Systemic treatment of liver cancer: Current status and future perspectives

Abstract

Primary liver cancer, a common malignant tumor of the digestive tract, ranks fifth in global cancer incidence and shows high morbidity and mortality. Liver cancer patients who are diagnosed early have the option of surgical resection, which offers the possibility of a radical cure. However, due to the insidious disease onset, most patients are diagnosed in the intermediate or advanced stages, and surgery is no longer a viable option. Therefore, systemic treatment options play an essential role in the management of advanced liver cancer. These treatments aim to suppress disease progression, prolong survival, and improve quality of life. This article reviews the latest research in the field of systemic therapy of liver cancer, including molecular targeted therapy, immunotherapy, and their combination strategies. At first, the application and efficacy of first-line molecularly targeted drugs are discussed. Next, the revolutionary advances in immune checkpoint blockers are presented. Subsequently, the clinical effects of the combination of molecularly targeted therapy and immunotherapy are analyzed. Finally, this article summarizes the current challenges faced by the systemic treatment of liver cancer and introduces the prospect of future treatment trends.

Key Words: Primary liver cancer; Systemic therapy; Molecularly targeted drugs; Immunosuppressive therapy; Combination therapy

Core Tip: Primary liver cancer is a malignant tumor with the fifth highest incidence in the world, and hepatocellular carcinoma is the most common form of primary liver cancer. Due to the insidious disease onset and rapid progression, most liver cancer patients are diagnosed in the intermediate or advanced stages, and surgery is no longer a viable option. This article summarizes the current challenges faced by the systemic treatment of liver cancer and introduces the prospect of future treatment trends.

INTRODUCTION

Liver cancer is one of the most prevalent malignancies globally, with a particularly high incidence in Asia and Africa, and a gradual upward trend in occurrence worldwide[1,2]. According to estimates from the World Health Organization[3], over 1 million patients will succumb to liver cancer by 2030. Existing data indicate that approximately 700000 individuals die from primary liver cancer annually[4]. Hepatocellular carcinoma (HCC) is the most prevalent form of primary liver cancer and is the third leading cause of cancer-related mortality globally. HCC has a dismal five-year survival rate of merely 18% and constitutes around 75-90% of all cases[5]. HCC predominantly affects patients with underlying liver diseases and is mainly induced by hepatitis B virus (HBV) or hepatitis C virus (HCV) infections or alcohol abuse. Considering the current state of clinical diagnosis and treatment, the imperfect early-screening system, and the liver's robust compensatory function, the majority of HCC patients seek medical attention due to symptoms such as abdominal masses or swelling, epigastric pain, jaundice, loss of appetite, and weight loss. By this time, the disease has already advanced to the middle and late stages, and the opportunity for radical surgical treatment has been missed[6,7]. In this context, the systemic treatment strategy centered on molecularly targeted drugs and immune checkpoint inhibitors (ICIs) has emerged as a crucial means of clinical intervention for advanced liver cancer. This study delves into the clinical advancements in the systemic treatment of HCC, focusing on the targets and synergistic mechanisms of multi-kinase inhibitors (TKIs), anti-angiogenic drugs, and programmed cell death protein 1 (PD-1)/PD-1 ligand (PD-L1) inhibitors. This systematic review analyzes key indicators such as the objective response rate (ORR) and overall survival (OS) under the RECIST criteria to explore the breakthrough progress of combination therapy in improving prognosis and controlling drug toxicity. The findings of this study will provide an evidence-based medical foundation for optimizing the treatment pathway of advanced liver cancer and offer theoretical support for the formulation of individualized treatment strategies.

