Management of Advanced Hepatocellular Carcinoma: A Review and Practical Guide

Abstract

Global incidence of hepatocellular carcinoma (HCC) is rising along with its mortality burden, and more than half of patients require systemic therapy for advanced disease. There is an ongoing epidemiological shift in risk factors for HCC from hepatotropic virus-related liver disease to alcohol and metabolic dysfunction-associated steatotic liver disease. While a diagnosis of HCC can be made with non-invasive radiological criteria, tissue biopsy is gaining a role, at least within the realm of clinical trials. Despite advances in targeted therapies, the role of molecular testing in HCC remains unclear. Liver function continues to play a vital role in the management of HCC across all stages. With the approval of immune checkpoint inhibitors and tyrosine kinase inhibitors targeting tumor angiogenesis, the treatment landscape of advanced HCC has evolved considerably in the last decade, leading to improvements in patient outcomes. However, optimal sequencing of these agents is not well defined. There are several ongoing trials evaluating systemic therapies with novel mechanisms of action including adoptive cell therapy. This review aims to provide practicing oncologists with a comprehensive overview of recent developments in systemic therapy for the management of advanced HCC.

Introduction

Hepatocellular carcinoma (HCC) constitutes approximately 80% of primary liver malignancies, posing a global health challenge requiring complex, individualized treatment decisions. Staging and treatment of HCC is often complicated by underlying liver dysfunction, necessitating therapeutic algorithms that incorporate the degree of liver dysfunction as well as patient performance status^{1 3}. Treatment modalities for HCC include multiple curative options, such as liver transplantation, surgical resection, and ablation for earlier stage disease, and palliative modalities such as transarterial embolization approaches, external beam radiation therapy, and systemic therapy for more advanced stages. Significant advances have occurred in the field of HCC in recent years, with particularly pivotal breakthroughs in systemic therapy regimens over the last five years⁴. In recent years, the American Society of Clinical Oncology (ASCO) and American Association for the Study of Liver Diseases (AASLD) have issued detailed guidelines on the management of HCC^{5 7}. This article synthesizes these recent updates to provide practical guidance on the diagnosis, staging, and management of patients with advanced HCC, with a focus on systemic therapy.

Screening and diagnosis

Primary liver cancer, which includes HCC (75–85%), cholangiocarcinoma (10–15%) and other rare tumor types, ranks sixth in global cancer incidence and is the third leading cause of cancer related mortality worldwide². Numerous risk factors are associated with HCC, and a common underlying characteristic often involves an initial insult that results in liver cirrhosis. Frequently associated risk factors include chronic infection with hepatitis B and C (HBV/HCV), environmental factors such as aflatoxin B1, and lifestyle factors such as alcohol and other substance use. Metabolic dysfunction-associated steatohepatitis (MASH) cirrhosis is an emerging risk-factor, particularly in Western countries with a high incidence of metabolic syndrome¹.

Because about 90% of HCC occurs in patients with cirrhosis, screening programs have been developed with the goal of diagnosing HCC at an early stage and hence reducing disease-specific mortality^5,8. Notably, the National Comprehensive Cancer Network (NCCN) and the American Association for the Study of Liver Diseases (AASLD) recommend biannual abdominal ultrasound with alpha-fetoprotein (AFP) screening in patients with cirrhosis and chronic HBV ⁵. However, early diagnosis of HCC is challenging because of low HCC screening rates and diagnostic delays in patients with abnormal screening tests^{8 10}. Additionally, 40% of patients with HCC can have normal AFP values, which may lead to sub-optimal sensitivity in using this marker as a screening tool for HCC; hence, the AASLD guidelines have since removed AFP from its diagnostic criteria⁵.

Non-invasive imaging has traditionally played an important role in the diagnosis of HCC, in contrast to other solid tumors for which biopsies are required for pathological diagnosis. Characteristic enhancement patterns on dynamic multiphasic CT or MRI can detect HCC with a high degree of sensitivity and specificity when stringent criteria are applied. Non-invasive radiological criteria (NIRC) as defined by the European Association for the Study of the Liver (EASL) state that a diagnosis of HCC can be made if a nodule greater than 1 cm demonstrates both arterial phase hyperenhancement as well as washout on portal venous and/or delayed phases in a patient with cirrhosis¹¹. In addition, the Liver Imaging Reporting and Data System (LI-RADS) is a comprehensive system now endorsed by the AASLD, which provides standardization across all aspects of HCC imaging and provides imaging algorithms for different clinical contexts¹¹. Diagnosing HCC based on LI-RADS criteria has been validated in patients with cirrhosis, noncirrhotic HBV infection at intermediate or high risk of HCC, and a history of prior HCC¹².

