The role of immunotherapy in the management of hepatocellular carcinoma

Overview

Hepatocellular carcinoma (HCC) represents the most common primary liver malignancy, accounting for approximately 75–80% of all liver cancer cases. The global incidence of hepatocellular carcinoma is increasing due to rising rates of underlying diseases, creating a significant cancer burden and a significant clinical challenge due to its often late presentation and limited effective treatment options. Immune checkpoint inhibitors have revolutionized the treatment approach in various malignancies. In the treatment of advanced hepatocellular carcinoma, immunotherapy has proven to be more effective than tyrosine kinase inhibitors, which have been a treatment option for a decade. Clinical trials such as the HIMALAYA and IMbrave150 have demonstrated significant survival benefits, showing superior efficacy compared to sorafenib. Despite these promising results, not all HCC patients respond to immunotherapy equally. There is a need to search for reliable prognostic and predictive biomarkers that can help predict which patients are most likely to benefit from immunotherapy, thereby personalizing treatment and improving outcomes. The purpose of this article is to provide a summary of clinical trials on immunotherapy for various stages of hepatocellular carcinoma.

Keywords:

liver cancer – hepatocellular carcinoma – immune checkpoint inhibitors – immunotherapy – combination regimens

Introduction

Primary liver cancer is the sixth most commonly diagnosed malignancy worldwide and the third most common cause of cancer-related death with continually rising incidence according to GLOBOCAN 2020 [1]. Liver cancer represents a very aggressive malignancy with a poor prognosis and is considered a major cancer burden. Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, with approximately 75–80% of cases [2]. The underlying etiology of HCC is represented by factors usually leading to cirrhosis such as alcoholic liver disease (ALD), chronic viral hepatitis (HBV, HCV), aflatoxin exposure, and the currently increasing incidence of liver cancer associated with metabolic dysfunction-associated steatotic liver disease (MASLD) related to metabolic syndrome [3]. Despite advances in surveillance and therapeutic approaches, HCC remains a significant clinical challenge due to its often late presentation and limited effective treatment options [4]. The liver is a vital organ that performs a wide range of essential functions necessary for maintaining overall health. These functions include metabolism, detoxification, bile production, synthesis of blood proteins, regulation of hormones, and immune functions. Therefore, using a conventional TNM (tumor, nodes, metastasis) staging system is not appropriate [5]. The most commonly used staging system for HCC is the Barcelona Clinic of Liver Cancer (BCLC) classification, which considers not only the assessment of the extent of the disease, but also the performance status of the patient, and preservation of the liver function using Child-Pugh classification. Additionally, there are some prognostic parameters for stratifying the patient‘s groups, such as the end-stage liver disease (MELD) score, the albumin-bilirubin (ALBI) score for stratification of compensated liver function, and inflammatory indices that are being intensively researched [4,6]. This classification distinguishes 5 stages (Scheme 1) helping to determine prognosis prediction and patient characterization for tailored treatment choices [6]. New insights into the tumor microenvironment (TME) of HCC have led to the hypothesis of the modifying effect of ICI in HCC treatment. Numerous immune mechanisms play a crucial role in the development and progression of HCC and are associated with patient prognosis. Namely, a dysfunctional interaction between the tumor and immune system can lead to immune evasion. This can occur through impaired antigen recognition or by creating an immunosuppressive tumor microenvironment (TME). Various molecular changes contribute to an immunosuppressive TME, including the presence of regulatory T cells, inhibitory B cells, myeloid-derived suppressor cells, and M2-polarized tumor-associated macrophages [7]. Immune checkpoint inhibitor (ICI) therapy has become an increasingly important treatment option for HCC due to several key benefits: enhanced immune response, durable responses, improved survival, reduced recurrence, and targeting the tumor microenvironment [8]. ICIs work by preventing the deactivation of T lymphocytes by blocking checkpoint proteins from interacting with their ligands. Research has shown that by enabling an efficient immune response, ICIs can help eliminate tumor cells, significantly improving cancer treatment outcomes [7].

