FormalPara Key Summary Points

Systemic therapies have been associated with adverse events in patients with unresectable hepatocellular carcinoma (uHCC), including bleeding, clotting, encephalopathy, and portal hypertension.

This study evaluated the incidence of clinically significant events (CSEs) and their impact on healthcare resource utilization (HCRU) and costs, in patients with uHCC treated with first-line atezolizumab plus bevacizumab, lenvatinib, or sorafenib in the USA.

Our findings indicated that the most common CSEs were clotting and bleeding in the atezolizumab plus bevacizumab cohort, clotting and encephalopathy in the lenvatinib cohort, and encephalopathy and portal hypertension in the sorafenib cohort.

HCRU and costs were similar across study cohorts. In addition, patients with ≥ 1 CSE had a numerically higher economic burden in all study cohorts compared to patients with no CSEs.

The occurrence of CSEs with systemic therapy raises concerns for patient safety while increasing the economic burden on the US healthcare system.

Newer treatments that reduce the risk of CSEs, while improving long-term survival in patients with uHCC, are warranted.

Introduction

Liver cancer is one of the most common fatal malignancies and was the third leading cause of cancer-related deaths worldwide in 2020 [1]. Hepatocellular carcinoma (HCC) is the most common form of liver cancer, accounting for approximately 90% of all cases [2]. Most patients with HCC present with advanced-stage disease and have a poor prognosis [3]. By 2030, it is estimated that there will be 56,229 HCC cases per year in the USA, with an estimated 5-year relative survival rate of 21.6% in patients with liver or intrahepatic bile duct cancer [4, 5].

In the USA, National Comprehensive Cancer Network (NCCN) guidelines recommend systemic therapy for patients with HCC who are not eligible for transplant or locoregional therapies [6]. Preferred regimens include tremelimumab (anti-cytotoxic T-lymphocyte-associated antigen 4) plus durvalumab (anti-programmed cell death ligand-1 [PD-L1]; Single Tremelimumab Regular Interval Durvalumab [STRIDE]) for all eligible patients and, for patients with Child–Pugh class A, atezolizumab (anti-PD-L1) plus bevacizumab (anti-vascular endothelial growth factor) [6]. Other recommended regimens include lenvatinib (multi-tyrosine kinase inhibitor [TKI]) for patients with Child–Pugh class A, sorafenib (multi-TKI) for patients with Child–Pugh class A or B7, and durvalumab (anti-PD-L1) or pembrolizumab (anti-programmed cell death-1 [PD-1]) for all eligible patients [6].

A key challenge with systemic therapies, including anti-angiogenic agents, is that they are associated with clinically significant events (CSEs) [2, 7]. Previous phase 3 clinical trials of patients with advanced HCC treated with atezolizumab plus bevacizumab, lenvatinib, or sorafenib have reported high incidences of Grade ≥ 3 adverse events (AEs) (atezolizumab plus bevacizumab [69.9%], lenvatinib [57.5–75.0%], sorafenib [41.0–75.0%]) [8], including bleeding, clotting, and hepatic encephalopathy, which is a serious complication of portal hypertension secondary to cirrhosis [7, 9,10,11,12].

For patients with HCC, AEs may result in a negative impact on patients’ health-related quality of life (HRQoL) [13, 14]. Indeed, analyses of patient-reported outcomes from clinical trials have shown that patients with unresectable HCC (uHCC) may experience a deterioration in quality of life, including after treatment with systemic therapies [15]. In addition, treatment of uHCC is associated with a substantial burden of healthcare resource utilization (HCRU), with AEs incurring substantial costs due to inpatient care [14, 16].

An important goal for new treatments for uHCC is to manage symptoms and maintain or improve patients’ HRQoL [17]. However, there is a lack of quantitative information about the incidence, treatment, and economic consequences of CSEs in the recent clinical landscape. In this study, we aimed to evaluate the real-world incidence of CSEs and their impact on HCRU and healthcare costs in patients with uHCC treated with first-line atezolizumab plus bevacizumab, lenvatinib, or sorafenib in the USA.

Methods

Data Source

This was a retrospective observational cohort study of patients diagnosed with uHCC in the USA between January 01, 2007 and June 30, 2021 (study period). The study used the Optum® Clinformatics® Data Mart, a database that records insurance claims for 64.3 million patients with Commercial and Medicare policies in the USA [18].

