Version July 2025
INTRODUCTION —
Hepatocellular carcinoma (HCC) is an aggressive tumor that usually occurs in the setting of chronic liver disease and cirrhosis [1]. Treatment options include surgical therapies (ie, resection and liver transplantation), liver-directed therapies (ie, radiofrequency ablation, microwave ablation, hepatic arterial embolization, radiation therapy [RT]), and/or systemic therapy. Treatments are generally selected based upon disease extent and underlying liver function (algorithm 1).
This topic will discuss systemic treatment approaches for patients with advanced unresectable or metastatic HCC for whom liver transplantation and liver-directed therapy are not appropriate. An overview of treatment for HCC, surgical treatment, liver-directed nonsurgical therapies, and the clinical manifestations and diagnosis of HCC are reviewed separately.
●(See "Overview of treatment approaches for hepatocellular carcinoma".)
●(See "Surgical resection of hepatocellular carcinoma".)
●(See "Liver transplantation for hepatocellular carcinoma".)
●(See "Clinical features and diagnosis of hepatocellular carcinoma".)
INDICATIONS FOR SYSTEMIC THERAPY —
Systemic therapy is an appropriate option for patients with advanced unresectable or metastatic HCC not amenable to curative or locoregional therapy, adequate performance status (table 1), and appropriate underlying liver function (table 2). Clinical trials are encouraged, where available.
Patients who are candidates for systemic therapy have any of the following clinical scenarios:
●Extrahepatic metastatic disease
●Tumors confined to the liver that progress after locoregional therapies
●Tumors with extensive vascular invasion (figure 1)
●Large intrahepatic tumor burden (ie, diffuse and/or bilateral lobar involvement) unsuitable for locoregional approaches (algorithm 1)
The management of patients with advanced unresectable HCC that is amenable to locoregional therapy is discussed separately. (See "Localized hepatocellular carcinoma: Liver-directed therapies for nonsurgical candidates eligible for local ablation" and "Localized hepatocellular carcinoma: Liver-directed therapies for nonsurgical candidates not eligible for local thermal ablation".)
PRETREATMENT EVALUATION
Postdiagnostic evaluation — In patients with a confirmed diagnosis of HCC, evaluation with imaging and laboratory studies is discussed separately. (See "Clinical features and diagnosis of hepatocellular carcinoma", section on 'Postdiagnostic evaluation'.)
Staging and prognostic scoring systems — The various staging and prognostic scoring systems for HCC are discussed separately. (See "Staging and prognostic factors in hepatocellular carcinoma", section on 'Staging and prognostic scoring systems'.)
Assessment of liver function — We use the Child-Pugh classification of severity of cirrhosis (table 2) to assign the degree of hepatic dysfunction, which influences the selection of systemic therapy. Among patients with HCC, overall survival (OS) often depends on the degree of hepatic dysfunction [2]. The Child-Pugh classification is commonly used in clinical practice and clinical trials to define liver function, and it is easy to understand. Of note, the Child-Pugh classification was not developed or validated in patients with HCC [3]. (See "Cirrhosis in adults: Overview of complications, general management, and prognosis", section on 'Child-Pugh classification'.)
Screening for viral hepatitis — We obtain universal hepatitis B virus (HBV) screening for all patients beginning systemic anticancer therapy (eg, chemotherapy, immunotherapy, molecularly targeted therapy) using the following tests: hepatitis B surface antigen (HbSAg), hepatitis B core antibody (anti-HBc), total immunoglobulin (Ig) or IgG, and antibody to hepatitis B surface antigen (anti-HBs) [4,5]. Many patients with HCC have underlying liver disease, especially infection with HBV or hepatitis C virus (HCV). Thus, they may be at risk for viral reactivation during active systemic therapy, including immune checkpoint inhibitors [6].
Patients who are found to have chronic HBV (ie, HbSAg-positive) or past HBV (ie, HbSAg-negative and anti-HBc-positive) infection require risk assessment for HBV reactivation to determine the need for antiviral prophylaxis. Their approach to HBV screening, monitoring, and antiviral prophylaxis (algorithm 2) is discussed in more detail separately. (See "Hepatitis B virus reactivation associated with immunosuppressive therapy".)
In addition, clinicians should also test for chronic HCV infection prior to initiating potentially immunosuppressive therapy [5]. Patients with chronic HCV infection who are receiving systemic therapy should undergo serial monitoring of liver function tests. If there is no dramatic change in liver function tests, continued systemic therapy without dose modification is appropriate. (See "Screening and diagnosis of chronic hepatitis C virus infection".)
INITIAL THERAPY FOR PATIENTS WITH CHILD-PUGH CLASS A CIRRHOSIS
Selection of therapy — For most patients with an Eastern Cooperative Oncology Group (ECOG) performance status less than 2 (table 1), no worse than Child-Pugh class A cirrhosis, and no prior history of liver transplantation, we suggest either atezolizumab plus bevacizumab or tremelimumab plus durvalumab rather than an antiangiogenic agent alone or a single-agent immune checkpoint inhibitor. Either regimen is appropriate as both improved overall survival (OS) relative to antiangiogenic agents in separate phase III trials, and they have not been directly compared in a randomized trial. Selection of therapy is based on patient symptoms, comorbidities, performance status, rate of tumor progression, and clinician preference. As examples:
●For patients whose disease is severely symptomatic or rapidly progressive, we offer atezolizumab plus bevacizumab due to the solid objective response rates (ORRs; up to 30 percent) seen with this regimen.
●For patients with a higher risk of bleeding, a recent arterial thrombotic event, active wounds, gastrointestinal perforation, or an absolute contraindication to bevacizumab, we offer tremelimumab plus durvalumab. One exception is a patient with treated esophageal varices within the past six months, for whom atezolizumab plus bevacizumab is also an option. Contraindications to bevacizumab, mainly based on data in colorectal cancer, and other risks of antiangiogenic agents are discussed separately. (See "Initial systemic therapy for metastatic colorectal cancer", section on 'Contraindications' and "Cardiovascular toxicities of molecularly targeted antiangiogenic agents".)
The initial management of patients with advanced or metastatic HCC that has recurred following orthotopic liver transplantation is discussed separately. (See 'Prior liver transplantation' below.)
Atezolizumab plus bevacizumab — Atezolizumab plus bevacizumab is one preferred option for initial therapy in patients with advanced unresectable or metastatic HCC. Patients who receive this regimen must have completed appropriate evaluation and treatment (if necessary) for esophageal varices within the past six months, due to the risk of bleeding with bevacizumab. In a phase III trial (IMBrave 150), atezolizumab plus bevacizumab improved OS relative to sorafenib and was well-tolerated [7-9].
