First-Line Serplulimab Plus HLX04 Shows Manageable Safety in Advanced HCC

Results from a phase 2 trial revealed serplulimab plus HLX04 elicited promising antitumor activity in patients with advanced hepatocellular carcinoma.

Serplulimab (Hansizhuang) in combination with the bevacizumab (Avastin) biosimilar HLX04 showed a manageable safety profile as a first-line treatment for patients with advanced hepatocellular carcinoma (HCC), according to results from a phase 2 trial (NCT03973112) published in Cancer Immunology, Immunotherapy.¹

Safety data revealed that of patients eligible for analysis who were treated with the combination therapy (n = 61), any-grade treatment-emergent adverse events (TEAEs) occurred in 60 (98.4%). Additionally, grade 3 or greater TEAEs occurred in 47.5%, with 27.9% of patients experiencing serious TEAEs. Grade 5 TEAEs occurred in 3 (4.9%) patients, including 1 patient death due to hepatic failure and disease progression possibly related to treatment.

Common any-grade TEAEs included increased aspartate aminotransferase (49.2%), decreased platelet counts (49.2%) and proteinuria (44.3%). TEAEs that lead to treatment discontinuation of both agents included individual instances of arrhythmia, blood bilirubin increase, gastrointestinal hemorrhage, hemorrhage intracranial, immune-mediated myocarditis, and proteinuria. Furthermore, 1 hepatic function abnormality led to discontinuation of serplulimab, and 2 proteinuria events lead to HLX04 discontinuation.

“This study demonstrated that serplulimab combined with HLX04 was well tolerated in patients with [advanced] HCC in the first-line setting,” Zhenggang Ren, MD, PhD director of Hepatic Oncology at Zhongshan Hospital, Fudan University in Shanghai, wrote in the publication with study coinvestigators.¹ “[The combination’s] promising antitumor activity and potential to prolong survival support further investigations of the serplulimab/HLX04 combination for the first-line treatment of HCC.”

A total of 238 patients were screened between September 24, 2019, and April 8, 2021, in the phase 2 trial, of whom 115 were excluded. Sixty-one patients were included in a cohort where serplulimab/bevacizumab was assessed, all of whom received at least 1 dose of study treatment.

Patients in this cohort received 3 mg/kg of intravenous serplulimab in combination with 10 mg/kg of HLX04 every 2 weeks for up to 2 years or until disease progression, unacceptable toxicity, death, withdrawal of consent, or other discontinuation criteria. In cycle 1 or in subsequent cycles for patients who experienced immune-related reactions during cycle 1, dosing was performed on 2 different days. Otherwise, infusions were given on the same day with at least a 30-minute interval between doses.

Treatment could be continued following the first instance of disease progression, provided the investigator found no clinical signs or symptoms of progressive disease, there was no rapid progressive disease at critical anatomical sites requiring alternative interventions, the patient had an improved or stable ECOG performance status, and the patient met laboratory test values defined in the inclusion criteria. Subsequent treatment was given 4 or more weeks from the documented disease progression at the investigator’s discretion.

Of the enrolled patients, 88.5% were male, the median age was 55.0 years (range, 31-73), and 41.0% had an ECOG performance status of 1. Most patients had infections with hepatitis B (98.4%) and Barcelona Clinic Liver Cancer stage C disease (82.0%), and all patients were classified as Child-Pugh class A. A total of 47.5% of patients received prior hepatectomy, 50.8% received prior transarterial chemoembolization, and 57.4% received alternative systemic cancer therapies outside of serplulimab/HLX04 after first disease progression.

The primary study end point was objective response rate (ORR) assessed by independent radiological review committee (IRRC).² Secondary end points included investigator-assessed ORR, overall survival (OS), progression-free survival (PFS), duration of response (DOR), and safety.

Efficacy findings from the trial revealed that among 58 patients in the efficacy evaluable set, IRRC-assessed ORR was 29.3% (95% CI, 18.1%-42.7%). The median PFS was 7.3 months (95% CI, 2.8-11.0), and 6- and 12-month PFS rates were 51.3% (95% CI, 37.5%-63.6%) and 27.6% (95% CI,16.4%-40.1%), respectively. The median OS was 20.4 months (95%, 15.0-not evaluable), with 6- and 12-month OS rates of 93.1% (95% CI, 82.7%-97.4%) and 74.1% (95% CI, 60.8%-83.5%), respectively.

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;74:69. doi:10.1007/s00262-024-03917-w
2. A clinical study evaluating the use of HLX10 in combination with HLX04 for the treatment of advanced hepatocellular carcinoma (HCC) patients. ClinicalTrials.gov. Updated January 12, 2022. Accessed January 22, 2025. https://tinyurl.com/ypzza88f