This was a retrospective study using anonymous data; therefore, ethics committee approval was not required. However, the data were certified as de-identified by an independent statistical expert following the statistical de-identification rules of the Health Insurance Portability and Accountability Act (HIPAA) and managed according to customer data use agreements.

Study Population

Adult patients (aged ≥ 18 years at HCC diagnosis) were included if they had a confirmed diagnosis of HCC (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] 155.0 or 155.2; ICD-10-CM C22.0, C22.8, or C22.9) during the study period. Patients who initiated systemic therapy with atezolizumab plus bevacizumab between June 01, 2020 and December 31, 2020, or with lenvatinib or sorafenib between January 01, 2016 and May 31, 2020, were included in the study. Atezolizumab plus bevacizumab was approved for uHCC in May 2020 [19]; hence, utilization of lenvatinib and sorafenib was captured prior to the US Food and Drug Administration (FDA) approval to mitigate the risk of confounding by indication and to reduce the impact of potential outcomes bias. Patients were required to have continuous insurance coverage for the 6 months prior to the index date (baseline period). The index date was the date of the first treatment with systemic therapy following HCC diagnosis. Additional study criteria are shown in Fig. 1. Patients were stratified into three cohorts based on index treatment: atezolizumab plus bevacizumab, lenvatinib, or sorafenib, and were followed from the index date until treatment discontinuation (defined as the earliest of starting second-line treatment or the 42nd consecutive day with no treatment claim), end of continuous insurance coverage, death, or end of study period (follow-up period).

Fig. 1
figure 1

Selection of study population. HCC hepatocellular carcinoma, ICD-9-CM International Classification of Diseases, Ninth Revision, Clinical Modification, ICD-10-CM International Classification of Diseases, Tenth Revision, Clinical Modification

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Study Variables

Patient demographics, including age, sex, race, region, insurance type, and calendar year of diagnosis were assessed on the index date. Time from diagnosis to treatment initiation, esophagogastroduodenoscopy (EGD) procedure, Child–Pugh classification, albumin-bilirubin (ALBI) grade, and risk factors for uHCC, were evaluated during the baseline period. Child–Pugh classification was determined using an algorithm incorporating laboratory measurements (albumin, bilirubin, International Normalized Ratio) and assessments of disease severity from ICD-9-CM/ICD-10-CM, National Drug Code, and Healthcare Common Procedure Coding System codes (ascites and encephalopathy). ALBI grade was calculated using the following formula: (log10 bilirubin [µmol/L] × 0.66) + (albumin [g/L] × −0.0852). Risk factors for uHCC were identified using ICD-9-CM/ICD-10-CM codes and included cirrhosis, metabolic disorders (hemochromatosis, alpha-1-antitrypsin deficiency, tyrosinemia, porphyria, metabolic syndrome, pre-diabetes, hyperglycemia, diabetes), viral hepatitis (hepatitis B or hepatitis C), alcoholic liver disease, obesity, non-alcoholic fatty liver disease, and toxic liver disease.

Treatment patterns, including duration of treatment and type of second- or third-line treatment received, were assessed during the follow-up period. Duration of treatment was estimated from the index date until the date of treatment discontinuation or death due to any cause, whichever occurred first.

CSEs, including bleeding (varices with bleeding, gastrointestinal [GI] ulcers with bleeding, other GI bleeding, intracranial bleeding, other diagnosed bleeding, and other bleeding symptoms, e.g., epistaxis or hemoptysis), clotting (embolism, thromboembolism, pulmonary embolism, portal clotting, and intestinal clotting), encephalopathy (hepatic and from other disorders of the brain), and portal hypertension, were evaluated over the follow-up period.

All-cause HCRU and healthcare costs, including outpatient medical visits, emergency department medical visits, inpatient medical visits, other medical services, and pharmacy claims, were assessed during the follow-up period. The medical care component of the Consumer Price Index was used to adjust the cost to 2020 US dollars.

