The treatment landscape of muscle-invasive bladder cancer (MIBC) continues to evolve, with neoadjuvant and perioperative immunotherapy becoming increasingly important components of treatment strategies. However, a substantial proportion of patients do not achieve a pathologic response, highlighting the need for additional therapeutic approaches, particularly for those who are ineligible for or decline cisplatin-based chemotherapy.
One potential strategy involves targeting growth differentiation factor-15 (GDF-15), a molecule implicated in tumor-associated immunosuppression and resistance to PD-1/PD-L1 blockade. By limiting T-cell infiltration into tumors, GDF-15 may contribute to reduced antitumor immune activity. Its neutralization has therefore emerged as a potential approach to enhance the effects of immune checkpoint inhibition.
On October 24, 2026, Nature Medicine published the results of the phase 2a GDFATHER-NEO trial in an article titled “Neoadjuvant nivolumab with or without visugromab in muscle-invasive bladder cancer: the phase 2a GDFATHER-NEO trial.”
Authors: Andrea Necchi, Chiara Mercinelli, Brigida A. Maiorano, Michela Piacentini, Antonio Cigliola, Roberto Iacovelli, Chiara Ciccarese, Chiara Ligato, Patrizia Giannatempo, Alessandro Rametta, Paolo Gontero, Francesco Soria, Christine Schuberth-Wagner, Joerg Wischhusen, Bernhard Rössler, Michael Metterlein, Stefan Ries, Thorsten Ross, Aasim Amin, Tobias Dreker, Frank Hermann, Lena Lemke, Kathrin Klar, Olga Mitina, Ana Kamova, Petra Fettes, Alexandra Auckenthaler, Sujata Rao, Eugen Leo, and Felix S. Lichtenegger.
About the GDFATHER-NEO Trial
GDFATHER-NEO (NCT06059547) was an exploratory, placebo-controlled, participant-blinded, nonrandomized phase 2a study conducted at four centers in Italy. It investigated whether combining nivolumab with visugromab, an investigational GDF-15-neutralizing monoclonal antibody, could improve antitumor responses in patients with newly diagnosed MIBC.
The trial enrolled 31 patients with clinical stage T2–T4aN0M0 disease who were either ineligible for or declined cisplatin-based chemotherapy. Patients were stratified according to clinical tumor stage and PD-L1 combined positive score (CPS), then allocated sequentially to one of two treatment groups:
- Nivolumab plus visugromab (n=16): Nivolumab 480 mg and visugromab 20 mg/kg, administered intravenously every four weeks for three cycles.
- Nivolumab plus placebo (n=15): Nivolumab 480 mg with matching placebo, administered on the same schedule.
Following neoadjuvant treatment, patients were scheduled to undergo radical cystectomy or, for those who declined cystectomy, repeat transurethral resection of the bladder tumor (re-TURBT). Surgery was planned four to eight weeks after the final treatment dose.
The trial had two primary endpoints: locally assessed pathologic complete response (pCR), defined as ypT0N0 or ypT0Nx according to the surgical procedure, and radiographic response according to RECIST version 1.1. Secondary endpoints included major pathologic response (MPR), independent central assessments of pathologic and radiographic response, event-free survival (EFS), pharmacokinetics, and safety.
What Were the Main Findings?
The addition of visugromab to nivolumab was associated with numerically higher pathologic and radiographic response rates compared with nivolumab plus placebo. Among the 28 patients evaluable for locally assessed pathologic response, pCR was achieved in 33% (5/15) of patients receiving nivolumab plus visugromab, compared with 8% (1/13) receiving nivolumab plus placebo. The corresponding 95% confidence intervals (CIs) were 12–62% and 0–36%, respectively.
Major pathologic response, which included patients with pCR or residual non-muscle-invasive disease (ypTa, ypTis, or ypT1), was also more frequent in the combination group:
- Nivolumab plus visugromab: 60% (9/15; 95% CI 32–84%).
- Nivolumab plus placebo: 23% (3/13; 95% CI 5–54%).
Independent central pathologic review showed a similar pattern. The centrally assessed pCR rate was 47% (7/15; 95% CI 21–73%) with nivolumab plus visugromab, compared with 17% (2/12; 95% CI 2–48%) in the placebo group. Centrally assessed MPR rates were 60% and 33%, respectively.
Radiographic Response
Radiographic assessments also showed higher observed response rates with the combination. According to local RECIST version 1.1 assessment, the objective response rate (ORR) was 60% (9/15; 95% CI 32–84%) with nivolumab plus visugromab, compared with 15% (2/13; 95% CI 2–45%) with nivolumab plus placebo.
In the combination group, seven patients achieved a radiographic complete response and two achieved a partial response, corresponding to a complete response rate of 47%. Independent central radiographic review reported ORRs of 50% (8/16; 95% CI 25–75%) and 33% (4/12; 95% CI 10–65%), respectively.