Based on the results of early-phase clinical trials [10], atezolizumab, a programmed cell death ligand-1 (PD-L1) inhibitor, plus bevacizumab, a vascular endothelial growth factor receptor (VEGFR) inhibitor, was evaluated in an open-label phase III trial (IMBrave 150) for the initial treatment of advanced HCC [7-9]. In this study, 501 patients with previously untreated, advanced unresectable HCC and no worse than Child-Pugh class A cirrhosis were randomly assigned 2:1 to receive either atezolizumab (1200 mg intravenous [IV] every three weeks) plus bevacizumab (15 mg/kg IV every three weeks, after atezolizumab) or sorafenib (400 mg twice daily). Due to the risk of bleeding, esophagogastroduodenoscopy (EGD) was performed within six months of treatment initiation and esophageal varices were treated when necessary. The trial excluded patients who had a myocardial infarction or stroke within the previous three months, were on therapeutic anticoagulation, or had coinfection with hepatitis C virus (HCV) or hepatitis B virus (HBV).
At a median follow-up of 16 months, compared with sorafenib, the combination of atezolizumab plus bevacizumab improved OS (median 19.2 versus 13.4 months, estimated hazard ratio [HR] for death 0.66, 95% CI 0.52-0.85) and the ORR (30 versus 11 percent) [9]. In a subsequent analysis, durable OS was also seen in those with partial responses or stable disease lasting longer than six months [11]. Treatment-related grade 3 or 4 toxicity rates were similar for both treatment arms (43 versus 46 percent). Hypertension, transaminase elevation, and proteinuria were more frequent with combined therapy whereas diarrhea was more common with sorafenib. In an analysis of patient-reported outcomes, relative to sorafenib, combination therapy delayed the time to deterioration of quality of life, physical and role functioning, and reduced the risk of deterioration due to several disease-related symptoms (eg, anorexia, diarrhea, fatigue, pain) [8].
Other data also support the efficacy of this combination. In a meta-analysis of eight trials comparing various first-line treatment options in 6290 patients with advanced HCC, OS was superior for atezolizumab plus bevacizumab compared with sorafenib (HR 0.58, 95% CI 0.42-0.80), lenvatinib (HR 0.63, 95% CI 0.44-0.89), and nivolumab (HR 0.68, 95% CI 0.48-0.98) [12].
The combination of atezolizumab plus bevacizumab is approved by the US Food and Drug Administration (FDA) for the treatment of adult patients with unresectable or metastatic HCC who have not received prior systemic therapy [13]. A subcutaneous form of atezolizumab (atezolizumab-hyaluronidase), in combination with bevacizumab, is also approved in multiple countries, including the United States.
Tremelimumab plus durvalumab — Tremelimumab plus durvalumab (also known as the STRIDE regimen) is another preferred option for initial therapy in patients with advanced unresectable or metastatic HCC. In a phase III trial, tremelimumab plus durvalumab improved OS over sorafenib and was well-tolerated [14-16].
Based on initial data from phase I/II clinical trials [17], tremelimumab, a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor, plus durvalumab, a PD-L1 inhibitor, was evaluated in an open-label phase III trial (HIMALAYA). In this study, 1171 patients with advanced HCC, no worse than Child-Pugh class A cirrhosis, and who were ineligible for locoregional therapy were randomly assigned to one of the following treatment arms [14,15]:
●Tremelimumab (a single dose of 300 mg administered on day 1) plus durvalumab (1500 mg every four weeks)
●Durvalumab monotherapy (1500 mg every four weeks)
●Sorafenib (400 mg twice daily)
●Tremelimumab plus durvalumab versus sorafenib – At a median follow-up of 49 months, relative to sorafenib, tremelimumab plus durvalumab improved OS (median 16.4 versus 13.8 months, four-year OS 25 versus 15 percent, HR 0.78, 95% CI 0.67-0.92), the ORR (52 versus 15 percent), and the complete response rate (12 versus 0 percent) [15]. At a median follow-up of 33 months, progression-free survival (PFS) was similar between the two treatment arms (median PFS 3.8 versus 4.1 months, HR 0.90, 95% CI 0.77-1.05) [14].
●Tremelimumab plus durvalumab versus durvalumab – At a median follow-up of 49 months, tremelimumab plus durvalumab demonstrated similar median OS relative to durvalumab monotherapy (16.4 versus 16.6 months) [15]. Although four-year survival rates were numerically higher with combined therapy over durvalumab alone (25 versus 19 percent), a formal comparative analysis was not reported. While the ORR was similar between the two treatment arms (52 versus 53 percent), the complete response rate was higher with combination therapy relative to durvalumab monotherapy (12 versus 6 percent).
Of note, enrollment to a fourth arm, tremelimumab 75 mg every four weeks plus durvalumab 1500 mg every four weeks, was discontinued when an interim analysis suggested similar results to durvalumab alone [14].
●Durvalumab versus sorafenib – The efficacy of durvalumab relative to sorafenib is discussed separately. (See 'Durvalumab' below.)
●Toxicity – Serious treatment-related toxicities were higher with tremelimumab plus durvalumab (18 percent) compared with durvalumab monotherapy (9 percent) and sorafenib monotherapy (10 percent) [15]. However, tremelimumab plus durvalumab conferred clinically meaningful benefits in patient global health status, quality of life, functioning, and symptoms [16].
The combination of tremelimumab plus durvalumab is approved by the FDA for the treatment of adult patients with unresectable HCC [13].
Ineligible for combination therapy — For patients who are ineligible for or are anticipated to poorly tolerate initial combination immunotherapy-based regimens with either atezolizumab plus bevacizumab or tremelimumab plus durvalumab, appropriate alternatives include an antiangiogenic tyrosine kinase inhibitor (TKI; lenvatinib preferred) or single-agent immunotherapy (durvalumab, tislelizumab, or pembrolizumab). Selection of therapy is based upon patient performance status and comorbidities as well as patient and clinician preference. (See 'Antiangiogenic agents' below and 'Single-agent immunotherapy' below.)
The initial management of patients with advanced or metastatic HCC that has recurred following liver transplantation is discussed separately. (See 'Prior liver transplantation' below.)
Antiangiogenic agents
Selection of therapy — For patients with no worse than Child-Pugh class A cirrhosis who select initial therapy with an antiangiogenic TKI, we suggest lenvatinib rather than sorafenib. Lenvatinib is better tolerated (especially for hand-foot skin reaction, alopecia, fatigue, and anorexia), and demonstrated higher ORRs, a longer time to tumor progression (TTP), and similar OS compared with sorafenib in a randomized trial (REFLECT) [18]. (See 'Lenvatinib' below.)