Statistical Analyses

Patient demographics and clinical characteristics, treatment patterns, CSEs, HCRU, and healthcare costs, were assessed using descriptive statistics. Continuous variables were summarized by the number of observations, mean, standard deviation (SD), median, and interquartile range (IQR). Categorical variables were summarized by frequency counts and percentages for each category. Incidence rates of CSEs were reported as the number of events per 100 patient-years (PY) of treatment. Calculation of PY of follow-up for each category was truncated at the date of incidence event for patients who experienced a CSE. HCRU and healthcare costs were summarized per patient per month (PPPM). Statistical analyses were performed using R version 4.1.

Subgroup Analysis

To evaluate the impact of CSEs on HCRU and healthcare costs, a subgroup analysis was performed to stratify the results by patients who had ≥ 1 CSE during the follow-up period versus those who did not.

Results

Patient Demographics and Clinical Characteristics

A total of 1379 patients diagnosed with HCC met the study selection criteria, including 271 (19.7%) patients in the atezolizumab plus bevacizumab cohort, 217 (15.7%) patients in the lenvatinib cohort, and 891 (64.6%) patients in the sorafenib cohort. Demographics and clinical characteristics of patients with HCC treated with first-line systemic therapy are shown in Table 1.

Table 1 Patient demographics and clinical characteristics
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The mean (SD) age at index date was 69.9 (8.1) years in the atezolizumab plus bevacizumab cohort, 68.5 (9.6) years in the lenvatinib cohort, and 68.0 (9.1) years in the sorafenib cohort (Table 1). In the atezolizumab plus bevacizumab, lenvatinib, and sorafenib cohorts, most patients were male (83.8%, 75.1%, and 74.0%, respectively), white (57.2%, 59.9%, and 49.0%, respectively), from the Southern region of the USA (52.4%, 50.7%, and 56.9%, respectively), and had Medicare insurance (86.7%, 67.7%, and 71.9%, respectively) (Table 1). In total, 32.5% of patients in the atezolizumab plus bevacizumab cohort, 23.5% of patients in the lenvatinib cohort, and 24.7% of patients in the sorafenib cohort had undergone EGD during the baseline period (Table 1).

During the baseline period, the most common risk factor for uHCC in the atezolizumab plus bevacizumab, lenvatinib, and sorafenib cohorts was cirrhosis (61.6%, 65.0%, and 68.0%, respectively) (Table 1). Other common risk factors (> 30% patients) for uHCC in the atezolizumab plus bevacizumab, lenvatinib, and sorafenib cohorts were metabolic disorders (48.3%, 46.5%, and 49.0%, respectively) and viral hepatitis (30.6%, 36.9%, and 43.9%, respectively) (Table 1).

Treatment Patterns

The median (95% CI) duration of treatment was 5.0 (4.3–6.5) months in the atezolizumab plus bevacizumab cohort, 3.6 (3.0–4.4) months in the lenvatinib cohort, and 3.4 (3.1–3.7) months in the sorafenib cohort (Table 2). In total, 44.3% of patients in the atezolizumab plus bevacizumab cohort, 32.9% of patients in the lenvatinib cohort, and 28.6% of patients in the sorafenib cohort, remained on treatment after 6 months of follow-up (Table 2). After 12 months of follow-up, 28.5%, 15.1%, and 13.4% of patients remained on treatment in the atezolizumab plus bevacizumab, lenvatinib, and sorafenib cohorts, respectively (Table 2).

Table 2 Treatment patterns
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In the atezolizumab plus bevacizumab cohort, 11.8% of patients received second-line treatment; the most common second-line treatment was lenvatinib (46.9%) (Table 2). In the lenvatinib and sorafenib cohorts, 31.8% and 27.2% of patients received second-line treatment, respectively; nivolumab was the most common second-line treatment received (44.9% and 63.2%, respectively) (Table 2).

Third-line treatment was received in 3.0% of patients in the atezolizumab plus bevacizumab cohort, 11.1% of patients in the lenvatinib cohort, and 7.5% of patients in the sorafenib cohort (Table 2).

