Systemic treatment in patients with Child–Pugh B liver dysfunction and advanced hepatocellular carcinoma

Abstract Hepatocellular carcinoma (HCC) is a major cause of death among patients with liver cirrhosis. The rise of immuno‐oncology has revolutionized treatment for advanced HCC. However, most pivotal randomized controlled trials have excluded patients with moderate liver dysfunction (Child–Pugh–Turcotte B), despite the high incidence of liver disease in patients with HCC at the time of diagnosis. Overall survival in patients with HCC and moderate liver dysfunction treated with sorafenib has been found to be only approximately 3–5 months, underlining the need for improved treatment algorithms for this increasingly important subgroup of patients. In this review, we summarize available data on the treatment of patients with HCC and moderate liver dysfunction. Opportunities, as well as clinical challenges, are discussed in detail, highlighting potential changes to the therapeutic landscape.


| INTRODUCTION
Chronic liver disease is a direct cause of around 2 million deaths worldwide every year 1 and is associated with viral infections including hepatitis B and C, nonalcoholic liver disease (mainly secondary to diabetes and morbid obesity), alcohol consumption, and other metabolic and exposure factors. [2][3][4][5][6] The severity and prognosis of liver disease is usually assessed using the Child-Pugh-Turcotte (also known as the Child-Pugh [CP]) classification system. 7,8 Hepatocellular carcinoma (HCC) is the fourth most common cause of death among patients with cirrhosis, [9][10][11] which coexists with HCC in most cases. The risk of HCC development at 15 years after the onset of cirrhosis is greater than 60%, depending on the underlying liver disease. 12,13 The balance of HCC and cirrhosis determines proportional prognostic relevance, and their separate clinical courses should be weighed for personalized patient management. 14 Despite screening programs for high-risk patients, 50% of new cases of HCC occur in patients diagnosed with advanced stages of the disease. 15 Patients with severe liver damage (CP C) should be considered for palliative care, but are usually ineligible for clinical trials. For patients with HCC and well-preserved liver function (CP A), transarterial chemoembolization alone or in combination with systemic therapies is an effective treatment option. Patients with advanced HCC and well-preserved liver function (CP A) have seen considerable improvement in treatment options since 2018, following completion of several Phase 3 studies in this population, including the studies IMbrave150, HIMALAYA, CheckMate 459, COSMIC-312, REFLECT, and LEAP-002. [16][17][18][19][20][21] There are now numerous therapeutic options in first, second, and later lines of therapy 22 and the introduction of effective immunotherapies has had a significant impact on patient outcomes. 15,23 Several groups of patients with intermediate and advanced HCC are, however, often excluded from clinical trials. 24 Active viral infection, active esophageal varices, moderate liver dysfunction (CP B), and limiting renal function are common exclusion criteria in most of the pivotal clinical trials. These patients usually present with poorly compensated liver disease and/or poor performance status (Eastern Cooperative Oncology Group performance status [ECOG PS] of 2) and empirical evidence of efficacy and safety is sparse in this population. Despite this, most of the approved drugs used to treat advanced HCC have been offered in this population. Here, we describe and discuss the current data on systemic treatment in patients with HCC and moderate liver dysfunction.