Lenvatinib — Lenvatinib, a multitargeted antiangiogenic TKI, is one option for the initial treatment of patients with advanced unresectable or metastatic HCC and no worse than Child-Pugh class A cirrhosis (table 2) who are ineligible for or are anticipated to not tolerate combination immunotherapy-based regimens. In a randomized trial, compared with sorafenib, lenvatinib demonstrated noninferior OS, achieved a higher ORR, delayed the TTP, and was better tolerated [18].
Based on data from a phase II trial [19], an open-label, noninferiority phase III trial (REFLECT) compared lenvatinib (12 mg once daily for body weight ≥60 kg, 8 mg daily for <60 kg) to sorafenib (400 mg twice daily for all patients) in 954 patients with unresectable HCC and no prior systemic therapy (99 percent with Child-Pugh class A cirrhosis) [18]. Exclusion criteria included tumor involvement of greater than 50 percent of the liver or tumor invasion of the main portal vein or biliary tree. At a median follow-up of 27 months, lenvatinib was noninferior to sorafenib for OS (median 13.6 versus 12.3 months, HR 0.92, 95% CI 0.79-1.06). However, lenvatinib improved the ORR (24 versus 9 percent) and prolonged the TTP (median 7.4 versus 3.7 months, HR 0.66, 95% CI 0.57-0.77), based on blinded independent review. Grade ≥3 toxicity rates for lenvatinib and sorafenib were 57 and 49 percent respectively. Lenvatinib more frequently caused grade 3 or 4 hypertension than sorafenib (23 versus 14 percent). By contrast, sorafenib more frequently caused hand-foot skin reaction (11 versus 3 percent) and any-grade alopecia (25 versus 3 percent) than lenvatinib.
Lenvatinib is approved by the FDA for the first-line treatment of unresectable HCC [13].
Studies are evaluating the addition of lenvatinib (and other agents) to TACE in patients with localized HCC. Further details are discussed separately. (See "Localized hepatocellular carcinoma: Liver-directed therapies for nonsurgical candidates not eligible for local thermal ablation", section on 'Systemic therapy plus TACE versus TACE alone'.)
Sorafenib — Sorafenib, a multitargeted antiangiogenic TKI, is another option for the initial treatment of patients with advanced unresectable or metastatic HCC and no worse than Child-Pugh class A cirrhosis who are ineligible for or are anticipated to not tolerate combination immunotherapy-based regimens. In randomized trials, sorafenib improved OS over best supportive care alone as well as chemotherapy. However, we prefer lenvatinib which is better tolerated and confers similar OS benefit compared with sorafenib. (See 'Lenvatinib' above.)
To improve early tolerability, we typically start sorafenib at a dose of 200 mg orally twice a day and increase the daily dose in 200 mg increments approximately every five days until the target dose of 400 mg twice daily is reached. Data suggest that this approach results in less toxicity and lower rates of drug discontinuation without compromising efficacy [20,21].
In a double-blind, international, placebo-controlled phase III trial (SHARP) conducted in multiple international centers (Europe, North and South America, and Australasia), 602 patients with advanced unresectable or metastatic HCC and good hepatic function (95 percent with Child-Pugh class A cirrhosis; 5 percent with Child-Pugh class B cirrhosis) were randomly assigned to either sorafenib (400 mg twice daily) or placebo [22]. Sorafenib improved OS relative to placebo (median OS 10.7 versus 7.9 months, one-year OS 44 versus 33 percent, HR 0.69, 95% CI 0.55-0.87) and radiographic time to progression (5.5 versus 2.8 months). Relative to placebo, sorafenib resulted in more grade 3 or 4 diarrhea (8 versus 2 percent) and hand-foot skin reaction (8 versus <1 percent). Rates of liver dysfunction or bleeding were similar between the treatment arms.
Similar results were seen in a subsequent double-blind, placebo-controlled phase III trial conducted in Asia (China, Republic of Korea, and Taiwan) [23]. In this study, 226 patients with Child-Pugh class A cirrhosis and no prior systemic therapy for advanced unresectable or metastatic HCC were randomly assigned to either sorafenib 400 mg twice daily or placebo. Sorafenib improved OS (median 6.5 versus 4.2 months, HR 0.68, 95% CI 0.50-0.93) and TTP (2.8 versus 1.4 months, HR 0.57, 95% CI 0.42-0.79). Grade 3 or 4 toxicities with sorafenib included hand-foot skin reaction (11 percent), diarrhea (6 percent), and fatigue (3 percent). Although the magnitude of the absolute OS benefit was less than seen in the SHARP trial, patients accrued to this trial were more ill at the start of therapy than those in the SHARP trial, with generally worse performance statuses and more advanced stages of disease [24].
Sorafenib is also more effective than chemotherapy. In a randomized phase II trial of 52 previously untreated patients with advanced HCC, sorafenib improved OS (median seven versus five months) and PFS (median six versus four months) over capecitabine [25].
Sorafenib is approved by the FDA for the systemic treatment of unresectable HCC [13].
The addition of sorafenib to transarterial chemoembolization (TACE) does not improve OS. Further details on studies are addressed in detail separately. (See "Localized hepatocellular carcinoma: Liver-directed therapies for nonsurgical candidates not eligible for local thermal ablation", section on 'Systemic therapy plus TACE versus TACE alone'.)
Toxicities — The various toxicities associated with antiangiogenic TKIs are discussed separately.
●Cardiovascular toxicities – (See "Neurologic complications of cancer treatment with molecularly targeted and biologic agents", section on 'Multiple tyrosine kinase inhibitors including VEGFR' and "Cardiovascular toxicities of molecularly targeted antiangiogenic agents".)
●Non-cardiovascular toxicities –
●Cutaneous toxicities – (See "Cutaneous adverse events of molecularly targeted therapy and other biologic agents used for cancer therapy", section on 'VEGFR/PDGFR inhibitors'.)
●Neurologic toxicities – (See "Neurologic complications of cancer treatment with molecularly targeted and biologic agents", section on 'Multiple tyrosine kinase inhibitors including VEGFR' and "Cardiovascular toxicities of molecularly targeted antiangiogenic agents".)
●Hepatic toxicities – (See "Hepatotoxicity of molecularly targeted agents for cancer therapy", section on 'Sorafenib' and "Hepatotoxicity of molecularly targeted agents for cancer therapy", section on 'Lenvatinib'.)
Single-agent immunotherapy — Single-agent immunotherapy is an option for patients with advanced unresectable or metastatic HCC, no worse than Child-Pugh class A cirrhosis, and no prior history of liver transplantation who are ineligible for combined therapy (with either atezolizumab plus bevacizumab or durvalumab plus tremelimumab). Treatment options include durvalumab, pembrolizumab, and tislelizumab. Any of these agents are appropriate as they have not been directly compared in randomized trials.
