In Korea, cancer remains a major cause of death, with liver cancer being the second most common cause of cancer-related deaths following lung cancer in 2020 (lung cancer: 36.4 deaths, liver cancer: 20.6 deaths per 100,000, according to statistics from the National Statistical Office) [1]. Furthermore, liver cancer represents the most substantial economic burden, particularly impacting individuals in their most productive years, underscoring its critical importance as a health issue in the country [2]. Thus, this paper aims to examine the latest treatment trends for advanced-stage hepatocellular carcinoma (HCC), referencing the newly revised 2022 HCC guidelines and the 2022 Barcelona Clinical Liver Cancer (BCLC) system [3].

HCC often develops in the context of chronic hepatitis, primarily driven by innate immune activation. However, certain causes are associated with specific immune dysfunctions. Chronic viral hepatitis can lead to liver cancer by initiating inflammatory innate immune responses and fostering an abnormal adaptive immune reaction that fails to eliminate the hepatitis virus [4]. Approximately half of HCC patients receive systemic therapy. Traditionally, sorafenib or lenvatinib were used as first-line treatments, followed by regorafenib, cabozantinib, or ramucirumab as second-line options. However, since 2020, immune checkpoint inhibitors (ICIs) have shown significantly improved overall survival rates compared to sorafenib. Therefore, the combination therapies of atezolizumab with bevacizumab and durvalumab with tremelimumab have become the preferred first-line treatments.

This review aims to provide an overview of recent advancements in treating advanced HCC, based on the updated 2022 HCC guidelines and the BCLC system. It specifically updates the following topics: first-line systemic therapy, second-line systemic therapy following the failure of first-line treatment, and the side effects of systemic chemotherapy agents.

Atezolizumab is an intravenous IgG1 monoclonal antibody that targets programmed death ligand 1 (PD-L1) on the surface of cancer cells, preventing its interaction with the receptor. Bevacizumab, another intravenous IgG monoclonal antibody, binds to vascular endothelial growth factor (VEGF), thereby inhibiting angiogenesis and tumor growth.

In the IMbrave150 study, patients with advanced HCC who were treated with a combination of atezolizumab and bevacizumab exhibited a significant increase in median overall survival and progression-free survival (PFS) compared to those treated with sorafenib (6.8 months; 95% CI, 5.7–8.3 vs. 4.3 months; 95% CI, 0.47–0.76, P<0.001). This marked improvement prompted the Food and Drug Administration (FDA) to approve the combination therapy in 2020. The study excluded patients with autoimmune diseases, concurrent HBV and HCV infections, or untreated esophageal or gastric varices. The primary causes of HCC were chronic infections, with HBV and HCV accounting for 49% and 21% of cases, respectively. All participants had preserved liver function (Child-Pugh class A), and 26% had low-risk varices at baseline, with 11% undergoing treatment. The study was halted at the first interim analysis after demonstrating significant improvements in both overall survival and PFS [5]. Recent updates indicate that after a median follow-up of 15.6 months, the combination of atezolizumab and bevacizumab achieved a median overall survival of 19.2 months, the longest recorded in any phase 3 trial for advanced HCC. Additionally, the overall response rate reached 30%, more than double that of sorafenib [6]. In 2023, a systematic literature review and network meta-analysis were conducted to indirectly compare the combination of atezolizumab and bevacizumab with other treatments for unresectable HCC. The analysis showed that this combination therapy leads to improved overall survival, supporting its use as a first-line treatment for patients with unresectable liver cancer. However, it is important to recognize that this combination may not be suitable for all patients, and careful evaluation is necessary to determine the most appropriate treatment for each individual [7–10].

Tremelimumab is an intravenous IgG2 monoclonal antibody that targets CTLA-4 on activated T-cells, thereby blocking its interaction with the ligands CD80 and CD86. Durvalumab, a fully human IgG1 antibody, binds to PD-L1, inhibiting its interaction with PD-1 and reversing peripheral tolerance against tumor cells [11,12].

