Neoadjuvant nivolumab with or without visugromab in muscle-invasive bladder cancer: the phase 2a GDFATHER-NEO trial

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 programmed cell death protein 1/programmed death ligand 1 (PDL1) blockade. We investigated the safety and efficacy of GDF-15 blockade in an exploratory, stratified, placebo-controlled, single-blinded, nonrandomized phase 2a trial (GDFATHER-NEO). Thirty-one cisplatin-ineligible or cisplatin-refusing patients with newly diagnosed MIBC (clinical T2–T4aN0M0) were stratified by tumor stage and PDL1 combined positive score (CPS) and allocated sequentially to receive three cycles of neoadjuvant nivolumab (N, 480 mg 4-weekly) plus the GDF-15-neutralizing antibody visugromab (V, 20 mg kg−1 4-weekly; n = 16) or placebo (P, n = 15), followed by radical cystectomy or repeat transurethral resection of the bladder tumor. Locally assessed pathologic complete response (pCR, ypT0N0/x) and Response Evaluation Criteria in Solid Tumors v1.1-based radiographic response served as dual primary endpoints. pCR was 33% (5 of 15, 95% confidence interval (CI) 12–62%) in patients receiving N + V versus 8% (1 of 13, 95% CI 0–36%) for N + P; major pathologic response was 60% (95% CI 32–84%) versus 23% (95% CI 5–54%), and radiographic overall response rate was 60% (95% CI 32–84%) versus 15% (95% CI 2–45%), respectively. 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 discontinuations or treatment-related delays to surgery; grade 3–4 treatment-related adverse events occurred in two (13%) and three (20%) patients treated with N + V or N + P, respectively. These findings support further evaluation of visugromab in MIBC. ClinicalTrials.gov identifier: NCT06059547 . As presented at the ESMO Congress 2026: In this exploratory, nonrandomized phase 2a trial, treatment of patients with immune checkpoint inhibitor-naive muscle-invasive bladder cancer with the GDF-15-neutralizing antibody visugromab and nivolumab produced encouraging pathological complete response and radiographic response rates with no new safety signals, supporting further evaluation in larger randomized studies.