Immunotherapy for early stage HCC

The mainstay therapies for patients with early stage liver cancer (BCLC 0 and BCLC A) are surgery and liver transplant (LT) [4]. Patients considered unsuitable for surgery or LT, with borderline resectabe tumors, might profit from neoadjuvant ICI treatment with the intention to shrink the tumor. Moreover, the unique immune microenvironment of the liver might be modulated by immunotherapy, being transformed from an immunosuppressive nature into an immune-supportive microenvironment [9]. There are several published and ongoing trials focused on the efficacy and safety of ICIs, targeted therapies, and their combinations in the neoadjuvant setting. To mention a few, a single-arm, open- -label phase II trial investigated cemiplimab, a PD-1 (programed cell death 1) inhibitor, in patients with resectable HCC. Participants received two doses of cemiplimab before surgery and eight cycles postoperatively. Among the 21 patients enrolled, 20% achieved a major pathological response (defined as more than 70% tumor necrosis), and 95% underwent hepatectomy successfully. This trial is ongoing, with long-term outcomes yet to be reported [10]. Another randomised, open-label, phase II trial investigating perioperative nivolumab (anti-PD-1) monotherapy vs. nivolumab + ipilimumab (anti-CTLA-4: cytotoxic T-lymphocyte associated protein 4) in resectable HCC showed (in preliminary efficacy results) that patients treated with neoadjuvant ICI combination can achieve a major pathological response (PR) with longer recurrence-free survival (RFS). In total, 27 patients were randomised and 20 patients underwent surgery while major PR proportions were 33% (3/9 patients; 95% CI 7.5–70.1%) with nivolumab and 27% (3/11 patients; 95% CI 6−61%) with nivolumab + ipilimumab. As a secondary end point, the estimated median progression free survival (PFS) was 9.4 months (95% CI; 1.47–not evaluable [NE]) for nivolumab compared to 19.53 months (95% CI 2.33–NE) for nivolumab + ipilimumab (HR 0.89 for nivolumab arm as reference, 95% CI 0.31–2.54) [11]. Administering ICIs before surgical resection or locoregional therapies aims to reduce tumor burden and induce systemic immune responses, potentially leading to improved surgical outcomes and reduced recurrence rate [9–11]. However, the use of systemic treatment as a neoadjuvant approach is still the subject of extensive research.

Adjuvant treatment for HCC has a significant potential to improve outcomes for patients undergoing curative treatments aiming to reduce recurrence and improving survival [12,13]. The global, open-label, phase III IMbrave050 trial showed that adjuvant treatment with the combination of atezolizumab (anti--PDL-1) and bevacizumab (anti-VEGF: vascular endothelial growth factor) at the prespecified interim analysis in October 2022 (median duration of follow-up was 17.4 months) achieved an improvement in RFS rates: 78% in the atezolizumab plus bevacizumab group compared to 65% in the surveillance group. This represented a 28% reduction in the risk of recurrence or death for patients in the treatment arm in patients with high-risk hepatocellular carcinoma following curative-intent resection or ablation. Median RFS has not been reached in either arm. However, additional data are needed to evaluate overall survival (OS) [12]. In comparison, a randomized, controlled phase II study of adjuvant sintilimab (anti-PD-1) in resected high- -risk HCC randomizing patients with HCC and MVI (microvascular invasion) into a group receiving monotherapy with sintilimab vs. active surveillance showed that sintilimab significantly improved RFS (median RFS; 27.7 vs. 15.5 months; HR 0.534; 95% CI 0.360–0.792; P = 0.002) in preliminary data [13]. There are some ongoing studies for high-risk early HCC whose results could enlighten the importance of ICI therapy in an adjuvant setting. For instance, EMERALD-2 is a phase III study of durvalumab (anti--PD-L1) with or without bevacizumab as adjuvant therapy in patients with hepatocellular carcinoma at high risk of recurrence after curative hepatic resection or ablation with the primary endpoint RFS and secondary endpoints including 2- and 3-year RFS, time to recurrence, overall survival, health-related quality of life measures, and safety [14]. Another in-progress trial, KEYNOTE-937, will assess the efficacy and safety of pembrolizumab as adjuvant treatment in patients with HCC who had a complete radiologic response after surgical resection or local ablation [15]. A very promising study for patients with HCC who are at high risk of recurrence after curative hepatic resection or ablation, a population for whom no effective therapies are currently available, is a phase 3, randomized, double-blind, placebo-controlled study which evaluates the safety and efficacy of adjuvant nivolumab (CheckMate-9DX). The primary endpoint of this trial is to assess RFS and determine whether nivolumab can delay or prevent the recurrence of HCC compared to placebo [16].