Although the direction of the findings was consistent across local and central assessments, differences in the estimated response rates highlighted the variability between assessment methods.
Importantly, the trial was exploratory and was not powered for formal between-group comparisons. The observed differences should therefore be interpreted descriptively rather than as evidence of statistically established treatment superiority.
Event-Free Survival and Follow-Up
At the July 15, 2026 data cutoff, the median follow-up was 15.7 months. A total of six EFS events had occurred, with three events recorded in each treatment group. Median EFS had not been reached in either group.
Notably, no EFS events occurred among patients who achieved a pathologic complete response. This included four patients in the nivolumab plus visugromab group who achieved pCR following re-TURBT without subsequent radical cystectomy. While this observation is relevant to ongoing research into response-guided bladder preservation, the small number of patients and limited follow-up prevent conclusions about the long-term safety of avoiding cystectomy.
The investigators emphasized that EFS findings remained descriptive, particularly because protocol-defined follow-up was limited to one year after surgery.
Exploratory Biomarker Findings
The trial also investigated whether baseline tumor immune characteristics or GDF-15 expression were associated with treatment response. Among patients receiving nivolumab plus visugromab, those who achieved MPR had higher baseline densities of total CD8+ T cells and proliferating CD8+Ki-67+ T cells than nonresponders.
These associations were observed for total CD8+ T-cell density (P=0.008) and proliferating CD8+Ki-67+ T-cell density (P=0.003). In contrast, no corresponding association was identified among patients receiving nivolumab plus placebo. Responses to the combination were observed across the range of PD-L1 CPS values. Neither baseline circulating GDF-15 concentrations nor intratumoral GDF-15 expression was associated with pathologic response.
These exploratory observations suggest that the preexisting functional state of intratumoral CD8+ T cells may be relevant to response following combined GDF-15 and PD-1 blockade. However, the findings require validation in larger cohorts before these characteristics can be considered predictive biomarkers.
Safety and Tolerability
The safety analysis included all 31 patients who received at least one treatment dose. Treatment-related adverse events (TRAEs) of any grade occurred in 88% (14/16) of patients receiving nivolumab plus visugromab and 53% (8/15) receiving nivolumab plus placebo.
Despite the higher frequency of any-grade TRAEs in the combination group, grade 3–4 TRAEs were reported in:
- 13% (2/16) of patients receiving nivolumab plus visugromab.
- 20% (3/15) of patients receiving nivolumab plus placebo.
Asthenia, pruritus, and hypothyroidism were numerically more frequent in the combination group. Three serious treatment-related adverse events were recorded: an immune-mediated hepatic disorder and interstitial lung disease in the combination group, and hypothyroidism in the placebo group.
No treatment-related deaths occurred. Two patients receiving nivolumab plus placebo discontinued systemic treatment because of treatment-related toxicity, compared with none in the combination group.
Furthermore, no delays to surgery or postoperative complications were attributed to neoadjuvant treatment. Overall, the combination demonstrated a manageable safety profile within this small study population.
What Do These Findings Mean?
GDFATHER-NEO provides early clinical evidence supporting the investigation of GDF-15 neutralization alongside PD-1 inhibition in previously untreated MIBC.
Across the locally assessed primary endpoints and independent central assessments, the combination of nivolumab and visugromab produced higher observed response proportions than nivolumab plus placebo. The translational findings also offer a potential biological explanation for treatment activity, with baseline CD8+ T-cell characteristics associated with pathologic response in the combination group.
Nevertheless, several limitations are important when interpreting these results. The study included only 31 patients, treatment allocation was sequential rather than randomized, and follow-up was relatively short. Additionally, pCR assessments included specimens obtained through both radical cystectomy and re-TURBT, complicating direct comparisons with other neoadjuvant MIBC trials. The study did not establish a survival benefit or demonstrate that the combination can safely replace radical cystectomy.
Takeaway
The phase 2a GDFATHER-NEO trial identified encouraging pathologic and radiographic responses with neoadjuvant nivolumab plus visugromab in patients with MIBC who were ineligible for or declined cisplatin-based chemotherapy.
The findings support further investigation of GDF-15 blockade as a potential strategy to enhance checkpoint inhibitor activity. Larger randomized trials with longer follow-up will be necessary to determine whether these early responses translate into improved long-term clinical outcomes and whether visugromab-based treatment could contribute to future bladder-preserving approaches.
Original publication: Necchi A, et al. Neoadjuvant nivolumab with or without visugromab in muscle-invasive bladder cancer: the phase 2a GDFATHER-NEO trial. Nature Medicine. Published October 24, 2026.
The full article is available in Nature Medicine.
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