The inclination towards non-invasive diagnosis has largely been due to the risk of tumor bleeding, inability to access certain lesions safely, and theoretical possibility of neoplastic seeding of the biopsy tract. Currently, a biopsy for diagnosis is not mandatory if a suspicious liver lesion meets NIRC or LI-RADS criteria in a high-risk patient with a history of cirrhosis, chronic HBV, or known HCC. However, for uncertain lesions and in patients without underlying liver disease who have a low-pretest probability of HCC, all guidelines are concordant in their recommendations for a histological diagnosis^5,7. Even in patients with cirrhosis, about 10% of patients can have missed or incorrect diagnoses, resulting in inappropriate treatment if imaging criteria alone are used for diagnosis^13,14. Hence, clinicians should consider obtaining a confirmatory tissue diagnosis in the appropriate clinical setting. The role of 18F-FDG PET/CT (fluorodeoxyglucose F18 positron emission tomography) in HCC diagnosis is limited because 50% of HCC lesions (especially well-differentiated HCC) are not FDG-avid¹⁵. Best practice guidelines do not currently recommend the routine use of tissue or blood-based molecular testing in HCC outside of clinical trials^5,7. Even with the increasing use of immunotherapy in the management of HCC, programmed cell death protein 1 (PD-1)/ programmed cell death ligand 1 (PD-L1) testing remains of limited utility given that PD-1/PD-L1 expression has not been consistently shown to correlate with clinical outcomes¹⁶.

Staging

Prior to starting systemic therapy, cross-sectional imaging of the chest, abdomen, and pelvis should be obtained to assess disease burden and to serve as a baseline to monitor future response to therapy. Multiple staging systems and prognostic scoring models exist for HCC, none of which have been universally adopted. Among these, the Barcelona Clinic Liver Cancer (BCLC) staging classification represents the most widely adopted for treatment planning and prognostic assessment^3,17. The BCLC classification defines five prognostic subgroups based on the extent of the primary lesion, performance status, and severity of underlying liver disease as assessed by the Child-Pugh score (CPS, Table 1). It emphasizes the importance of personalizing HCC treatment decisions based on an expert multidisciplinary evaluation that consider factors such as patient comorbidities, baseline and projected post-treatment liver function, and the availability of local expertise. The BCLC 2022 update includes the use of the albumin-bilirubin (ALBI) grade and AFP to help stratify patients’ prognosis based on liver function and tumor burden, respectively. Also, in this update, patients with BCLC-B HCC are stratified into three groups: (1) patients with well-defined HCC nodules who may be candidates for liver transplantation (LT) based on extended institutional criteria; (2) LT-ineligible patients who may still qualify for locoregional therapies (LRT) based on preserved portal flow and defined tumor burden; and (3) patients with diffuse, infiltrative, extensive HCC who are best served with systemic therapy. In this paper, we refer to patients with BCLC stage B or C HCC that is not amenable to LT or LRT as non-LRT-eligible HCC. This BCLC system also defines two concepts that are relevant to the management of patients with non-LRT-eligible HCC: (1) treatment stage migration (TSM) and (2) untreatable progression. In clinical practice, first-line treatment options may be limited by individual clinical Factors, necessitating “migration” to the next suitable option. For example, a patient with BCLC stage B disease for whom LRT is not an ideal option may be best treated with systemic therapy. Untreatable progression refers to failure of the initial selected treatment approach, warranting utilization of treatment options that may correspond to more advanced stages. For example, a patient with BCLC stage B disease for whom upfront LRT does not achieve an adequate response may necessitate the use of systemic therapy. Finally, the BCLC 2022 update classifies patients who have radiological progression based on whether they have developed new or enlarging lesions intra-hepatically (termed “BCLCP-B” or “BCLCp-C1” as per their baseline stage) versus new vascular invasion or extra-hepatic disease (termed “BCLCp-C2”).