Incidence Rates of CSEs

In total, 147 (54.2%) patients in the atezolizumab plus bevacizumab cohort, 121 (55.8%) patients in the lenvatinib cohort, and 481 (54.0%) patients in the sorafenib cohort experienced CSEs. The incidence rate (95% CI) of clotting and bleeding per 100 PY was 94.9 (74.1–119.7) and 88.1 (68.3–111.9), respectively, in the atezolizumab plus bevacizumab cohort, 78.6 (60.4–100.6) and 57.5 (42.5–76.0), respectively, in the lenvatinib cohort, and 68.3 (59.7–77.7) and 53.3 (45.8–61.6), respectively, in the sorafenib cohort (Table 3). The incidence rate (95% CI) of encephalopathy and portal hypertension per 100 PY was 66.6 (50.0–86.9) and 85.7 (66.0–109.4), respectively, in the atezolizumab plus bevacizumab cohort, 66.3 (50.4–85.5) and 63.5 (47.0–84.0), respectively, in the lenvatinib cohort, and 73.0 (64.0–82.9) and 72.3 (63.1–82.4), respectively, in the sorafenib cohort (Table 3).

Table 3 Incidence rates of CSEs
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Economic Outcomes

HCRU was high across study cohorts for pharmacy claims and outpatient medical visits. The mean (SD) number of pharmacy claims and outpatient medical visits PPPM was 4.0 (2.7) and 3.9 (2.0), respectively, in the atezolizumab plus bevacizumab cohort, 5.2 (3.6) and 3.1 (2.2), respectively, in the lenvatinib cohort, and 5.4 (3.5) and 2.9 (2.1), respectively, in the sorafenib cohort.

Mean (SD) costs PPPM for inpatient medical visits and emergency department medical visits were $6922 ($14,463) and $963 ($3215), respectively, in the atezolizumab plus bevacizumab cohort, $9883 ($22,325) and $1499 ($8885), respectively, in the lenvatinib cohort, and $8233 ($17,839) and $1079 ($3180), respectively, in the sorafenib cohort (Fig. 2). Mean (SD) total all-cause healthcare costs PPPM were $32,742 ($23,501) in the atezolizumab plus bevacizumab cohort, $35,623 ($36,533) in the lenvatinib cohort, and $29,173 ($29,335) in the sorafenib cohort (Fig. 2).

Fig. 2
figure 2

HCRU costs PPPM. Error bars represent the standard deviation. HCRU healthcare resource utilization, PPPM per patient per month

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Subgroup Analysis

Patient demographics were generally similar across study cohorts in patients who had ≥ 1 CSE during the follow-up period versus those who did not (Table S1). Across study cohorts, mean (SD) total all-cause healthcare costs PPPM were higher in patients who had ≥ 1 CSE versus those who did not (atezolizumab plus bevacizumab, $34,304 [$20,570] versus $30,889 [$26,361]; lenvatinib, $39,591 [$38,473] versus $30,621 [$33,459]; sorafenib, $31,022 [$25,161] versus $27,003 [$33,479]). Mean (SD) costs PPPM for inpatient medical visits, emergency department medical visits, and other medical services were all higher across study cohorts in patients who had ≥ 1 CSE versus those who did not (Fig. 3).

Fig. 3
figure 3

HCRU costs PPPM in patients with no CSEs or ≥ 1 CSE. Error bars represent the standard deviation. CSE clinically significant event, HCRU healthcare resource utilization, PPPM per patient per month

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Discussion

This retrospective study evaluated the incidence of CSEs, including bleeding, clotting, encephalopathy, and portal hypertension, and their impact on HCRU and costs in patients with uHCC who initiated atezolizumab plus bevacizumab, lenvatinib, or sorafenib in the first-line setting in the USA. Our findings indicated that the most common CSEs in the atezolizumab plus bevacizumab cohort were clotting and bleeding, whereas clotting and encephalopathy were the most common CSEs in the lenvatinib cohort, and encephalopathy and portal hypertension were the most common CSEs in the sorafenib cohort. In addition, patients with ≥ 1 CSE had a numerically higher economic burden in all study cohorts compared with patients with no CSEs.

