Multicenter phase 2a trial of neoadjuvant nivolumab with or without visugromab in muscle-invasive bladder cancer

Growth differentiation factor-15 (GDF-15) is overexpressed in muscle-invasive bladder cancer (MIBC) and was recently identified as a potential therapeutic target to overcome resistance to PDL1 blockade. The multicenter phase 2a GDFATHER-NEO trial in Italy investigated the safety and efficacy of GDF-15 blockade in cisplatin-ineligible or cisplatin-refusing patients receiving neoadjuvant nivolumab for newly diagnosed MIBC (clinical T2-T4aN0M0). Thirty-one patients were stratified by tumor stage and PDL1 combined positive score (CPS) allocated to receive three cycles of neoadjuvant nivolumab (N, 480 mg every 4 weeks) plus the GDF-15 neutralizing antibody visugromab (V, 20 mg/kg every 4 weeks; n=16) or placebo (P, n=15), followed by radical cystectomy or repeat transurthral resection of the bladder tumor. Pathologic complete response (pCR) and radiographic response were dual primary endpoints. pCR rate was 33% (95% CI 12-62) among patients receiving N+V versus 8% (0-36) in patients receiving N+P; major pathologic response rate was 60% (32-84) versus 23% (5-54), and radiographic overall response rate was 60% (32-84) versus 15% (2-45). Responses to N+V were associated with higher baseline densities of total and proliferating (Ki-67⁺) CD8⁺ T cells but independent of CPS and baseline GDF-15 levels in serum and tumor. There were no treatment-related discontinuation of treatment-related delays of surgery; grade 3-4 treatment-related adverse events occurred in two (13%) patients receiving N+V and three (20%) patients receiving N+P. The authors conclude that these findings support further evaluation of visugromab in MIBC.