BGB-B2033 Gains FDA Fast Track Status in Advanced HCC

The FDA has granted fast track designation to BGB-B2033, a novel GPC3x4-1BB bispecific antibody, for the treatment of advanced hepatocellular carcinoma (HCC).¹

As the sixth most common cancer worldwide, HCC is often diagnosed at advanced stages, with limited options beyond palliative locoregional and systemic therapies.² This designation, given in recognition of BGB-B2033’s potential to offer a more effective and targeted therapy, will help facilitate clinical development as it progresses in an ongoing, first-in-human phase 1 study (NCT06427941).

"The FDA awards [f]ast [t]rack [d]esignation to therapies that show potential to address an unmet medical need in serious or life-threatening conditions. The FDA’s decision reflects the encouraging profile of BGB-B2033 in advanced [HCC], where patients continue to face limited treatment options," said Julie Lepin, senior vice president and chief regulatory affairs officer at BeOne Medicines, in a news release.¹

Mechanism of Action

The IgG-based agent is directed against the T-cell costimulatory immunoreceptor 4-1BB as well as GPC3, a tumor-specific antigen that is overexpressed in 70% to 80% of HCC tumors.³ Leveraging its ability to bind to target proteins with high specificity and affinity, it has demonstrated potent, dose-associated antitumor activity as well as synergy with anti–PD-1 antibodies in preclinical models.

The agent’s reduced antibody-dependent cellular cytotoxicity is another core component of its design, allowing for efficacy without triggering systemic toxicity.

About the Phase 1 Study

The global, multicenter phase 1 dose-escalation and -expansion study is assessing the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of BGB-B2033 as intravenous monotherapy and in combination with tislelizumab (Tevimbra), with or without bevacizumab (Avastin), in advanced or metastatic solid tumors.⁴ Specific indications to be studied include HCC, alpha-fetoprotein-producing gastric cancer, germ cell tumors (extragonadal yolk sac tumors and non-dysgerminomas), or GPC3-positive squamous non–small cell lung cancer.

The study is actively recruiting up to 140 patients across 16 sites in the US, China, New Zealand, and South Korea. For inclusion in the study, those with HCC must have histologically or cytologically confirmed HCC that is either Barcelona Clinic Liver Cancer (BCLC) stage C or BCLC stage B that is not amenable to or has progressed on or after locoregional therapy.

Exclusion criteria include, but are not limited to, prior GPC3- or 4-1BB-directed therapy, active leptomeningeal disease or autoimmune disease, uncontrolled or untreated brain metastases, and certain comorbidities involving the lungs, heart, bleeding conditions, or active infections.

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/ycx7aabv

2. Moris D, Martinino A, Schiltz S, et al. Advances in the treatment of hepatocellular carcinoma: An overview of the current and evolving therapeutic landscape for clinicians. CA A Cancer J Clin. 2025;75(6):498-527. doi:10.3322/caac.70018

3. Li J, Yuan X, Ji R, et al. Abstract 6009: BGB-B2033, a novel 4-1BB/GPC3 bispecific antibody, exhibits potent in vitro and vivo antitumor activity in preclinical models. Cancer Res. 2025;85(8_Supplement_1):6009-6009. doi:10.1158/1538-7445.am2025-6009

4. 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://www.clinicaltrials.gov/study/NCT06427941