Immune checkpoint inhibitor therapy for hepatocellular carcinoma

HCC: approach to therapy

The National Comprehensive Cancer Network provides a framework for current therapeutic guidelines for HCC. Once the diagnosis of HCC has been confirmed, it is important to conduct a comprehensive evaluation [12]. This evaluation must include imaging studies to visualize the lesion, a thorough history of the presenting illness as well as a viral hepatitis panel to assist in determining the etiology [12]. Additionally, laboratory testing is crucial to glean information about the synthetic function of the liver, as well as obtaining parameters for calculation of a Child-Pugh score [12]. The Child-Pugh score uses the parameters of encephalopathy, ascites, albumin, prothrombin time and bilirubin to calculate a score correlated with the operative risk [12]. Class A is described as a score of 5-6 points, and indicates a good operative risk [12]. Class B refers to a score of 7-9 points, and Class C to 10-15 points, with operative risks of moderate and poor, respectively [12]. These elements of the evaluation will factor into determining whether the patient is a candidate for liver resection or transplant. The Milan criteria provide a framework to assess a patient’s suitability for liver transplantation [13]. This information contributes to formulating a therapeutic regimen, as candidacy for surgical intervention requires certain parameters to be met. If a patient has inadequate hepatic reserve, such that surgical excision of the cancer legion plus margins would leave the patient with insufficient hepatic tissue for survival, the cancer is considered inoperable [12]. Other reasons for deeming HCC inoperable include inaccessible or precarious location of the HCC around a major blood vessel [12]. Additionally, to be considered for surgical excision, a patient must be deemed fit for major surgery. Considering that most cases of HCC develop in a setting of chronic liver disease and cirrhosis, surgical excision is not a possibility in the majority of HCC cases, given the previously poor health status of affected patients who have a low baseline hepatic synthetic functional reserve [14]. A chronically impaired liver typically correlates with notable laboratory values indicating thrombocytopenia, prolonged prothrombin time (high international normalized ratio), low albumin, among various other possible derangements. A high risk of gastrointestinal bleeding based on the above concerns plays a major role in determining which therapeutic options may be considered for an individual patient. Bleeding may ensue as a result of portal hypertension causing ruptured varices, or from the impaired ability to clot a minor lesion. The risk of blood loss and coagulopathies, as well as low albumin, suggesting a poor baseline state of health and therefore a risk of a poor outcome, present a major challenge specific to HCC, as various other solid tumor lesions rely in part on surgical excision as a mainstay of treatment. The addition of treatments with different mechanisms of action provides alternative options for patients who do not meet criteria for the limited previously available options, as well as those refractory to first-line therapies. Expanded criteria for determining treatment plans were set out by the Barcelona Clinic Liver Cancer staging system [14].

Standard chemotherapeutic options

The current therapeutic approach to HCC is multifactorial and consists broadly of surgical therapies, nonsurgical local/regional directed therapies, and systemic therapies. Surgical therapies include liver resection and transplantation [15]. Nonsurgical local/regional directed therapies include radiofrequency ablation (RFA), percutaneous ethanol injection (PEI), microwave ablation (MWA), transarterial chemoembolization (TACE), and transarterial radioembolization (TARE) [16]. RFA employs oscillating electrical currents surrounding a strategically placed electrode, which generates resistive heating and hyperthermia in tissue [16]. Though more research is needed to harness the full therapeutic potential of RFA, Galanakis et al reported that, in the early stages of disease, RFA or MWA are equivalent to surgical resection [17]. Though numerous individual studies report promising results surrounding use of RFA, a Cochrane meta-analysis conducted by Weiss et al found that surgical intervention was superior to RFA when considering survival [18]. Regarding TACE and TARE, Galanakis et al suggested that the limitations of each individual therapy may be augmented by combination therapies [16]. Tandem therapy has shown superior outcomes to monotherapy, with improved overall survival statistics and no significant differences in complications [16]. Analysis by Peng et al supports the use of combination therapy, reporting that RFA and TACE were superior to RFA alone for patients with HCC less than 7 cm, leading to improved survival [19]. Additional percutaneous targeted therapies include PEI, MWA, laser therapy, high-intensity focused ultrasound, stereotactic body radio-ablation therapy, and cryoablation [13]. The concept of nonsurgical locoregional therapeutic techniques is the precise delivery of cytotoxic agents to a specific tumor target, resulting in death to tumor cells with preservation of surrounding healthy tissue [13].

