BOND-003 Cohort C

Background

Single-arm, international, registrational phase 3 trial at 41 community and academic centres in North America, Asia and Australia (NCT04452591). 115 enrolled, 112 treated. High-risk, BCG-unresponsive non-muscle-invasive bladder cancer with carcinoma in situ, with or without resected high-grade Ta or T1 disease; ECOG 0–2; median age 74.0 years (IQR 68.5–79.5), 74% male. Cretostimogene grenadenorepvec is an intravesical oncolytic adenoviral immunotherapy with dual mechanism — it replicates in and lyses tumour cells carrying retinoblastoma–E2F pathway alterations while amplifying the local immune response.

Results

Interventions and follow up: Arm A: Intravesical cretostimogene grenadenorepvec 1 × 10¹² viral particles per 0.8 mL, weekly × 6 as induction, followed by maintenance; re-induction permitted for persistent disease at 3 months (n=112 treated)
Arm B: None — single-arm design, no randomized comparator
Primary endpoint: Centrally confirmed complete response at any time
mFollow up: 25.8 mo (IQR 22.1–33.1)
Results: CR at any time: 75% (83 of 110; 95% CI 66.3–83.2)
Median DOR: NR in the primary report
Cystectomy-free survival: NR in the primary report
PFS / OS: NR — not endpoints of this registrational cohort

Adverse events

Any treatment-related AE: 63% (71 of 112)
Local / urinary: bladder spasm 25%, pollakiuria 22%, micturition urgency 21%
Grade 3 or 4 treatment-related: none (0%)
Serious treatment-related: 2% (2 of 112) — one grade 2 non-infective cystitis, one grade 2 bladder haemorrhage
Discontinuation: no treatment-related discontinuations
Treatment-related deaths: none

Conclusions

Intravesical cretostimogene produced a centrally confirmed any-time complete response in 75% of patients with high-risk BCG-unresponsive NMIBC with carcinoma in situ, sustained across a median 25.8 months of follow-up, with no grade 3 or 4 treatment-related adverse events, no treatment-related discontinuations and no treatment-related deaths. For a population whose guideline-endorsed alternative is radical cystectomy, an effective bladder-sparing option whose toxicity is almost entirely low-grade and transient local urinary symptoms is clinically meaningful.

Key Limitations

Single-arm design with no randomized comparator — efficacy rests on comparison with historical benchmarks, and cross-trial comparison against pembrolizumab (KEYNOTE-057), nadofaragene firadenovec and nogapendekin alfa inbakicept is confounded by differing eligibility definitions, central review standards, re-induction allowances and follow-up duration. Complete response at any time, rather than at a fixed landmark such as 3 or 12 months, is a permissive endpoint that accumulates with longer follow-up and is inflated by protocol-permitted re-induction. Only 112 patients were treated, and the population is elderly (median 74) and predominantly male, limiting generalizability. The outcomes that actually matter to patients — durability of response, cystectomy-free survival, and progression to muscle-invasive or metastatic disease — are not the primary endpoint and are not reported here. The trial is ongoing and follow-up remains immature for progression events. Study sites were selected through a sponsor-led qualification process, which may favour higher-performing centres.

Clinical Context

High-risk BCG-unresponsive NMIBC with carcinoma in situ is a setting where radical cystectomy remains the guideline-endorsed standard, and every currently available bladder-sparing alternative — pembrolizumab, nadofaragene firadenovec, and nogapendekin alfa inbakicept plus BCG — was approved on single-arm data benchmarked the same way. Cretostimogene holds FDA Breakthrough Therapy and Fast Track designations for this indication, and CG Oncology initiated a rolling biologics license application in late 2025 with BOND-003 Cohort C as the registrational dataset; no approval decision has been announced. If approved, its distinguishing feature is tolerability — zero grade 3–4 treatment-related events compares favourably with the immune-mediated toxicity of systemic pembrolizumab in a population with a median age of 74. NCCN, AUA/SUO and EAU continue to recommend radical cystectomy for BCG-unresponsive disease while endorsing intravesical and systemic alternatives for patients who decline or are unfit for surgery.

References