A Phase 2b, Randomized, Blinded Trial Investigating the Efficacy and Safety of Visugromab in Combination With Nivolumab and Lenvatinib Compared to Double Placebo and Lenvatinib in Participants With Unresectable or Metastatic Hepatocellular Carcinoma and Compensated Liver Function (Child-Pugh A) After Failure of First-Line Treatment That Included an Approved Anti PD-(L)1 Compound (GDFATHER HCC-01)

Overview

Visugromab (CTL-002) is a first‑in‑class, humanized monoclonal antibody that neutralizes growth differentiation factor 15 (GDF‑15), a TGF‑β superfamily cytokine implicated in tumor immune evasion and resistance to PD‑(L)1 inhibitors. A combined first‑in‑human phase 1/2a study (GDFATHER; NCT04725474) reported objective responses and durable remissions when visugromab was combined with nivolumab in patients with checkpoint‑refractory solid tumors, with a generally manageable safety profile. Additional randomized phase 2 data in neoadjuvant muscle‑invasive bladder cancer (MIBC) were presented at ESMO 2025. (pmc.ncbi.nlm.nih.gov)

Mechanism of action

Tumor‑derived GDF‑15 impairs LFA‑1/ICAM‑1–mediated adhesion, blocking effector T‑cell extravasation into tumors and dampening antitumor immunity. Neutralization of GDF‑15 increases intratumoral T‑cell infiltration, upregulates interferon‑γ–related genes, and can resensitize tumors to PD‑1 blockade in preclinical models and patients. In the first‑in‑human study, sequential biopsies after visugromab showed increased T‑cell density and inflammatory signatures; expression of T‑cell exhaustion markers was not induced. (pmc.ncbi.nlm.nih.gov)

Recommended phase 2 dosing from PK/PD modeling was 10 mg/kg every 2 weeks with nivolumab; higher baseline GDF‑15 may require higher/less‑frequent doses to sustain neutralization. (pmc.ncbi.nlm.nih.gov)

Efficacy

• Phase 1 dose escalation (mixed solid tumors; last‑line; visugromab ± nivolumab): confirmed responses included three partial responses (mesothelioma, hepatocellular carcinoma [HCC], cancer of unknown primary); mean duration of response (DOR) 12.9 months, median 7.1 months. (pmc.ncbi.nlm.nih.gov)

• Phase 2a expansion cohorts (visugromab + nivolumab in anti‑PD‑(L)1–relapsed/refractory populations):

• Non‑small cell lung cancer (NSCLC): ORR 14.8% (4/27) overall; all responses in non‑squamous NSCLC (ORR 19.0%, 4/21). Median DOR 16.6 months (mean 15.3); 3/4 responses ongoing at cutoff. Responses occurred in both PD‑L1–positive and –negative tumors. (pmc.ncbi.nlm.nih.gov)
• Urothelial cancer (UC): ORR 18.5% (5/27); median DOR 14.4 months (mean 16.4), including an ongoing complete response >20 months at cutoff. (pmc.ncbi.nlm.nih.gov)

• Hepatocellular carcinoma (HCC): interim ORR 20% (3 PR, 1 CR among 20 evaluable); expansion ongoing at the time of report. No relevant activity was seen in melanoma or MSS colorectal cancer. (pmc.ncbi.nlm.nih.gov)

• Neoadjuvant MIBC (GDFATHER‑NEO; randomized, single‑blinded phase 2; nivolumab + visugromab vs nivolumab + placebo; NCT06059547): primary results presented at ESMO 2025 showed higher efficacy with the combination:

• Pathologic complete response (pCR): 33.3% vs 7.1–7.7%
• Major pathologic response (MPR): 66.7% vs 21.4–23.1%
• Radiologic ORR: 60% (7 CR, 2 PR) vs 14–15% (0 CR, 2 PR) These findings are from conference presentations and company communications; a peer‑reviewed manuscript has not yet been identified. (catalym.com)