Systemic therapy includes chemotherapy, molecular target-directed therapy (e.g., multikinase inhibitors), and immunotherapy with immune checkpoint inhibitors (ICI) [20].

Surgical intervention is a mainstay of treatment for any solid tumor, yet therapy for HCC requires a multidisciplinary approach to therapy, employing multiple different tactics. Even if surgical criteria are met and resection of cancerous tissue is successfully completed, patients often suffer recurrences [21]. While the mechanism of recurrence following resections with clean margins is not fully understood, one hypothesis proposes that preexisting subclinical micro-foci of cancerous cells exist in a diffusely damaged and cirrhotic liver [21]. Therefore, resection alone is typically not adequate in the treatment of HCC and the integration of nonsurgical with systemic neoadjuvant therapies is integral to successful therapy and prolonged survival. Nonsurgical local/regional therapies can also be paired with surgical interventions [13].

Exploration of locoregional therapies paired with surgical interventions is underway, as is the study of locoregional therapies combined with multikinase inhibitors [22]. The combination of locoregional therapies with ICI therapies remains to be investigated, and is a likely future direction of progress in immunotherapy. As the data from ICI therapy in the context of HCC become more robust, a necessary direction of research to understand the true potential of ICI therapy is to pursue investigations of its combination with locoregional therapies.

Advances in the therapy for HCC are most notably occurring in the realm of systemic therapy. The SHARP trial marked a major turning point in HCC therapy. Prior to the SHARP trial, there were no systemic chemotherapy agents in existence for HCC [23]. This trial demonstrated the multikinase inhibitor sorafenib as the first systemic chemotherapy agent shown to increase the overall survival in HCC [24]. The SHARP trial was a phase III double-blinded, placebo-controlled trial, where 602 patients with advanced HCC were given either the multikinase inhibitor sorafenib or placebo [17]. Patients were randomly assigned and had no previous systemic therapy. This study demonstrated a 3-month longer median survival time for those receiving sorafenib compared to placebo [17]. A systematic review investigating the mechanism of action behind the success of sorafenib suggests modulation of the tumor microenvironment, as well as various immune cells [25]. Since the incorporation of sorafenib into HCC therapy, an array of new therapeutic options has been the focus of research and inclusion into HCC therapy regimens.

HCC is a complex form of cancer. The wide variety of pathogenic processes causing cirrhosis is likely to contribute to the large number of genomic alterations observed [26]. Common genetic aberrations in hepatocellular signaling cascades include mutations to genes involved in cellular growth signaling pathways. Notable genes include endothelial growth factor receptor, as well as Ras/ERK, PI3K/MTOR, HGF/MET, Wnt, Hedgehog, and other apoptotic signaling components, including those outlined in Table 1 alongside corresponding therapeutic interventions [26]. While each mutation holds potential for chemotherapeutic molecular targeting, the number of mutations also contributes to the challenge of treating HCC.

Table 1 Landmark clinical trials in the treatment of hepatocellular carcinoma

Trials of molecular therapies were aimed at the various genetic markers implicated in HCC. The EVOLVE-1 trial investigated the use of everolimus, an mTOR inhibitor, in patients with advanced HCC after failed therapy with sorafenib [27]. Unfortunately, no significant survival difference was observed [27]. Similarly, investigation of brivanib, a vascular endothelial growth factor receptor inhibitor, failed to demonstrate any significant findings in the BRISK-PS study [28].

