FDA Grants Fast Track Designation to GPC3x4-1BB Bispecific Antibody in HCC

The FDA has granted fast track designation to BGB-B2033, a GPC3x4-1BB bispecific antibody, as a treatment for adult patients with hepatocellular carcinoma (HCC) who experienced disease progression on or after prior systemic therapy, according to a press release from the developer, BeOne Medicines.¹

BGB-B2033 targets both the tumor-specific antigen GPC3, which is highly expressed in HCC, as well as 4-1BB, which is a co-stimulatory receptor associated with T-cell activation and tumor reactivity in HCC. The molecule was designed with reduced antibody-dependent cytotoxicity to prevent systemic toxicity.

Currently, the agent is under investigation in a global, multi-center, first-in-human phase 1 trial (NCT06427941), which is evaluating the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of BGB-B2033 as monotherapy or in combination with the PD-1 inhibitor tislelizumab-jsgr (Tevimbra), with or without bevacizumab (Avastin), in patients with advanced or metastatic solid tumors.²

“The FDA awards fast track designation to therapies that show potential to address an unmet medical need in serious or life-threatening conditions,” stated Julie Lepin, the senior vice president and chief regulatory affairs officer at BeOne, in the press release.¹ “The FDA’s decision reflects the encouraging profile of BGB-B2033 in advanced [HCC], where patients continue to [have] limited treatment options.”

The phase 1 trial has an estimated enrollment of 140 patients, was initiated on July 23, 2024, and is estimated to be completed on December 31, 2026. Eligible patients in the trial were 18 years or older and had histologically or cytologically confirmed HCC that is either Barcelona Clinic Liver Cancer (BCLC) stage C or stage B and not amenable to, or has progressed after, loco-regional therapy and is not eligible for curative treatment; alpha-fetoprotein-producing gastric cancer, germ cell tumors; and GPC3-positive squamous non–small cell lung cancer. Patients also had at least 1 evaluable lesion for dose escalation, at least 1 measurable lesion for safety expansion, adequate organ function, and an ECOG performance status of 1 or lower.

Exclusion criteria included prior therapy targeting GPC3 or 4-1BB, active leptomeningeal disease or uncontrolled brain metastases; active autoimmune disease or history of autoimmune disease with potential for relapse; any malignancy other than the investigated cancer type diagnosed 2 years or less before the first study dose; requirement for systemic corticosteroids within 14 days prior to the first dose of study drug; and certain comorbidities involving the lung, heart, bleeding conditions, or active infections.

In part A of the trial, patients received ascending dose levels of BGB-B2033 monotherapy administered via intravenous infusion; in part B, patients received BGB-B2033 in combination with tislelizumab with or without bevacizumab. In part B, all agents were administered via intravenous infusion.

The primary end points of the trial were the incidence of adverse events (AEs) and serious AEs, the maximum tolerated and administered doses of BGB-B2033, and the recommended phase 2 dose of BGB-B2033. Secondary end points included overall response rate, duration of response, disease control rate, progression-free survival, serum concentration of BGB-B2033, and the number of patients with anti-drug antibodies to the agent.

Notably, the investigators stated that the incidence of HCC, which already accounts for 80% of all primary liver cancers, is expected to double between 2022 and 2050.³ Among patients diagnosed with HCC, 80% have advanced stages of the disease, and the 5-year survival rates for the population are lower than 20%.⁴

“New treatment options are needed beyond currently available systemic therapy,” the company noted in the press release.¹

References

1. BeOne Medicines granted U.S. FDA fast track designation for BGB-B2033 as treatment for hepatocellular carcinoma. News release. BeOne Medicines. December 18, 2025. Accessed December 18, 2025. https://tinyurl.com/4hy9nmrv
2. A phase 1 study of BGB-B2033, alone or in combination with tislelizumab with or without bevacizumab, in participants with advanced or metastatic solid tumors. ClinicalTrials.gov. Updated December 17, 2025. Accessed December 18, 2025. https://tinyurl.com/mryz9rm7
3. Chan SL, Sun HC, Xu Y, et al. The Lancet Commission on addressing the global hepatocellular carcinoma burden: comprehensive strategies from prevention to treatment. Lancet. 2025;406(10504):731-778. doi:10.1016/S0140-6736(25)01042-6
4. Li D, Sedano S, Allen R, Gong J, Cho M, Sharma S. Current treatment landscape for advanced hepatocellular carcinoma: patient outcomes and the impact on quality of life. Cancers (Basel). 2019;11(6):841. doi:10.3390/cancers11060841