Patients with hepatocellular carcinoma (HCC) are often diagnosed at an advanced, unresectable stage of the disease. The multikinase inhibitors (sorafenib and lenvatinib) are the mainstay of first-line systemic therapy for these patients. However, the survival benefit with these agents is modest, and associated side effects may impact patients’ quality of life. Given the hypervascularity and high immunogenicity of HCC, the role of antiangiogenic and immunotherapy combinations in advanced HCC are now the research focus of several clinical trials. In the IMbrave 150 trial, a significant survival benefit with the anti-PD-L1 inhibitor, atezolizumab, and anti-VEGF inhibitor, bevacizumab, was reported and has led to regulatory approvals of this combination.

At the ESMO Asia virtual congress, which took place on 20–22 November 2020, results from the ORIENT-32 trial were presented by Zhenggang Ren, MD, PhD (Zhongshan Hospital, Fudan University, Shanghai, China). In this randomized, open-label, multi-center, phase II/III trial, the efficacy and safety of the anti-PD-1 antibody, sintilimab (200 mg intravenous [IV] every 3 weeks [Q3W]), in combination with a bevacizumab biosimilar (15 mg/kg IV Q3W), was compared with sorafenib (400 mg orally, twice-daily) as first-line treatment for patients with advanced, systemic-treatment-naïve HCC. The stratification factors included macrovascular invasion and/or extrahepatic metastases, baseline alfa fetoprotein (<400 ng/mL or ≥400 ng/mL) and ECOG performance status (0 or 1). According to previously reported results of the phase II part of the study, the combination showed an acceptable safety profile. Among 571 patients, over 95% had Child-Pugh A cirrhosis (score 5–6), and over 90% had hepatitis B virus infection etiology. The co-primary endpoints were overall survival (OS) and progression-free survival (PFS) by independent radiologic review committee (IRRC) per RECIST version 1.1. At a median follow-up of 10.0 months, the sintilimab plus bevacizumab arm showed a statistically significant improvement in OS compared with the sorafenib arm (not evaluable [NE] versus 10.4 months, respectively; hazard ratio [HR], 0.57; P<0.0001). The co-primary endpoint was also reached with a median PFS of 4.6 versus 2.8 months, respectively (HR, 0.57; P<0.0001). The PFS and OS benefits were generally consistent across all subgroups. The confirmed overall response rate by IRRC (a secondary endpoint) was 20.5% in the combination arm versus 4.1% in the sorafenib arm (P<0.0001), and the duration of response was NE versus 9.8 months, respectively. The incidence of adverse events was generally similar between the two arms: treatment-related adverse events (TRAEs) were reported in 88.7% of patients in the combination arm versus 93.5% in the sorafenib arm, and grade 3–4 TRAEs occurred in 33.7% versus 35.7%, respectively. There were no unexpected safety signals reported. AEs leading to discontinuation of any study treatment occurred in 13.7% of patients in the combination arm versus 5.9% in the sorafenib arm, and TRAEs leading to death in 1.6% versus 1.1% of patients, respectively. Among patients who were evaluable for anti-drug antibodies (ADA), only 3.3% of patients tested positive for treatment-emergent ADA of sintilimab. Additionally, the investigators assessed the impact of the COVID-19 pandemic on drug administration and radiographic assessment and found that around 25% of patients in the combination arm experienced delays in treatment and/or tumor assessments, and up to 15% of patients in the sorafenib arm.

Based on the data, Dr Ren concluded that sintilimab plus bevacizumab biosimilar could be a new first-line treatment option for patients with unresectable or metastatic HCC. A discussant of the ORIENT-32 trial data, Sara Lonardi, MD (Veneto Institute of Oncology IOV – IRCCS, Padova, Italy) agreed that the data are very positive and noted that the development of anti-VEGF and immune checkpoint inhibitor combinations increases the treatment options for patients with advanced HCC. She highlighted that while treatment sequencing and biomarker data are still anticipated, there are now multiple choices along the continuum of care for patients with advanced HCC.

References

Ren Z, et al. ESMO Asia 2020; Abstract LBA2.