| Classification of liver function
Historically, the CP system has been the most widely used tool for classifying liver function. The CP classification is based on clinical signs of liver function, including ascites, encephalopathy, bilirubin, albumin, and prothrombin time/international normalized ratio. Each measure is scored 1-3 according to severity, and patients are classified as CP A (5-6 points) for normal liver function, CP B (7-9 points) for moderate dysfunction, or CP C (10-15 points) for severe dysfunction. 25 Subclassifications of CP have been proposed, but need further validation. 26 The CP system is frequently used as the basis for inclusion criteria in clinical trials in intermediate and advanced HCC. 23,27 More recently, the albumin-bilirubin (ALBI) system for classification of liver function has been introduced as an alternative method for predicting treatment efficacy and survival in patients with liver damage and HCC. 8,25,27 The ALBI system assigns patients to one of three prognostic categories (ALBI 1-3) according to: where Grade 1 ≤−2.60; Grade 2 >−2.60 and ≤−1.39; and Grade 3 >1.39. 25 ALBI grading has been evaluated in multiple geographical locations and clinical settings, 25 and has been correlated with other classification systems for liver function and HCC and with outcomes in clinical trials. 28 In a multicenter cohort study, ALBI grade was highly concordant with CPbased classification (n = 3696). 29,30 The overall prognostic performance of ALBI grading is particularly good in intermediate-and advanced-stage disease. [31][32][33][34][35][36] (Figure 1). Subdivision of ALBI 2 has also been proposed. 38 New drugs for HCC are initially tested in patients with adequate liver function, but results may not translate to patients with moderate liver dysfunction.

| Oral multikinase inhibitors (MKIs)
Several MKIs have been approved for the treatment of advanced HCC based on improvements in overall survival (OS). 20,[39][40][41] The Phase 3 randomized controlled trials supporting these approvals primarily included patients with CP A. Efficacy data for patients with baseline ALBI 2 or CP B are typically only available from ad hoc or post hoc analyses of Phase 3 trials, prospective Phase 2 trials, and retrospective studies. Sorafenib is one exception, with Phase 3 data from patients with CP B available. The National Comprehensive Cancer Network (NCCN) Clinical Practical Guidelines in Oncology (www.nccn.org/guide lines) recommends this drug for the treatment of advanced HCC in patients with moderate liver dysfunction (i.e. CP B7).

Sorafenib
Sorafenib, an oral inhibitor of Raf-1, B-Raf, vascular endothelial growth factor receptors (VEGFRs) 1, 2, and 3, and platelet-derived growth factor receptor (PDGFR), improved OS compared with placebo in the SHARP Phase 3 trial. 40 In a Phase 2 study of first-line sorafenib in patients with advanced HCC, those with CP B (n = 38 [28%]) fared worse than those with CP A, with 12.9 weeks therapy duration, 13 weeks median progression-free survival (PFS), 14 weeks OS, and encephalopathy and worsening ascites in 11% and 18% of patients, respectively. 42,43 In another Phase 2 study, 14.3% of patients with baseline ALBI 2 (n = 162) discontinued treatment early and mortality was higher in patients with worsening liver function than in those with normal function. 44 In a retrospective study of 300 patients with advanced HCC, 58 patients with CP B had a median OS of 3.8 months compared with 10.0 months for patients with CP A (n = 234). 45 Linear predictor = log10 bilirubin mol∕L × 0.66 + albumin g∕L × 0.085 GIDEON was a prospective, observational registry study to evaluate the real-world safety of sorafenib in patients with HCC. Data from 669 treatment-naive patients with CP B were included. 46 The median treatment duration of 9.9 weeks in patients with CP B was longer in those with CP B7 (11.1 weeks) than in those with CP B8 (9.3 weeks) and CP B9 (7.6 weeks). The median OS was 5.2 months in those with CP B (CP B7, 6.2 months; CP B8, 4.8 months; CP B9, 3.7 months), much shorter than in CP A (13.6 months). Patients with CP B also had higher rates of adverse events (AEs) than those with CP A (Table 1). 46 The recommended continuous dose of sorafenib is 400 mg twice daily in patients with normal liver function. 40 A Phase 1 study of sorafenib in patients with liver or kidney dysfunction found that those with moderate to severe liver dysfunction cannot tolerate a starting dose of 400 mg sorafenib. Elevated bilirubin was a dose-limiting toxicity 47 and dose adjustment was recommended for this population. 46