Other multikinase inhibitor therapies, such as cabozantinib and regorafenib, were investigated in the CELESTIAL trial and RESOURCE trial, respectively. Cabozantinib resulted in severe and common adverse effects and is not recommended as a first-line treatment because of its low tolerability [29]. Though many trials failed to improve survival, regorafenib demonstrated a potential to enhance outcomes for those already taking sorafenib [30]. Additionally, the REFLECT trial found that lenvatinib was noninferior to sorafenib in terms of overall survival, while having similar safety and side effect profiles [31].

Other notable studies include REACH-2, a phase III second-line, randomized, double-blind study comparing ramucirumab with placebo, as well as studies on apatinib in a Phase II first-line randomized, multicenter, open-label trial [32]. Ramucirumab is a monoclonal antibody that functions by inhibiting angiogenesis, making it a useful adjunctive therapy for various forms of cancer [33]. Tremelimumab, a monoclonal antibody acting as a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor, has also been investigated as a therapeutic option, demonstrating potential antiviral effects in HCC patients with hepatitis C virus [34]. Results support the need for further research to generate more data on the use of tremelimumab [34].

The next breakthrough in systemic therapy development developed through data from the CheckMate 040 study, which demonstrated the potential utility of checkpoint inhibitors in the treatment of HCC [35]. The goal of this trial was to evaluate the safety and efficacy of nivolumab [35]. While previous research had focused on molecular target-directed therapy, specifically multikinase inhibitors, CheckMate040 highlighted the potential of checkpoint inhibitor therapy for treatment of HCC.

Checkpoint inhibitor therapy

In recent years, several new biologic therapies tested in clinical trials have demonstrated a potential for increased progression-free survival and overall survival (Table 2) [20]. The advancements in HCC treatment are largely due to the application of ICI therapy. Integrating ICI therapy into the clinical management of various malignancies has changed the landscape of cancer treatment at large [36]. The proven efficacy of ICI therapy in treating various other forms of malignancy has led to its application in the setting of HCC [27]. Prior to the introduction of ICI systemic chemotherapy agents for the treatment of HCC, the multikinase inhibitor sorafenib was the mainstay of systemic treatment, along with surgical intervention when possible [26]. Therefore, most research compares new pharmaceutical agents with the standard of care in systemic therapy.

Table 2 Child-Pugh score and FDA-approved systemic therapy options

Understanding the pathophysiology of HCC is important for developing tactical treatment strategies when approaching this complex form of cancer. The environment of chronic liver disease in which HCC frequently develops results from repeated pathologic insult to hepatic parenchyma. Chronic injury results in long-term exposure to inflammatory molecules [37]. A prolonged inflammatory state leads to impairment of a delicate balance of immunological factors [37]. The immune tolerance system is comprised of many different types of cells and cellular components, including antigen-presenting cells, T cells, immune checkpoint proteins, and influence by circulating inflammatory cytokines [37].

In a physiologic state, the system fluxes in balance, destroying unhealthy cells and preserving functional healthy cells [37]. In chronic liver disease, inflammation and tissue injury cause dysfunction and upregulation of immunotolerant signals, thus diminishing immune responses and reducing the destruction of aberrant or damaged cells [37]. This state of diminished ability to mount an immune response is referred to as T-cell anergy [37]. The immune system in this exhausted T-cell state is not able to effectively detect and thwart abnormal cell growth, rendering the patient susceptible to HCC [37]. The concept of ICI therapy is to reestablish a balanced state in the immune tolerance system. Restoring immune function can be accomplished through priming immunological components to regain function and decrease immunotolerance, thus recognizing the neoplastic cells as a threat and destroying the HCC.