PROGRESS IN TARGETED THERAPY OF ADVANCED HCC: FROM SINGLE-TARGET TO MULTI-TARGET INHIBITION

Targeted therapy drugs play a pivotal role in the systemic treatment framework of HCC[8]. These drugs specifically and selectively inhibit discrete molecular targets intrinsic to tumor cells, effectively curtailing the growth and dissemination of tumors[9]. Sorafenib, a landmark agent in the targeted treatment of advanced HCC, was the first multi-kinase inhibitor to receive regulatory approval for this indication. Sorafenib exerts its pharmacological effects on multiple signaling pathways, including the vascular endothelial growth factor receptor (VEGFR) and fibroblast growth factor receptor (FGFR) present on the surface of tumor cells, along with the platelet-derived growth factor receptor (PDGFR), Raf kinases, KIT, FLT-3, etc. Sorafenib primarily functions by impeding the signaling cascades that are fundamental for tumor cell growth and division. This action engenders a dual beneficial effect: The inhibition of angiogenesis, which restricts the tumor's blood supply, and the suppression of tumor cell proliferation. Moreover, numerous pre-clinical and clinical investigations have reported that sorafenib effectively increases the apoptosis rate of diverse tumor cell types[10,11]. The SHARP study[12] revealed that sorafenib could prolong the median survival of patients with advanced HCC by 2.8 months compared to the placebo group. The median survival times were 10.7 months in the sorafenib-treated cohort and 7.9 months in the placebo-treated cohort. This survival advantage was achieved through the blockade of tumor angiogenesis-associated signaling and the induction of apoptosis. The Oriental study[13] found that, compared with the placebo group, sorafenib could significantly prolong the time to disease progression (2.8 months vs 1.4 months) and the overall survival rate (6.5 months vs 4.2 months) of patients with advanced liver cancer in the Asia-Pacific region. In recent years, sorafenib has attracted extensive attention in the field of liver cancer treatment, with clinical research showing substantial breakthroughs. The results indicate significantly slower disease progression and markedly longer survival time in liver cancer patients. Nevertheless, its ORR remains below 20% and may involve major adverse effects (such as fatigue, diarrhea, hypertension, and skin rash). Furthermore, no distinct survival benefit has been found in HBV-positive patients, highlighting its limitations in the current therapeutic needs for advanced liver cancer[11].

Building upon this foundation, lenvatinib is another key targeted therapy drug that has been extensively employed in the first-line treatment of liver cancer. In contrast to sorafenib, lenvatinib exhibits a more expansive targeting profile. Its principal targets include vascular endothelial growth factor receptor 1–3, fibroblast growth factor receptor 1–4, PDGFR, KIT, and RET[14,15]. It inhibits the formation of new tumor blood vessels by suppressing multiple targets such as VEGFR, PDGFR, and FGFR, thereby reducing the blood supply to the tumor and inhibiting the growth and metastasis of the tumor. In addition, lenvatinib also exerts its effects by inhibiting multiple other related signaling pathways (such as Raf/Mek/Erk). Notably, the fibroblast growth factor (FGF) signaling pathway holds unique biological significance in the context of tumor angiogenesis and is regarded as one of the critical mechanisms underlying the development of resistance to anti-VEGF therapy. In comparison, the targeting efficacy of sorafenib on this pathway is relatively circumscribed[16]. The REFLECT study, a phase III randomized controlled global multicenter noninferiority clinical trial[17,18], revealed that lenvatinib demonstrated remarkable clinical advantages in patients with unresectable HCC. The OS in the lenvatinib-treated group was 13.6 months, which was significantly longer than the 12.3 months observed in the sorafenib-treated arm. However, it has more adverse reactions (hypertension occurs in 42% of patients), and the rate of decreased appetite is higher than that in the sorafenib group. Moreover, according to a meta-analysis, its ORR and disease control rate were 25.6% and 58.1%, respectively, which were substantially superior to the 3.6% and 23.6% recorded in the sorafenib-treated arm[19]. Furthermore, an updated quality-of-life analysis conducted in 2021 indicated that lenvatinib effectively delayed the exacerbation of symptoms such as fatigue [hazard ratio (HR) = 0.83], pain (HR = 0.80), and diarrhea (HR = 0.52) compared with patients treated with sorafenib, thereby maintaining a more favorable health-related quality of life[18]. In addition, Casadei Gardini et al[20] reported that lenvatinib may have a more significant survival benefit in HBV-infected HCC patients compared with sorafenib. Although the available clinical data confirm the therapeutic advantages of lenvatinib over sorafenib, the efficacy of these two clinically authorized targeted therapies in prolonging survival is limited to less than 2 to 3 months[21,22].