Lenvatinib
In the REFLECT Phase 3 trial, lenvatinib, an inhibitor of VEGFRs 1, 2, and 3, fibroblast growth factor receptors 1, 2, 3, and 4, PDGFR-α, and RET and KIT proto-oncogenes, was noninferior to sorafenib in OS in patients with HCC. 20 In a post hoc analysis, the median OS among patients with F I G U R E 1 Albumin and bilirubin levels (panel B) are used in the CP classification (panel C) and ALBI grading systems (panel A) for liver dysfunction. Albumin and bilirubin levels are combined to provide an ALBI grading of 1, 2A, 2B, or 3. The CP system additionally assigns points for clinical criteria so that patients are allocated one of five classes across CP A (5-6 points) and CP B (7-9 points). The overlap in albumin and bilirubin combinations means that patients with CP A5 or A6 could be assigned to ALBI   baseline ALBI 1 and 2 was 17.4 months and 8.6 months, respectively. 48 In a Phase 2 study, patients with ALBI 2 had a time to treatment failure of 5.3 months and a higher rate of AE-related treatment discontinuation than patients with ALBI 1 (p < 0.01). 49 There are no Phase 3 data to support the use of lenvatinib in patients with CP B; sorafenib is often used as the first-line treatment in this population. 50 In a retrospective cohort study of patients receiving either sorafenib or lenvatinib as first-line treatment, those with baseline ALBI 2B had a longer median overall treatment duration (4.5 months) than patients with baseline ALBI 3 (3.0 months). 38

Regorafenib
Regorafenib is an inhibitor of oncogenic kinases including RET, RAF-1, and KIT and appears to be more potent than sorafenib. 51 In the RESORCE Phase 3 trial, regorafenib improved OS compared with placebo in patients previously treated with sorafenib. 39 Patients with ALBI 2 receiving regorafenib had significantly worse OS than those with ALBI 1 (hazard ratio [HR] 0.432; p = 0.001). 52 In a multicenter retrospective study in patients receiving regorafenib after sorafenib, median PFS and OS were 1.8 and 4.6 months, respectively, in the CP B cohort (n = 59), which was significantly worse than the CP A cohort (p = 0.008 and p < 0.001, respectively). 53 In another multicenter retrospective study of patients with CP A receiving regorafenib after sorafenib (N = 440), median PFS and OS were 3.2 and 12.1 months, respectively. 54 ALBI grade can be used to identify patients suitable for first-and second-line regorafenib treatment and those at high risk of liver function deterioration with treatment, according to a retrospective cohort study of regorafenib treatment in patients with progressive disease previously treated with sorafenib. 51,55 Cabozantinib Cabozantinib inhibits tyrosine kinases, including VEGFRs 1-3, MET, and AXL, and was approved based on the CELESTIAL Phase 3 trial. 41

Anti-VEGF monotherapy with ramucirumab
In the REACH Phase 3 trial, ramucirumab, a recombinant immunoglobulin G1 monoclonal antibody that binds to VEGFR-2, failed to demonstrate improvement against placebo in OS in patients with advanced HCC previously treated with sorafenib. 61 The original protocol included patients with CP B, but a protocol amendment later excluded these patients from the analysis. In an exploratory analysis of 78 patients with CP B7-8 at baseline, there was no difference in median OS between the treatment arms (HR 1.00, 95% CI 0.62, 1.60; p ≥ 0.99) and there was a higher incidence of Grade 3 or 4 toxicity than in patients with CP A. 62 Stratification of median OS by ALBI in the REFLECT, RESORCE, CELESTIAL, and REACH trials showed that MKIs and ramucirumab were no better than sorafenib in patients with advanced HCC and moderate liver dysfunction.

