Visugromab Plus Nivolumab Shows Durable Response in Refractory Tumors

Long-term follow-up data from the phase 1/2a GDFATHER-01 trial (NCT04725474) suggest that neutralizing growth differentiation factor 15 (GDF-15) may reverse resistance to immunotherapy in heavily pretreated patients with advanced solid tumors.^1,2

The investigational antibody visugromab, combined with nivolumab (Opdivo), achieved a median duration of response (DOR) exceeding 2 years in patients with non–small cell lung cancer (NSCLC), urothelial cancer (UC), and hepatocellular carcinoma (HCC) who were refractory to prior anti–PD-1/PD-L1 therapy.¹

The findings, based on a data cutoff of August 21, 2025, underscore the potential of GDF-15 as both a therapeutic target and a mechanism of immune escape in the tumor microenvironment.

Reinvigorating Immune Response in Refractory Disease

The GDFATHER-01 trial evaluated the safety and efficacy of visugromab (10 mg/kg every 2 weeks) combined with the PD-1 inhibitor nivolumab. The analysis focused on 77 patients across 3 cohorts: nonsquamous NSCLC (n = 22), UC (n = 27), and HCC (n = 28).

The study population was heavily pretreated, with a median of 2 prior systemic therapies. Crucially, 100% of patients had received prior anti–PD-1/PD-L1 therapy and were strictly defined as relapsed or refractory, having demonstrated progression either as a primary refractory event or after an initial response.

Despite this challenging clinical profile, the combination therapy demonstrated an objective response rate of 16.9% (95% CI, 9.3%-27.1%) across all cohorts. Notably, the depth of response was significant, with 10.4% of patients achieving a complete response (CR) or complete metabolic response.

Durability Exceeds Prior Lines of Therapy

The most distinct finding from the long-term follow-up was the durability of the responses induced by the combination. The median DOR was 28.8 months (95% CI, 7.4-38.0 months) for the overall population. In the NSCLC cohort specifically, the median DOR extended to 32.2 months.

Investigators noted that for the 13 responders, the quality and DOR to visugromab plus nivolumab frequently exceeded outcomes from the patients' initial checkpoint inhibitor therapy. Data indicated that 61.5% of responders achieved a deeper response (eg, achieving CR vs a prior partial response), and 76.9% experienced a longer DOR compared with their previous successful anti–PD-(L)1 regimen (median 28.8 months vs 12.2 months).

At the time of the data cutoff, 53.8% of responses were ongoing. The median overall survival was 10 months (95% CI, 5.7-2.7), and the disease control rate was 42.9%.

GDF-15 as a Resistance Factor and Cachexia Driver

GDF-15 is a member of the TGF-β superfamily and is frequently overexpressed in malignancies, where its presence is associated with poor prognosis. It functions as a dual-pathology mediator, as follows:

1. Local Immunosuppression: In the TME, GDF-15 prevents immune cell infiltration and activation, contributing to checkpoint inhibitor resistance.
2. Systemic Wasting: Acting on the GFRAL receptor in the brainstem, GDF-15 drives nausea, emesis, and cancer cachexia.

In GDFATHER-01, visugromab demonstrated a dual effect by addressing both tumor progression and metabolic dysregulation. In a subpopulation of patients with baseline cachexia (defined as >5% weight loss or body mass index <20 with >2% weight loss), treatment resulted in a mean weight gain of 2.3% by cycle 5. This stands in contrast to a mean weight loss of 6.5% experienced by these patients in the 6 months prior to study entry. Patients without baseline cachexia did not experience significant weight changes, suggesting the drug reverses pathological wasting rather than inducing indiscriminate weight gain.

Safety Profile

The safety profile of the combination was consistent with that of nivolumab monotherapy. Treatment-related adverse events (TRAEs) of any grade occurred in 58.4% of patients. Grade 3 or higher TRAEs were reported in 13% of patients. The most common TRAEs included pyrexia (12%), rash (10%), and increased alanine aminotransferase (8%).

Discontinuation due to TRAEs was low, occurring in 3.9% of patients. Two grade 5 events (multiple organ dysfunction syndrome and respiratory failure) were reported in the NSCLC cohort.

“[A] definitive safety assessment will only be possible after database lock and will require larger sample sizes in future trials,” Ignacio Melero Bermejo, MD, Clinica Universidad de Navarra, said in a presentation of the study.

REFERENCES

1. Melero Bermejo I, de Migue Luken M, Garralda Cabanas E, et al. Long-term follow-up of the GDFATHER-1/2a trial: GDF-15 neutralization combined with nivolumab can enable deep, long-termremission in heavily pretreated, anti-PD1/-L1 relapsed/refractory metastatic non-squamous non-small cell lung cancer, urothelial cancer and hepatocellular cancer. Presented at: European Society for Medical Oncology Congress 2025; October 17-21, 2025; Berlin, Germany. Abstract 1513O.

2. First-in-human study of the GDF-15 neutralizing antibody visugromab (CTL-002) in patients with advanced cancer (GDFATHER) (GDFATHER). ClinicalTrials.gov. Updated August 9, 2024. Accessed November 21, 2025. https://www.clinicaltrials.gov/study/NCT04725474