Durvalumab — In an open-label phase III trial (HIMALAYA), 1171 patients with no worse than Child-Pugh class A cirrhosis and ineligible for locoregional therapy were randomly assigned to either tremelimumab plus durvalumab, durvalumab alone, or sorafenib [14-16]. The results of tremelimumab plus durvalumab versus durvalumab monotherapy and sorafenib monotherapy are described separately. (See 'Tremelimumab plus durvalumab' above.)
At a median follow-up of 49 months, durvalumab monotherapy demonstrated noninferior OS compared with sorafenib monotherapy (median OS 16.6 versus 13.8 months, four-year OS 19 versus 15 percent, HR 0.86, 95% CI 0.74-1.01) [15]. At a median follow-up of 33 months, PFS was also similar between these treatment arms (median PFS 3.7 versus 4.1 months, HR 1.02, 95% CI 0.88-1.19) [14]. Durvalumab also improved ORR relative to sorafenib (53 versus 16 percent).
In the initial analysis, durvalumab was better tolerated than sorafenib (grade 3 or 4 toxicity rates of 13 versus 37 percent) and fewer patients discontinued therapy (4 versus 11 percent) [14]. Durvalumab also conferred clinically meaningful benefits for patient global health status, quality of life, functioning, and symptoms [16]. In extended follow-up, serious treatment-related adverse event rates were similar between the two treatment arms (9 versus 10 percent) [15].
Tislelizumab — In a phase III trial (RATIONALE-301) of systemic therapy-naïve patients with advanced unresectable HCC, tislelizumab demonstrated noninferior (but not superior) OS (median 15.9 versus 14.1 months, HR 0.85, 95% CI 0.71-1.02) and similar PFS (median 2 versus 3 months) relative to sorafenib [26].
Pembrolizumab — In a nonrandomized, open-label phase II trial (KEYNOTE-224), 51 patients with advanced HCC and no prior systemic therapy were treated with pembrolizumab [27]. The ORR was 16 percent (all partial responses), and the median duration of response was 16 months. Median PFS and OS durations were 4 and 17 months, respectively. There were no new toxicity signals, and the most common treatment-related adverse events were diarrhea, fatigue, hypothyroidism, and myalgias. One patient died of immune-mediated myocarditis and hepatitis.
Toxicities — Patients with HCC who are treated with immune checkpoint inhibitors may have a substantial increase in transaminases as compared with patients receiving these drugs for other cancers. However, this has not translated into premature treatment discontinuation or treatment-related mortality [28,29]. Liver function tests should be monitored during therapy with these agents. (See "Hepatic, pancreatic, and rare gastrointestinal complications of immune checkpoint inhibitor therapy", section on 'Hepatotoxicity'.)
Management of other toxicities related to immune checkpoint inhibitors are discussed separately. (See "Overview of toxicities associated with immune checkpoint inhibitors".)
Other regimens — Some regimens are also effective initial therapies for advanced HCC but are only available in certain countries and/or do not have regulatory approval in this setting.
●Camrelizumab plus rivoceranib (apatinib) – For fit patients with advanced or metastatic HCC and no worse than Child-Pugh class A cirrhosis, initial therapy with camrelizumab plus rivoceranib (ie, apatinib) improved PFS and OS relative to sorafenib in an international phase III trial. However, this combination is not available outside of China.
In an international, open-label phase III trial (CARES-310), 543 patients with systemic-therapy naïve, unresectable or metastatic HCC and Child-Pugh class A liver function were randomly assigned to either camrelizumab (a programmed cell death protein 1 [PD-1] inhibitor) plus rivoceranib (ie, apatinib, an antiangiogenic agent that targets VEGFR2) or sorafenib [30]. Patients were included from China, Hong Kong, Taiwan, and Republic of Korea (83 percent) as well as Europe and the United States (17 percent). Patients with partial occlusion of the main trunk of the portal vein or complete occlusion of a branch portal vein were allowed to enroll, but those with vena cava invasion or complete occlusion of the main trunk of the portal vein were excluded. Compared with sorafenib alone, camrelizumab plus rivoceranib improved PFS at a median follow-up of eight months (5.6 versus 3.7 months, HR 0.52, 95% CI 0.41-0.65), OS at a median follow-up of 15 months (22 versus 15 months, HR 0.62, 95% CI 0.49-0.80), and ORRs (25 versus 6 percent). Grade ≥3 toxicity rates were higher for the combination (81 versus 52 percent).
Camrelizumab and rivoceranib are approved as a first-line treatment for patients with liver cancer by the Chinese National Medical Products Administration (NMPA) [31].
●Nivolumab plus ipilimumab – For patients with unresectable HCC and no worse than Child-Pugh class A cirrhosis, initial therapy nivolumab plus ipilimumab improved OS relative to sorafenib or lenvatinib [32]. These data are promising, and we await regulatory approval of nivolumab plus ipilimumab as initial therapy in advanced unresectable HCC prior to routine clinical use.
In an open-label phase III trial (Checkmate 9DW), 668 patients with unresectable HCC, no prior systemic therapy, and no main portal vein invasion (Vp4) (figure 1) were randomly assigned to either nivolumab plus ipilimumab (for up to four cycles, followed by maintenance nivolumab) or investigator's choice of either lenvatinib or sorafenib. In preliminary results, at a median follow-up of 35 months, relative to lenvatinib or sorafenib, nivolumab plus ipilimumab improved OS (median 24 versus 21 months, HR 0.79, 95% CI 0.65-0.96) and ORR (36 versus 13 percent) [32]. While nivolumab plus ipilimumab demonstrated higher two-year PFS (28 versus 12 percent), it initially resulted in earlier disease progression (prior to nine months) compared with antiangiogenic therapy; median PFS was similar between the two treatment arms (median PFS nine months each, HR 0.87, 95% CI 0.87-1.06). Toxicity was higher for nivolumab plus ipilimumab relative to antiangiogenic therapy.
The use of nivolumab plus ipilimumab as second-line therapy for advanced unresectable or metastatic HCC is discussed separately. (See 'Nivolumab plus ipilimumab' below.)
●Sintilimab plus bevacizumab – The combination of sintilimab, a PD-1 inhibitor, with a bevacizumab biosimilar improved OS and PFS compared with sorafenib alone in a randomized trial (ORIENT-32) conducted in China [33]. Sintilimab is available in China but does not have regulatory approval in the United States.
●Donafenib – Donafenib is a derivative of sorafenib with a more favorable pharmacokinetic profile, largely because of reduced susceptibility to hepatic drug-metabolizing enzymes. In a randomized trial of patients with advanced HCC, initial therapy with donafenib modestly improved OS and was better tolerated than sorafenib [34]. Donafenib is approved in China for treatment of patients with unresectable HCC who have not previously received systemic treatment [35].