Table 1:

Child-Pugh classification to assess severity of liver disease⁶⁷

Parameter	Points assigned
	1	2	3
Ascites	Absent	Slight	Moderate
Bilirubin	<2 mg/dL	2 to 3 mg/dL	>3 mg/dL
Albumin	>3.5 g/dL	2.8 to 3.5 g/dL	<2.8 g/dL
Prothrombin time
Seconds over control	<4 s	4–6 s	>6 s
International Normalized Ratio (INR)	<1.7	1.7–2.3	>2.3
Encephalopathy	None	Mild to moderate (Grade 1 or 2)	Severe (Grade 3 or 4)
Child-Pugh Class A: 5 to 6 (2-yr survival rate: 85–100%)
Child-Pugh Class B: 7 to 9 (2-yr survival rate 60–80%)
Child-Pugh Class C: 10 to 15 (2-yr survival rate 35–45%)

Systemic therapy for HCC: General treatment approach

Patients with non-LRT-eligible HCC with adequate performance status and liver function are ideal candidates for systemic therapy, as prognosis in the absence of cancer-directed therapy ranges between three and ten months¹⁸. Supportive care alone is recommended for patients with non-LRT-eligible HCC and CPS-C cirrhosis or poor performance status. Occasionally, patients may have CPS-B/C disease due to acute decompensation of their cirrhosis; these patients may become eligible for systemic therapies pending improvement in their hepatic function over time¹⁹. Until 2017, sorafenib was the only FDA-approved drug for patients with non-LRT-eligible HCC. Since then, the advent of newer multikinase inhibitors, immune checkpoint inhibitors (ICIs), and anti-angiogenic agents have led to several FDA-approved single-agent and combination regimens (Table 2)⁴. Several factors should be considered when selecting the most appropriate treatment for patients with non-LRT-eligible HCC: baseline comorbidities including liver function, risk of variceal bleeding, and contraindications to ICI.

Table 2:

Pivotal phase III trials evaluating systemic therapies in HCC that led to FDA approval