Furthermore, although first-line targeted drugs such as sorafenib and lenvatinib have manifested potent anti-tumor activity in HCC, a subset of patients invariably develops acquired resistance to treatment. This acquired resistance significantly attenuates the treatment efficacy, highlighting the urgent need for second-line treatment options to ameliorate patient prognosis. Moreover, cabozantinib has been established as an oral multi-targeted TKI and serves as the standard second-line treatment for patients with advanced HCC who have previously received sorafenib treatment[23]. Its mechanism of action involves effectively blocking tumor angiogenesis and immune escape pathways by synergistically inhibiting key targets such as VEGFR2, MET, and AXL. In the CELESTIAL-1 study[24], cabozantinib significantly improved median overall survival (mOS) to 10.2 months compared with placebo, demonstrating an improvement of 2.2 months compared with the control group, and an absolute benefit of 3.3 months in progression-free survival (PFS) (5.2 vs 1.9 months), showing significant advantages in disease control.

Notably, the new drug donafenib, independently developed in China, is a deuterium derivative of sorafenib[25] and is the world’s first deuterated tyrosine kinase inhibitor approved for the first-line treatment of advanced HCC[26]. Its molecular structure has been precisely modified on the basis of sorafenib to optimize anti-tumor activity and toxicity reduction by enhancing the inhibition of the VEGFR, PDGFR, and RAF/MEK/ERK signaling pathways. In addition, it can improve the tumor immune microenvironment, thereby reducing the resistance to anti-PD-1/PD-L1 antibodies, generating a synergistic effect on tumor treatment, and enhancing the therapeutic effect. In the ZGDH3 study[27], the median OS of patients in the donafenib group (12.1 months) was significantly longer than that of the sorafenib group (10.3 months). Additionally, the incidence of grade 3 adverse events was lower in the donafenib-treated group compared to the sorafenib group (57.4% vs 67.5%). More remarkably, in some sensitive patients, the OS could reach up to 21 months, which is significantly superior to that achieved by traditional treatment approaches, signifying its substantial therapeutic potential. The above commonly used drugs are summarized in Tables 1 and 2.

Table 1 Comparison of core mechanisms of four targeted drugs.

Drug	Target of action	Mechanism of action	Main indications	Key clinical data	Common adverse reactions
Sorafenib	VEGFR1-3, PDGFRβ, Raf kinase, KIT, FLT-3	Inhibit angiogenesis (VEGFR/PDGFR), block the Raf/MEK/ERK pathway, inhibit tumor proliferation, and enhance the immune response	Liver cancer, kidney cancer, thyroid cancer	The SHARP study: Median OS was 10.7 months vs 7.9 months (placebo). The Oriental study: In the Asia-Pacific population, the OS was 6.5 months vs 4.2 months	Diarrhea, fatigue, skin allergy, and hypertension
Lenvatinib	VEGFR1-3, FGFR1-4, PDGFRα, RET, KIT	Inhibit angiogenesis through multiple targets (VEGFR/FGFR/PDGFRα), block the proliferation of tumor cells (RET/KIT), and synergistically inhibit the Raf/Mek/Erk pathway	Liver cancer, thyroid cancer, kidney cancer	The REFLECT study: Median OS was 13.6 months vs 12.3 months (Sorafenib)	Hypertension, proteinuria, hand-foot syndrome, gastrointestinal reactions
Cabozantinib	MET, VEGFR1-3, RET, AXL, ROS1, NTRK, KIT	Inhibit the MET pathway (regulating tumor invasion and metastasis), block angiogenesis (VEGFR), inhibit drug resistance-related targets (AXL, ROS1), and regulate the immune microenvironment (reduce regulatory T cells, Treg cells)	Liver cancer, thyroid cancer, kidney cancer, non-small cell lung cancer	The CELESTIAL study: Median OS was 10.2 months vs 8.0 months (placebo)	Diarrhea, fatigue, loss of appetite, hypertension
Donafenib	VEGFR, PDGFR, Raf kinase (structural optimization of deuterated sorafenib)	Deuterium modification improves metabolic stability, inhibits the Raf/MEK/ERK pathway (more potent than sorafenib), suppresses angiogenesis (VEGFR/PDGFR), and improves the tumor immune microenvironment (enhances the efficacy of anti-PD-1)	Unresectable hepatocellular carcinoma (first-line treatment)	The ZGDH3 study: Median OS was 12.1 months vs 10.3 months (sorafenib)	Hand-foot skin reaction, diarrhea, thrombocytopenia

