Phase 2 Study Evaluates Serplulimab Plus HLX04 as First-Line Treatment for Advanced Hepatocellular Carcinoma

An open-label, multicenter phase 2 study (NCT03973112) conducted in China aimed to investigate the safety and initial effectiveness of serplulimab (Hansizhuang; Shanghai Henlius Biotech Inc) a new programmed death (PD)-1 inhibitor, when used alone or in combination with bevacizumab biosimilar HLX04 (Shanghai Henlius Biotech Inc) as a first-line treatment option for individuals with advanced hepatocellular carcinoma (HCC).¹

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HCC occurs when a tumor grows on the liver—accounting for 12,000 annual deaths in the US.² According to GLOBOCAN 2020, primary liver cancer is a significant global health concern, with HCC being the most prevalent subtype, and China experiencing a considerable burden of the disease. Hepatitis B virus (HBV) infection is a major risk factor for HCC in China, often leading to poorer outcomes. While surgical interventions are effective in early stages, systemic therapies are crucial for managing advanced HCC, which is common due to late diagnosis.¹

Current guidelines in both China and the US recommend immune checkpoint blockade (ICB) combined with anti-angiogenesis as a first-line treatment for advanced HCC (aHCC), with varying specific regimens. While clinical trials have shown promising overall survival with ICB plus anti-angiogenesis, achieving significant improvements in progression-free survival remains a challenge for most current regimens.¹

Serplulimab is a fully humanized monoclonal antibody that targets PD-1 and was approved by the China National Medical Products Administration (NMPA). The study authors noted that the drug was granted approval for the treatment of microsatellite instability-high solid tumors, squamous non-small cell lung cancer, extensive-stage small cell lung cancer, and PD-ligand 1-positive esophageal squamous cell carcinoma. Additionally, the bevacizumab biosimilar HLX04 was also approved by the NMPA, demonstrating a similar efficacy and safety profile to reference bevacizumab.¹

The open-label, multicenter, single-arm, phase 2 clinical trial that assessed treatment with serplulimab alone or in combination with HLX04 in patients with aHCC consisted of 4 groups. The study authors noted that groups A, B, and C enrolled patients with prior systemic therapies, and group D enrolled previously untreated patients. However, the current report presented data on safety and efficacy from individuals in group D that were treated with combination therapy with serplulimab and HLX04. The study included adult patients with histologically or clinically diagnosed aHCC, meeting specific Barcelona Clinic Liver Cancer (BCLC) stage criteria, with measurable disease, acceptable organ function, and no prior systemic HCC therapy.¹

The study authors noted that a total of 238 were screened from September 24, 2019, to April 8, 2021. A total of 61 patients were included in group D and received intravenous serplulimab followed by HLX04 every 2 weeks. Treatment continued for up to 2 years or until disease progression, unacceptable toxicity, or other specified reasons. Limited treatment continuation after the first documented disease progression was allowed at the investigator's discretion under specific conditions.¹

The results demonstrated that, of the 61 enrolled patients followed for a median of 25.5 months, 47.5% experienced grade 3 or higher treatment-emergent adverse events, including hypertension and proteinuria, with 1 treatment-related death. The objective response rate, as assessed by an independent radiological review committee, was 29.3%, with a median progression-free survival of 7.3 months and a median overall survival of 20.4 months, according to study authors.¹

The safety profile displayed that no infusion-related reactions were observed with serplulimab plus HLX04, in contrast to 10.9% of patients treated with atezolizumab (Tecentriq; Genentech) plus bevacizumab. However, the incidence of grade 4 gastrointestinal hemorrhage was higher with serplulimab plus HLX04 (1.6%) compared to atezolizumab plus bevacizumab (0.9%).¹

The study authors noted that limitations of the study include its small sample size, lack of a comparator arm, and the optional nature of endoscopic evaluation for varies, which may have differed from other trials.¹

The findings suggest that serplulimab plus HLX04 demonstrated a favorable safety profile in patients with advanced HCC, with promising antitumor activity and potential for survival benefit, affirming further evaluation in larger, controlled clinical trials.¹

REFERENCES

1. Ren Z, Shao G, Shen J, et al. Phase 2 study of serplulimab with the bevacizumab biosimilar HLX04 in the first-line treatment of advanced hepatocellular carcinoma. Cancer Immunol Immunother. 2025;74(2):69. Published 2025 Jan 3. doi:10.1007/s00262-024-03917-w

2. Johns Hopkins Medicine. Liver Cancer (Hepatocellular Carcinoma). Accessed January 9, 2025. https://www.hopkinsmedicine.org/health/conditions-and-diseases/liver-cancer-hepatocellular-carcinoma#