	SHARP	REFLECT	IMbrave150	HIMALAYA	RESOURCE	CELESTIAL	REACH-2
FDA approval	November 2007	August 2018	May 2020	October 2022	April 2017	January 2019	May 2019
Line of therapy	First	First	First	First	Second	Second/third	Second
Key Inclusion and Exclusion criteria	Included: Advanced HCC, CPS-A	Included: Advanced HCC, CPS-A. Excluded: 50% or higher liver involvement by tumor, obvious invasion of bile duct, main portal vein invasion	Included: Advanced HCC, CPS-A Excluded: Autoimmune disease, coinfection with HBV or HCV, untreated or incompletely treated esophageal or gastric varices	Included: Advanced HCC, CPS-A. Excluded: Clinically meaningful ascites, main portal vein thrombosis, or coinfection with HBV or HCV, history of autoimmune disease	Included: Advanced HCC progressed on Sorafenib only, CPS-A	Included: Advanced HCC progressed on Sorafenib, upto two prior systemic therapies for HCC, CPS-A.	Included: Advanced HCC progressed on or intolerant to Sorafenib, CPS-A, AFP > 400 ng/dL.
Experimental and control arms (No. of patients)	Sorafenib (299) vs Placebo (302)	Lenvatinib (478) vs Sorafenib (476)	Atezolizumab/Bevacizumab (336) vs Sorafenib (165)	STRIDE (393), Durvalumab (389) vs Sorafenib (389)	Regorafenib (379) vs Placebo (194)	Cabozantinib (470) vs Placebo (237)	Ramucirumab (197) vs Placebo (95)
Study design	Randomized, double-blind, placebo controlled, phase III	Randomized, open-label, non-inferiority, phase III	Randomized (2:1), open-label, superiority, phase III	Randomized, open-label, sponsor-blind, superiority (STRIDE vs Sorafenib), phase III	Randomized (2:1), double-blind, placebo-controlled, phase III	Randomized (2:1), double-blind, placebo-controlled, phase III	Randomized (2:1), double-blind, placebo-controlled, phase III
Etiologic factors between experimental and control group-no. (%)	HBV: 56 (19) vs 55(18) HCV: 87 (29) vs 82 (27) Alc: 79 (26) vs 80 (26) Other: 77 (25) vs 85 (29)	HBV: 251 (53) vs 228 (48) HCV: 91 (19) vs 126 (26) Alc: 36 (8) vs 21 (4) Other: 100 (21) vs 105 (21)	HBV: 164 (49) vs 76 (46) HCV: 72 (21) vs 36 (22) Other: 100 (30) vs 53 (32)	HBV: 122 (31), 119 vs 119 HCV: 110 (28), 107 (27.5) vs 104 Other: 161 (41), 163 (41.9) vs 166 (42.7)	HBV: 143 (38) vs 73 (38) HCV: 78 (21) vs 41 (21) Alc: 90 (24) vs 55 (28) Other: 119 (31) vs 55 (28)	HBV: 178 (38) vs 89 (38) HCV: 113 (24)vs 55 (23) Alc: 112 (24) vs 39(16) Other: 150 (32) vs 90 (39)	HBV: 71 (36) vs 36 (38) HCV: 48 (24) vs 28 (29) Alc: 48 (24) vs 21 (22) Other: 48 (25) vs 90 (39)
Median overal survival (months)	10.7 vs 7.9	13.6 vs 12.3	19.2 vs 13.4	STRIDE: 16.4 Durvalumab: 16.6 vs Sorafenib: 13.8	10.6 vs 7.8	10.2 vs 8	8.5 vs 7.3
Median progression-free survival (months)	5.5 vs 2.8	7.3 vs 3.6	6.9 vs 4.3	STRIDE: 3.8 Durvalumab: 3.7 vs Sorafenib: 4.1	3.1 vs 1.5	5.2 vs 1.9	2.8 vs 1.6
Objective response rate (%)	2 vs 1	41 vs 12	30 vs 11	STRIDE: 20 Durvalumab: 17 vs Sorafenib: 5	7 vs 3	4 vs <1	5 vs 1
Complete response rate (%)	0 vs 0	<1 vs <1	8 vs <1	STRIDE: 3 Durvalumab: 2 vs Sorafenib: 0	11 vs 4	0 vs 0	0 vs 0
Disease control rate (%)	43 vs 32	73 vs 59	74 vs 55	STRIDE: 60 Durvalumab: 55 vs Sorafenib: 61	1 vs 0	64 vs 33	60 vs 39
Most common grade ≥3 TRAEs	Diarrhea: 8% vs 2% Hand-foot skin reaction : 8% vs <1%	Hypertension: 23% vs 14% Bilirubin increase: 7% vs 5% Decreased weight: 8% vs 3%	Hypertension: 12% vs 9% AST increase: 5% vs 3% Proteinuria: 4% vs <1%	AST/ALT increase : 7.8%, 9.8% vs 5.1% Diarrhea: 4.4%, 1.5% vs 4.3%	Hand-foot skin reaction: 13% vs 1% Hypertension: 13% vs 3% Fatigue: 6% vs 2%	Palmar-plantar erythrodysesthesia: 17% vs 0% Hypertension: 16% vs 2% Fatigue: 10% vs 4% Diarrhea: 10% vs 2%	Hypertension: 8% vs 2%
Patient reported outcome data (measure)	Median time to symptomatic progression: 4.1 vs 4.9 months (FHSI8)	Fatigue, pain, diarrhea, diet, and body image better (EORTC QLQ-C30 and HCC18)	Appetite, diarrhea, fatigue, and pain better (EORTC QLQ-C30 and HCC18)	Appetite, diarrheat fatigue, pain better (EORTC QLQ-C30 and HCC18)	No difference in HRQoL (FACT-Hep, EQ-5D, EQ-VAS)	HRQoL and QALY better (EQ-5D-5L)	Median time to symptomatic progression: 3.3 vs 1.9 months (FHSI8); No difference in HRQoL (EQ-5D-5L)

