ABSTRACT

As the most frequent primary hepatic malignancy and the third cause of cancer-related death, hepatocellular carcinoma (HCC) occurs primarily in cases of underlying chronic liver disease, being infection with hepatitis B and C the main cause. However, there are other relevant risk factors that contribute as well, such as non-alcoholic fatty liver disease (NAFLD) and its progressive subtype non-alcoholic steatohepatitis (NASH), obesity and diabetes among others. Currently there are several agents available for the systemic treatment of HCC and the guidelines support atezolizumab plus bevacizumab as the first-line therapy. However, some data show that non-viral HCC might benefit less from the treatment with immunotherapy. This article reviews the systemic treatment for advanced HCC focusing more on the results for non-viral causes.

Key words: hepatocellular carcinoma, non-viral causes, systemic treatment

INTRODUCTION

Hepatocellular carcinoma (HCC) is the most frequent primary hepatic malignancy and the third leading cause of cancer related deaths in the world.[1] HCC appears in cases of underlying chronic liver disease, such as hepatitis or cirrhosis of viral origin, such as hepatitis B virus (HBV) or hepatitis C virus (HCV).[2] However, there are other risk factors linked as well. Among them, non-alcoholic steatohepatitis (NASH) has rapidly emerged as a cause for HCC in western countries.[3–6]

Unfortunately, a significant number of cases are diagnosed in the advanced stages, mainly because of the lack of symptoms in early phases. This reduces the effective therapeutic options, limiting them to only palliative approaches. And it is in this context where systemic treatment may help.

Up until 2007, we did not have effective therapies for these cases. However, sorafenib became the only systemic drug at that time approved by the US Food and Drug Administration (FDA) as the standard first-line treatment.[7] Since then, much research has been carried out and several other drugs have been approved with this aim, including other molecular targeted agents, checkpoint inhibitors or a combination of both.

Taking into account that there are different causes of HCC, it has been questioned if the treatments should be different in relation to the aetiology. This review will focus more on non-viral cases of HCC.

AETIOLOGY OF hepatocellular carcinoma

Most HCCs develop in a liver with an already known underlying pathology, such as chronic hepatitis or cirrhosis caused by viruses, hepatitis B virus (HBV) and hepatitis C virus (HCV).[2,3]

However, nowadays, thanks to the progress made in antiviral treatments that achieve good control of HBV and HCV, we are seeing a reduction of HCC of viral origin and an increase in other cases, mainly those linked to metabolic dysfunction-associated steatotic liver disease (MASLD).[8,9] This change have also contributed to the fact that obesity, diabetes and metabolic syndrome, along with subsequent development of non-alcoholic steatohepatitis (NASH) are rapidly rising in the west.[8,10] Moreover, non-alcoholic fatty liver disease (NAFLD) is becoming a common cause of HCC, especially in Western countries compared with Asian countries, where hepatitis B-related HCC continues to be most frequent.[2,3] Other non-viral causes of HCC are iron overload syndromes, aflatoxin exposure, the use of tobacco, alcohol or oral contraceptive.[11]

Recent evidence suggests a multifactorial causes of HCC, including viral and non-viral factors, which makes more difficult to draw conclusions at the time of interpreting the results from the trials of systemic therapy that include small subgroups representing different risk factors.[11]

SYSTEMIC THERAPY FOR ADVANCED HCC

Multikinase inhibitors

Sorafenib

This is a multikinase inhibitor that blocks tyrosine kinases and pathways that are crucial in angiogenesis and cell proliferation, such as vascular endothelial growth factor receptors (VEGFR)-1, 2 and 3, KIT, RET, PDGFR-β, RAS/RAF/MAPK, FLT-3, and Janus kinase/signal transducer and activator of transcription protein.[12]

In July 2006, sorafenib obtained European Medicines Agency approval for the treatment of HCC. The FDA followed in November 2007.[7] The drug was approved in 2007 as the first agent to treat advanced HCC. This was based on the results of two pivotal studies, the multicenter phase III European Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol (SHARP) and the Asia-Pacific trial.[13–15] Both trials randomly assigned patients with advanced unresectable HCC to receive either sorafenib or placebo.