On October 15, 2021, the HIMALAYA study demonstrated that combination therapy significantly improved survival compared to sorafenib, with survival times of 16.43 months versus 13.77 months, respectively (hazard ratio [HR], 0.78; 96.02% CI, 0.65–0.92, P=0.0035). This finding met the primary endpoint of the study. The trial enrolled patients with BCLC stage B or C, Child-Pugh class A, ECOG PS 0 or 1, and at least one measurable lesion according to RECIST 1.1 criteria. Patients requiring non-drug treatment for ascites, those with major portal vein thrombosis, or those co-infected with HBV and HCV were excluded from the study. Patients requiring non-drug treatment for ascites, those with major portal vein thrombosis, or those co-infected with HBV and HCV were excluded. The dosing regimen was determined based on pharmacokinetic studies. The STRIDE regimen, which involves administering 300 mg of tremelimumab once, followed by 1,500 mg of durvalumab in the first cycle and then 1,500 mg of durvalumab alone every 4 weeks, proved effective. It was noted that a high dose of tremelimumab could enhance CD8+ T cell levels in peripheral blood, potentially boosting the efficacy of the combination therapy. This study led to the FDA approval of the combination therapy in October 2022, and it received approval from the European Medicines Agency in January 2023 for the treatment of unresectable HCC. An update in January 2023 from the HIMALAYA study indicated that the median follow-up periods for STRIDE, durvalumab, and sorafenib were 49.12 months (95% CI, 46.95–50.17 months), 48.46 months (95% CI, 46.82–49.81 months), and 47.31 months (95% CI, 45.08–49.15 months), respectively [12–14].

Sorafenib is an oral multi-tyrosine kinase inhibitor (TKIs) that targets various receptors, including VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-β, Raf-1, and c-kit. Its anticancer effects are derived from the dual inhibition of angiogenesis and tumor cell proliferation. Additionally, sorafenib inhibits the phosphorylation of the initiation factor eIF4E and promotes cancer cell death by reducing the levels of the anti-apoptotic protein Mcl-1.

The landmark phase 3 SHARP trial enrolled 602 HCC patients, with 97% classified as Child-Pugh class A. This study involved a comparison between a placebo group of 303 patients and a sorafenib group of 299 patients. Among these, 70% had advanced HCC, with underlying conditions including HBV infection (18%), HCV infection (28%), and alcohol-related diseases (26%). Sorafenib was administered orally at a dosage of 400 mg twice daily and significantly increased the median overall survival to 10.7 months, compared to 7.9 months for the placebo group (P<0.001). Therefore, in 2007, sorafenib was approved by the FDA as the first treatment for HCC [15–18].

Lenvatinib, administered orally at a dosage of 12 mg/day for individuals weighing over 60 kg and 8 mg/day for those under 60 kg, is a molecular targeted therapy. It targets multiple receptors, including VEGFR-1/2/3, FGFR-1/2/3/4, PDGFR-α, RET, and c-kit. This therapy inhibits angiogenesis and disrupts fibroblast growth factor signaling in human HCC models [19]. In the multinational phase 3 REFLECT study, lenvatinib demonstrated non-inferiority to sorafenib in terms of survival, with survival times of 13.6 months versus 12.3 months (HR 0.92, 95% CI, 0.79–1.06). Consequently, in 2018, lenvatinib was approved as the first-line systemic treatment for HCC, representing the first such approval in a decade since sorafenib [20,21].

Although immunotherapy is highly effective, its use is limited in patients with recurrent HCC after liver transplantation due to the high risk of allograft rejection. However, retrospective studies have indicated that sorafenib and lenvatinib are safe for these patients. In a retrospective cohort study of 45 patients with recurrent HCC post-liver transplantation treated with lenvatinib, the median overall survival was 14.5 months (95% CI, 0.8–28.2), with a median PFS of 7.6 months (95% CI, 5.3–9.8) and an objective response rate of 20% [22]. This suggests that lenvatinib is a valuable first-line treatment option for advanced HCC, especially in patients concerned about resistance, those unable to undergo timely upper gastrointestinal endoscopy, or for whom immunotherapy is contraindicated. Lenvatinib was also evaluated in a multinational, multicenter trial assessing the clinical outcomes of multiple kinase inhibitors in cancer patients whose disease had progressed following combination therapy with atezolizumab and bevacizumab. The study included patients classified as Child-Pugh class A and BCLC stage B or C. The results showed that patients treated with lenvatinib experienced a longer median PFS of 6.1 months (95% CI, 1.6–10.5) compared to those treated with sorafenib, which was 2.5 months (95% CI, 1.3–3.8, P=0.004). However, overall survival was similar between the two groups (median overall survival, 16.6 months [95% CI, 3.6–29.6] vs. 11.2 months [95% CI, 2.7–19.6]; P=0.347). Lenvatinib has shown promising efficacy and tolerable safety as a second-line treatment following atezolizumab-bevacizumab therapy. Therefore, recent guidelines from NCCN, ASCO, ESMO, EASL, and the KLCA-NCC in Korea recommend considering lenvatinib as a second-line option after atezolizumab-bevacizumab treatment. Furthermore, transarterial chemoembolization, the standard treatment for BCLC-B liver cancer, has been shown to be effective in extending PFS and overall survival when used sequentially or in combination with lenvatinib, as demonstrated in studies conducted in China and Japan. However, additional prospective research, including studies with Western populations, is necessary to confirm these benefits. Finally, the combination therapy of lenvatinib with ICIs has been explored across various cancer types and has received FDA approval for use in advanced renal cell carcinoma. The combination of lenvatinib with pembrolizumab is particularly noteworthy, as lenvatinib suppresses angiogenesis and immune inhibition in the tumor microenvironment, enhancing the anti-tumor immune response of pembrolizumab through a synergistic effect. In this context, the phase 3 LEAP-002 study, which evaluates the effectiveness of lenvatinib combined with pembrolizumab versus lenvatinib monotherapy in advanced HCC, has been conducted. Although there were numerical improvements in PFS and overall survival, the combination therapy did not reach statistical significance in enhancing overall survival and PFS compared to placebo. Nonetheless, this study is significant as it suggests that combining lenvatinib with immunotherapy could be a viable strategy for treating advanced HCC [23].

