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 .