OS: Overall survival; VEGFR1-3: Vascular endothelial growth factor receptor 1-3; PDGFRβ: Platelet-derived growth factor receptor β; Raf kinase: Rapidly accelerated fibrosarcoma kinase; KIT: KIT proto-oncogene, receptor tyrosine kinase; FLT-3: FMS-like tyrosine kinase 3; MEK: Mitogen-activated protein kinase kinase; ERK: Extracellular signal-regulated kinase; FGFR1-4: Fibroblast growth factor receptor 1-4; PDGFRα: Platelet-derived growth factor receptor α; RET: RET proto-oncogene, receptor tyrosine kinase; MET: Mesenchymal-epithelial transition factor, receptor tyrosine kinase; AXL: AXL receptor tyrosine kinase; ROS1: ROS1 proto-oncogene, receptor tyrosine kinase; NTRK: Neurotrophin receptor tyrosine kinase; anti-PD-1: Anti-programmed cell death protein 1 antibody; ZGDH3: Zinc finger DHHC-type containing 3.

Table 2 Correlation between targets and pathogenesis of diseases.

Target category	Related signaling pathways	Pathogenesis of the disease	Representative drugs
Angiogenesis targets	VEGF/VEGFR, PDGFR, FGFR	Excessive tumor angiogenesis promotes tumor growth and metastasis	Sorafenib, lenvatinib, donafenib
Proliferation-related targets	Raf/MEK/ERK, MET, RET	Abnormally activated proliferation signals (such as Raf mutations and MET amplifications) drive tumor progression	Sorafenib, cabozantinib, donafenib
Targets related to drug resistance/metastasis	AXL, ROS1, NTRK	Mediate tumor drug resistance (such as resistance to EGFR inhibitors) and metastatic spread	Cabozantinib
Regulation of immune microenvironment	STAT3, PD-1 cooperative pathway	The immunosuppressive state in the tumor microenvironment (for example, the activation of STAT3 inhibits the activity of immune cells)	Donafenib, sorafenib

PD-1: Programmed cell death protein 1; VEGF: Vascular endothelial growth factor; VEGFR: Vascular endothelial growth factor receptor; Raf kinase: Rapidly accelerated fibrosarcoma kinase; MEK: Mitogen-activated protein kinase kinase; ERK: Extracellular signal-regulated kinase; FGFR: Fibroblast growth factor receptor; RET: RET Proto-oncogene, receptor tyrosine kinase; MET: Mesenchymal-epithelial transition factor, receptor tyrosine kinase; AXL: AXL receptor tyrosine kinase; ROS1: ROS1 proto-oncogene, receptor tyrosine kinase; NTRK: Neurotrophin receptor tyrosine kinase; PDGFR: Platelet-derived growth factor receptor; EGFR: Epidermal growth factor receptor; STAT3: Signal transducer and activator of transcription 3.

ADVANCES IN IMMUNOTHERAPY OF ADVANCED HCC: REGULATING T CELL-MEDIATED ANTI-TUMOR IMMUNE RESPONSE THROUGH PD-1/PD-L1 AXIS

ICIs play a crucial role in augmenting the body's anti-tumor immune response by effectively obstructing the immunosuppressive signaling pathways within the tumor microenvironment. Currently, pembrolizumab and nivolumab, which target the PD-1 and its PD-L1, have been approved as second-line treatment options for advanced HCC and are regarded as representative ICI drugs. Their mechanism of action involves the activation of T cells to assail tumor cells by targeting the PD-1 or PD-L1 pathways. Clinically, nivolumab has shown good therapeutic effects in patients with untreated, HER2-negative, unresectable advanced gastric cancer. The efficacy of nivolumab was validated in the CheckMate 040 clinical trial and was the first PD-1 inhibitor to be approved for the treatment of HCC[28]. This trial revealed that advanced HCC patients in the sorafenib dose escalation cohort exhibited a 15% ORR, including three cases of complete response. Notably, the patients showed a median duration of response of 17 months (95%CI: 6-24 months) and a two-year survival rate of more than 80%, significantly better than those of patients treated with conventional regimens[29]. Similarly, clinical studies of pembrolizumab have focused on HCC patients who have not responded to first-line regimens such as sorafenib[30]. Data from multiple trials have shown that the drug can produce a significant anti-tumor response, with some patients experiencing sustained anti-tumor responses; however, its overall efficacy and optimal patient selection criteria remain areas of active research[31,32]. As demonstrated in multiple trials[29,33,34], both ICIs are currently recommended for patients with advanced HCC who have failed sorafenib or have intolerable toxicity. In addition, ramucirumab, a monoclonal antibody against VEGFR2, can significantly improve the survival and prognosis of patients with alpha-fetoprotein (AFP) ≥ 400 ng/mL or advanced liver cancer who have received prior systemic therapy[35]. In the REACH-2 study[36], in the second-line treatment of advanced liver cancer with AFP ≥ 400 ng/mL, the median overall survival of the ramucirumab group was significantly better than that of the placebo group (8.5 months vs 7.3 months), and it was well tolerated (the incidence of grade ≥ 3 hypertension was only 13%). The PFS also showed a statistically significant prolongation. This breakthrough progress has made it an important treatment option for the population positive for this biomarker.

