Andrea Necchi, MD, Vita-Salute San Raffaele University, Milan, Italy, discusses results from the phase 2 GDFather-NEO trial comparing visugromab plus nivolumab versus nivolumab plus placebo in cisplatin-ineligible or cisplatin-refusing patients with muscle-invasive bladder cancer.

The study showed that the visugromab plus nivolumab tripled the pathologic complete response rate and achieved substantially higher major pathologic and objective response rates versus nivolumab alone, with excellent tolerability. These findings highlight GDF-15 blockade as a promising strategy to enhance PD-1–based neoadjuvant therapy in muscle-invasive bladder cancer. 

These findings were presented at the 2025 European Society for Medical Oncology (ESMO) Congress.

Transcript: 

I am Andrea Necchi, I'm an aassociate professor of oncology at Vita-Salute San Raffaele University in Milan, Italy, and director of GU medical oncology at San Raffaele Hospital in Milan, Italy. It's a pleasure to be here today at the ESMO meeting presenting the primary findings of the GDFather-NEO trial. 

The GDFather-NEO trial is a study testing visugromab in combination with nivolumab as neoadjuvant therapy in patients with muscle-invasive bladder cancer who were ineligible for or refused cisplatin-based chemotherapy. The target of the antibody visugromab is called GDF-15. GDF-15 was initially found to be highly expressed by the placenta and acts as a protective factor against the maternal immune system. Subsequently, in further studies, it was discovered as one of the highly expressed cytokines in cancer and one of the most highly expressed targets in multiple tumor types, including urothelial cancer. Visugromab is a GDF-15–neutralizing antibody directed against this target. It was initially tested in combination with nivolumab in immunotherapy-resistant tumors in a phase 1 study, with initial data—including urothelial cancer—that were quite promising and reported in Nature a few months ago and updated this year at the ESMO meeting with long-term follow-up.

The GDFather-NEO trial is the first study testing this combination therapy, nivolumab plus visugromab, in the front-line setting in patients with immunotherapy-naïve, muscle-invasive bladder cancer not previously exposed to any systemic therapy. The trial randomized patients to receive the combination therapy for 3 cycles every 4 weeks intravenously, or nivolumab plus placebo for 3 cycles intravenously before radical cystectomy, with the option of providing patients with radiotherapy or bladder preservation therapy —that is, endoscopic resection instead of radical surgery—depending on the response and patient preference. The primary end point was the pathologic complete response (pCR). 

pCR was reported in 33% of patients in the combination therapy arm, compared with only 7% with nivolumab monotherapy. Pathologic downstaging was reported in 67% of patients in the combination therapy arm. Clearly, the results suggest an improvement with the combination therapy, tripling the rate of pathologic complete responses. When looking at radiologic responses, the objective response rate with the combination therapy was up to 60%, compared with very few patients achieving an objective or complete response with nivolumab monotherapy. The safety profile was quite good—no grade 4 side effects, and only a few grade 3 immunotherapy-related adverse events—so treatment was well manageable.

Overall, the data indicate there could be an opportunity to provide patients with an effective and well-tolerated therapeutic option, or at least a strategy to test further, in a landscape that is becoming increasingly complex, with multiple studies providing data on this space and ADC–IO combinations emerging as potential new options in this patient population.

Source:

Necchi A, Mercinelli C, Maiorano BA, et al. A blinded, exploratory phase 2 trial of nivolumab and the GDF-15 neutralizing antibody visugromab or placebo as neoadjuvant treatment of patients with muscle-invasive bladder cancer (MIBC): Primary results of the GDFather-NEO trial. Presented at the 2025 ESMO Congress. October 17-21, 2025; Berlin, Germany. LBA110