●Lenvatinib plus TACE – Additional experience with lenvatinib plus TACE is needed in Western populations, in which the cause of HCC is more often cirrhosis due to alcohol use than hepatitis B virus (HBV), before it can be concluded that this combination is a preferred approach over systemic therapy alone, especially upfront immunotherapy.
Better outcomes with combined lenvatinib plus TACE versus lenvatinib alone were suggested in the Chinese phase III LAUNCH trial in which 338 patients with advanced HCC (predominantly HBV-related) and no prior local or systemic treatment were randomly assigned to lenvatinib or lenvatinib plus "on-demand" TACE [36]. Although median OS was significantly longer with combined therapy (17.8 versus 11.5 months, HR 0.45, 95% CI 0.34-0.55), grade 3 or 4 adverse events were also more common. This trial is described in more detail separately. (See "Overview of treatment approaches for hepatocellular carcinoma", section on 'Lenvatinib alone or with TACE'.)
Regimens not used
●Nivolumab – We do not offer initial therapy with nivolumab in patients with advanced unresectable or metastatic HCC, as this agent failed to improve OS in a phase III trial (CheckMate 459) [37]. In this study, 743 patients with advanced, previously untreated HCC were randomly assigned to nivolumab or sorafenib [37]. At a minimum follow-up of 23 months, nivolumab did not improve OS relative to sorafenib (median 16.4 versus 14.7 months, HR 0.85, 95% CI 0.72-1.02). Grade 3 or 4 treatment-related toxicity rates were similar for nivolumab and sorafenib (12 versus 11 percent).
Although the FDA initially granted accelerated approval to nivolumab for the treatment of HCC in patients previously treated with sorafenib, this approval was withdrawn when nivolumab failed to improve OS over sorafenib as initial therapy in CheckMate 459 [37]. (See 'Other immunotherapy agents' below.)
●Cabozantinib plus atezolizumab – We do not use the combination of cabozantinib plus atezolizumab as initial systemic therapy for advanced unresectable or metastatic HCC. In a randomized phase III trial (COSMIC-312) of 837 patients with systemic therapy-naïve advanced HCC, cabozantinib plus atezolizumab failed to improve OS and increased treatment-related toxicity relative to sorafenib [38].
●Lenvatinib plus pembrolizumab – We do not offer the combination of lenvatinib plus pembrolizumab as initial therapy for advanced unresectable or HCC. Although initial studies suggested clinical benefit for this combination [39], the addition of pembrolizumab to lenvatinib did not meet the prespecified boundaries for PFS and OS in a randomized phase III trial (LEAP-002) [40].
●Sorafenib plus chemotherapy – There is no established role for combining sorafenib with chemotherapy as initial treatment for advanced HCC, as randomized trials have failed to demonstrate an OS or PFS benefit for this approach [41-43].
●Other chemotherapy regimens – For patients with Child-Pugh class A disease, conventional chemotherapy has largely been replaced with other agents that are more active and better tolerated. (See 'Chemotherapy' below.)
Special populations
Prior liver transplantation — For patients who recur with advanced unresectable or metastatic HCC after orthotopic liver transplantation, we suggest initial therapy with an antiangiogenic agent rather than other systemic agents. Options include sorafenib or lenvatinib. (See 'Antiangiogenic agents' above.)
We do not offer regimens that contain immunotherapy following liver transplantation because of the high rate of allograft rejection, which is attributed to stimulation of the host immune response by these agents. Although limited data are available on the safety of immunotherapy following liver transplantation, allograft rejection rates may be as high as 39 percent [44]. Patients interested in immunotherapy should be treated in the context of a clinical trial and with transplant hepatology support.
For patients with a recurrence of HCC following liver transplantation, both sorafenib [45] and lenvatinib [46] are effective and feasible to administer in conjunction with immunosuppressive therapy (such as mammalian target of rapamycin [mTOR] inhibitors or calcineurin inhibitors). Data also suggest an antitumor effect with mTOR inhibitors in liver transplant recipients with a history of HCC. (See "Liver transplantation in adults: Initial and maintenance immunosuppression", section on 'Patients with hepatocellular carcinoma (HCC)'.)
However, other studies have suggested higher rates of treatment-related toxicity when combining antiangiogenic TKIs (with most data in sorafenib) and immunosuppression, such as acute hepatitis, diarrhea, hand-foot skin reaction, and myelosuppression [47-49]. As such, patients should be closely monitored during treatment for potential toxicities and the need for dose modification of the selected antiangiogenic agent.
NTRK fusion-positive tumors — For the rare patient with a neurotrophic tyrosine receptor kinase (NTRK) fusion-positive advanced or metastatic HCC, we suggest initial treatment with a TRK-inhibitor rather than other systemic agents due to the high ORRs and durable treatment responses seen with these agents. Options include larotrectinib, entrectinib, and repotrectinib. Further details are discussed separately. (See "TRK fusion-positive cancers and TRK inhibitor therapy".)
ASSESSING TREATMENT RESPONSE —
Patients who are receiving initial systemic therapy for advanced or metastatic HCC should continue treatment until disease progression or intolerance. To assess for treatment response, we evaluate the patient's clinical status, obtain imaging studies, and serially measure the tumor marker alpha-fetoprotein (AFP; if initially elevated). Reimaging to assess treatment response is typically carried out using contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) of the abdomen and pelvis after six to eight weeks of therapy and then every two to three months thereafter. (See "Assessment of tumor response in patients receiving systemic and nonsurgical locoregional treatment of hepatocellular cancer", section on 'Techniques for assessment of treatment response'.)
Assessing response to regimens with targeted agents — For patients treated with regimens that contain targeted agents (such as antiangiogenic therapy), we assess for treatment response using modified Response Evaluation Criteria in Solid Tumors (RECIST) for HCC (table 3) rather than standard RECIST criteria (table 4) for solid tumors. These criteria, which mainly measure tumor viability after treatment with targeted agents, were proposed by an HCC expert consensus panel [50-52]. Conventional response criteria, such as the standard RECIST criteria may not accurately reflect response to treatment or tumor viability, particularly with antiangiogenic agents which are cytostatic rather than cytotoxic. Although these criteria may also be used to assess tumor response in patients who receive combination of immunotherapy and antiangiogenic agents (eg, atezolizumab plus bevacizumab), clinicians should review the results of such imaging studies with radiology and/or a multidisciplinary tumor board. (See "Assessment of tumor response in patients receiving systemic and nonsurgical locoregional treatment of hepatocellular cancer", section on 'Measuring tumor dimensions versus tumor viability'.)