Immunotherapy combined with local treatment at the intermediate stage

The combination of immunotherapy with local treatments, especially transarterial chemoembolization (TACE), has emerged as a promising strategy in the management of HCC. This approach aims to improve treatment effectiveness by capitalizing on the strengths of both modalities [17,18]. An overview of ongoing clinical trials for unresectable hepatocellular carcinoma eligible for embolization is summarized in Tab. 1. EMERALD-1 is a phase III, randomized, placebo-controlled study of TACE combined with durvalumab with or without bevacizumab in participants with unresectable HCC eligible for embolization. In total, 616 patients with BCLC stage A (25.8%), stage B (57.3%), and stage C (16.1%) were randomized to durvalumab (D) + bevaizumab (B) + TACE (N = 204), D + TACE (N = 207), or TACE (N = 205). Demographic and baseline characteristics were generally balanced across arms. At the final PFS analysis (Graph 1), the primary objective was met: PFS significantly improved for D + B + TACE vs. TACE (median [ m] PFS 15.0 vs. 8.2 m; HR 0.77; 95% CI 0.61–0.98; P = 0.032 [threshold 0.0434]). These results showed statistically significant and clinically meaningful improvement in PFS in patients with embolization-eligible unresectable HCC treated with a D + B + TACE regimen and manageable safety [17]. The EMERALD-3 trial is an ongoing phase III study investigating the efficacy of combining tremelimumab (anti-CTLA4) and durvalumab, with or without lenvatinib (multiple receptor tyrosine kinases [RTKs] targeting vascular endothelial growth factor receptor [VEGFR1-3]), in conjunction with TACE in patients with locoregional HCC who are not eligible for curative treatments like surgery or transplantation. This combination regimen is being explored for its potential to enhance the anti-tumor immune response initiated by TACE. The results are still being eagerly awaited to determine whether the regimen might significantly improve PFS and OS compared to TACE alone [18]. A very promising trial that may establish a new standard of care for intermediate-stage HCC, combining local treatment with systemic immunotherapy to enhance overall treatment efficacy is a phase IIIb, randomized, multicenter, open-label, investigator-initiated trial of atezolizumab + bevacizumab vs. TACE in intermediate stage HCC with a high tumor burden exceeding the Milan criteria-ABC-HCC trial with a novel primary endpoint to determine the time to failure of the treatment strategy [20].

Immunotherapy in the treatment of unresecable advanced or metastatic HCC

Immunotherapy has become a crucial treatment option for patients with inoperable, advanced, or metastatic HCC [8]. The combination of immunotherapy and antiangiogenic monoclonal antibody has become a new standard for the treatment of advanced HCC due to encouraging results from the IMbrave150 phase III trial [7,8,21]. The IMbrave150 trial was a global, open-label pivotal phase III study investigating the efficacy and safety of combining atezolizumab + bevacizumab vs. sorafenib (TKI) in patients with unresectable HCC who had not received prior systemic therapy. The primary endpoints were OS and PFS, while secondary endpoints included objective response rate (ORR), duration of response, and safety profile. At the time of the primary analysis, the trial demonstrated that the combination of atezolizumab and bevacizumab significantly improved both OS and PFS compared to sorafenib. Median OS for the combination of atezolizumab and bevacizumab was 19.2 months, compared to 13.4 months with sorafenib. The hazard ratio for death was 0.58, indicating a 42% reduction in the risk of death of patients in the combination therapy group compared to the sorafenib group. Median PFS was 6.8 months in the combination arm vs. 4.3 months in the sorafenib arm. The combination therapy also showed a higher ORR compared to sorafenib [21]. Another combination of ICI and targeted treatment has been demonstrated in the CARES-310 study. It is a significant phase III clinical trial that assessed the effectiveness and safety of camrelizumab, a PD-1 inhibitor, combined with rivoceranib, a tyrosine kinase inhibitor, compared to sorafenib as a first-line treatment for unresectable HCC. In total, 543 patients with unresectable or metastatic HCC from 13 countries were randomly assigned to receive either camrelizumab (200 mg every two weeks) plus rivoceranib (250 mg daily) or sorafenib (400 mg twice daily) until disease progression or unacceptable toxicity. The primary endpoints were OS and PFS. Secondary endpoints included the ORR and safety profile. The combination therapy has significantly improved median OS to 22.1 months compared to 15.2 months with sorafenib, HR of 0.62; this indicates a 38% reduction in the risk of death (P <0.0001). The median PFS was also significantly improved, reaching 5.6 months with combination therapy vs. 3.7 months for sorafenib (HR = 0.52; P <0.0001). The ORR was 26.8% for the combination group compared to 5.9% for the sorafenib group, with responses lasting longer in the combination group (median duration of 17.5 vs. 9.2 months) [22].