Both trials showed that sorafenib was more effective in those cases from hepatitis C origin.[16] Despite this, the Asia-Pacific recruited more patients with extrahepatic disease, more liver lesions, worse PS and a higher rate of AFP elevation.[14] These facts may explain the shorter survival in the sorafenib group in the Asia-Pacific trial (6.5 mo) than in the SHARP study (10.7 mo).[13–15] In a subgroup analysis, sorafenib showed higher efficacy in those patients without extrahepatic dissemination, with HCV and with a low neutrophil-to-lymphocyte ratio.[14] Bruix et al. found that sorafenib consistently improved median overall survival (OS) and disease control rate (DCR) compared to placebo, regardless of any of the subgroups studied. It also improved median time to progression (TTP), except in HBV.[15] These results need careful interpretation due to the small patient numbers in some of the subgroups.

Sorafenib was further investigated in two large prospective observational studies:

GIDEON (Global Investigation of Therapeutic DEcisions in HCC and of its Treatment with Sorafenib) and INSIGHT.

The GIDEON is one of the largest studies carried out in advanced HCC. This assessed the safety and tolerability of sorafenib in routine use.[17] This research predefined several sub-analyses to check potential predictive and prognostic factors, such as Child-Pugh score, Barcelona Clinic Liver Cancer stage and aetiology. It also confirms that sorafenib is well tolerated in the clinical setting and that its safety profile is similar regardless of Child-Pugh score, BCLC stage or initial sorafenib dose. Although it is a non-controlled, non-interventional study, the opportunity to evaluate > 3000 patients with advanced HCC in clinical practice, including patients with a greater liver dysfunction, is of considerable clinical interest and relevance.

The INSIGHT is a noninterventional, prospective, multicenter, observational study performed in 124 sites across Austria and Germany carried out between 2008 and 2014.[18] The results of this study showed a overall survival (mOS) and time to progression dependent on Barcelona Clinic Liver Cancer (BCLC) stage at baseline, Child-Pugh liver function and performance status. Age was not found to influence the results. The results concluded that sorafenib was effective in a real-life context, as previous trials have shown.

Lenvatinib

Lenvatinib is another oral multikinase inhibitor that targets VEGF receptors 1, 2, and 3; fibroblast growth factor (FGF) receptors 1, 2, 3, and 4; platelet-derived growth factor receptor α (PDFGRα), RET, and KIT.[19] It showed clinical activity in a phase 2 trial of patients with advanced HCC with an acceptable safety profile.

Later the REFLECT trial, a multicenter, phase III, randomized, open-label, non-inferiority study compared lenvatinib given at 12 mg once daily (for bodyweight ≥ 60 kg) or 8 mg daily (for bodyweight < 60 kg) vs. sorafenib given at 400 mg twice daily in 28-day cycles.[20] This study showed mOS of 13.6 mo for lenvatinib, compared to 12.3 mo with sorafenib (HR 0.92; 95% CI, 0.79 to 1.06). The mPFS was 7.4 mo vs. 3.7 mo (HR, 0.66; P < 0.0001) favouring lenvatinib, same as overall response rate (ORR) 24.1% compared to 9.2% (OR 3.13; P < 0.0001).

The benefits of lenvatinib and sorafenib on mOS was consistent across the subgroups according to baseline features. Although the alpha-fetoprotein level was not a pre-specified criteria, patients with a baseline alpha-fetoprotein levels < 200 ng/mL had longer OS than those with alpha-fetoprotein levels ≥ 200 ng/mL in both treatment arms. Median time to progression was 8.9 mo (95% CI, 7.4 to 9.2 months) in the lenvatinib arm vs. 3.7 mo (95% CI, 3.6 to 5.4 mo) for the sorafenib (HR: 0.63; 95% CI, 0.53 to 0.73; P < 0.0001). ORR also favoured lenvatinib (24.1% vs. 9.2%; P < 0.0001).