Patients who exhibit sorafenib resistance may consider regorafenib as a second-line treatment. Regorafenib operates through three primary mechanisms: angiogenesis inhibition, cell proliferation control, and tumor microenvironment regulation. This oral multi-kinase inhibitor targets a variety of receptors, including VEGFR 1-3, TIE-2, PDGFR-β, c-KIT, RET, RAF-1, and BRAF. The simultaneous blockade of VEGF and TIE-2 receptors is thought to significantly improve the constriction of tumor blood vessels. Studies indicate that regorafenib also possesses immune-modulating properties; it helps prevent immune suppression, regulates macrophages, and enhances the proliferation and activation of CD8+ T cells, thereby boosting the anti-tumor immune response.

The RESORCE study demonstrated that patients treated with regorafenib experienced a significantly longer median overall survival compared to the control group (10.6 months vs. 7.8 months; HR 0.63; 95% CI, 0.50–0.79; P<0.001). This finding established regorafenib as the first second-line systemic therapy to show a survival benefit, culminating in its FDA approval in April 2017 for use as a second-line treatment [25–28].

This oral molecular targeted therapy simultaneously inhibits MET, VEGFRs, RET, and KIT, making it effective even in cases resistant to sorafenib. It functions by inhibiting the activity of multiple tyrosine kinases and preventing receptor phosphorylation, thereby halting signal transduction. This mechanism results in the death of cancer cells, decreased proliferation, inhibition of metastasis, reduced tumor blood vessel formation, and ultimately, tumor shrinkage.

A similar result was observed in the multinational phase 3 CELESTIAL trial, where cabozantinib significantly extended median overall survival compared to the placebo group (10.2 months vs. 8.0 months; HR, 0.76; 95% CI, 0.63–0.92; P=0.005). Therefore, cabozantinib received approval from the EMA and FDA for the treatment of HCC patients who had previously been treated with sorafenib, recommending a daily dose of 60 mg. In November 2021, findings from the COSMIC-132 trial, which investigated the combination of atezolizumab and cabozantinib, were published. The study showed a significant improvement in PFS, with an HR of 0.63. However, interim data did not show a significant improvement in overall survival compared to sorafenib, pending the final analysis [29]. Similarly, the final results of the COSMIC-312 study, reported in 2024, indicated that although the combination of atezolizumab and cabozantinib continued to show a significant benefit in PFS, it did not enhance overall survival compared to sorafenib. In 2020, a matching-adjusted indirect comparison was performed to indirectly compare the outcomes of the CELESTIAL and RESORCE trials in patients who had received sorafenib as first-line therapy. This comparison assessed the efficacy and safety profiles of cabozantinib and regorafenib. The findings demonstrated that cabozantinib, compared to regorafenib, achieved a similar overall survival and a longer PFS in patients with advanced HCC whose disease had progressed following sorafenib treatment [30–32].

Ramucirumab is an intravenous monoclonal antibody that specifically targets VEGFR-2. Unlike bevacizumab, ramucirumab exhibits a broader inhibitory profile by blocking all forms of VEGF from binding to VEGFR-2, thereby effectively halting angiogenesis due to its high binding affinity. Elevated AFP levels are typically associated with poor prognosis and increased angiogenesis, as well as heightened VEGFR expression. In the REACH-2 trial, which included patients with serum AFP levels of 400 ng/mL or higher, BCLC-B/C, ECOG PS 0/1, and Child-Pugh class A, participants who received 8 mg/kg of ramucirumab biweekly demonstrated a significant improvement in overall survival compared to those in the placebo group (8.5 months vs. 7.3 months; HR, 0.71; 95% CI, 0.531–0.949; P=0.0199) [33–35].

