Cretostimogene Demonstrates Promising Activity in High-Risk BCG-Unresponsive Bladder Cancer

Key Takeaways

• In the phase 3 BOND-003 Cohort C trial, intravesical cretostimogene produced a complete response in 75% of patients with high-risk, BCG-unresponsive non-muscle-invasive bladder cancer (NMIBC) with carcinoma in situ.

• After a median follow-up of 25.8 months, the treatment demonstrated a favorable safety profile, with no grade 3 or 4 treatment-related adverse events, treatment-related discontinuations, or treatment-related deaths.

• Most treatment-related adverse events were low grade and localized to the urinary tract.

• The findings support further evaluation of cretostimogene as a potential bladder-sparing treatment option for patients with limited alternatives after BCG failure.

Patients with high-risk, BCG-unresponsive non-muscle-invasive bladder cancer (NMIBC) have limited bladder-sparing treatment options, particularly after failure of intravesical Bacillus Calmette-Guérin (BCG). Results from the phase 3 BOND-003 Cohort C study suggest that cretostimogene grenadenorepvec, an investigational intravesical oncolytic immunotherapy, may offer meaningful clinical activity with a favorable tolerability profile in this setting.

The international, single-arm trial enrolled 115 patients with pathologically confirmed, high-risk, BCG-unresponsive NMIBC with carcinoma in situ, with or without resected high-grade Ta or T1 disease. Of these, 112 patients received at least one dose of cretostimogene. Participants received six weekly intravesical instillations followed by maintenance therapy, with re-induction permitted for persistent disease at three months.

At a median follow-up of 25.8 months, a centrally confirmed complete response at any time was achieved in 83 of 110 evaluable patients, corresponding to a complete response rate of 75% (95% CI, 66.3%–83.2%).

Treatment was generally well tolerated. Seventy-one of 112 patients (63%) experienced at least one treatment-related adverse event, most commonly bladder spasm (25%), pollakiuria (22%), and urinary urgency (21%). Investigators reported no grade 3 or 4 treatment-related adverse events, no treatment-related discontinuations, and no treatment-related deaths. Two patients experienced serious treatment-related adverse events—one case each of grade 2 non-infective cystitis and urinary bladder hemorrhage.

Cretostimogene is an investigational oncolytic immunotherapy designed with dual mechanisms of action. It selectively replicates in and lyses tumor cells with alterations in the retinoblastoma–E2F pathway while also stimulating an antitumor immune response.

The investigators concluded that cretostimogene demonstrated clinically meaningful antitumor activity with an adverse event profile characterized predominantly by low-grade, transient events. They noted that the therapy may represent a promising bladder-sparing option for patients with high-risk, BCG-unresponsive NMIBC with carcinoma in situ, although the ongoing trial will continue to evaluate the durability of response and longer-term outcomes.