And the analyses by subgroups showed that the HRs for OS were 0.83 (95% CI, 0.68 to 1.02) in patients with HBV, 0.91 (95% CI, 0.66 to 1.26) in HCV, and 1.03 (95% CI, 0.47 to 2.28) in those with alcohol-related aetiology. The HRs of PFS were 0.62 (95% CI, 0.50 to 0.75) in HBV, 0.78 (95% CI, 0.56 to 1.09) in HCV and 0.27 (95% CI, 0.11 to 0.66) in alcohol related cases. Analysis of a Chinese subgroup showed extremely favourable prognosis, indicating that lenvatinib may be most effective in patients with hepatitis B.[21]

Immune check-point inhibitor combined with VEGF inhibitor

Atezolizumab plus bevacizumab

Bevacizumab is a VEGF monoclonal antibody and atezolizumab, an anti-programmed cell death ligand 1 (PD-L1) antibody, have been combined for first line of advanced HCC patients.[22,23] VEGF increases the expression of PD-1 on neoplasm-infiltrating T cells. By targeting the VEGF, the immune suppression is reduced and combined with immune check-point inhibitors it improves immune reactivation by increasing T cell activation and tumour cell penetration.[22,23]

The phase III trial IMbrave150 randomised 501 patients, to receive atezolizumab-bevacizumab or sorafenib in a 2:1 ratio.[24] The results showed that atezolizumab and bevacizumab improved OS by 67.2% (95%CI, 61.3% to 73.1%) at 12 mo while sorafenib improved OS by 54.6% (95%CI, 45.2% to 64.0%). ORR was 27.3% (95%CI, 22.5% to 32.5%) for the combination vs. 11.9% (95%CI, 7.4% to 18.0%) for sorafenib. These findings have led to the FDA approval of this strategy as the preferred treating option for advanced HCC. The HR for OS over sorafenib was 0.58 (95% CI, 0.42 to 0.79).

The analyses by subgroups found that HRs for OS were 0.58 (95% CI, 0.40 to 0.83) in patients with HBV, 0.43 (95% CI, 0.25 to 0.73) in HCV and 1.05 (95% CI, 0.68 to 1.63) in those with non-viral aetiology. HRs for PFS were 0.51 (95% CI, 0.37 to 0.70) in HBV, 0.68 (95% CI, 0.42 to 1.10) in HCV and 0.80 (95% CI, 0.55 to 1.17) in those with non-viral aetiology. This trial did not find any difference in OS and PFS between atezolizumab plus bevacizumab and sorafenib in non-viral cases.[28]

Anti-PD-L1 combined with CTLA-4 antibody

Durvalumab and tremelimumab

The phase 3 clinical Trial HIMALAYA checked tremelimumab combined with multiple doses of durvalumab (the STRIDE regimen) or multiple doses of durvalumab alone.[29] These therapies were compared with sorafenib in advanced HCC.

A total of 1171 patients were randomly assigned to STRIDE (n = 393), durvalumab (n = 389), or sorafenib (n = 389).[25] mOS 16.43 mo (95% CI, 14.16 to 19.58) with STRIDE, 16.56 mo (95% CI, 14.06 to 19.12) with durvalumab and 13.77 mo (95% CI, 12.25 to 16.13) with sorafenib. OS at 36 mo was 30.7%, 24.7% and 20.2%, respectively. OS HR for STRIDE vs. sorafenib was 0.78 (96.02% CI, 0.65 to 0.93; P = 0.0035). OS for durvalumab monotherapy was noninferior to sorafenib (HR 0.86; 95.67% CI, 0.73 to 1.03; noninferiority margin, 1.08). mPFS was not significantly different among the three groups.