Dual immune checkpoint blockade, the combination of two types of ICIs, is considered an effective approach in the treatment of advanced HCC, as indicated by the results of the HIMALAYA trial [23]. The trial was a phase III clinical study designed to evaluate the efficacy and safety of combining durvalumab and tremelimumab compared to the standard treatment with sorafenib in patients with advanced HCC who have not received prior systemic therapy. Patients were divided into three arms:

1.
the first arm, the STRIDE regimen, was treated with a single tremelimumab regular Interval durvalumab regimen, involving a single priming dose of tremelimumab (300 mg) followed by regular durvalumab (1,500 mg every four weeks);

2.
the second arm: durvalumab monotherapy, given as 1,500 mg every four weeks;

3.
the control arm: sorafenib, administered at 400 mg orally twice daily. The results of the trial suggest that the STRIDE regimen (durvalumab and tremelimumab) offers a viable and potentially superior alternative to sorafenib for patients with advanced HCC. The STRIDE regimen achieved a median OS of 16.4 months, compared to 13.8 months for sorafenib. This difference was statistically significant with an HR of 0.78 (P = 0,0035), indicating a 22% reduction in the risk of death compared to sorafenib [8,22].

The four-year OS update from the Phase III HIMALAYA trial demonstrated sustained benefits for the STRIDE regimen. Four-year OS rates were 25.2% with STRIDE vs. 15.1% with sorafenib, and OS HR (95% CI) for STRIDE vs. sorafenib was 0.78 (0.67–0.92) [24]. While promising, immunotherapy for HCC faces challenges such as variable patient responses, immune-related adverse events, and the need for biomarkers to predict treatment efficacy. Research continues to focus on optimizing combination therapies and discovering biomarkers to guide therapy selection [19].

Conclusion

Liver cancer continues to be a significant global health issue due to its increasing incidence [1,2]. Unfortunately, most cases are diagnosed at advanced stages, which limits the feasibility of treatment options such as ablation, TACE, and other local treatments for many patients [4,17]. Tyrosine kinase inhibitors have been the main therapeutic approach for advanced HCC patients for nearly a decade. Ongoing research into the immune microenvironment of HCC and successful use of immunotherapy in treating various solid tumors have ushered in a new era in the treatment of HCC [8]. Despite significant advancements, not all patients respond to these therapies, emphasizing the crucial need for prognostic biomarkers, such as inflammatory indexes, to guide treatment decisions [19]. NLR (neutrophil to lymphocyte ratio), PLT (platelet to lymphocyte ratio), and SII (systemic immune-inflammation index) are widely accepted effective predictors of overall survival [25–27]. For further evaluation of their efficacy, a collective of authors performed HeCaRe. This project is the first prospective longitudinal study of 16 centers in Slovakia, focusing on epidemiology, etiological data, concomitant medication, prognostic factors (such as NLR, PLT, SII, ALBI, etc.), and their influence on survival parameters (disease free survival [DFS], PFS, OS), objective response rate, and disease- -control rate [28].