Nivolumab is an intravenous PD-1 inhibitor and a recombinant human IgG4 monoclonal antibody. It functions by binding to the PD-1 receptor on T cells' surfaces, thereby restoring their ability to attack cancer cells. Ipilimumab targets the CTLA-4 receptor on the cell membrane, blocking its interaction with the ligands CD80 and CD86. This combination is conditionally approved by the FDA as a second-line treatment following sorafenib. The CheckMate 040 trial assessed the efficacy and safety of nivolumab and ipilimumab in patients with advanced HCC who had previously received sorafenib treatment. The study demonstrated that the combination therapy led to significant and durable responses, resulting in the approval of the regimen in the United States. This regimen involves administering nivolumab at 1 mg/kg and ipilimumab at 3 mg/kg every 3 weeks for four doses, followed by nivolumab at 240 mg every two weeks. However, this combination has not yet been incorporated into domestic or BCLC guidelines [36–38]. In 2024, the 5-year results from this cohort were published, confirming the initial findings. The combination therapy in arm A showed clinically meaningful responses and extended survival benefits for patients with advanced HCC previously treated with sorafenib, further endorsing its use as a second-line treatment [39,40].

Pembrolizumab is a human IgG4 monoclonal antibody that targets the PD-1 receptor, inhibiting its interaction with PD-L1 and PD-L2. Although the KEYNOTE-240 study, which compared pembrolizumab with a placebo, did not achieve statistically significant results in its final analysis, the findings still underscore the drug's antitumor activity as a second-line treatment for HCC. These results have also set the stage for further investigations [41]. In November 2018, pembrolizumab was granted accelerated approval by the FDA, following the outcomes of the global phase 2 KEYNOTE-224 study that included patients with advanced HCC who had previously been treated with sorafenib.

In 2022, the phase 3 KEYNOTE-394 study evaluated pembrolizumab as a second-line treatment compared to a placebo in Asian patients. Pembrolizumab was administered at a dose of 200 mg every three weeks, mirroring the placebo group's regimen. The study results indicated a significant improvement in median overall survival (14.6 vs. 13.0 months; HR for death, 0.79; 95% CI, 0.63–0.99, P=0.0180) and PFS (2.6 vs. 2.3 months; HR for progression or death, 0.74; 95% CI, 0.60–0.92, P=0.0032). Furthermore, the objective response rate was markedly better (12.7% vs. 1.3%, P<0.0001), reinforcing the recommendation to use pembrolizumab as a second-line treatment for this patient group [42,43].

Although sorafenib offers significant benefits to patients, it also has side effects similar to those of other TKIs. Sorafenib targets the VEGF receptor pathway and Raf kinase, both of which are essential for maintaining physiological functions and homeostasis in the body. Inhibiting these signaling pathways can result in therapeutic benefits but also potential side effects. Currently, side effects such as hypertension, thyroid dysfunction, hand-foot syndrome, and fatigue are associated with the inhibition of various tyrosine kinases. Additionally, hypertension, arterial thromboembolism, proteinuria, wound complications, bleeding, and gastrointestinal perforation are closely linked to the VEGF pathway. While most side effects are manageable, severe adverse reactions like cardiac shock or hemorrhage can be life-threatening and may lead to the discontinuation of chemotherapy. Therefore, it is crucial to review these side effects thoroughly [44,45].

Immune checkpoint molecules are pivotal in regulating anti-cancer T-cell responses and are expressed on T-cells, antigen-presenting cells such as dendritic cells and macrophages, and tumor cells. These molecules are essential for naturally suppressing T-cell activity and maintaining self-tolerance. Major inhibitory receptors of immune checkpoints include PD-1, PD-L1, CTLA-4, LAG-3, and TIM-3, while co-stimulatory proteins such as CD25, GITR, and OX40 promote T-cell expansion. Consequently, ICIs that target PD-1, PD-L1, CTLA-4, TIM-3, and LAG-3 have shown significant safety and efficacy in treating HCC. Additionally, immunotherapeutic drugs are not metabolized in the liver, which may lead to predictable pharmacokinetic profiles in patients with cirrhosis [49]. In the treatment of advanced HCC, ICIs have improved survival rates compared to sorafenib, but they are also associated with a spectrum of adverse effects that necessitate careful monitoring. Although the precise mechanisms are not fully understood, these effects are often related to the depletion and exhaustion of regulatory T cells, which play a vital role in maintaining tolerance induced by ICI therapy, especially through CTLA-4 blockade. The depletion of these cells can result in decreased anti-inflammatory cytokines, increased proliferation of CD8+ T cells, and early B-cell alterations, potentially leading to immune-related adverse events. These side effects differ from those associated with traditional chemotherapy, as they can be more unpredictable in their onset and may persist longer. This article will discuss the specific side effects associated with key ICIs, including nivolumab, ipilimumab, atezolizumab, bevacizumab, tremelimumab, and durvalumab, in sequence [50,51].