Authors concluded that STRIDE significantly improved OS vs. sorafenib, while durvalumab was non-inferior to sorafenib for patients with unresectable HCC. This trial did not find a benefit from the combination in hepatitis C virus-related HCC patients.[25]

Multikinase combined with immune checkpoint inhibitors

COSMIC-312 is an open-label, randomised, phase 3 trial carried out at 178 centres in 32 countries. This trial recruited patients with untreated advanced HCC who were randomly assigned (2:1:1) to cabozantinib plus atezolizumab, sorafenib or single agent cabozantinib.[26]

It randomised patients by disease aetiology, geographical region, and presence of extrahepatic disease or macrovascular invasion.

The combination showed longer mPFS than sorafenib (6.8 mo [99% CI, 5.6 to 8.3] vs 4.2 mo [2.8 to 7.0]), but not mOS at the first interim analysis (15.4 mo [96% CI 13.7 to 17.7] for cabozantinib plus atezolizumab vs 15.5 mo [12.1 to not estimable] for sorafenib). This interim analysis found a benefit from the combination as well in those cases with viral-related HCC, mainly HBV, but no benefit in non-viral cases.[26]

All these emerging data are very interesting and are leading the research to focus on the different aetiologies underlying the pathogenesis of HCC. It has been hypothesized that viral and/or non-viral cases could influence the immune context of HCC and as such explaining the different responses to different treatments.[27]

Other studies

Pfister and collaborators carried out a meta-analysis of three phase III immunotherapy trials[28] (CheckMate 459, Imbrave150, and KEYNOTE-240) studing the OS depending on aetiology (viral vs. non-viral). They found that in non-viral HCC, immunotherapy did not show an improvement in OS.

Based on these results, Rimini et al.[29] have recently carried out a multicenter retrospective analysis on a large cohort of patients treated with lenvatinib as first-line for advanced HCC and showed that NASH-related aetiology is an independent positive prognostic and predictive factor for OS, suggesting a potential role of aetiology in the selection of patients candidate to lenvatinib. Moreover, they concluded that lenvatinib is associated with a significant OS benefit compared to atezolizumab plus bevacizumab, in particular in those patients with NAFLD/NASH-related HCC.

Second-line systemic therapy

Regorafenib

Regorafenib inhibits the tumour growth, progression and metastases by blocking the proliferation of malignant cells and the creation of new tumour vessels. This drug is another multi-kinase inhibitor that targets tumour cells and the tumour microenvironment. Its kinase inhibition profile includes kinases involved in angiogenesis, oncogenesis, metastases and tumour immunity by blocking vascular endothelial growth factor receptor (VEGFR) 1-3, tyrosine kinase with immunoglobulin-like and epidermal growth factor (EGF)-like domains 2, blocking KIT stem cell factor receptor, RET, and BRAF, platelet-derived growth factor receptor (PDGFR)-β, fibroblast growth factor receptor (FGFR) and tumour immunity by the inhibition of colony-stimulating factor 1 receptor (CSF1R).[30]

The RESORCE trial assessed the efficacy and safety of regorafenib in patients with advanced HCC who had progressed during sorafenib.[30] The results showed regorafenib improves OS with a HR of 0.63 (95% CI, 0.50 to 0.79; one-sided P < 0.0001); mOS was 10·6 mo (95% CI, 9.1 to 12.1) for regorafenib vs. 7.8 mo (6.3 to 8.8) for placebo. Subgroup analysis showed the HRs for OS were 0.58 (95% CI, 0.41 to 0.82) in HBV and 0.79 (95% CI, 0.49 to 1.26) in HCV. HRs for PFS were 0.39 in HBV and 0.59 in HCV.

Ramucirumab

Ramucirumab is a recombinant human immunoglobulin G1 monoclonal antibody that binds to the extracellular domain of VEGFR-2 and prevents the binding of VEGFR ligands: VEGF-A, VEGF-C, and VEGF-D.[31]

This drug was assessed in a randomised phase 3 trial REACH-2.[31] REACH-2 met its primary endpoint, showing improved OS for ramucirumab compared with placebo in patients with advanced HCC and α-fetoprotein concentrations of at least 400 ng/mL who had previously received sorafenib. The HRs for OS were 0.74 (95% CI, 0.55 to 0.99) in patients with HBV, 0.82 (95% CI, 0.55 to 1.23) in HCV and 0.56 (95% CI, 0.40 to 0.79) in those with other aetiologies. The HR for PFS was 0.549 (95% CI, 0.41 to 0.74) in HBV, 0.58 (95% CI, 0.39 to 0.88) in HCV and 0.57 (95% CI, 0.41to 0.79) in other aetiologies.