In recent years, significant breakthroughs have been made in combination therapy strategies for HCC treatment. The IMbrave150 study demonstrated for the first time[37] that the combination of the anti-PD-L1 monoclonal antibody atezolizumab and the anti-vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab significantly improved first-line survival benefit, with the median OS in the combination group (19.2 months) being significantly longer than that of the sorafenib monotherapy group (13.4 months). This combination has not only demonstrated a stronger therapeutic effect but also a high safety profile, and has now emerged as a new standard for the first-line treatment of advanced HCC[38,39].

Continuous research on combination therapy has led to major advances in dual immunotherapy. Notably, the combination of PD-1 and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors (such as nivolumab and ipilimumab) has shown unique advantages. PD-1 predominantly causes T cell depletion in the tumor microenvironment, while CTLA-4 inhibits activated and regulated T cells in lymphoid organs. Based on the findings of the CheckMate040 study[40], nivolumab in combination with ipilimumab achieved excellent efficacy in patients with advanced HCC with an ORR of 34% and a median OS of 22.2 months, demonstrating a clinically meaningful response and long-term survival benefit that is significantly superior to monotherapy. This combination has been approved by the United States Food and Drug Administration as a second-line treatment option for HCC, providing new hope for survival in treated patients[41]. The above commonly used drugs are summarized in Tables 3 and 4.

Table 3 Comparison of core mechanisms of three immunotherapy drugs.

Drug	Target of action	Mechanism of action	Main indications	Key clinical data	Common adverse reactions
Pembrolizumab	PD-1	Block the binding of PD-1 to its ligands PD-L1/PD-L2, relieve the immunosuppression of T cells, activate tumor-specific T cells, enhance the ability of the immune system to attack tumors, and restore the immune surveillance function through the inhibition of immune checkpoints	Melanoma, non-small cell lung cancer, head and neck cancer, gastric cancer, liver cancer, etc.	KEYNOTE-394: The median OS with pembrolizumab was 14.6 months, the 2-year OS rate reached 34.3%	Immune-related adverse reactions (pneumonia, colitis, thyroiditis), fatigue, skin rash
Nivolumab	PD-1	It binds to PD-1, blocks the PD-L1/PD-L2 signaling pathway, enhances the proliferation of T cells and the release of cytokines. When combined with CTLA-4 inhibitors, it can synergistically enhance the anti-tumor effect	Melanoma, non-small cell lung cancer, gastric cancer, renal cancer, etc.	CheckMate-040: The objective response rate (ORR) in the dose escalation cohort: 15%. ATTRACTION-4: The median OS for gastric cancer patients is 26.6 months	Immune-mediated pneumonia, hepatitis, endocrine diseases, infusion reactions
Ramucirumab	VEGFR2	It specifically binds to VEGFR2, inhibits VEGF-A-mediated angiogenesis, reduces the blood supply to tumors, and suppresses tumor growth and metastasis	Gastric cancer, liver cancer, non-small cell lung cancer, colorectal cancer	REACH-2 trial: The median overall survival for liver cancer patients with AFP ≥ 400 ng/mL is 8.5 months (compared with 7.3 months for the placebo group)	Hypertension, proteinuria, bleeding risk, gastrointestinal reactions

PD-1: Programmed cell death protein 1; PD-L1: Programmed death-ligand 1; PD-L2: Programmed death-ligand 2; OS: Overall survival; ORR: Objective response rate; CTLA-4: Cytotoxic T-lymphocyte-associated protein 4; VEGFR2: Vascular endothelial growth factor receptor 2; AFP: Alpha-fetoprotein.

