A Phase 2/3, Randomized Study to Evaluate the Dose Optimization, Safety, and Efficacy of Livmoniplimab in Combination With Budigalimab in Subjects With Locally Advanced or Metastatic Hepatocellular Carcinoma (HCC) Who Have Not Previously Received Systemic Treatment

Overview

Budigalimab (ABBV-181; PR-1648817) is an investigational, humanized IgG1 monoclonal antibody that targets PD‑1. Early-phase clinical development has included monotherapy and combinations across advanced solid tumors. Phase 1 monotherapy expansion cohorts in head and neck squamous cell carcinoma (HNSCC) and non–small cell lung cancer (NSCLC) reported objective responses and a safety profile consistent with approved PD‑1 inhibitors. Ongoing studies are evaluating combinations, notably with the anti–GARP–TGF‑β1 antibody livmoniplimab (ABBV‑151) in hepatocellular carcinoma (HCC). (link.springer.com)

Mechanism of action

Budigalimab binds PD‑1 and blocks interaction with its ligands PD‑L1 and PD‑L2, restoring T‑cell activity. It is an engineered IgG1 with L234A/L235A (LALA) Fc mutations to minimize Fcγ receptor engagement and effector function, functioning as a pure antagonist. Pharmacodynamic assessments demonstrate rapid and sustained saturation of peripheral PD‑1–positive T cells at clinically explored doses. (link.springer.com)

Efficacy

• Monotherapy (Phase 1 expansion, NCT03000257): In 81 PD‑1/PD‑L1‑naïve patients (HNSCC n=41; NSCLC n=40) treated at 250 mg Q2W or 500 mg Q4W, objective response rates (ORR) were 13% (90% CI, 5.1–24.5) in HNSCC and 19% (90% CI, 9.2–32.6) in NSCLC; median progression‑free survival was 3.6 months (95% CI, 1.7–4.7) and 1.9 months (95% CI, 1.7–3.7), respectively. Responses included one complete response in NSCLC. (link.springer.com)

• Combination signals (early-phase): In a phase 1 program of livmoniplimab (ABBV‑151) plus budigalimab, an HCC cohort (post first‑line, PD‑1/PD‑L1‑naïve) reported ORR 42% (5/12) in meeting abstracts, prompting randomized phase 2 and a phase 2/3 study versus STRIDE (tremelimumab + durvalumab). Detailed peer‑reviewed efficacy for this combination is pending. (ascopubs.org)

Safety

• Class‑consistent profile: In the phase 1 HNSCC/NSCLC expansion, the most frequent grade ≥3 treatment‑emergent adverse event was anemia (HNSCC 22%; NSCLC 13%); no treatment‑related deaths were reported. Immune‑related AEs commonly included hypothyroidism, diarrhea, hyperthyroidism, pruritus, and rash. Overall, safety was considered similar to other PD‑1 inhibitors. (link.springer.com)

• Dose finding and broader phase 1 experience: Across dose‑escalation and multihistology expansion cohorts, immune‑related AEs occurred in 18.6% (11/59) of patients, with grade ≥3 in 1.7% (1/59). Exposure–safety analyses did not show an exposure‑response relationship and supported flat dosing regimens. (pubmed.ncbi.nlm.nih.gov)

Dosing and pharmacokinetics (investigational)

Population PK/PD modeling and clinical data support flat dosing regimens of 250 mg every 2 weeks, 375 mg every 3 weeks, or 500 mg every 4 weeks, providing comparable exposure and sustained PD‑1 receptor saturation. PK is approximately dose‑proportional in the studied range. (ascpt.onlinelibrary.wiley.com)

Development status and selected trials

• Monotherapy and combinations in advanced solid tumors, including with venetoclax or rovalpituzumab tesirine in the first‑in‑human study (NCT03000257; phase 1 completed March 29, 2022). (cdek.pharmacy.purdue.edu)
• Ongoing combination development with livmoniplimab in HCC (phase 2 and phase 2/3 programs; NCT06109272). (ascopubs.org)

Further reading

• First‑in‑human phase 1 expansion in HNSCC and NSCLC (open access): Cancer Immunology, Immunotherapy, 2022. (link.springer.com)
• Model‑informed dosing and phase 1 results: Clinical and Translational Science, 2021. (ascpt.onlinelibrary.wiley.com)
• PubMed record of the CTS article (quick summary/metadata). (pubmed.ncbi.nlm.nih.gov)
• ASCO 2024 meeting abstracts on livmoniplimab + budigalimab in HCC (phase 2 and phase 2/3 designs; early activity signal noted in phase 1). (ascopubs.org)
• AbbVie pipeline overview for mechanism and program context. (abbviescience.com)

Notes: Budigalimab remains investigational; no regulatory approvals as of October 7, 2025. Reported combination outcomes outside of peer‑reviewed publications are primarily from conference abstracts and should be interpreted cautiously pending full reports. (ascopubs.org)

Last updated: Oct 2025

Overview

Livmoniplimab (ABBV-151; formerly ARGX-115) is a first‑in‑class humanized monoclonal antibody being developed by AbbVie that targets the GARP–TGF‑β1 complex. It has been evaluated as monotherapy and, more prominently, in combination with the anti–PD‑1 antibody budigalimab (ABBV‑181) in advanced solid tumors, with ongoing development in hepatocellular carcinoma (HCC) and other indications. A first‑in‑human phase 1 study reported manageable safety and early signs of antitumor activity for the combination; subsequent cohort/trial expansions are underway, including phase 2 and a phase 2/3 program in HCC. (frontiersin.org)