Cabozantinib

Cabozantinib blocks tyrosine kinases, including VEGFR 1, 2, and 3, MET, and AXL,[32] which are involved in the progression of HCC and the development of resistance to sorafenib.

CELESTIAL trial is a randomized, phase 3 trial assessing cabozantinib in comparison to placebo in previously treated advanced HCC.[32]

At the second planned interim analysis, the trial showed significantly longer OS with cabozantinib with a mOS of 10.2 months with cabozantinib and 8.0 months with placebo (HR for OS 0.76; 95% CI, 0.63 to 0.92; P = 0.005). For different aetiology, HRs for OS was 0.69 (95% CI, 0.51 to 0.94) for HBV, 1.11 (95% CI, 0.72 to 0.94) in HCV and 0.72 (95% CI, 0.54 to 0.96) in other aetiologies. HRs for PFS was 0.31 (95% CI, 0.23 to 0.42) in HBV, 0.61 (95% CI, 0.42 to 0.88) in HCV and 0.48 (95% CI, 0.36 to 0.63) in other cases.

Other immune checkpoint inhibitors

Checkmate 459

Nivolumab had shown durable responses and positive effect on survival in patients with advanced HCC in the phase 1-2 CheckMate 040 trial.[33]

The Checkmate 459 was a randomised phase 3 trial carried out across 22 countries in Asia, Australasia, Europe, and North America. Although first-line nivolumab did not significantly improve OS compared with sorafenib, it had shown clinical activity in patients with advanced HCC and as such it could be considered as an option.

Pembrolizumab

Pembrolizumab had shown antineoplastic activity in the phase II KEYNOTE-224 trial in previously treated patients with advanced HCC.[34]

The KEYNOTE-240 was then carried out to assess the efficacy and safety of pembrolizumab in this group of patients.[39] This trial did not reach statistical significance per specified criteria, although the results were consistent with those of the previous KEYNOTE-224, supporting a favourable risk-to-benefit ratio for pembrolizumab in this population.[35]

Drug-combination of PD-1 and CTLA-4 antibody

Nivolumab and ipilimumab

Ipilimumab targets the CTLA-4 molecule, which is a key signalling checkpoint needed for T-cell activation. This combination was approved by the FDA as a second-line treatment in 2020. This decision was based on the results of the CHECKMATE-040, a phase I/II trial that recruited 148 patients.[36]

The study assessed 3 different regimens, all combining nivolumab plus ipilimumab and concluded that arm A (nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for 4 cycles, followed by biweekly nivolumab 240 mg) had the best ORR (32%) with a complete response of 8% and partial response of 24%. Duration of the response was 17 mo. However, larger trials are needed to confirm the findings.[36]

FUTURE PERSPECTIVES

Several trials have shown a collaborative interaction between tyrosine kinase inhibitors and immune checkpoint inhibitors.[37–39]

A phase II trial (RESCUE) assessed the efficacy and safety of camrelizumab [an anti-PD-1 mAb] plus apatinib (a VEGFR-2 tyrosine kinase inhibitor) in patients with advanced HCC.[40] The results showed that the ORR was 34.3% in first-line and 22.5% in second-line. mPFS in both groups was 5.7 and 5.5 mo respectively. The 12-mo OS was 74.7% and 68.2% respectively. The authors concluded that camrelizumab plus apatinib had a promising efficacy with manageable toxicity profile in advanced HCC in both first and second-line.[40]

The CARES-310 trial[41] is an open-label, international phase III that compares the efficacy and safety of the anti-PD-1 antibody camrelizumab plus the VEGFR2-targeted tyrosine kinase inhibitor apatinib versus sorafenib as first-line for advanced HCC. The study concluded that the combination had shown a statistically significant and clinically meaningful improvement in PFS and OS when compared with sorafenib for this group of patients and as such it is a new effective first-line therapy for advanced HCC. The FDA is considering this combination for first-line treatment in advanced HCC and in fact the target action date is May 16, 2024.