Safety

• Phase 1: no dose‑limiting toxicities; one grade ≥4 TEAE (acute respiratory failure) deemed not treatment‑related; grade 3 TEAEs in 48% of patients in this heavily pretreated population. (pmc.ncbi.nlm.nih.gov)
• Phase 2a NSCLC cohort: any grade ≥3 TEAE in 59.3%; grade ≥3 treatment‑related AEs (TRAEs) in 7.4%. One patient experienced grade 4 hepatic failure/acute kidney injury progressing to grade 5 multi‑organ dysfunction; this occurred in the context of prior renal damage from earlier therapy. (pmc.ncbi.nlm.nih.gov)
• Phase 2a UC cohort: any grade ≥3 TEAE in 51.8%; grade ≥3 TRAEs in 7.4% (no grade 4/5 TRAEs). (pmc.ncbi.nlm.nih.gov)
• Weight gain was observed particularly in patients with elevated baseline GDF‑15, consistent with systemic GDF‑15’s role in cachexia; this potential benefit is being further explored. (pmc.ncbi.nlm.nih.gov)
• Neoadjuvant MIBC: safety of nivolumab + visugromab was described as similar to nivolumab + placebo with no unexpected toxicities in the presented data. (catalym.com)

Development status and key trials

• First‑in‑human/expansion: GDFATHER (NCT04725474) — ongoing phase 1/2a evaluating visugromab with nivolumab across multiple solid tumors. (pmc.ncbi.nlm.nih.gov)
• Neoadjuvant MIBC: GDFATHER‑NEO (NCT06059547) — phase 2 randomized, single‑blinded study; primary results presented October 2025 at ESMO. (cdek.pharmacy.purdue.edu)
• First‑line nsqNSCLC: GDFATHER‑NSCLC‑01 (NCT07098988) — randomized phase 2b of chemoimmunotherapy ± visugromab initiated September 30, 2025. (catalym.com)

Further reading

• Neutralizing GDF‑15 can overcome anti‑PD‑1 and anti‑PD‑L1 resistance in solid tumours (clinical phase 1/2a results and translational analyses). Nature, 2024. (pmc.ncbi.nlm.nih.gov)
• Tumor‑derived GDF‑15 blocks LFA‑1–dependent T‑cell recruitment and suppresses responses to anti‑PD‑1 treatment (mechanistic study). Nature Communications, 2023. (pmc.ncbi.nlm.nih.gov)
• GDFATHER (NCT04725474) — first‑in‑human/expansion trial record. (ichgcp.net)
• GDFATHER‑NEO (NCT06059547) — neoadjuvant MIBC trial overview and ESMO 2025 summary. (cdek.pharmacy.purdue.edu)
• Phase 2b first‑line nsqNSCLC trial initiation (GDFATHER‑NSCLC‑01). (catalym.com)

Notes: Some efficacy and safety figures above derive from a peer‑reviewed report (cutoffs through mid‑2024), while neoadjuvant MIBC data reflect primary results presented at ESMO 2025 and sponsor communications pending journal publication. (pmc.ncbi.nlm.nih.gov)

Last updated: Nov 2025

Main Inclusion Criteria:

* Histologically confirmed diagnosis of unresectable or metastatic HCC, not amenable to a curative treatment approach.

* Measurable disease as per RECIST v1.1 as determined by the Investigator based upon local radiologist assessment.

* Must have failed one line of prior systemic treatment for unresectable or metastatic HCC containing an approved anti PD (L)-1 checkpoint inhibitor (CPI) with a minimum treatment duration of 12 weeks exposure for the CPI with no documented progression in this period.

* Age ≥ 18 years on the day of signing the informed consent.

* Life expectancy of at least 3 months as assessed by the Investigator.

* ECOG performance status ≤1.

* Child-Pugh score of A6 or better.

Main Exclusion Criteria:

* Known fibrolamellar HCC, sarcomatoid HCC or mixed cholangiocarcinoma.

* More than 1 line of prior systemic treatment for unresectable or metastatic HCC.

* Received or completed any palliative radiotherapy for symptoms within 28 days of the first dose of IMP.

* Expected to require any other form of antineoplastic therapy during the trial.

* Clinically active inflammatory bowel disease, active diverticulitis, intra-abdominal abscess, and/or gastrointestinal obstruction.

* Known history of other prior malignancy unless participant has undergone potentially curative therapy with no evidence of that disease recurrence for 5 years since initiation of that therapy.

* Known or detected clinically active central nervous system (CNS) involvement by HCC or other tumors.

* Have one of the following cardiovascular risk factors: myocardial infarction, peri/myocarditis, or history of ischemic stroke in the past 3 months before planned treatment start, uncontrolled heart failure, uncontrolled ventricular arrhythmia, QT interval corrected for heart rate using Fridericia's formula interval ≥ 470 ms regardless of sex.

* An active autoimmune disease that has required systemic treatment in past 3 months before planned treatment start.

* Comedication with metformin or metformin-containing antidiabetics in participants with type II diabetes.

* Chronic systemic corticosteroid treatment for other reasons.

* Prior liver or other organ transplantation.