Early assessment of response to molecularly targeted agents can be challenging since tumor necrosis, extension, and radiologic appearance can be inhomogeneous. As an example, the predominant patterns of HCC response after sorafenib on dynamic contrast-enhanced MRI are T1 hyperintensity due to coagulation, T2 tumor hyperintensity due to edema, and diminished enhancement in the arterial phase due to necrosis. On CT, sorafenib decreases HCC enhancement without necessarily affecting tumor size. As with locoregional therapies, residual thick and nodular foci of arterial enhancement within HCC suggest residual viable tumor. Similarly, the use of bevacizumab may result in a meaningful decrease in vascular enhancement without change of lesion size, which is indicative of a good early response. Furthermore, an increase in tumor size due to necrosis has been reported in patients treated with antiangiogenic tyrosine kinase inhibitors (TKIs), a phenomenon referred to as "pseudoprogression" [53].
Further details on assessing tumor response to systemic therapy in HCC are discussed separately. (See "Assessment of tumor response in patients receiving systemic and nonsurgical locoregional treatment of hepatocellular cancer".)
Assessing response to immunotherapy — The patterns of response to treatment with immunotherapy (eg, immune checkpoint inhibitors) alone differ from those with molecularly targeted agents or chemotherapy. Immune-related response criteria have been proposed to properly recognize the nontraditional patterns of response occasionally seen with immunotherapy. This subject is discussed separately. (See "Principles of cancer immunotherapy", section on 'Immunotherapy response criteria'.)
SECOND-LINE THERAPY FOR PATIENTS WITH CHILD-PUGH CLASS A CIRRHOSIS —
For patients with no worse than Child-Pugh class A cirrhosis who progress on initial systemic therapy, selection of second-line therapy is generally based on prior treatments received as well as patient performance status and comorbidities. The optimal approach is not established, and clinical trial enrollment is encouraged, where available.
Prior immunotherapy-containing regimen
Lenvatinib — For patients who progress on initial therapy that contains immunotherapy (eg, atezolizumab plus bevacizumab, durvalumab plus tremelimumab, or single-agent immunotherapy), we suggest second-line therapy with lenvatinib rather than other systemic agents. Appropriate alternatives include cabozantinib, regorafenib, sorafenib, or ramucirumab (for alpha-fetoprotein [AFP] ≥400 ng/mL).
For patients with advanced HCC who progress on immunotherapy-containing regimens, there are limited data for the optimal approach to second-line therapy and further randomized trials are needed. The rationale for the empiric use of second-line antiangiogenic agents in disease refractory to immunotherapy alone is the lack of exposure to these agents, so the tumors should theoretically be susceptible. Additionally, patients who were previously treated with atezolizumab plus bevacizumab, a vascular endothelial growth factor (VEGF) inhibitor, demonstrate treatment responses to alternative antiangiogenic agents [54].
Although data are limited, most observational studies in patients who progress on atezolizumab plus bevacizumab support the use of second-line lenvatinib over other antiangiogenic agents, which is associated with longer overall survival (OS) [54-56]. Lenvatinib has also been evaluated in early-phase clinical trials in this population [57].
●A retrospective study evaluating various second-line regimens included 233 patients with advanced HCC who progressed on initial therapy with atezolizumab plus bevacizumab [54]. Second-line regimens used included lenvatinib, sorafenib, cabozantinib, regorafenib, ramucirumab, and immunotherapy. Among the 233 patients who progressed on atezolizumab plus bevacizumab, second-line therapy with lenvatinib was associated with longer OS (median OS 17 months) relative to sorafenib (median OS 14 months) and cabozantinib (median OS 12 months). There was no difference in OS for sorafenib versus cabozantinib or other second-line therapies. Similar results favoring lenvatinib over sorafenib have been seen in other observational studies [56].
●In an open-label phase II trial, 50 patients with advanced HCC who progressed on atezolizumab plus bevacizumab were treated with lenvatinib at 12 mg or 8 mg orally daily until disease progression or unacceptable toxicity. In preliminary results, median progression-free survival (PFS) and OS were five and nine months [57]. The objective response rate (ORR) and disease control rates were 12 and 48 percent, respectively. No new toxicity signals with lenvatinib were noted.
Prior antiangiogenic tyrosine kinase inhibitors — For most patients with no worse than Child-Pugh class A cirrhosis who progress on initial therapy with antiangiogenic tyrosine kinase inhibitors (TKIs; eg, lenvatinib or sorafenib) and have no prior history of liver transplantation, we suggest second-line therapy with nivolumab plus ipilimumab rather than other immunotherapy options or an alternative antiangiogenic TKI. Pembrolizumab is an appropriate alternative for those who are anticipated to not tolerate the potential toxicities of nivolumab plus ipilimumab. Immunotherapy offers the potential for higher ORRs (including some complete responses) with a more favorable toxicity profile than antiangiogenic agents. (See 'Immunotherapy' below.)
For those patients who progress on initial therapy with sorafenib or lenvatinib and are ineligible for immunotherapy, options include alternative antiangiogenic agents such as regorafenib, cabozantinib, or ramucirumab (for AFP ≥400 ng/mL). (See 'Regorafenib' below and 'Cabozantinib' below and 'Ramucirumab' below.)
Immunotherapy
Nivolumab plus ipilimumab — For patients with advanced unresectable or metastatic HCC who progress on initial therapy with an antiangiogenic TKI, the combination of nivolumab plus ipilimumab (table 5) is an option for second-line therapy that resulted in durable responses in a randomized phase I/II trial [28,58].
Nivolumab is administered at 1 mg/kg followed by ipilimumab 3 mg/kg on the same day, every three weeks for four doses, then nivolumab alone (240 mg every two weeks or 480 mg every four weeks).
In a randomized, open-label phase I/II trial (CheckMate 040), 148 patients with advanced HCC with no worse than Child-Pugh class A cirrhosis who previously received sorafenib were randomly assigned to one of the following three treatments [28,58]:
●Nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every three weeks for four doses, followed by nivolumab 240 mg every two weeks.
●Nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every three weeks for four doses, followed by nivolumab 240 mg every two weeks.
●Nivolumab 3 mg/kg every two weeks plus ipilimumab 1 mg/kg every six weeks.
