Addition of Intravesical Recombinant BCG to Perioperative Chemo-Immunotherapy in Muscle-Invasive Bladder Cancer: Primary Analysis of the Single-Arm Phase 2 Trial SAKK 06/19

PURPOSE: Intravesical Bacillus Calmette-Guérin (BCG) is highly effective in non-muscle-invasive bladder cancer but has not been evaluated in muscle-invasive bladder cancer (MIBC). The recombinant BCG vaccine VPM1002BC (rBCG) has potentially enhanced immunogenicity and an improved safety profile. We investigated neoadjuvant intravesical rBCG combined with chemo-immunotherapy in MIBC. PATIENTS AND METHODS: SAKK 06/19 was an open-label single-arm phase II trial for cT2-T4a N0-1 MIBC eligible for cisplatin and radical cystectomy with lymphadenectomy (RC-LND). rBCG was instilled weekly x3 starting day 1. Atezolizumab was administered on day 1 for a total of 4 doses and cisplatin/gemcitabine started on day 22 for 4 cycles followed by RC-LND. Adjuvant atezolizumab was only administered in case of >yT1 ypN0. The primary endpoint was centrally reviewed pathological complete response (pCR, ypT0 ypN0). Based on Simon's minimax 2-stage design with H0 pCR ≤ 35%, H1 pCR ≥ 55%, 1-sided alpha 5% and power 80%, 46 patients were needed. Secondary endpoints included pathological overall response (PaR, ≤ypT1 ypN0), event-free survival (EFS), overall survival (OS) and safety. RESULTS: 47 patients were included between 04/2022 and 04/2025. Seven patients did not undergo RC-LND (6 declined, 1 unfit for surgery). rBCG was instilled in 95%, 78% had all 3 doses. Centrally reviewed pCR was 68% (27/40; one-sided 95% CI lower boundary 53%) and PaR was 83% (33/40; 95% CI 67% - 93%). Treatment-related adverse events (any grade, grade 3, grade 4) were 42%, 9%, 0% for rBCG; 55%, 15%, 2% for atezolizumab; and 96%, 38%, 17% for chemotherapy. CONCLUSION: This is the first trial combining intravesical rBCG with chemo-immunotherapy in MIBC, demonstrating high pCR and PaR rates that warrant further investigation in prospective randomized trials.