According to data from the GLOBOCAN 2020 database, liver cancer is a pronounced health burden worldwide, ranking sixth in incidence (4.7%) and third in mortality (8.3%) among all cancers [1]. Hepatocellular carcinoma (HCC) accounts for 75–85% of primary liver cancer cases [2]. Due to difficulties in early diagnosis, most HCC patients are diagnosed at an advanced stage and miss opportunities for radical treatment, thus effective systematic treatment is in high demand for them [3].

According to the results from the SHARP [4] and sorafenib (SOR) Asia-Pacific trials [5], SOR was the only targeted therapy allowed for HCC patients from 2007 until 2018, which significantly prolonged patients’ overall survival (OS). During that decade, many other compounds, including erlotinib, brivanib, sunitinib, linifanib, and everolimus, were tested in the first-line treatment of HCC, but they did not show superiority or noninferiority to SOR [6]. In 2018, lenvatinib (LEN) was found to be non-inferior to SOR and represented a long-awaited alternative option to SOR for the first-line systemic treatment of patients with unresectable HCC (uHCC) [7]. In recent years, clinical trials of a variety of combination regimens have generated mixed results. The results of IMbrave150 led to the largest change in the treatment landscape of uHCC, which showed that the combination of atezolizumab and bevacizumab was significantly superior to SOR with an improved median OS and comparable rates of ≥ 3 grade adverse events [8]. The results of the ORIENT-32 were also positive for OS and progression-free survival (PFS) [9]. With the combination of camrelizumab and apatinib, CARES-310 observed the longest OS (22.1 months) among all phase III trials for uHCC in 2023 [10]. However, the LEAP-002 trial showed that pembrolizumab plus LEN did not meet its dual primary endpoints of OS and PFS as a first-line treatment for patients with uHCC [11]. Similarly, treatment with atezolizumab with cabozantinib in COSMIC-312 significantly improved PFS compared to SOR, but it did not reach statistical significance for OS [12].

Based on the above studies, immunotherapy combined with targeted therapy is a widely used first-line therapy for uHCC and can be roughly divided into two types: anti-programmed death 1/ligand-1 (anti-PD-1/L1) antibody combined with vascular endothelial growth factor (VEGF)-antibody and anti-PD-1/L1 antibody combined with VEGF receptor (VEGFR)-targeted tyrosine kinase inhibitor (TKI) [13]. However, the choice of anti-PD-1/L1 antibody + VEGF-antibody (A + A) or anti-PD-1/L1 antibody + VEGFR-targeted TKI (A + T) for the first-line treatment of uHCC is a practical problem and a challenge for clinicians. Due to the absence of head-to-head clinical trials, we conducted a network meta-analysis (NMA) to indirectly compare the efficacy and safety between A + A and A + T.

To our knowledge, this is the first NMA to evaluate the clinical efficacy and safety of combining two combination regimens in patients with unresectable or locally advanced HCC as the first-line treatment [16, 17]. The VEGF antibodies included in our study were bevacizumab and its biosimilar, which target VEGF-A and act by inhibiting the biological activity of human VEGF. However, TKIs participating in this NMA include SOR and LEN, whose targets include fibroblast growth factor receptor, platelet-derived growth factor receptor, and the main target VEGFR. Although only a few studies were included in this study, the six included studies were all high-quality randomized controlled studies with a low risk of bias and similar baseline characteristics of patients.

This study showed anti-PD-1/L1 antibody combined with VEGF-antibody appeared to be the most effective therapeutic strategy in reducing the risk of death, while anti-PD-1/L1 antibody combined with VEGFR-targeted TKI was more likely to bring longer PFS and higher ORR in patients at the cost of lower safety rate.