FDA, Food and Drug Administration; HCC, hepatocellular carcinoma; CPS, Child-Pugh score; HBV, hepatitis B; HCV, hepatitis C; Alc, alcohol; AFP, alpha-fetoprotein; TRAE, treatment related adverse event; EORTC QLQ-C30, European organization for research and treatment of cancer quality of life questionnaire; HCC18, European organization for research and treatment of cancer quality of life questionnaire hepatocellular carcinoma 18-question module; FHSI8, Functional Assessment of Cancer Therapy–Hepatobiliary Symptom Index 8; HRQoL, health-related quality of life; FACT-Hep, Functional Assessment of Cancer Therapy – Hepatobiliary; EQ-5D, EuroQoL 5 Dimension; EQ-VAS, EuroQoL visual analog scale; QALY, quality-adjusted life year; EQ-5D-5L, EuroQoL 5 Dimension 5 Level.

First-line systemic therapy

Sorafenib, an oral multikinase inhibitor, was approved by the FDA in 2007 as the first systemic therapy for patients with previously untreated non-LRT-eligible HCC. In the SHARP trial, patients in the sorafenib arm had a median overall survival (OS) of 10.7 months versus 7.9 months among patients in the placebo arm²⁰. Lenvatinib, another oral multikinase inhibitor, was shown to be non-inferior to sorafenib in the REFLECT study, leading to FDA approval in 2018²¹. Lenvatinib or sorafenib continue to be the first-line drug of choice for patients who are not candidates for ICI due to active autoimmune disease or post-liver transplant, favoring the former rather than the latter due to improved tolerability.

In the IMBrave150 trial, the ICI atezolizumab in combination with the VEGF inhibitor bevacizumab was compared with sorafenib with a median OS of 19.2 months versus 13.5 months, respectively²². This combination was FDA-approved in 2020, establishing it as the first-line systemic therapy option of choice for eligible patients. Because bevacizumab is associated with a high risk of hemorrhagic events in patients with cancer (all-grade:30%, grade ≥ 3: 4%)²³, patients in the IMBrave150 trial were mandated to have undergone esophagogastroduodenoscopy (EGD) within 6 months prior to initiation of study treatment; those with untreated or incompletely treated esophageal or gastric varices were excluded from the study. Adverse events included hypertension (grade ≥ 3: 12%), proteinuria (grade ≥ 3: 4%), and immunotherapy-related liver injury (irLI) (grade 1–2: 8.8%, grade 3–4: 2.4%), recognizing that the diagnosis of irLI may have been challenging in patients with HCC due to underlying liver dysfunction²². Atezolizumab/bevacizumab has been associated with a higher incidence of irLI compared to patients with other solid tumors receiving ICI (all grades: 2.6%), but the development of low-grade irLI in patients with HCC has also been shown to be associated with longer OS compared to those without irLI²⁴. Subsequent observational studies have confirmed the clinical benefit of atezolizumab/bevacizumab, albeit less pronounced compared to the outcomes reported in IMBrave150^{25 28}. Atezolizumab/bevacizumab is generally well tolerated and is associated with better global and disease-specific patient-reported outcomes (PRO) data compared to sorafenib.²⁹

The HIMALAYA trial evaluated the superiority of the Single Tremelimumab Regular Interval Durvalumab (STRIDE) regimen compared to sorafenib as well as the non-inferiority of durvalumab compared to sorafenib³⁰. The median OS was 16.4 months, 16.6 months, and 13.8 months in the STRIDE, durvalumab, and sorafenib arms respectively. Although median OS was numerically similar between the STRIDE and durvalumab arms, this trial was not powered to compare the two arms. Patients randomized to the STRIDE regimen reported better global health status/quality of life, functioning, and disease specific symptoms compared to those in the sorafenib group.³¹ The STRIDE regimen was approved by the FDA in October 2022 and serves as an ideal first-line systemic therapy option for patients with non-LRT-eligible HCC for whom bevacizumab use is contraindicated due to untreated esophageal/gastric varices, uncontrolled hypertension, or other severe cardiovascular comorbidities. Single-agent durvalumab was also shown to be non-inferior to sorafenib and can be considered for those who are at high risk of toxicity from the STRIDE regimen. Of note, patients with main portal vein thrombosis were excluded from the HIMALAYA trial, while about 40% of the study population in the IMBrave150 trial had macrovascular invasion, which has been shown to have a greater association with mortality than extrahepatic spread or performance status in untreated patients with HCC³².