ICI therapies, also known as biologics, are a means of cancer treatment that enlist the patient’s own immune system to destroy neoplastic cells. Checkpoint inhibitors are a class of systemic chemotherapy agents that function by modulating immune system cellular interactions with tumor cells [28]. This is accomplished by directing monoclonal antibodies towards cellular checkpoint proteins [38]. Checkpoint proteins must be inactivated in order for the immune system to recognize atypical cells as a threat and trigger an immune response [29]. ICIs are monoclonal antibodies that prevent the interaction between checkpoint proteins on cancer cells and checkpoint proteins on immune cells [37]. Subsequently, immune cells recognize the cancerous cells as a threat, and mount an immune response [39]. The ability to mobilize and focus the existing mechanisms of the immune response towards the destruction of cancer cells is a remarkable application of pharmaceutical technology.

Many ICIs target the programmed cell death 1 cellular pathway (Fig. 1) [39]. The 2 main molecules in this pathway are programmed cell death receptor protein (PD-1), found on the surface membrane of immune cells, and programmed cell death ligand (PD-L1), expressed physiologically on cells. Common PD-1 inhibitors include nivolumab and pembrolizumab, and the most notable PD-L1 inhibitor is atezolizumab [40]. At the molecular level, these checkpoint inhibitors mainly function by blocking the PD-1 receptor on T cells, or PD-L1 ligand on cancer cells. Preventing the PD-1 and PD-L1 interaction allows the T cell to recognize the cancer cell as a threat [39]. Expression of PD-L1 is one common mechanism by which cancer cells elude destruction by the immune system [38]. Therefore, PD-1 and PD-L1 checkpoint proteins have become a popular molecular target for biologic chemotherapy development. Similarly, increased expression of CTLA-4 can further impair T-cell function [31]. Therefore, CTLA-4 is an additional immune checkpoint protein that is a target for ICI therapy [41].

Figure 1 Schematic diagram of (A) PD-1 protein on T-cells binding to PD-L1 protein on the tumor cells, which inhibits the destruction of tumor cells. (B) Anti PD-1 and anti-PD-L1 interventions, known as immune checkpoint inhibitors, inhibit binding between tumor cells and T cells, which allows T-cell-mediated killing of tumor cells

CTLA-4 is an inhibitory coreceptor found on the surface of certain immune cells. It impairs T-cell activation and proliferation, and neoplastic cells often express CTLA-4, leading to a diminished immune response. Inhibition of CTLA-4 enables T cells to function more effectively. This process is described in Fig. 2. The most widely used ICI targeting CTLA-4 is ipilimumab [34]. ICI therapy has demonstrated the ability to restore T-cell function in various other malignancies through inhibition of PD-1/PD-L1 and CTLA-4 [27]. The focus of research is primarily on PD-1 and PD-L1 inhibition rather than CTLA-4, as blockade of PD-1 and PD-L1 proteins demonstrated objective response rates up to 20% higher in the treatment of advanced HCC [37].

Figure 2 Schematic diagram of (A) cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) receptor on T cells binding to B7 receptors on antigen-presenting cells, which inhibits destruction of tumor cells. (B) Anti-CTLA-4 antibodies comprise another form of immune checkpoint inhibitor. These antibodies inhibit binding between antigen presenting cells and T cells, which allows T-cell-mediated killing of tumor cells

Integration of ICI therapy into the clinical management of HCC has demonstrated strong response rates and improved overall mean survival in various landmark studies. Notable studies include CheckMate 040, a phase 1/2, open-label, non-comparative, dose escalation and expansion trial that examined the therapeutic potential of nivolumab, a monoclonal antibody targeting inhibition of PD-1 checkpoint protein [35]. In 2017 nivolumab was among the first FDA-approved additions to sorafenib in systemic therapy for HCC [35]. Findings indicated that nivolumab had therapeutic potential in the treatment of HCC [35]. While the majority of systemic therapies are available for Child-Pugh class A only, nivolumab monotherapy is also approved for Child-Pugh class B [41]. However, the Checkmate 459 trial later found that nivolumab monotherapy failed to demonstrate advantage over sorafenib in Child-Pugh class A, and is therefore reserved for Child-Pugh class B as an alternative therapy option in cases where patients were not candidates for multikinase inhibitors [41]. Options for Child-Pugh classes B and C remain very limited, as shown in Table 1.

