In 2022, approximately 865,000 new hepatocellular carcinoma (HCC) cases and 664,000 deaths were reported worldwide [1]. HCC accounts for 75–85% of primary liver cancer cases and remains the sixth most common cancer and the third leading cause of cancer-related mortality globally. The disease burden is particularly significant in low- and middle-income countries, where viral hepatitis remains the primary risk factor. However, its incidence is increasing in some highly developed regions, largely driven by alcohol-related cirrhosis and the rising prevalence of metabolic risk factors such as obesity and diabetes.

The therapeutic landscape for HCC is complex, with a diverse array of treatment options depending on the tumor stage. The Barcelona Clinic Liver Cancer (BCLC) staging system considers intra- and extrahepatic tumor burden, liver function, and the patient’s performance status (PS) [2]. Patients with BCLC stage C, characterized by extrahepatic spread or macrovascular invasion, good PS, and preserved liver function, are candidates for systemic treatments. Additionally, systemic therapy may be considered in the intermediate (BCLC-B) disease when the intrahepatic burden precludes locoregional management.

Until 2020, first-line treatment options for advanced hepatocellular carcinoma (aHCC) were limited to two tyrosine kinase inhibitors (TKIs), sorafenib and lenvatinib (Fig. 1). However, the advent of immunotherapy, particularly immune checkpoint inhibitors (ICIs), has transformed the management of this malignancy. This paradigm shift has redefined the role of molecularly targeted agents (MTAs), which are now primarily utilized following disease progression on ICIs or in patients ineligible for immunotherapy. However, a major challenge in this evolving treatment landscape is the limited high-quality evidence supporting the efficacy of MTAs in the post-immunotherapy setting. Moreover, advancements in treatment strategies have significantly improved patient outcomes, expanding the number of patients eligible for second-line and subsequent therapies.

Fig. 1The alternative text for this image may have been generated using AI.

Timeline of advancements in systemic treatment for advanced hepatocellular carcinoma. 1L- first line

This review synthesizes the current evidence supporting systemic therapies beyond first-line treatment in aHCC, with a particular focus on the post-immunotherapy setting. Additionally, we address the alignment of these therapies with clinical guidelines and highlight key gaps in knowledge and evidence that need to be addressed.

First-line Systemic Management – The Evolving Paradigm

Until recently, therapeutic options for aHCC were remarkably limited. Conventional systemic chemotherapy conferred abysmal response rates and had a questionable impact on overall survival (OS) [3]. As a result, early clinical efforts focused on molecular vulnerabilities, leading to the approval of several molecularly targeted agents (MTAs). Hepatocarcinogenesis is driven by the progressive acquisition of molecular alterations, including telomerase (TERT) promoter mutations, TP53 inactivation, Wnt/β-catenin pathway activation (via CTNNB1, AXIN1, and APC mutations), and dysregulation of the Ras/Raf/MAPK and PI3K/AKT-mTOR signaling. While most of these alterations are not directly druggable, they drive pathway rewiring, neoangiogenesis, and tumor growth dependent on receptor tyrosine kinases (RTKs). HCC is further characterized by excessive vascular endothelial growth factor A (VEGF-A) production, which promotes angiogenesis and hepatocyte growth factor (HGF) secretion, thereby stimulating tumor proliferation via MET receptor. Furthermore, elevated VEGF levels contribute to immunotolerant, pro-tumorigenic microenvironment. Finally, a subset of tumors exhibits amplifications of CCND1, FGF19, MYC, or MET, leading to overexpression of RTKs or their ligands [4, 5].

Consequently, the first approved systemic treatments for aHCC were multi-TKIs, such as sorafenib and lenvatinib. Sorafenib targets VEGF receptors (VEGFR1, VEGFR2, VEGFR3), platelet-derived growth factor receptors (PDGFRs), RET, c-Kit, and RAF kinases (RAF1, BRAF), while lenvatinib inhibits VEGFR1-3, fibroblast growth factor receptors (FGFR1-4), PDGFRs, RET, and c-Kit. Sorafenib, approved in 2008 for first-line treatment of aHCC, marked a major breakthrough in aHCC therapy. Its efficacy was established through the phase III SHARP and ASIA–PACIFIC trials, which demonstrated significant improvements in time-to-progression and OS compared to placebo [6, 7]. The REFLECT trial later established lenvatinib as a non-inferior alternative to sorafenib in terms of OS while offering superior overall response rate (ORR) and progression-free survival (PFS) [8].