Mechanism of action

• Target: GARP (glycoprotein A repetitions predominant), a cell‑surface receptor that presents latent TGF‑β1 on regulatory T cells (Tregs) and other cells. Livmoniplimab binds the GARP–latent TGF‑β1 complex and prevents activation/release of active TGF‑β1, aiming to reduce TGF‑β–mediated immunosuppression in the tumor microenvironment. (frontiersin.org)
• Structural and preclinical support: Structural work shows antibodies can stabilize GARP:latent TGF‑β1 and block activation; preclinical models demonstrate that selective blockade of TGF‑β1 from GARP+ Tregs can overcome resistance to PD‑1/PD‑L1 blockade and enhance antitumor immunity. (pubmed.ncbi.nlm.nih.gov)
• Tumor microenvironment effects: Early translational data presented at ASCO suggest the livmoniplimab + budigalimab combination reduces myeloid‑derived suppressor cells and macrophages while increasing cytotoxic T‑cell effector function, consistent with TGF‑β1 pathway inhibition. (ascopubs.org)

Efficacy

• Phase 1 (NCT03821935), dose escalation (advanced solid tumors):
• Monotherapy: No objective responses observed.
• Combination with budigalimab: Objective response rate (ORR) 15% with a median duration of response (DOR) 8.4 months in heavily pretreated patients. (frontiersin.org)
• Urothelial carcinoma (UC) expansion cohort (ASCO 2024 poster from NCT03821935):
• Among 45 response‑evaluable, platinum‑ and checkpoint inhibitor–pretreated patients, best response rate 24%; confirmed ORR 18%; median restricted mean DOR 7.9 months; median PFS 1.8 months. (ascopubs.org)
• Hepatocellular carcinoma (HCC):
• Signal in phase 1: ORR 42% (5/12; 4 per RECIST v1.1, 5 per iRECIST) for livmoniplimab + budigalimab in patients who had progressed after first‑line systemic therapy not including PD‑1/PD‑L1 inhibitors, which motivated further study. (ascopubs.org)
• Ongoing trials: A dedicated phase 2 study in patients who progressed after first‑line ICI‑containing regimens and a phase 2/3 study comparing livmoniplimab + budigalimab vs STRIDE (tremelimumab + durvalumab), with overall survival as the phase 3 primary endpoint (NCT06109272). (ascopubs.org)

Note: As of October 2025, randomized efficacy results have not yet been reported publicly. The most mature human data are from the phase 1 study and ASCO 2024 disease‑specific cohorts. (frontiersin.org)

Safety

• Phase 1 dose escalation (advanced solid tumors):
• Monotherapy (n=23): Common treatment‑emergent AEs (TEAEs) included fatigue (44%), anemia (35%), and nausea (30%); grade 3–4 TEAEs in 39%; no dose‑limiting toxicities (DLTs); no treatment discontinuations due to treatment‑related AEs (TRAEs). (frontiersin.org)
• Combination with budigalimab (n=34): Common TEAEs included pruritus (47%), fatigue (41%), nausea (41%), and anemia (38%); grade 3–4 TEAEs in 68%; DLT in 1 patient (elevated ALT); TRAE‑related discontinuation in 15%; no treatment‑related deaths; no maximum tolerated dose reached. (frontiersin.org)
• UC expansion cohort: TRAEs were reported in 60% (livmoniplimab‑related) and 54% (budigalimab‑related); pruritus and rash were the most common; safety characterized as manageable. (ascopubs.org)

Further reading

• First‑in‑human phase 1 dose‑escalation results (Frontiers in Oncology, 2024) – open access: https://www.frontiersin.org/articles/10.3389/fonc.2024.1376551/full (frontiersin.org)
• ASCO 2024 HCC phase 2 trial design (TPS4189): https://ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.TPS4189 (ascopubs.org)
• ASCO 2024 HCC phase 2/3 platform (TPS4190; NCT06109272): https://ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.TPS4190 (ascopubs.org)
• ASCO 2024 UC cohort results (e16555): https://ascopubs.org/doi/abs/10.1200/JCO.2024.42.16_suppl.e16555 (ascopubs.org)
• Preclinical rationale: selective inhibition of TGF‑β1 from GARP+ Tregs overcomes resistance to PD‑1/PD‑L1 (Nature Communications, 2020): https://doi.org/10.1038/s41467-020-17811-3 (ouci.dntb.gov.ua)
• Structural basis for antibody blockade of GARP‑mediated TGF‑β1 activation (2018): https://pubmed.ncbi.nlm.nih.gov/30361387/ (pubmed.ncbi.nlm.nih.gov)

Conflicts of interest and sponsorship details for the phase 1 report are disclosed in the article. (pubmed.ncbi.nlm.nih.gov)

Last updated: Oct 2025

Inclusion Criteria:

* Locally advanced or metastatic and/or unresectable hepatocellular carcinoma (HCC) with diagnosis confirmed by histology or cytology or clinically by American Association for the Study of Liver Diseases criteria for participants with cirrhosis.

* Barcelona Clinic Liver Cancer (BCLC) Stage B or C.

* Child-Pugh A or B7 classification (i.e., total Child-Pugh score of 5, 6, or 7).

* Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 1.

Exclusion Criteria:

* Prior systemic therapy for HCC.

* Symptomatic, untreated, or actively progressing CNS metastases.

* History of malignancy other than HCC.