Addition of Intravesical Recombinant Bacillus Calmette-Guérin to Perioperative Chemoimmunotherapy in Muscle-Invasive Bladder Cancer: Primary Analysis of the Single-Arm Phase II Trial SAKK 06/19

Abstract

PURPOSE Intravesical Bacillus Calmette-Guérin (BCG) is highly effective in non–muscle-invasive bladder cancer (MIBC) but has not been evaluated in MIBC. The recombinant BCG vaccine VPM1002BC (rBCG) has potentially enhanced immunogenicity and an improved safety profile. We investigated neoadjuvant intravesical rBCG combined with chemoimmunotherapy 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 lymph node dissection (RC-LND). rBCG was instilled once per week three times starting on day 1. Atezolizumab was administered on day 1 for a total of four doses, and cisplatin/gemcitabine was started on day 22 for four cycles followed by RC-LND. Adjuvant atezolizumab was only administered in the case of >yT1 ypN0. The primary end point was centrally reviewed pathologic complete response (pCR, ypT0 ypN0). Based on Simon's minimax two-stage design with H0 pCR ≤35%, H1 pCR ≥55%, one-sided alpha 5%, and power 80%, 46 patients were needed. Secondary end points included pathologic overall response (PaR, ≤ypT1 ypN0), event-free survival (EFS), overall survival (OS), and safety. RESULTS Forty-seven patients were included between April 2022 and April 2025. Seven patients did not undergo RC-LND (six declined, one unfit for surgery). rBCG was instilled in 95%, and 78% had all three doses. Centrally reviewed pCR was 68% (27 of 40; one-sided 95% CI lower boundary 53%), and PaR was 83% (33 of 40; 95% CI, 67 to 93). Treatment-related adverse events (any grade, grade 3, grade 4) were 42%, 9%, and 0% for rBCG; 55%, 15%, and 2% for atezolizumab; and 96%, 38%, and 17% for chemotherapy. CONCLUSION To our knowledge, this is the first trial combining intravesical rBCG with chemoimmunotherapy in MIBC, demonstrating high pCR and PaR rates that warrant further investigation in prospective randomized trials.