The more recent CheckMate 9DW trial evaluated ipilimumab/nivolumab against lenvatinib or sorafenib as first-line systemic therapy for patients with unresectable HCC³³. At a median follow-up of 35.2 months, the median OS was 23.7 months and 20.6 months, and objective response rate was 36% and 13% with the doublet ICI combination and lenvatinib/sorafenib groups, respectively. This combination is not currently FDA approved.

Patients with CPS-B/C cirrhosis and/or Eastern Cooperative Oncology Group (ECOG) score 2 have traditionally been excluded from prospective clinical trials of systemic therapies for non-LRT-eligible HCC. However, sorafenib, atezolizumab/bevacizumab, and single agent nivolumab have been shown in observational studies to have similar tolerability in patients with CPS-B7 to B9 cirrhosis but inferior OS when compared to patients with CPS-A cirrhosis. These benefits are modest, and treatment decisions should be made on a case-by-case basis, taking into account whether a patient’s liver dysfunction is related to their tumor burden versus underlying cirrhosis ^34–37.

Other key trials evaluating first-line systemic therapy include LEAP 002³⁸, ORIENT-32³⁹, CARES-310⁴⁰, RATIONALE-301⁴¹ and COSMIC-312⁴². LEAP 002 evaluated the superiority of pembrolizumab and lenvatinib against sorafenib in the first-line setting and did not meet its dual primary endpoints of progression-free survival (PFS) and OS³⁸. ORIENT-32 evaluated sintilimab (anti-PD-1 antibody) and a bevacizumab biosimilar (IBI305); this combination showed a significant OS benefit when compared to sorafenib, but results have yet to be confirmed outside of China³⁹. The COSMIC-312 trial evaluating first-line cabozantinib and atezolizumab versus sorafenib failed to show an OS benefit⁴². CARES-310 studied the combination of camrelizumab (anti-PD-1 antibody) and rivoceranib (VEGFR2 TKI) versus sorafenib in the first-line setting and median OS was 22.1 months and 15.2 months respectively⁴⁰. FDA approval for this combination is under review currently. The RATIONALE-301 trial demonstrated non-inferiority of tislelizumab versus sorafenib in the first-line setting⁴¹. However, tislelizumab is unlikely to add to the established first-line combinations of atezolizumab/bevacizumab and the STRIDE regimen, which have demonstrated superiority versus sorafenib.

Second-line systemic therapy

Among patients who participated in the pivotal trials evaluating first-line systemic therapy for non-LRT-eligible HCC, only 40–50% received second-line treatment⁴³, and observational studies have shown that fewer than 20% of patients in the United States receive second-line therapy in real-world practice, likely due to factors such as worsening liver function and declining performance status^28,44. Regorafenib, cabozantinib, and ramucirumab (if AFP ≥400 ng/Ml) have been FDA-approved for the second-line treatment of patients with non-LRT-eligible HCC who have progressed on or are intolerant to sorafenib based on the RESOURCE⁴⁵, CELESTIAL⁴⁶, AND REACH-2⁴⁷ trials, respectively (Table 2). With recent approvals of atezolizumab/bevacizumab and the STRIDE regimen in the first-line setting, there are no randomized controlled trials to guide systemic therapy for patients who have progressed on these regimens and the role of using an alternate first-line option among these patients in the second-line setting is unclear. Enrolling these patients in clinical trials should be prioritized whenever feasible. Though quality of evidence is low, AASLD and ASCO guidelines recommend sorafenib or lenvatinib as second-line therapy following first-line treatment with atezolizumab/bevacizumab or the STRIDE regimen^5,6,48. For patients who progress on sorafenib or lenvatinib as first-line treatment, atezolizumab/bevacizumab or the STRIDE regimen should be offered if patients are candidates for these therapies. For those who are ineligible for ICI and who have progressed on first-line sorafenib or lenvatinib, ramucirumab (if AFP ≥400 ng/mL) can be considered given its different mechanism of action. Until further prospective data on treatment sequencing is available, these decisions should be individualized. Subsequent systemic therapy (third-line and beyond) should be based on the mechanism of action of previous agents used, safety profile, performance status, and liver function. If interested and able, these patients should be encouraged to participate in early-phase clinical trials.