With the advent of immunotherapy, the therapeutic landscape of aHCC has undergone a profound transformation. A considerable proportion of HCC cases exhibit immune tolerance, driven by a persistently inflamed and/or cirrhotic microenvironment. This immunosuppressive milieu is shaped by multiple factors, including elevated transforming growth factor β (TGFβ) and VEGF signaling, dysfunctional CD8 + T cells, increased number of regulatory T (Treg) cells, and the overexpression of immune checkpoints [4, 9,10,11]. These mechanisms collectively contribute to immune evasion, underscoring the rationale for targeting immune checkpoint pathways in HCC.

Pivotal phase III trials published in 2020–2021 established immunotherapy (IO)-based regimens as superior to TKIs for first-line treatment of aHCC. In the IMbrave150 trial, the combination of atezolizumab (anti-PD-L1 antibody) plus bevacizumab (anti-VEGF-A antibody) improved ORR (30% vs 11%), PFS (median 6.8 vs 4.3 months), OS (median 19.2 vs 13.4 months; hazard ratio [HR] 0.58) and quality of life compared with sorafenib [12, 13]. Similar benefits were observed in the ORIENT-32 trial where sintilimab (anti–PD-1) combined with a bevacizumab biosimilar (IBI305) demonstrated improved outcomes in Chinese population [14]. Furthermore, the HIMALAYA trial showed that durvalumab (anti-PD-L1 antibody) with a single priming dose of tremelimumab (anti-CTLA4 antibody), the STRIDE regimen, resulted in superior ORR and OS compared with sorafenib (median 16.4 vs 13.8 months, HR 0.78) [15, 16]. ICI monotherapy with durvalumab or tislelizumab (anti-PD-1 antibody) demonstrated non-inferiority to sorafenib, offering an alternative for patients unsuitable for combination therapy [15, 17]. Finally, in the CheckMate-9DW, trial nivolumab (anti-PD1 antibody) plus ipilimumab (anti-CTLA4), achieved longer OS and higher ORR compared with physician’s choice of lenvatinib or sorafenib (median OS 23.7 vs. 20.6 months, HR 0.79; ORR 36% vs. 13%) [18].

Interestingly, most ICI–TKI combinations have not improved survival in phase III trials. Specifically, in the COSMIC-312 trial, atezolizumab plus cabozantinib failed to improve OS compared to sorafenib, and in the LEAP-002 trial, pembrolizumab (anti-PD1 antibody) plus lenvatinib did not show OS superiority over lenvatinib plus placebo [19, 20]. An exception is the predominantly Asia-based CARES-310 trial, in which camrelizumab (anti–PD-1 antibody) plus rivoceranib (a TKI, also known as apatinib) improved OS versus sorafenib but was associated with substantial toxicity (81% rate of grade ≥ 3 adverse events, AEs) [21].

As a result, IO-based regimens—atezolizumab-bevacizumab, durvalumab-tremelimumab (STRIDE) and nivolumab-ipilimumab—are now the preferred first-line treatments for aHCC, recommended by major clinical societies, including the European Society of Medical Oncology (ESMO), the American Society of Clinical Oncology (ASCO), the National Comprehensive Cancer Network (NCCN), the European Association for the Study of the Liver (EASL), and the American Association for the Study of Liver Diseases (AASLD) [2, 22,23,24,25,26]. Other first-line treatment options include camrelizumab–rivoceranib, tislelizumab, and durvalumab monotherapy. MTAs are now primarily considered second-line treatments following immunotherapy failure, except when ICIs are contraindicated. In such cases, lenvatinib and sorafenib remain the preferred first-line options as per current guidelines.

