Biosimilar-Backed Triplet Regimen Shows Feasibility in Heavily Pretreated Liver Cancer

For people with advanced hepatocellular carcinoma whose disease has progressed despite prior immunotherapy, treatment options have remained limited and largely empirical. New findings from the phase 2 ReUNION-1 trial suggested that integrating stereotactic body radiotherapy (SBRT) with continued immune checkpoint inhibition and a bevacizumab biosimilar may offer a strategy to overcome resistance while maintaining an acceptable safety profile.1

The open-label, single-arm ReUNION-1 study, published in Nature Communications, evaluated SBRT followed by sintilimab (a PD-1 inhibitor) plus a bevacizumab biosimilar in people with unresectable hepatocellular carcinoma (HCC) whose disease had progressed after at least one prior anti–PD-1–based regimen. Immune checkpoint inhibitor resistance remains a substantial challenge in HCC, where objective response rates to monotherapy have historically ranged from 13% to 20%, and where second-line standards have largely been extrapolated from sorafenib-pretreated populations.2,3

Between March 2022 and April 2024, investigators screened 25 patients and enrolled 21. All participants were included in the intention-to-treat analysis. The median age was 55 years, and 81.0% were men. All patients had Child-Pugh class A liver function and an Eastern Cooperative Oncology Group performance status of 0 or 1. Chronic hepatitis B virus infection was the predominant underlying liver disease (85.7%). Most patients (61.9%) had received one prior line of systemic therapy, and 71.5% had extrahepatic metastases. Nearly all had previously received a tyrosine kinase inhibitor plus a PD-1 inhibitor combination.

Patients underwent SBRT (median dose 8 Gy per fraction for 5 fractions) directed at a selected lesion, followed by sintilimab 200 mg and bevacizumab biosimilar 15 mg/kg every 3 weeks until disease progression or unacceptable toxicity. The primary end point was objective response rate (ORR) in nonirradiated lesions per RECIST v1.1 criteria.

At a median follow-up of 9.1 months, the ORR in nonirradiated lesions was 33.3%, with 7 of 21 patients achieving a confirmed partial response. Stable disease was observed in 7 additional patients, resulting in a disease control rate (DCR) of 66.7%. Notably, irradiated lesions demonstrated a 100% local-regional control rate, and 76.2% achieved an objective response within the treated field. Durable disease control lasting at least 6 months was observed among patients with partial response or prolonged stable disease.

Median progression-free survival (PFS) was 6.2 months (95% CI, 3.7-15.1), with 6- and 12-month PFS rates of 57.1% and 14.3%, respectively. The estimated median overall survival (OS) was 24.4 months (95% CI, 9.2 months–not reached). Eight deaths had occurred at data cutoff.

Treatment-related adverse events (TRAEs) of any grade occurred in 81.0% of patients. Grade 3 or higher TRAEs were reported in 33.3%, including decreased platelet count, neutropenia, and gastrointestinal hemorrhage. Two grade 4 gastrointestinal hemorrhages were managed with endoscopic intervention, and 1 patient experienced grade 3 anaphylaxis requiring discontinuation of sintilimab. No treatment-related deaths were reported, and 14.3% discontinued therapy due to serious TRAEs.

The study also incorporated serial proteomic and immune profiling analyses. Responders had lower baseline interferon-γ (IFN-γ) levels and higher IL-6 and TNF-α levels compared with nonresponders. Lower baseline IFN-γ levels were associated with longer PFS and OS; patients with low IFN-γ had a median OS of 24.4 months compared with 9.3 months in those with high IFN-γ (HR, 4.12; 95% CI, 1.36-12.46). SBRT was associated with increased circulating IL-6, IL-15, and CD70 levels and decreased VEGFA levels, suggesting immune modulation that may have contributed to renewed sensitivity to PD-1 blockade.

The investigators acknowledged several limitations, including the small sample size, single-arm design, and enrollment at a limited number of centers in China, where hepatitis B–related HCC predominates. The relatively short follow-up period and lack of a comparator arm limited definitive conclusions regarding survival benefit. In addition, prior treatment heterogeneity may have influenced outcomes.

For managed care stakeholders monitoring the evolving biosimilar landscape, the use of a bevacizumab biosimilar in combination with immunotherapy and radiotherapy demonstrated feasibility in a heavily pretreated population. Although confirmatory randomized trials are needed, the findings suggested that combining locoregional and systemic approaches may represent a viable strategy for people with HCC whose disease has progressed on prior PD-1–based therapy.

References

1. Tang J, Yang Y, Liu D, et al. Stereotactic body radiotherapy with sintilimab and bevacizumab biosimilar in anti-PD-1 refractory hepatocellular carcinoma: the ReUNION-1 phase 2 trial. Nat Commun. 2025;17(1):823. doi:10.1038/s41467-025-67528-4

2. Abou-Alfa GK, Lau G, Kudo M, et al. Tremelimumab plus durvalumab in unresectable hepatocellular carcinoma. NEJM Evid. 2022;1(8):EVIDoa2100070. doi:10.1056/EVIDoa2100070

3. Qin S, Kudo M, Meyer T, et al. Tislelizumab vs Sorafenib as first-line treatment for unresectable hepatocellular carcinoma: a phase 3 randomized clinical trial. JAMA Oncol. 2023;9(12):1651-1659. doi:10.1001/jamaoncol.2023.4003