Additional care considerations for patients with HCC

Several unique challenges complicate the diagnosis and management of HCC. The staging, diagnosis, and treatment of HCC are complicated by non-specific symptoms at presentation as well as underlying liver dysfunction in most patients. In addition to experiencing an uncertain disease course related to both HCC and chronic liver disease, patients with HCC often face considerable stigma due to commonly associated risk factors such as substance use, sexually transmitted infections (STIs), and metabolic diseases⁴⁹. Due to the complex pathophysiology of the disease and constantly evolving treatment strategies, a multidisciplinary care (MDC) approach is essential for promoting individualized treatment decisions. MDC requires the expertise of diverse specialties, including medical oncology, hepatology⁵⁰, radiation oncology, diagnostic and interventional radiology, pathology, transplant surgery, and palliative care⁵¹. Similarly, support from ancillary services such as nutrition⁵², physical and occupational therapy⁵³, social work, psychology, psychiatry^{54 57}, and substance use counseling is crucial. MDC allows for active communication between different specialties, resulting in a patient-centered approach to decision-making⁵⁸. A meta-analysis of 12 studies including 15,365 patients with HCC found that MDC was associated with improved OS⁵⁹. Several international guidelines, including BCLC, AASLD, and EASL, collectively endorse individualizing treatment decisions through MDC^3,5,7, including timely referral to tertiary centers for optimal management and facilitation of MDC⁶⁰.

Future directions

With the advent of improved systemic therapies in HCC, efforts are now being made to identify the role for combining systemic therapy with established LRT approaches with the hope that LRT may induce hypoxia, tumor angiogenesis, and neoantigen presentation, thereby enhancing the efficacy of anti-angiogenic agents and ICIs, respectively (Table 3). EMERALD-1 was the first global trial to demonstrate that combining transarterial chemoembolization with durvalumab and bevacizumab resulted in better PFS for patients with embolization-eligible unresectable HCC, although OS data remain immature⁶¹. Additional immunomodulatory approaches are also under investigation, including the inhibition of novel checkpoints such as TIGIT (anti-T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains). In the phase 1b-2 MORPHEUS-Liver study, the combination of tiragolumab (an anti-TIGIT monoclonal antibody) and atezolizumab/bevacizumab resulted in an objective response rate of 43% compared to 11% in the placebo and atezolizumab/bevacizumab group for patients with treatment-naïve non-LRT-eligible HCC⁶²; the phase 3 IMBrave 152 study investigating tiragolumab in combination with atezolizumzb/bevacizumab is ongoing⁶³. Finally, earlier-phase trials are investigating cellular therapy approaches targeting glypican-3 (GPC-3), given the overexpression and specificity of GPC-3 IN HCC^64,65. In a phase 1 study of C-CARO31, an autologous GPC3-directed chimeric antigen receptor T-cell product armored with dominant negative transforming growth factor-β receptor ll, 24 patients with heavily pre-treated non-LRT-eligible HCC had an objective response rate of 50% with a manageable safety profile⁶⁶.

Table 3:

Selected ongoing phase III trials evaluating systemic therapies in HCC

NCT No.	Status (As of Oct 1, 2024)	Study population	Study design	Interventions	Primary end point
NCT01730937 (NRG/RTOG 1112)a	Active, not recruiting	BCLC stage B/C HCC, unsuitable for surgery, ablation or TACE, CPS ≤ 7, ≤ 5 HCCs (total sum ≤ 20 cm), and distant metastasis ≤ 3 cm	Phase III RCT, global	- SBRT + sorafenib - sorafenib	OS
NCT03778957 (EMERALD-1)	Active, not recruiting	Embolizati on eligible, unresecta ble HCC, CPS ≤ 7	Phase III RCT, double blinded, global	- TACE + durvalumab + placebo - TACE + durvalumab + bevacizumab - TACE + placebo + placebo	PFS
NCT04246177 (LEAP-012)a	Active, not recruiting	HCC localized to the liver, without MVI and not amenable to curative treatment, CPS ≤ 6	Phase III RCT, double blinded, global	- TACE + pembrolizumab + lenvatinib - TACE + placebo + placebo	PFS, OS
NCT03905967 (LAUNCH)a	Unknown status	Advanced/unresectable HCC, systemic therapy naïve, CPS ≤ 6	Phase III RCT, open-label, China only	- TACE + lenvatinib - Lenvatinib	OS
NCT05301842 (EMERALD- 3)	Recruiting	Embolization eligible, unresectable HCC, single HCC lesion ≤ 10 cm or multiple (≤ 10 foci) with tumor burden ≤ 50%, CPS ≤ 6	Phase III RCT, open-label, global	-TACE + durvalumab + tremelimumab + Lenvatinib - TACE + durvalumab + tremelimumab - TACE	PFS
NCT04340193 (Checkmate 74W)	Terminated	Embolization eligible, unresectable HCC, CPS ≤ 6	Phase III RCT, double blinded, global	- TACE + nivolumab + Ipilimumab - TACE + nivolumab - TACE + placebo	PFS, OS
IMBrave 152	Recruiting	Unresectable/advanced HCC, CPS ≤ 6, treatment naïve	Phase III RCT, double blinded, global	- Atezolizumab + bevacizumab + tiragolumab - Atezolizumab + bevacizumab + placebo	PFS, OS
NCT04523493	Active, not recruiting	Unresectable/advanced HCC, CPS ≤ 6, treatment naïve	Phase III RCT, double blinded, global	- Toripalimab + lenvatinib - Placebo + lenvatinib	OS
NCT05003895 a	Recruiting	Unresectable/advanced HCC, CPS ≤ 6, progressed/intolerant to prior first-line of systemic therapy, GPC3 expression >25%	Phase I	- GPC3 targeted CAR-T cell therapy	Safety and feasiblity
NCT05201404	Recruiting	Unresectable/advanced HCC, CPS ≤ 7, progressed on atleast one prior line of systemic therapy	Phase III RCT, double blinded, global	- Namodenoson - Placebo	OS
NCT05337137	Recruiting	Unresectable/advanced HCC, CPS ≤ 6, treatment naïve	Phase I/II RCT, double blinded, global	- Nivolumab + relatlimab + bevacizumab - Nivolumab + bevacizumab + placebo	DLT, ORR

NCT No., national clinical trial number; HCC, hepatocellular carcinoma; BCLC, Barcelona Clinic Liver Cancer; CPS, Child-Pugh score; TACE, transarterial chemoembolization; RCT, randomized controlled trial; SBRT, Stereotactic body irradiation; OS, overall survival, PFS, progression-free survival; MVI, macrovascular invasion; GPC3, gypican-3; CAR-T cell therapy, Chimeric antigen receptor T-cell therapy; DLT, drug limiting toxicity; ORR, overall response rate.

^aResults available.

Conclusion

Several FDA approvals have changed the treatment landscape of non-LRT-eligible HCC over the past five years. Patient performance status, comorbidities, HCC stage, and underlying liver function remain key factors in individualizing treatment decisions via an MDC approach. ICI combinations and anti-angiogenic agents have established their role in the treatment of patients with non-LRT-eligible HCC. Additional work is needed to determine the optimal sequencing of systemic therapies, explore the role for systemic therapy in earlier-stage disease, and identify strategies to address the unique needs of patients with this complex disease.

Figure 1:

Approach to systemic therapy in advanced HCC

HCC, hepatocellular carcinoma; BCLC, Barcelona Clinic Liver Cancer; CPS, Child-Pugh score; TACE, transarterial chemoembolization; TARE, transarterial radioembolization; ECOG, Eastern Cooperative Oncology Group score; AFP, alpha-fetoprotein; STRIDE, Single Tremelimumab Regular Interval Durvalumab.

^a Patients should be enrolled on clinical trials whenever feasible.

^b Risk of variceal bleeding high if untreated or incompletely treated varices on esophagogastroduodenoscopy within six months of treatment initiation.

^CNot currently approved for first-line use by the Food and Drug Administration.

^dThe role of atezolizumab/bevacizumab, durvalumab/tremelimumab, and nivolumab/ipilimumab in the second-line setting is unclear and decisions should be individualized in eligible patients.