Our finding that CSEs occurred in patients treated with atezolizumab plus bevacizumab, lenvatinib, or sorafenib aligns with results reported in phase 3 clinical trials [7, 9, 10]. For example, in IMbrave150 (NCT03434379), 25.2% of patients treated with atezolizumab plus bevacizumab and 17.3% of patients treated with sorafenib experienced bleeding/hemorrhage, with clotting (thromboembolic events; 5.7% and 4.5%, respectively), and hepatic encephalopathy (1.5% and 1.9%, respectively) also observed [7]. In the REFLECT trial (NCT01761266), hemorrhagic events occurred in 23% of patients treated with lenvatinib and 15% of patients treated with sorafenib, and hepatic encephalopathy was reported in 8% of patients and 3% of patients, respectively [20]. Although similar to rates observed in the placebo group, CSEs were also reported among sorafenib-treated patients in the phase 3 SHARP trial (NCT00105443), including hemorrhage/bleeding in 18.0% of patients and liver dysfunction in 11.0% of patients [9, 21]. The incidence rate for bleeding events in this study was numerically higher for patients treated with atezolizumab plus bevacizumab (88.1 events per 100 PY) compared with sorafenib (53.3 events per 100 PY). These findings are generally consistent with results from the IMbrave150 clinical trial [7].

NCCN guidelines recommend that patients treated with atezolizumab plus bevacizumab undergo adequate endoscopic evaluation and management for esophageal varices in the 6 months prior to treatment, or according to institutional practice, and based on the assessment of bleeding risk [6]. In this study, only 32.5% of patients treated with atezolizumab plus bevacizumab had an EGD procedure reported pre-index, indicating that either treatment guidelines were not followed, that most patients were not determined to have a bleeding risk, or that this information was not recorded in the database, possibly as a result of lack of access/availability of EGD centers within the community setting.

The median duration of treatment with atezolizumab plus bevacizumab (5.0 months), lenvatinib (3.6 months), and sorafenib (3.4 months) in the current study was lower than that reported for the respective agents in pivotal phase 3 trials (7.4 months in IMbrave150, 5.7 months in REFLECT, and 5.3 months in SHARP) [7, 9, 10]. After 12 months of follow-up, more patients treated with atezolizumab plus bevacizumab (28.5%) remained on treatment in this study, compared with lenvatinib (15.1%) or sorafenib (13.4%). Lenvatinib was the most common second-line treatment received in patients treated with atezolizumab plus bevacizumab in this study, and nivolumab was the most common second-line treatment received in patients treated with lenvatinib or sorafenib. The high number of patients receiving treatment with second-line nivolumab may reflect the US FDA approval of nivolumab in 2017 for patients with HCC who had previously been treated with sorafenib [22].

Few studies have evaluated the impact of CSEs on economic burden in patients with uHCC treated with first-line systemic therapy. A previous retrospective cohort study assessed the economic burden of patients with advanced HCC treated with first-line sorafenib in the USA [23]. The mean total healthcare costs PPPM in patients treated with first-line sorafenib in this study ($18,559) appear lower than those reported with first-line sorafenib in our study ($29,173), although differences in study design, as well as patient demographics and clinical characteristics, were seen [23]. Healthcare costs in patients with advanced/metastatic HCC treated with first-line TKIs, including lenvatinib, sorafenib, and regorafenib, have also been reported in a retrospective observational claims study in the USA [16]. The mean total healthcare costs for patients treated with first-line TKIs ($19,823) were also lower than those reported for treatment with first-line lenvatinib ($35,623) or sorafenib ($29,173) in our study [16]. Several factors may have contributed to the higher healthcare costs observed in our study, such as the inclusion of “outpatient costs” and “other medical costs,” as well as higher pharmacy costs [16].

Findings from the subgroup analysis of this study showed that patients with ≥ 1 CSE had higher healthcare costs compared with patients with no CSEs. High costs in patients with ≥ 1 CSE were driven mainly by pharmacy claims and inpatient medical visits. These results are consistent with a previous retrospective observational claims study in patients treated with first-line TKIs in the USA that showed 90% of total AE-related healthcare costs PPPM were attributable to inpatient care [16]. The occurrence of AEs, including CSEs, following treatment with systemic therapy, has been associated with a decrease in HRQoL in patients with HCC [24]. Given the high cost of CSEs and their potential impact on patients’ HRQoL, patients with uHCC who are treated with systemic therapy should be frequently evaluated for CSEs to enable early detection [25]. This will enable more effective multidisciplinary management in order to improve patient outcomes and reduce the need for costly pharmacy services and inpatient stays [25]. A previous study demonstrated that experience in the management of sorafenib-related AEs can prolong survival and treatment duration in patients with HCC, highlighting the importance of effective AE management in this setting [26]. Ultimately, healthcare providers should work towards reducing the occurrence of CSEs and the risk of complications following systemic treatment by educating patients, providing preventative measures, and identifying and treating CSEs as early as possible.