ICI monotherapy
The single-agent PD-1 inhibitors nivolumab 63 16,68 After an additional 12 months of follow-up of IMbrave150, atezolizumab plus bevacizumab maintained a clinically meaningful survival benefit over sorafenib and had a safety profile consistent with the primary analysis. 68 This combination is now standard of care for first-line treatment for advanced HCC in patients with good liver function. 69 When stratified by ALBI, the IMbrave150 trial found no difference in median OS between atezolizumab plus bevacizumab (11.7 months) and sorafenib (12.2 months) in patients with ALBI 2. 68 In a separate retrospective real-world study of 147 patients treated with atezolizumab plus bevacizumab, 73 patients would have been excluded from the IMbrave150 trial based on at least one major exclusion criterion. Median OS was 6.0 months for IMbrave150-ineligible patients, and was significantly longer in IMbrave150-eligible patients (p < 0.001), while median OS in patients with ALBI 2 and 3 was 8.6 months and 3.2 months, respectively. 70 In a real-world retrospective study of 216 patients with HCC treated consecutively with atezolizumab and bevacizumab, 154 patients with CP A had a median OS of 16.8 months versus 6.7 months for 48 patients with CP B (p = 0.0003). 71 Other ICI combination therapies. Tremelimumab plus durvalumab also showed superiority over sorafenib as first-line therapy in patients with advanced HCC and CP A in the Phase 3 HIMALAYA trial. 17 These data demonstrate the importance of PD-L1 and CTLA-4 in the cellular immune response to HCC.
Several studies combining IO agents with MKIs and other biological agents in first-and second-line therapy are ongoing. A complete list of studies can be found in a recent review. 23

Remaining challenges in immunotherapy for HCC
Despite the advances in IO agents for treating advanced HCC, several challenges remain. Phase 3 trials of IO agents in HCC have typically been restricted to a group of patients with good liver function (CP A) and their use in patients with moderate liver dysfunction has not been fully evaluated. Owing to a lack of available therapies, patients with some residual liver function (CP B7) may receive prescriptions for IO agents, even though supporting data are restricted to CP A and there are few or no data for CP B.
Even among patients with advanced HCC and good liver function, there remains a need for validated biomarkers for predicting and assessing responses to IO agents 72 ; up to 70% of patients with advanced HCC treated with ICIs may not benefit from immunotherapy. 73 PD-L1 expression, tumor mutational burden, microsatellite instability status, and gut microbiota are among the biomarkers being assessed. 73 Combining ICIs with non-ICI treatments in first-line therapy might be beneficial for reducing the risk of early death associated with the use of ICIs alone; 74 one suggested combination is an ICI, an anti-VEGF agent, and 90 Yttrium transarterial radioembolization. 75 Such strategies should be further explored.

| Complications of liver disease
Cirrhosis represents a late stage of progressive hepatic fibrosis and is generally considered irreversible in its advanced stages. Cirrhosis accounted for approximately 50,000 deaths in the US in 2010 and was the eighth leading cause of death. 76 There are several complications associated with cirrhosis, and patients can have a significantly reduced life expectancy. 77 This creates challenges in the design and conduct of prospective clinical trials in HCC because the confounding risk of cirrhosis can bias evaluation of the efficacy of anticancer therapy. Moreover, reducing tumor burden does not necessarily lead to improvements in liver function and survival.
Risk factors for cirrhosis complications include bleeding, infection, alcohol consumption, medication use, dehydration, constipation, and obesity. [78][79][80][81] Many of the complications of cirrhosis are associated with high mortality. Variceal hemorrhage is associated with a 30-day mortality of 15%-30%, despite improvements in techniques for controlling bleeding. 82 Portal hypertensive gastropathy (congestive gastropathy), a common complication in patients with portal hypertension, can also cause gastrointestinal bleeding and anemia. 83 Patients with cirrhosis are at increased risk of developing portal vein thrombosis, which in turn increases the risk of portal hypertension. 84 Ascites is another common, major complication of cirrhosis and can lead to patients requiring repeated therapeutic paracenteses or placement of a transjugular intrahepatic portosystemic shunt. 85 Spontaneous bacterial peritonitis is common in patients with end-stage liver disease and is associated with high mortality without early antibiotic treatment. 86 Complications of cirrhosis can also involve other organs. Progressive hepatic injury leading to reductions in renal perfusion can culminate in hepatorenal syndrome. Without an improvement in hepatic function or liver transplantation the prognosis of hepatorenal syndrome is poor. 87 Estimates of the prevalence of hepatopulmonary syndrome range from 4% to 47% in patients with cirrhosis, depending on the diagnostic criteria and methods used. There are no effective medical therapies for hepatopulmonary syndrome and it must be excluded in clinical trials if radioembolization is planned. 88 Other complications include cardiac dysfunction, which is observed in up to half of patients with advanced cirrhosis undergoing liver transplantation, 89 and hepatic encephalopathy. 90