Further trials with camrelizumab are ongoing but two posters have been presented at ASCO GI this year. The updated results presented in two posters examined post hoc analyses of clinical data and patient reported outcomes in CARES-310 trial. The results demonstrated that the combination of camrelizumab and afatinib is superior to sorafenib regardless of the baseline liver function. The analysis that focused on patient-reported outcomes, showed that the combination had improved several quality-of-life items when compared to sorafenib regardless of the age of the patients (under 65 and 65 or over).[42,43]

There is another study that combines in a phase Ib trial, lenvatinib and pembrolizumab. The study showed a mPFS, OS, and ORR of 9.7, 20.4 mo, and 46% respectively, which looks a significant anti-tumour efficacy.[44]

Llovet et al carried out a phase III study (LEAP-002) assessing the addition of pembrolizumab to lenvatinib versus lenvatinib and placebo in first-line for advanced HCC.[45] This randomised, double-blind trial enrolled at 172 global sites. This study is registered with ClinicalTrials.gov, NCT03713593, and is active but not recruiting. At a median follow up of 32.1 mo, mOS is 21.2 mo with lenvatinib plus pembrolizumab vs. 19.0 mo for lenvatinib plus placebo (HR 0.84; 95% CI 0.71 to1.00; stratified log-rank P = 0.023). mPFS is 8.2 mo vs. 8.0 mo for lenvatinib plus pembrolizumab and lenvatinib plus placebo respectively (HR 0.87; 95% CI 0.73 to 1.02; stratified log-rank P = 0.047).

In previous studies, this combination used as first-line had shown promising clinical activity. However, this trial concluded that lenvatinib plus pembrolizumab had not met the prespecified significance for improved OS or PFS vs. lenvatinib plus placebo, and as such these results would not support a change in clinical practice.[45]

CONCLUSION

Systemic therapy for HCC has significantly progressed since the approval of sorafenib in 2007. Multiple tyrosine kinase inhibitors have demonstrated significant benefits in the treatment of advanced HCC and more recently, the introduction of immune check-points inhibitors, have shown even further benefits.

Keeping in mind that there are multiple risk factors involved in the development of HCC, recently it has been questioned if the aetiology should be taken into consideration at the time of selecting the treatment. However, there is no adequate data supporting the selection of a particular systemic therapy based on aetiology. Therefore, atezolizumab plus bevacizumab continues to be the first choice in first-line setting. It is in this context where patients’ condition measured by liver functional status, ECOG PS, etc. is key at the time of deciding which agent to select.

But the topic of aetiology and treatment selection continuous open. Pfister and colleagues have shown that atezolizumab plus bevacizumab is perhaps not as good when treating HCC of non-viral origin and in those cases, it has been suggested that an early assessment for response should be carried out to allow for a prompt change in treatment if not showing any benefit.[28] In addition, Rimini et al. carried out a retrospective analysis on a large number of advanced non-viral HCC cases and demonstrated for the first time that lenvatinib had a significant OS benefit when compared to atezolizumab plus bevacizumab, particularly in NAFLD/NASH-related HCC.[27]

Taken all together, the currently available evidence points to no need to select therapy based on aetiology, but further large studies, although difficult to conduct, should be considered to get firm conclusions.

DECLARATIONS

Author contributions

Cidon EU and Martinez PA wrote and revised the article.

Informed Consent

Not applicable.

Ethical Approval

Not applicable.

Conflicts of interest

There is no conflict of interest among the authors.

Data sharing statement

No additional data is available.

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