Table 4 Correlation between targets and pathogenesis of the disease.

Target category	Related signaling pathways	Pathogenesis of the disease	Representative drugs
Immune checkpoints	PD-1/PD-L1	Tumor cells evade immune surveillance and inhibit the activity of T cells through the overexpression of PD-L1	Pembrolizumab, nivolumab
Angiogenesis targets	VEGF/VEGFR2	Abnormal proliferation of tumor blood vessels promotes nutrient supply and metastasis	Ramucirumab
Synergistic treatment targets	CTLA-4 (combined with PD-1 inhibitors)	Dual inhibition of immune checkpoints enhances T cell activation and tumor infiltration	Nivolumab + ipilimumab

PD-1: Programmed cell death protein 1; PD-L1: Programmed death-ligand 1; VEGF: Vascular endothelial growth factor; VEGFR2: Vascular endothelial growth factor receptor 2; CTLA-4: Cytotoxic T-lymphocyte-associated protein 4.

ADVANCES IN TREATMENT OF ADVANCED HCC: A MULTIFACETED MODEL OF SYNERGY

With the progressive and in-depth exploration of the molecular biology characteristics and tumor microenvironment of HCC, the treatment paradigm for advanced HCC has transitioned from monotherapy to integrated therapeutic approaches. In recent years, multi-dimensional combinatorial strategies, integrating molecularly targeted drugs, ICIs, and local interventional therapies, have led to significant improvements in therapeutic efficacy through synergistic anti-tumor mechanisms. The LEAP-002 global multicenter phase III study has firmly established the synergistic application of targeted therapy and ICIs[42], demonstrating a median overall survival of 21.2 months in the lenvatinib plus pembrolizumab arm, as opposed to 19.0 months in the lenvatinib plus placebo arm. This substantial extension of median survival not only highlights a clinically significant survival benefit but also underscores the potential of such combinations. Furthermore, the ORIENT-32 study revealed[43] that sintilimab, a humanized IgG4 PD-1 monoclonal antibody[44], is a PD-1 inhibitor. It restores the anti-tumor activity of T cells by blocking the PD-1/PD-L1 pathway. The treatment regimen combining sintilimab with the bevacizumab biosimilar IBI305, has manifested breakthrough efficacy in Chinese patients with unresectable HCC. The median progression-free survival was significantly longer than that of sorafenib alone (4.6 months compared to 2.8 months, as evaluated by an independent imaging review committee), and the overall survival was significantly prolonged. With an acceptable safety profile, this combination provides a novel treatment alternative for patients with advanced HCC. The steps and treatment procedures of the above-mentioned treatment are shown in Table 5.

Table 5 Steps of systematic treatment for liver cancer and corresponding treatment procedures.

Treatment stage	Type of recommendation	Recommended regimen	Applicable population	Evidence level
First-line treatment	Immune + anti-angiogenesis regimen (preferred)	Atezolizumab + bevacizumab	For unresectable patients with Child-Pugh class A who have not received previous systemic treatment	IA
		Sintilimab + bevacizumab biosimilar	For unresectable or metastatic liver cancer patients who have not received previous systemic anti-tumor treatment	IA
	Single-agent targeted therapy	Lenvatinib	For advanced liver cancer patients with unresectable liver function of Child-Pugh class A	IA
		Donafenib	For unresectable liver cancer patients who have not received previous systemic anti-tumor treatment	IA
		Sorafenib	For patients with liver function of Child-Pugh class A/B	IA
Second-line treatment	Targeted therapy	Cabozantinib	Hepatocellular carcinoma patients with Child-Pugh class A liver function who have previously received sorafenib treatment and failed	IA
		Ramucirumab	Treatment of hepatocellular carcinoma patients who have previously received sorafenib treatment and have an AFP level of ≥ 400 ng/mL	IA
	Single-agent immunotherapy	Pembrolizumab	Hepatocellular carcinoma patients who have previously received sorafenib or chemotherapy containing oxaliplatin	IA
		Nivolumab	Hepatocellular carcinoma patients who have progressed after previous sorafenib treatment or cannot tolerate sorafenib	IA
	Combination of dual immunotherapies	Nivolumab + ipilimumab	Hepatocellular carcinoma patients who have progressed after previous sorafenib treatment or cannot tolerate sorafenib	IA

AFP: Alpha-fetoprotein.