Second-line Agents: Evidence from the Pre-First-Line Immunotherapy Era

For patients who do not respond to first-line TKIs, second-line treatment options primarily consist of three MTAs: regorafenib, cabozantinib, and ramucirumab. These therapies were approved based on randomized, placebo-controlled phase III trials, and target distinct molecular pathways. Additionally, IO-based treatments may also be considered in the second-line setting, though supporting evidence for their efficacy remains less robust compared to MTAs. The mechanisms of action of agents used in the systemic treatment of HCC are illustrated in Fig. 2.

Fig. 2The alternative text for this image may have been generated using AI.

A simplified scheme of therapeutic agents in advanced hepatocellular carcinoma. Abbreviations: FGFR-fibroblast growth factor receptor; GzmB-granzyme B; IFNγ-interferon-gamma; KIT-receptor tyrosine kinase; MET- mesenchymal-epithelial transition factor receptor; MHC- major histocompatibility complex; PD-1-programmed cell death protein 1; PD-L1-programmed cell death-ligand 1; PDGFR-platelet-derived growth factor receptors; PFN-perforin; TCR-T-cell receptor; TNFα-Tumor necrosis factor-alpha; VEGF-vascular endothelial growth factor; VEGFR-vascular endothelial growth factor receptor

Regorafenib

Regorafenib is a structurally related but more potent multikinase inhibitor than sorafenib that targets VEGFR1–3, TIE2, PDGFR-β, FGFRs, c-Kit, RET, RAF1, and BRAF, thus retaining inhibition of core sorafenib targets while providing broader and stronger blockade of proliferation, angiogenesis, anti-apoptotic, and immune-modulatory pathways [5]. Evidence from preclinical in vitro and in vivo models indicates that regorafenib outperforms sorafenib in inhibiting HCC growth and tumor angiogenesis [27].

Regorafenib has been endorsed for the treatment of aHCC in patients with disease progression on sorafenib. Its approval is based on the results of a placebo-controlled RESORCE phase III trial [28]. Given the molecular similarity and comparable toxicity profile of sorafenib and regorafenib, eligibility criteria mandated good prior sorafenib tolerance. Among study participants, 98% had Child–Pugh class A liver function, 29% demonstrated macrovascular invasion, and 70% had extrahepatic spread. Compared to placebo, regorafenib improved OS (median 10.6 vs. 7.8 months; HR, 0.63; 95% CI, 0.50–0.79), PFS (median 3.1 vs. 1.5 months; HR 0.46; 95% CI, 0.37–0.56), and ORR per modified RECIST for HCC (mRECIST) criteria (11% vs. 4%). Grade 3 or 4 AEs occurred in 67% of regorafenib-treated patients, compared to 39% in the placebo group. The most common AEs included hypertension, palmar-plantar erythrodysesthesia, fatigue, and diarrhea.

Real-world data reveal mOS varying from 6.5 to 17.3 months for patients receiving regorafenib as the post-TKI therapy, with outcomes influenced by liver function, performance status, and access to subsequent therapy [29,30,31,32,33,34]. The prospective, observational REFINE study further evaluated the efficacy of regorafenib in 1,005 patients, of whom 62% had BCLC-C stage disease and 61% had Child–Pugh A liver function [35]. Nearly all participants (96%) had previously received sorafenib, with regorafenib used as a second-line therapy in 84% and as a third-line or later therapy in 14%. The mOS was 13.2 months in the whole cohort and 13.9 months in the second-line group. Treatment tolerance aligned with findings from the pivotal RESORCE trial.

Cabozantinib

Cabozantinib, another TKI approved for sorafenib-refractory aHCC, inhibits VEGFR2, MET, AXL, RET, ROS1, TYRO3, and c-Kit. Utilization of cabozantinib in the post-TKI setting is supported by preclinical evidence demonstrating that HGF/c-MET axis promotes resistance to sorafenib and lenvatinib in HCC [36,37,38]. By blocking the hepatocyte growth factor (HGF)-stimulated MET pathway, cabozantinib inhibits HCC cell migration and invasion, preventing lung and liver metastases in murine models [39]. Additionally, HCC cells frequently exhibit upregulated AXL signaling, where the AXL ligand growth arrest-specific 6 (Gas6) enhances cell migration, invasiveness, and epithelial-mesenchymal transition (EMT) [40]. Notably, AXL activation has been associated with resistance to VEGFR inhibitors (sunitinib, sorafenib, lenvatinib) in renal carcinoma and HCC [41,42,43]. Cabozantinib's simultaneous inhibition of MET, VEGFR, and AXL kinases may thus overcome resistance to more selective VEGFR inhibitors.