Recent evidence supports that combination treatment with immune checkpoint inhibitors (ICIs) may be able to improve outcomes when compared with monotherapy in patients with HCC [27]. While findings from IMbrave150 support this concept, the findings from our study indicate that despite improved efficacy, safety and occurrence of CSEs associated with this regimen still remain a concern [7]. In addition, long-term efficacy and safety data for atezolizumab plus bevacizumab are not available as a result of atezolizumab plus bevacizumab not demonstrating an overall survival (OS) benefit beyond 19.2 months [11]. These findings suggest that the toxicity profile of atezolizumab plus bevacizumab could be a reason for limited benefit.

The treatment landscape for uHCC has recently evolved with the approval of two ICIs for first-line combination therapy: tremelimumab (anti-cytotoxic T-lymphocyte-associated antigen 4) and durvalumab (anti-PD-L1), also known as the STRIDE regimen [28, 29]. While the STRIDE regimen was not included in this analysis, due to it not being approved within the window of the study, recent findings from an exploratory analysis of the phase 3 HIMALAYA trial (NCT03298451) reported unprecedented OS rates for STRIDE (25.2%) compared with sorafenib (15.1%) after 4 years of follow-up [30]. This analysis continued to demonstrate that STRIDE was generally well tolerated, with no new serious safety events from the primary analysis [30]. Additional studies are warranted to evaluate the real-world incidence of CSEs and their impact on HCRU and healthcare costs in patients with uHCC treated with first-line STRIDE in the USA.

Limitations

Our study has several limitations. Firstly, the claims data used in this analysis were for reimbursement purposes only and were not designed for research. As a result, several outputs were not able to be analyzed, including disease severity, disease progression, grade/severity of CSEs, Barcelona Clinic Liver Cancer stage, and histology. An additional limitation of this study is that we were unable to identify whether EGD procedures were performed in an academic versus community setting. Additionally, determination of Child–Pugh classification and ALBI grade based on laboratory measurements was not possible for all patients due to missing values. In cases where they were provided, access to the patients’ medical charts was not available, so confirmation of their true Child–Pugh classification or ALBI grade was not possible. Another limitation is that patients with HCC were identified using ICD-9-CM/ICD-10-CM diagnosis codes for HCC; however, the presence of a diagnosis does not necessarily indicate the presence of disease. The analysis may also have been limited by the small number of patients who received atezolizumab plus bevacizumab compared with sorafenib/lenvatinib as a result of differences in the length of time that these agents have been approved for uHCC within the USA and by the different time periods used to select patients who initiated treatment with atezolizumab plus bevacizumab or sorafenib/lenvatinib. In addition, this analysis only included certain CSEs of interest (bleeding, clotting, encephalopathy, and portal hypertension). The evaluation of additional CSEs, including those that may be related to baseline liver function (e.g., cardiac toxicity or thyroid disorders), remains to be determined. Finally, patients included in this analysis were selected from a managed care population, using a convenience sample meeting eligibility criteria; therefore, study results may not be generalizable to other groups, such as patients with Medicare Fee-for-Service or Medicaid insurance plans or those who are uninsured.

Conclusions

High levels of CSEs were observed in patients with uHCC who received first-line treatment with atezolizumab plus bevacizumab, lenvatinib, or sorafenib in the USA, highlighting important safety concerns, regardless of treatment modality (immunotherapy combination or TKIs). Moreover, in addition to issues of patient safety, the occurrence of CSEs was associated with higher healthcare costs, indicating an increased economic burden to the healthcare system. Patients with uHCC who are treated with systemic therapy should be frequently evaluated for CSEs to enable their early detection and provide the opportunity for more effective multidisciplinary management. Newer treatment options that prolong survival while reducing CSEs are warranted in order to improve patient outcomes in the USA.