In this study, OS was chosen as the primary endpoint, which could provide the most objective clinical assessment of efficacy for cross-trial comparison. The results showed that there was no significant difference in OS between the two treatment regimens, which was similar to the results of a recent retrospective study [18]. In the subgroup analysis, the clinical efficacy results were generally consistent with the primary results of patient analyses based on geographic region, etiology, ECOG score, and BCLC grade. A + T showed a better ability to address MVI and EHS. Compared with those without MVI, HCC with MVI is usually characterized by worsening liver function, vulnerability to blood metastasis, a higher incidence of complications associated with portal hypertension, and intolerance to treatment [19]. Patients with EHS usually have a poor prognosis, but the specific situation is closely related to the site of distant metastasis. Peritoneal metastasis and bile duct involvement in HCC patients treated with Immune checkpoint inhibitors may indicate significantly poor OS but have no significant impact on the prognosis of ORR [20]. In a prospective trial of LEN plus pembrolizumab, EHS was not an independent risk factor for OS, which may be related to front-line therapy in some patients [21]. Thus, we do not deny that the inadequacy of the included studies has contributed to the error in the results, so more high-quality trials should be promoted.

Different from the results of OS, A + T had a better effect in prolonging patients’ PFS and reducing the size of solid tumours. The results are consistent with previous clinical studies. A pilot study involving 10 HCC patients with vascular infiltration showed that after treatment with anti-PD-1 antibody combined with VEGFR-targeted TKI, 7 patients achieved PR, 3 patients achieved CR, and all 10 patients underwent surgery with a recurrence-free survival rate of 75% within 12 months [22]. Another study also indicated that this conversion therapy strategy can be effective and safe for hepatectomy after careful preparation and patient evaluation [23]. At the same time, A + T combination treatment of renal cell carcinoma and non-small cell lung cancer also has an excellent tumour reduction effect with a high ORR [24, 25].

A + T showed higher toxicity with significantly higher incidences of all grade TRAEs and grade ≥ 3 TRAEs than A + A. As an important organ of drug metabolism, the liver is one of the most susceptible organs to cancer immunotherapy, and the liver damage caused by immunotherapy is often referred to as immune-mediated hepatitis (IMH) and often can be diagnosed by the increase in abnormally elevated serum liver enzymes [26]. The rate of abnormal elevation of serum liver enzymes in patients in the A + T group was higher than that in the A + A group (Table S3). On the other hand, it reflected that A + T might effectively improve the effect of immunotherapy as overactivity of T cells may lead to the destruction of immune tolerance in the liver, making it susceptible to acute inflammation and hepatitis [27, 28]. To control IMH, the guidelines recommend a detailed examination of the patient's liver condition prior to the use of the drug, cessation of immunotherapy as soon as IMH occurs, and the use of corticosteroids as treatment agents [29–31]. In the A + A group, the most common TRAEs were hypertension and proteinuria, which were closely related to the nephrotoxicity caused by VEGF antibodies [32, 33]. For the sake of patient safety, if patients suffer from complications such as diabetes or kidney disease, comprehensive renal function evaluation should be performed before A + A therapy, and patients’ hypertension must be well controlled [33].

This NMA also has limitations that need further consideration and exploration. First, among the included trials, the data of two trials were obtained from the conference presentation, and the data were incomplete, which would eventually lead to the deviation of the estimation of the relative effect. In addition, the varied follow-up time among the trials and the open-label nature of one included trial may have introduced bias. Hence, more high-quality prospective studies are needed to better evaluate the optimal treatment. Second, a meta-analysis found that the Child-Pugh score was subjective to a certain extent, and the Albumin Bilirubin score could better stratify patients [34]. Therefore, how to conduct more accurate stratification and precise treatment for patients before the implementation of treatment may be a major direction of our future research. Third, a recent study showed that discontinuation of A + T in the absence of other therapeutic adjustments was associated with poor outcomes [35]. However, the included studies did not mention drug dose changes and discontinuation in detail, and only three studies mentioned the use of TKIs for subsequent maintenance therapy (LEAP-002: 34.9%; COSMIC-312: 14%; CARES-310: 29.8%), which prevented us from exploring this aspect further. Thus, the search for the best follow-up regimen or drug use sequence will become an important challenge in the management of HCC.

In conclusion, we suggested that A + A had the greatest probability of delivering the longest OS, while A + T was correlated with larger PFS benefit at the cost of a lower safety rate.