The phase III CELESTIAL trial evaluated cabozantinib in patients who had previously received one (71%) or two (27%) lines of systemic therapy, including sorafenib [44]. Among 707 patients randomized to receive 60 mg of cabozantinib once daily or a placebo, all had preserved liver function (Child–Pugh A), with 78% exhibiting extrahepatic spread, and 30% having macrovascular invasion,. Cabozantinib significantly improved OS, the primary endpoint (median 10.2 months vs. 8.0 months for cabozantinib and placebo, respectively; HR 0.76; 95%, CI 0.63–0.92) and PFS (median 5.2 months vs. 1.9 months; HR 0.44; 95% CI, 0.36–0.52). The ORR was also higher in the cabozantinib group (4% vs. 1%). Grade 3–4 AEs occurred in 68% of patients receiving cabozantinib, including hand-foot skin reactions (17%), hypertension (16%), elevated AST (12%), fatigue, and diarrhea. Treatment with cabozantinib caused a transient deterioration of the quality of life in the first few weeks of therapy [45]. The benefit of cabozantinib was more pronounced in the second than in the third line setting (HR for OS, 0.74; 95% CI, 0.59–0.92; and 0.90; 95%, 0.63–1.29, respectively). Among patients who received only sorafenib as the prior treatment, cabozantinib and placebo yielded mOS of 11.3 and 7.2 months, respectively (HR, 0.70; 95% CI, 0.55–0.88) [46]. A Japanese prospective phase II trial reported exceptionally long mOS of 19.3 months in a cohort of 20 patients treated with cabozantinib after progressing on sorafenib, likely due to more favorable clinical characteristics than those in the CELESTIAL trial [47].

Cabozantinib was also evaluated in the first-line COSMIC-312 phase III, multicenter trial including 837 patients who were randomized to receive cabozantinib (40 mg daily) plus atezolizumab (1200 mg every 3 weeks), sorafenib (400 mg twice daily), or cabozantinib alone (60 mg daily) [19]. In a secondary endpoint analysis, cabozantinib monotherapy demonstrated an mPFS of 5.8 months vs. 4.3 months with sorafenib (HR 0.78; 95% CI, 0.56–0.97). ORR was numerically higher for cabozantinib plus atezolizumab (11%) than for cabozantinib alone (6.4%) and sorafenib (3.7%). Grade 3–4 AEs occurred in 66%, 57%, and 48% of patients in the combination regimen, cabozantinib monotherapy, and sorafenib arms, respectively.

In routine clinical practice, cabozantinib is frequently utilized as a third-line treatment. Real-world data indicate that mOS with cabozantinib in the post-TKI setting varies between 6.9 and 12.1 months, reflecting geographic and clinical differences [48,49,50,51,52].

Ramucirumab

Ramucirumab, the third agent approved in the post-sorafenib setting, is a monoclonal antibody targeting VEGFR2. Elevated VEGFR2 expression in HCC, a central mediator of angiogenesis, has been associated with poor outcomes in aHCC treated with sorafenib, thereby supporting VEGFR2 blockade as a strategy to overcome resistance [53].

While the initial REACH clinical trial did not demonstrate a survival benefit over placebo, subgroup analysis suggested potential efficacy in patients with high baseline serum alpha-fetoprotein (AFP) levels [54]. Subsequently, the phase III REACH-2 trial confirmed this finding, demonstrating significantly improved OS and PFS in patients with baseline AFP ≥ 400 ng/mL treated with ramucirumab compared to placebo (mOS 8.5 vs. 7.3 months, HR 0.71; 95% CI, 0.53–0.95; mPFS 2.8 vs. 1.6 months, HR 0.45; 95% CI, 0.34–0.60) [55]. ORR per RECIST 1.1 criteria were 5% vs. 1%, respectively. Serious AEs occurred in 35% of ramucirumab-treated patients vs. 29% in the placebo group. The most common grade 3–4 AEs in the experimental arm included hypertension (13%), hyponatremia (6%), and elevated AST (3%).