At a median follow-up of 63 months, nivolumab 1 mg/kg plus ipilimumab 3 mg/kg dosing demonstrated higher OS (median OS 22 months, five-year OS 29 percent) relative to nivolumab 3 mg/kg plus ipilimumab 1 mg/kg (median OS 13 months, five-year OS 19 percent) and nivolumab every two weeks plus ipilimumab every six weeks (median OS 13 months, five-year OS 21 percent), although the differences were not statistically significant [58]. This combination also demonstrated a nonstatistically significant trend towards higher ORRs (34 percent) relative to the two other treatment arms (27 and 29 percent, respectively). Median duration of response was also longer for this combination (median 51 months) relative to the other two treatment arms (15 and 22 months, respectively). However, grade 3 to 4 toxicity rates were higher with this combination (55 percent) relative to the other treatment arms (31 and 35 percent, respectively) [58]. In all three groups combined, virologic breakthrough (defined as a one-log increase in hepatitis B virus [HBV] deoxyribonucleic acid [DNA] or hepatitis C virus [HCV] ribonucleic acid [RNA] from baseline) was observed in 9 percent of patients infected with HBV patients and 10 percent of patients infected with HCV [28]. (See 'Screening for viral hepatitis' above.)
Based on these data, nivolumab in combination with ipilimumab has accelerated approval from the US Food and Drug Administration (FDA) for adult patients with HCC who have been previously treated with sorafenib [13].
Pembrolizumab — In patients with advanced unresectable or metastatic HCC with no worse than Child-Pugh class A cirrhosis who progressed on sorafenib or lenvatinib and have not previously received immunotherapy, pembrolizumab (table 6) is a reasonable alternative to nivolumab plus ipilimumab. Pembrolizumab is particularly useful for patients who are anticipated to not tolerate the potential toxicities of combination immunotherapy.
The efficacy of pembrolizumab in advanced HCC refractory to sorafenib was initially demonstrated in a phase II trial (KEYNOTE-224) [59,60]. In subsequent placebo-controlled phase III trials, pembrolizumab improved ORRs; it also improved OS and PFS in one of the trials conducted in patients from Asia (KEYNOTE-394) [61,62]. Data are as follows:
●In an international, double-blind, placebo-controlled phase III trial (KEYNOTE-240), 413 patients with advanced HCC and Child-Pugh class A cirrhosis with radiographic progression or intolerance of sorafenib were randomly assigned 2:1 to either pembrolizumab or placebo, in addition to best supportive care [61]. At a median follow-up of approximately 14 months, relative to placebo, pembrolizumab did not demonstrate a statistically significant difference in OS (median 14 versus 11 months, hazard ratio [HR] 0.78, 95% CI 0.61-0.998) or PFS (median 3 versus 2.8 months, HR 0.72, 95% CI 0.57-0.90) because prespecified efficacy boundaries were not reached. However, pembrolizumab improved the ORR over placebo (18 versus 4 percent) and had more complete responders (six versus none). Treatment responses to pembrolizumab were also durable (median duration of response 14 months, range of 2 to ≥24 months).
●In another double-blind, placebo-controlled phase III trial (KEYNOTE-394), 413 patients with advanced, treatment-refractory HCC from Asia (mainland China, Hong Kong, the Republic of Korea, Malaysia, and Taiwan) were randomly assigned to either pembrolizumab or placebo, in addition to best supportive care [62]. Patients had Child-Pugh class A cirrhosis and had either progressed on or were intolerant to sorafenib or oxaliplatin-based chemotherapy. At a median follow-up of 34 months, compared with placebo, pembrolizumab improved PFS (median 2.6 versus 2.3 months, HR 0.74, 95% CI 0.60-0.92) and OS (median 15 versus 13 months, HR 0.79, 95% CI 0.63-0.99). Pembrolizumab also improved ORR over placebo (13 versus 1 percent), including six complete responders (2 percent). The grade ≥3 toxicity rate for pembrolizumab was 14 percent.
Pembrolizumab is approved by the FDA for the treatment of patients with HCC secondary to hepatitis B who have received prior systemic therapy other than a programmed cell death protein 1 (PD-1)/programmed cell death ligand-1 (PD-L1) containing regimen [13].
Other immunotherapy agents
●Nivolumab – We do not offer nivolumab monotherapy as second-line therapy in patients with advanced HCC who progress on or are intolerant of TKIs such as sorafenib.
Efficacy for nivolumab was initially suggested in a phase I/II study (CheckMate 040) of patients with advanced HCC and Child-Pugh class A or B (total score of 7 or less (table 2)) cirrhosis who progressed on, refused, or were intolerant of sorafenib [63,64] or were sorafenib-naïve [64]. Although the FDA initially granted accelerated approval to nivolumab for the treatment of HCC in patients previously treated with sorafenib, this approval was withdrawn when nivolumab failed to improve OS over sorafenib as initial therapy in a phase III trial (CheckMate 459) [37]. (See 'Regimens not used' above.)
●Avelumab – The role of avelumab is not established in patients with advanced HCC and no worse than Child-Pugh class A cirrhosis who previously received sorafenib. In a phase II trial of 30 such patients, avelumab resulted in three partial responses (10 percent) and prolonged stable disease in 19 patients (63 percent) [65]. Tumoral overexpression of PD-L1 did not affect the antitumor response. The median time to tumor progression (TTP) and OS durations were 4 and 14 months, respectively. Treatment was well tolerated with few grade 3 toxicities.
Tyrosine kinase inhibitors
Regorafenib — Regorafenib is an option for patients with HCC and no worse than Child-Pugh class A cirrhosis who progress on sorafenib or lenvatinib and are ineligible for immunotherapy. We also offer it to patients who progress on initial immunotherapy-containing regimens. We do not offer regorafenib to patients who were intolerant of sorafenib, given the pharmacologic similarities between these two drugs. We start regorafenib at a lower dose (typically 80 mg once daily) and escalate the dose as tolerated.
Regorafenib was evaluated in a double-blind, placebo-controlled phase III trial (RESORCE) of 573 patients with advanced HCC and Child-Pugh class A liver function who progressed on sorafenib [66]. At a median follow-up of seven months, regorafenib improved OS relative to placebo (median 10.6 versus 7.8 months, HR 0.63, 95% CI 0·50-0·79). Regorafenib also improved ORRs (11 versus 4 percent) and disease control (65 versus 36 percent), which were assessed using modified RECIST for HCC. The most common grade 3 or 4 toxicities with regorafenib were hypertension (15 versus 5 percent relative to placebo), hand-foot skin reaction (13 versus 1 percent), fatigue (9 versus 5 percent), and diarrhea (3 versus 0 percent). Regorafenib also required dose modification more frequently for adverse events than placebo (68 versus 31 percent).
A meta-analysis of five placebo-controlled randomized trials of patients with advanced HCC who progressed on sorafenib evaluated various second-line therapies (pembrolizumab, cabozantinib, regorafenib, ramucirumab, brivanib) [12]. In this study, an OS advantage relative to placebo was limited to second-line regorafenib (HR 0.62, 95% CI 0.51-0.75) and second-line cabozantinib (HR 0.76, 95% CI 0.63-0.92). Indirect comparisons between the individual drugs were uninformative.