| Clinical development in patients with moderate liver dysfunction
Complications of cirrhosis limit clinical development of treatments for HCC in patients with moderate liver dysfunction. Heterogeneity of the population and the shorter life expectancy and increased risk of sudden death events in those with CP B versus CP A limit the ability to assess efficacy in prospective clinical trials. Hepatic deterioration during treatment is also observed in patients with moderate liver dysfunction. This could be related to toxicity of treatment or progression of the tumor burden resulting in intrahepatic obstruction of the biliary tree and/or portal vein. 11,91,92 The unpredictable events associated with moderate liver dysfunction led to a different survival distribution among patients with CP B and those with CP A. In the GIDEON study, the survival distribution of treatment-naive patients with CP B treated with sorafenib could be modeled using an exponential distribution function (Figure 2). 46 Interventions involving a balanced approach to treatment of both cirrhosis and tumor burden would likely improve the long-term survival and QOL of patients with HCC and moderate liver dysfunction (Figure 3).

| Endpoints in clinical trials of HCC treatments in patients with moderate liver dysfunction
The optimal efficacy endpoint for clinical trials in patients with HCC and moderate liver dysfunction is a topic for consideration. OS is objective and clinically relevant and is the usual primary endpoint used in randomized Phase 3 clinical trials. OS is therefore the basis of most regulatory approval processes for drugs and other treatment interventions. However, OS is likely to be disproportionately affected by early death rates in patients with moderate liver dysfunction compared with those with normal liver function. 93 Early death (death occurring within 3 months from the date of diagnosis) has been observed in patients with HCC and severe cirrhosis. A recent study in the Surveillance, Epidemiology, and End Results database reported that 44.6% of patients with tumor, node, metastases (TNM) stage IVA and 62.8% of patients with TNM stage IVB HCC experienced early death. 94 Simulations of incremental treatment-related improvements in 3-month OS for patients with CP B predict meaningful improvements in long-term OS, suggesting that prevention of early death may represent an improved efficacy outcome (Figure 4). The main surrogate endpoints in oncology such as PFS, time to progression, and objective response rate could also be affected by early death in patients with CP B, although these endpoints seem to correlate with median OS similarly in those with CP B and those with CP A. 56,95 Apart from CP classification and comorbidities, other clinical characteristics and tumor-related variables may contribute to early death rates. 94 Detailed assessment of treatment-related toxicity is vital because safety is especially relevant for this population of patients with moderate liver dysfunction. HCC clinical trials require that patients are assessed for radiological response every 6-8 weeks. 93 Investigators should consider that a significant proportion of patients may die before radiological assessment, especially when toxic interventions are studied prospectively in patients with severe cirrhosis. Figure 5 shows that nearly half of the patients with CP B had died at 3-month follow-up in the GIDEON study.
These uncertainties in interpreting clinical trial results mean that it is difficult to evaluate whether patients with CP B are likely to achieve similar benefits from treatment as patients with CP A.