A Japanese real-world study reported similar efficacy, with a mOS of 10.3 months in the second-line setting and 10.4 months in later lines among patients with high serum AFP levels [56]. An open-label expansion cohort of REACH-2 evaluated ramucirumab specifically in patients with AFP ≥ 400 ng/mL following failure of non-sorafenib therapies, showing comparable safety and efficacy to the original trial (mPFS 1.7 months, mOS 8.7 months) [57].

Other TKIs

Rivoceranib (apatinib), a potent VEGFR2 inhibitor, is the latest TKI demonstrating efficacy in previously treated aHCC. The phase III AHELP trial, conducted in China, enrolled patients who had progressed on or were intolerant to at least one prior line of chemotherapy or targeted therapy [58]. OS and PFS were significantly longer with rivoceranib compared to placebo, with HRs of 0.79 (95% CI, 0.617–0.998) and 0.47 (95% CI, 0.37–0.60), respectively. The most common grade 3 or 4 treatment-related AEs in the rivoceranib arm included hypertension (28% vs. 2% in the placebo arm), hand–foot syndrome (18% vs. 0%), and thrombocytopenia (13% vs. 1%). Given that the AHELP trial was conducted exclusively in China, further studies are needed to validate its efficacy and safety in non-Asian populations.

Another TKI, brivanib, a dual VEGF/FGFR inhibitor, improved ORR and PFS but failed to confer an OS benefit in a phase III trial in patients with sorafenib-refractory or sorafenib-intolerant HCC [59]. Lenvatinib, though approved as a first-line alternative to sorafenib, has also shown efficacy after prior sorafenib treatment [60,61,62]. A Japanese retrospective study involving 132 Child–Pugh A patients treated with lenvatinib showed comparable mPFS (5.2 vs. 4.8 months) and mOS (13.3 months vs. not reached) between first-line and subsequent-line use [61]. Conflicting data exist on the ORR of later-line lenvatinib, with some studies showing comparable rates between sorafenib-naïve and sorafenib-experienced patients (17% vs. 14% per RECIST; 44% vs. 34% per mRECIST, respectively) [60, 61], while others report a lower ORR in sorafenib-experienced group (26% vs. 62% per mRECIST) [62].

Second-line Immunotherapy

Second-line options after TKIs include nivolumab monotherapy and nivolumab-ipilimumab, evaluated in the phase I/II CheckMate 040 trial [63,64,65]. In sorafenib-pretreated patients, nivolumab alone produced an ORR of 14% (per RECIST 1.1), mOS of 15.1 months, and a five-year OS of 12%. The combination, particularly at 1 mg/kg nivolumab plus 3 mg/kg ipilimumab, achieved superior outcomes (ORR of 34%, mOS 22.2 months, five-year OS 29%) [66]. NCCN guidelines endorse this combination for MTA-refractory aHCC [24].

Pembrolizumab results have been inconsistent: while KEYNOTE-240 did not show significant PFS or OS improvements,, the Asian KEYNOTE-394 trial demonstrated superior efficacy over placebo (mOS 14.6 vs. 13.0 months, HR 0.781; 95% CI, 0.611–0.998) [67, 68].

The standard first-line atezolizumab-bevacizumab regimen has occasionally been utilized after MTA failure. A retrospective French study including 50 patients after one to four lines of TKI reported an ORR of 14%, disease control rate (DCR) of 56%, mPFS of 8.0 months, and mOS of 17.1 months [69]. Survival outcomes were comparable regardless of the treatment line, with an mOS of 14.8 months in patients receiving one prior TKI and 17.1 months in those after two or more prior TKI lines. Retrospective Japanese studies also support the efficacy of atezolizumab-bevacizumab in post-TKI settings [70,71,