A clinical study[45] confirmed that sorafenib combined with transarterial chemoembolization (TACE) significantly improved the efficacy of patients with intermediate-stage liver cancer who relapsed after R0 hepatectomy and microvascular invasion compared with TACE alone[46], with a median overall survival of 22.2 months (vs 15.1 months) and progression-free survival of 16.2 months (vs 11.8 months) in the combination group. According to the modified response criteria for solid tumors, the ORR can also be increased to 80.2% (vs 58.0%).

Notably, triple therapy regimens based on multi-dimensional therapeutic mechanisms, such as the combination of donafenib, hepatic arterial infusion chemotherapy (HAIC), and tislelizumab, have exhibited excellent potential[47]. Clinical data[48] have shown significantly reduced levels of tumor markers (AFP, PIVKA-II) in HCC patients after treatment with this regimen, accompanied by a significantly increased partial response rate of imaging evaluation, and even achieving pathological complete response in some cases. These findings highlight the potential of triple therapy regimens for the treatment of advanced liver cancer.

At the same time, the combination of TACE + atezolizumab + bevacizumab has also demonstrated good therapeutic efficacy[49]. Through TACE, tumor antigens are induced to be released. As a VEGF inhibitor, bevacizumab can counteract the anti-tumor immunity induced by TACE and reverse the immunosuppressive microenvironment. Meanwhile, the PD-L1 inhibitor (atezolizumab) activates the T-cell response. The study found that the ORR of the triple combination therapy (TACE + atezolizumab + bevacizumab) was 43.6%, which was significantly higher than that of the TACE-alone group (29.6%). However, the EMERALD-1 study only included patients with Child-Pugh class A, excluding individuals with poor liver function or severe complications (such as tumor thrombus in the main portal vein), which may lead to certain limitations. Moreover, the incidence of adverse events of grade ≥ 3 was 26.5%, among which the incidence of bleeding events reached 8.4%, significantly higher than that of the control group. Therefore, it is necessary to dynamically monitor liver function, coagulation indicators, etc., and adjust the dosage in combination to balance the therapeutic effect and risk.

DISCUSSION

HCC is a malignant tumor characterized by high incidence and mortality rates globally due to the challenging diagnosis and treatment. Abundant clinical data have consistently demonstrated that early diagnosis and radical surgical resection represent pivotal strategies for enhancing prognosis. Nevertheless, the insidious disease onset, rapid progression, and the absence of specific clinical manifestations have resulted in over 60% of patients being diagnosed at stage B/C of the Barcelona Clinic Liver Cancer staging system, thereby forfeiting the opportunity for radical treatment. In advanced HCC patients, systemic therapy remains an indispensable pillar for comprehensive management.

In the domain of molecularly targeted therapy, the clinical implementation of TKIs has engendered significant breakthroughs in the treatment of HCC. Multi-kinase inhibitors, including sorafenib and lenvatinib, effectively impede angioproliferation and tumor cell generation by inhibiting crucial signaling pathways, such as VEGFR and PDGFR. Multiple studies have reported that molecularly targeted drugs like sorafenib and lenvatinib can effectively extend the median survival of patients with advanced liver cancer[14]. Moreover, Kudo et al’s research[17] has demonstrated that second-line treatment with lenvatinib extended the median OS to 13.6 months, which showed significantly superior results compared to traditional chemotherapy regimens.

Building upon this foundation, ICIs have emerged as a cornerstone of liver cancer treatment. The "target-immune combination" strategy, exemplified by the combination of PD-1 inhibitors, such as pembrolizumab, and anti-angiogenic drugs (e.g., bevacizumab), has manifested remarkable efficacy in the IMbrave 150 study. The combination group achieved a median OS of 19.2 months, nearly 6 months longer than that of the sorafenib monotherapy group. Notably, the synergistic utilization of such systemic therapies with local treatments, such as TACE and HAIC[49], can significantly augment the ORR and may facilitate the release of tumor antigens through immune activation mechanisms. This, in turn, creates the possibility of achieving a radical cure for some patients who initially present with unresectable disease.