Nivolumab was followed by FDA approval of pembrolizumab, also a PD-1 inhibitor. It is worth noting that nivolumab and pembrolizumab have not yet received approval from the European Medicines Agency (EMA). The KeyNote 224 study, conducted by Zhu et al, examined the safety and efficacy of pembrolizumab, finding that it was both safe and tolerable for patients previously treated with sorafenib for advanced HCC [42]. Further research in 2 Phase III clinical trials followed, leading to approval of pembrolizumab as a second-line treatment for HCC [42]. Although Phase III trials of nivolumab monotherapy as a first-line agent and pembrolizumab monotherapy as a second-line agent failed to demonstrate statistically significant improvements in outcome, variability was noted among the data, suggesting that monotherapy with these agents may be effective in certain subsets of patients [20].

While monotherapy with ICIs is an important step towards understanding their therapeutic potential, major advances in therapeutic outcomes have come from studies implementing combination therapies, such as additional arms of CheckMate 040 that used nivolumab + ipilimumab to target both PD-1 and CTLA-4 checkpoint inhibitor molecules [32]. An arm of the CheckMate 040 randomized clinical trial examined the efficacy and safety of combination therapy with nivolumab and ipilimumab in patients with advanced HCC who had previously been treated with sorafenib [43]. This trial found that the nivolumab plus ipilimumab combination showed manageable safety, stable responses, and potential for improved clinical outcomes.

The IMBrave150 study paired atezolizumab + bevacizumab in combination therapy, targeting the PD-L1 checkpoint inhibitor protein and the vascular endothelial growth factor kinase receptor [32]. The IMBrave150 study is among the most successful advances in HCC treatment, and the results piloted the current first line of systemic therapy. The IMBrave150 study compared combination therapy with atezolizumab and bevacizumab vs. standard monotherapy with sorafenib in patients with unresectable HCC and no previous systemic treatment [44]. Findings showed better overall and progression-free survival outcomes with the use of atezolizumab and bevacizumab combination therapy compared to sorafenib, with an improvement in 1-year survival rate from 54.6-67.2% [44].

Future directions in the treatment of HCC may also combine multikinase inhibitors with ICIs. Research is underway with combination therapy pairing lenvatinib and pembrolizumab in therapy for patients with unresectable HCC [44]. This Phase Ib study investigated the immunomodulatory properties of lenvatinib, a multikinase inhibitor, when paired with pembrolizumab, an ICI inhibitor of PD-1 [32]. The investigators report that combination therapy with lenvatinib and pembrolizumab show promising anti-tumor activity in unresectable HCC [44]. For patients with advanced, unresectable HCC, systemic therapy options were previously limited, and the outcomes have not been favorable. The advent of immunotherapy as a means for treating HCC holds promise for more effective therapy options becoming available for treating this highly prevalent disease. There is evidence suggesting that ICI therapy benefits certain subsets of patients more effectively than others. Unfortunately, the identification of specific biomarkers associated with implications for therapeutic impact have yet to be identified [45]. The most notable biomarker related to HCC is a-fetoprotein, but many new markers of inflammatory processes at the molecular level are currently being investigated.