| Clinical trials including patients with moderate liver dysfunction
A few prospective systemic treatment clinical trials including patients with CP B are ongoing, two of which restrict eligibility to patients with CP B only. Cabozantinib is being tested in a Phase 1/2 study as a first-and secondline therapy in 32 patients (NCT04497038) and 20 patients (NCT04454762) with CP B7-8 and ECOG PS 0-1. The primary endpoint is maximum tolerated dose for a Phase 2 study and the secondary endpoints are PFS, OS, and median time to progression. Atezolizumab and bevacizumab are being tested in a Phase 2 study as first-line therapies in 50 patients with CP B7 and ECOG PS 0-1 (NCT04829383). The primary endpoint is frequency and severity of toxicities, and the secondary endpoints are overall response, disease control rate, duration of response, OS, and PFS. The other study lists CP B7 or CP A as inclusion criteria (NCT03439891).

| Impact of chronic liver disease on QOL
Ongoing symptoms, treatment-related issues such as AEs and disease progression, and other emotional, physical, and social factors such as anxiety, fatigue, and stigmatization, all negatively impact QOL in patients with chronic liver diseases. 96 The National Cancer Institute's Patient-Reported Outcomes version of the Common Terminology Criteria for AEs provides a standard method to assess symptomatic AEs from the perspective of the physician. 97 Systematic measurement of QOL using patient-reported outcomes is a standard method and enables comparison F I G U R E 5 (A) Relative and (B) absolute percentage of surviving patients by month of follow-up based on treatment-naive patients with CP B (n = 669, stratified by CP B7-9) treated with sorafenib in the GIDEON study. 46 CP, Child-Pugh. of outcomes between treatment arms (including placebo). The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire and the Functional Assessment of Cancer Therapy-Hepatobiliary questionnaire are two established methods used in HCC clinical trials. [98][99][100] These data can inform and support the development of new therapies in HCC. Patients experiencing maintained QOL scores should generally also have improvement in OS; 101,102 however, this correlation still needs to be shown in patients with CP B. Sequential measurement using QOL questionnaires can be a sensitive procedure to identify early benefits of a treatment intervention. Time to deterioration in QOL may correlate with median OS and long-term survival, and can be combined with other efficacy endpoints such as PFS and OS in patients with CP B.

| Future directions
Effective treatment of patients with advanced HCC and CP B is an important unmet need. New treatment strategies are promising based on demonstrated activity and tolerability in patients with advanced HCC, including IO agents alone, in combination with existing therapies, or in combination with new targeted agents such as MKIs. However, for patients with moderate liver dysfunction, avoiding further impairment of liver function and maintaining QOL are important considerations for the development of treatments for HCC. Treatments targeting multiple immune mechanisms appear to be especially promising in CP B, although a better understanding of the mechanisms of action at molecular and cellular levels is needed. Validated biomarkers could guide the development of IO agents in patients with HCC and CP B. The use of medical devices, such as tumor-treating fields, 103 as well as adoptive cell transfer, vaccination, and virotherapy represent possible new treatments to be studied in this patient population.

| Limitations of this review
This paper is not a systematic literature review and was not performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The quality of evidence in the included articles was not assessed. The main limitation of this review is that it may be subject to selection and confirmation bias. In addition, the review may have been limited by the availability and discovery of relevant data, as well as publication bias.

| CONCLUSIONS
There are insufficient data on the efficacy of treatments for advanced HCC in patients with moderate liver dysfunction (specifically CP B). This is a neglected subgroup of patients and given the high frequency of liver dysfunction in patients with HCC there is a significant need for research into the efficacy and safety of new and existing treatments in this population. Sorafenib is the only available therapy for HCC with reasonable efficacy and safety data collected in patients with moderate liver dysfunction. Studies comparing sorafenib and newer treatment alternatives have yielded similar results, but systemic treatment in patients with moderate liver dysfunction is associated with high toxicity and early death rates. New prospective clinical trials focused on the CP B population are urgently needed, with study designs that consider the impact of both liver disease and tumor burden. Understanding the risk characteristics of this patient population and what is considered a meaningful clinical outcome is fundamental in the design of new clinical trials.