many responses were maintained through 2 years, and treatment-related adverse events were predominantly mild and transient. The study was reported by Tyson et al in The Lancet Oncology.
Study Details
The international, single-arm phase III trial was conducted at 41 community and academic centers in North America, Asia, and Australia. Eligible patients were aged 18 years or older and had high-risk, BCG-unresponsive, NMIBC with carcinoma in situ, with or without resected high-grade Ta or T1 disease, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.
Cretostimogene grenadenorepvec selectively replicates in and destroys cancer cells with retinoblastoma–E2F pathway alterations while stimulating an antitumor immune response. Patients received the treatment intravesically through a urinary catheter once a week for 6 weeks. Those with persistent disease at 3 months could receive a second 6-week induction course, and patients who achieved a complete response could continue maintenance treatment.
The primary endpoint of the trial was centrally confirmed complete response at any time, including responses seen at 3 months or, after re-induction, at 6 months. Secondary endpoints included complete response at 12 months, duration of response, progression-free survival, cystectomy-free survival, overall survival, and safety.
A total of 115 patients were enrolled, and 112 received at least one dose of cretostimogene grenadenorepvec and were included in the safety analysis. The efficacy analysis included 110 patients who completed the 3-month assessment. Among enrolled patients, the median age was 74 years, 74% were male, and the group had received a median of 12 previous BCG instillations.
Key Findings
As of June 2025, after a median follow-up of 25.8 months, 83 of 110 patients (75%) achieved a complete response at any time. This significantly exceeded the prespecified historical benchmark of 20% (P < .0001). Fourteen of the complete responses occurred after re-induction.
At 12 months, 46% of patients had achieved a complete response, and 42% were still in complete response at 24 months. Among patients who achieved a complete response, the estimated probability of remaining disease-free was 64.2% at 12 months and 60.1% at 24 months. The estimated median duration of response was 27.9 months.
Cystectomy-free survival was 89% at 12 months and 81% at 24 months. Eighteen patients underwent radical cystectomy after cancer recurrence or progression. Disease progressed to a higher stage in 12% of patients, including four who developed muscle-invasive disease.
Treatment-related adverse events occurred in 63% of patients and were predominantly grade 1 or 2 bladder symptoms. The most common were bladder spasm in 25%, pollakiuria in 22%, and urinary urgency in 21%. No grade 3 or higher treatment-related adverse events were reported, and no treatment-related adverse events led to discontinuation or death. Two patients had serious treatment-related adverse events, both grade 2: one case of noninfective cystitis and one case of urinary bladder hemorrhage. The investigators noted that most patients remained progression-free and avoided radical cystectomy.
Radical cystectomy remains the guideline-recommended treatment for this population, underscoring the need for effective bladder-sparing approaches. The investigators concluded, “Cretostimogene grenadenorepvec is a novel, intravesical, potentially practice-changing therapy for patients with high-risk, BCG-unresponsive, [NMIBC] with carcinoma in situ—a population with few alternative treatment options.”
Mark D. Tyson II, MD, MPH, of the Department of Urology, Mayo Clinic, Phoenix, Arizona, is the corresponding author of the article in The Lancet Oncology.
DISCLOSURE: The study was funded by CG Oncology. For full disclosures of the study authors, visit thelancet.com.
