Phase 3 Intravesical Immunotherapy Trial: Tumors Completely Disappeared in Three-Quarters of Patients, With an 81% Bladder-Preservation Rate at Two Years

For patients with high-risk bladder cancer, the next step after standard immunotherapy fails is often removal of the entire bladder. Now, an international phase 3 trial suggests that cretostimogene grenadenorepvec, an experimental oncolytic immunotherapy administered directly into the bladder, may allow some patients to delay or avoid this life-altering surgery.

Cohort C of the BOND-003 trial was conducted at 41 medical centers across North America, Asia, and Australia. It enrolled 115 patients with high-risk non-muscle-invasive bladder cancer that was unresponsive to bacillus Calmette-Guérin (BCG) treatment; 112 received treatment, and 110 were evaluable for the primary efficacy endpoint. All patients had carcinoma in situ, with or without concurrent high-grade Ta or T1 papillary tumors, and were either medically unsuitable for radical cystectomy or had declined the surgery.

Among evaluable patients, 83 achieved a centrally confirmed complete response at some point after treatment, meaning that cancer was no longer detected, for a complete response rate of 75.5%; the 95% confidence interval was 66.3% to 83.2%. At a median follow-up of 25.8 months, the median duration of response reached 27.9 months. Among patients who achieved a complete response, the estimated proportions who remained in response at 12 and 24 months were 64.2% and 60.1%, respectively.

Bladder-preservation outcomes also received considerable attention. The trial estimated that approximately 89% of patients had not undergone cystectomy 12 months after treatment began, compared with approximately 81% at 24 months. However, these figures should not be interpreted directly as showing that the drug spared all of these patients from surgery: participants were required from the outset to be unsuitable for or to decline cystectomy, and whether they subsequently underwent surgery could also be affected by personal choice, changes in the disease, and clinical judgment.

In terms of safety, 63% of treated patients experienced treatment-related adverse events. Common events included bladder spasms, urinary frequency, urinary urgency, painful urination, and blood in the urine; most were transient and mild. The study recorded no grade 3 or 4 treatment-related adverse events, and no patients discontinued treatment or died because of treatment side effects; two patients experienced serious but grade 2 treatment-related events.

The main limitation of these results is the trial’s open-label, single-arm design, with no direct comparison between cretostimogene and other bladder-preserving therapies or cystectomy. In addition, the primary endpoint was a complete response occurring “at any time,” so the 75.5% figure alone cannot establish long-term comparative benefit. Controlled studies, longer follow-up of recurrence and survival, and review by regulatory authorities are still needed. Cretostimogene remains an investigational therapy and has not been approved by the US Food and Drug Administration or other health authorities.