A notable and serious limitation of the therapeutic potential of ICIs is described by Pfister et al, whose study generated data lending insight into the role of T cells specifically in a setting of NASH/NAFLD [46]. These data indicate that ICI therapy in HCC cases developing from NASH/NAFLD is not only ineffective, but also associated with poor outcomes [46]. This finding is problematic when considering the shifting epidemiologic landscape of HCC, where NASH/NAFLD is becoming the pervasive mechanism of chronic liver inflammation. A subsequent study further suggested there may be a relationship between therapy selection and the etiology of inflammatory processes. This multicenter retrospective investigation by Hiraoka et al found that lenvatinib may be a suitable option for HCC therapy, irrespective of HCC etiology [47]. Biomarker associations and identification of suitable candidates for different therapies remain ambiguous, despite guidelines set forth in the Barcelona Clinic Liver Cancer algorithm [48]. Nevertheless, studies are demonstrating more concrete evidence that combination therapies are more efficacious than monotherapy with ICI agents [36]. This innovative approach to cancer therapy holds potential, yet studies are finding variable results [39]. Further investigation of biomarkers is required to make predictions about ICI responses on an individual patient basis [39].

Cost effectiveness

The advent of ICIs has profoundly influenced the field of cancer therapy. As ICI use grows to play an established role in the clinical management of HCC, it is important to consider the cost. Understanding costs is a salient component of bringing new therapies to the forefront of clinical care.

Chiang et al recognized the success of the IMBrave150 trial, which showed that combination therapy with atezolizumab plus bevacizumab can achieve statistically significant improvement in survival outcomes compared to sorafenib monotherapy [49]. The same investigators assessed the combination therapy from the USA payer perspective, analyzing the data from the standpoint of 3 main outcomes: life years, quality-adjusted life years, lifetime costs, and incremental cost-effectiveness ratio [49]. Importantly, the atezolizumab plus bevacizumab combination showed a 44% gain in quality-adjusted life years, with an additional cost of $79,074 [49]. The data revealed that atezolizumab plus bevacizumab is cost-effective in some scenarios but not others [49]. This investigation suggests that cost-effectiveness could be achieved by either instituting a maximum duration of therapy of one year, or reducing the dosage of atezolizumab plus bevacizumab to less than 10 mg/kg [39]. Though not yet deemed cost-effective in all scenarios, analyses of this kind suggest that the use of ICI has the potential to become a mainstream and cost-effective therapy for HCC [49]. In addition to cost considerations, further research is needed to identify biomarkers that may relate to therapeutic effectiveness and assist with streamlining therapy in contexts where a favorable outcome is reliably predicted [26]. Better understanding of biomarkers should also help reduce the cost of care in the future through more focused therapeutic interventions.

An additional cost consideration of ICI therapy emerges in the form of immune-related adverse events [50]. Instead of the traditional chemotherapeutic paradigm of infusing therapy to induce apoptosis in all cells with high mitotic activity, ICI therapy employs the patient’s own immune system to perform the task of identifying and eliminating cancerous cells. The hope inherent in this concept is to more accurately identify the problematic cells and reduce the adverse effects associated with traditional chemotherapy, which result in the collateral deaths of many healthy cells. However, the intended effect of ICIs in promoting the activation and clonal expansion of T cells holds novel challenges for patient management. Given the novel approach that ICI therapy follows, the fundamental intended target of increasing the activity of the immune system presents an array of adverse effects that differ from traditional chemotherapy. T cells have the ability to infiltrate nearly all organs, and are therefore capable of causing adverse effects in nearly any bodily system [50]. Additionally, these effects can vary in appearance and in time from exposure to presentation, making them more difficult to detect and attribute to ICI therapy. A further challenge lies in the lack of identifiable intrinsic risk factors to guide suitable candidates for this therapy. The first-line therapy for managing immune-related adverse events (irAEs) involves systemic corticosteroids to dampen the overstimulated immune response, with the intention of reducing the adverse symptoms [50]. The manifestations of irAEs include a broad spectrum of rheumatologic conditions [50]. Among the more severe are drug rash with eosinophilia and systemic symptoms, Stevens-Johnson syndrome, encephalitis, pneumonitis, hepatitis, and myocarditis [50]. It is important to maintain awareness that novel approaches beget novel adverse effects, and irAEs may have a significant bearing on the evaluation of cost-effectiveness [50].