As treatment strategies are improved, triple therapy (TKI + ICI + local therapy) shows promising potential in the treatment of advanced HCC. In a prospective study[50], triple therapy resulted in an ORR of > 50% and median PFS of 15 months, and the treatment protocol was well tolerated. This multidimensional intervention model significantly prolongs survival time and improves quality of life. Although this study suggests that combination treatment regimens (such as TACE combined with targeted immunotherapy) can significantly prolong survival, its conclusions need to be viewed critically. In this trial, only 42 patients were included. There may be a situation where a small sample size amplifies the efficacy signal while underestimating the possible incidence of rare adverse reactions.

Nonetheless, with the continuous progress of systemic treatment for liver cancer, issues such as adverse reactions caused by drugs, drug resistance, and patient heterogeneity have gradually come to light. Although the combination of targeted therapy and immunotherapy significantly enhances the therapeutic effect, the adverse reactions that it causes cannot be overlooked. For example, in the IMbrave150 study of atezolizumab plus bevacizumab, the incidence rates of grade 3 and above hypertension and immune-related hepatitis have increased compared to before. Therefore, dynamic monitoring and management are required. It should be emphasized that multidisciplinary teamwork is crucial for balancing the therapeutic effect and safety. For instance, for patients with Child-Pugh class B liver function, regorafenib may be preferentially chosen over sorafenib because it has a lower risk of hepatotoxicity. Over the course of drug treatment, patients gradually develop resistance to the drugs, rendering the initially effective medications ineffective, which may lead to disease recurrence and even accelerate disease progression. Therefore, the mechanisms of drug resistance and the development of new drugs require further research. In addition, a study showed that[51] the inclusion criteria mainly focused on patients with Child-Pugh class A liver function. However, in the real world, approximately 30% of patients with advanced liver cancer have liver insufficiency (Child-Pugh class B/C). Since this group of patients are excluded due to the exclusion criteria, it may lead to the evaluation of the therapeutic effect deviating from the actual clinical needs. The significant differences in pathogenic factors (e.g., HBV/HCV infection and alcoholic liver disease) and molecular typing (e.g., proliferative, immune) among HCC patients lead to significant heterogeneity in clinical efficacy[52,53]. For example, HBV-associated liver cancer is more sensitive to immunotherapy, whereas HCV-infected patients are susceptible to cirrhosis progression, thereby limiting the use of systemic therapy[54]. Therefore, treatment should be personalized based on individual differences, such as gene mutation characteristics, tumor microenvironment status, and underlying diseases. Additionally, reliable biomarkers for accurate prediction of patients' response and prognosis after systemic treatment for liver cancer are lacking. Hence, the optimal patient group for a certain treatment regimen cannot be predicted, exacerbating uncertainty in treatment. Some studies are exploring potential candidate markers for targeted therapy and immunotherapy. However, the predictive value in liver cancer is limited, and a mature and widely used clinical detection index system has not yet been established. Therefore, further research should be conducted to construct a dynamic biomarker system based on multi-omics.

At present, the strategy of precision medicine based on molecular typing is being further promoted. The dynamic monitoring of circulating tumor DNA by liquid biopsy[55,56], the correlation between PD-L1 expression levels and treatment response[57], and the clinical trials of novel therapeutic targets[58] (targeting c-MET[59] and TIGIT[60]) and CAR-T cell therapy[61] demonstrate promising potential for the treatment of HCC. In the future, liquid biopsy and next-generation therapeutic targets may enable more accurate assessment of liver cancer tumors and metastases, enabling the formulation of individualized treatment plans, and improving the success rate and survival rate.

CONCLUSION

Systemic treatment of liver cancer has entered the "2.0 era" of the combination of targeted therapy and immunotherapy. Current research has confirmed that treatment regimens represented by the combination of anti-angiogenic drugs (bevacizumab) and PD-1/PD-L1 inhibitors can inhibit the formation of new tumor blood vessels, activate T cells, promote the release of tumor antigens, reduce the growth and metastasis of tumors, and significantly increase the ORR and mOS. However, in clinical practice, bottlenecks such as drug resistance, heterogeneity, and toxicity management still need to be overcome. In the future, through the integration of precision medicine, innovative therapies, and multidisciplinary diagnosis and treatment, it is expected to achieve the leap from "prolonging survival" to "functional cure".