Regorafenib is approved by the FDA for the treatment of adult patients with HCC who had been previously treated with sorafenib [13].
Cabozantinib — Cabozantinib, a multitargeted antiangiogenic TKI, is an option for patients with HCC and no worse than Child-Pugh class A cirrhosis who progress on sorafenib or lenvatinib and are ineligible for immunotherapy. We also offer it to patients who progress on initial immunotherapy-containing regimens.
Based on data from a phase II trial [67], cabozantinib was evaluated in a double-blind, placebo-controlled phase III trial (CELESTIAL) of 707 patients with advanced and progressing HCC and no worse than Child-Pugh class A cirrhosis [68]. Among patients receiving second- or third-line treatment after prior treatment with sorafenib, cabozantinib improved OS relative to placebo (median 10.2 versus 8 months), and the difference was more pronounced when the analysis was limited to patients whose only prior therapy was sorafenib (median OS 11.3 versus 7.2 months). In a subsequent analysis, cabozantinib improved outcomes versus placebo across a range of baseline AFP levels [69]. The most common grade 3 or 4 adverse events with cabozantinib were palmar-plantar erythrodysesthesia (17 versus 0 percent in the placebo group), hypertension (16 versus 2 percent), increased aspartate aminotransferase (12 versus 7 percent), fatigue (10 versus 4 percent), and diarrhea (10 versus 2 percent) [68].
Cabozantinib is approved by the FDA for the treatment of adult patients with HCC who have been previously treated with sorafenib [13].
Ramucirumab — Ramucirumab is an option for patients with HCC, no worse than Child-Pugh class A cirrhosis, and high AFP levels (≥400 ng/mL) who progress on sorafenib or lenvatinib and are ineligible for immunotherapy. We also offer it to patients who progress on initial immunotherapy-containing regimens.
Ramucirumab is a recombinant monoclonal antibody of the immunoglobulin G subclass 1 (IgG1) class that binds to vascular endothelial growth factor receptor (VEGFR-2), blocking receptor activation. A modest degree of activity in patients with no prior systemic treatment was suggested in a phase II trial of 42 patients; the ORR was 10 percent, and median OS was 12 months [70]. However, in the absence of a trial directly comparing ramucirumab with sorafenib, first-line ramucirumab cannot be considered a standard approach.
On the other hand, ramucirumab is an appropriate second-line option after failure of sorafenib, but benefit appears limited to those with initially high AFP levels:
●A trial of ramucirumab versus placebo in patients with advanced HCC following first-line therapy with sorafenib (the REACH trial) failed to show a significant survival advantage relative to placebo (median OS 9.2 versus 7.6 months) [71]. An unplanned subset analysis suggested the potential for a survival benefit in patients with a high initial level of AFP (>400 ng/mL) at diagnosis (median survival 7.8 versus 4.2 months).
●Benefit in this subgroup was confirmed in a randomized phase III trial (the REACH-2 trial), which randomly assigned 292 patients with HCC, no worse than Child-Pugh class A cirrhosis, and a serum AFP ≥400 ng/mL who had disease progression on first-line sorafenib to ramucirumab versus placebo [72]. Ramucirumab was associated with significantly better OS (8.5 versus 7.3 months, HR 0.71, 95% CI 0.53-0.95), although the magnitude of benefit (1.2 months) was numerically less than that seen in the subset of patients with a high AFP enrolled in the REACH trial (3.6 months). Ramucirumab also was associated with a higher ORR (5 versus 1 percent) and overall disease control rate (60 versus 39 percent). One potential advantage of ramucirumab over other molecularly targeted treatments for second-line therapy after progression on sorafenib is the absence of hand-foot skin reaction.
Ramucirumab is approved by the FDA for second-line treatment of adult patients with HCC who have an AFP level ≥400 ng/mL and have been previously treated with sorafenib [13].
Other agents
●Apatinib – In a placebo-controlled phase III trial of 393 patients with advanced HCC who were refractory to sorafenib or oxaliplatin-based chemotherapy and no worse than Child-Pugh class A or B (≤7) cirrhosis, apatinib, an oral VEGFR-2 inhibitor, improved OS and was well-tolerated [73]. Apatinib only available in China where it is approved for second-line treatment of advanced gastric cancer.
Special populations
RET fusion-positive tumors — For patients with advanced unresectable or metastatic HCC whose tumors test positive for a rearranged during transfection (RET) gene fusion, who progress on prior systemic therapies, and have no other acceptable treatment options, we offer selpercatinib. In a phase I/II basket trial (LIBRETTO-001) of various treatment-refractory cancer histologies that were RET-fusion positive, selpercatinib demonstrated durable treatment responses and was well-tolerated [74]. However, no patients with HCC were included in this trial.
Selpercatinib has accelerated approval from the FDA for the treatment of adult patients with locally advanced or metastatic solid tumors with a RET gene fusion that has progressed on or following prior systemic treatment or who have no satisfactory alternative treatment options [13].
dMMR/MSI-H tumors — Most patients with advanced unresectable or metastatic HCC receive immunotherapy as part of treatment. For the rare patients with a mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) tumor who progress on prior systemic therapies and have not received prior immunotherapy, options include pembrolizumab or dostarlimab. Further details are discussed separately. (See "Overview of advanced unresectable and metastatic solid tumors with DNA mismatch repair deficiency or high tumor mutational burden", section on 'Primary site-independent approaches'.)
PATIENTS WITH CHILD-PUGH CLASS B CIRRHOSIS
Immunotherapy — For patients with advanced HCC and Child-Pugh class B cirrhosis (table 2), Eastern Cooperative Oncology Group (ECOG) performance status <2 (table 1), and minimal comorbidities, we suggest initial therapy with single-agent immunotherapy rather than other systemic agents. Immunotherapy is generally safe and can achieve modest objective responses and disease control in this population [75,76]. Options for single-agent immunotherapy are the same as those with Child-Pugh class A disease (durvalumab, tislelizumab, pembrolizumab). However, single-agent immunotherapy is generally less effective in patients with advanced HCC and Child-Pugh class B compared with Child-Pugh class A disease [76]. (See 'Single-agent immunotherapy' above.)
A systematic review and meta-analysis of 22 randomized clinical trials and observational studies evaluated the efficacy and safety of immunotherapy in 699 patients with advanced HCC and Child-Pugh class B disease and 2114 patients with advanced HCC and Child-Pugh class A [76]. Single-agent immunotherapy agents evaluated included nivolumab, pembrolizumab, camrelizumab, and atezolizumab. For patients with Child-Pugh class B disease treated with single-agent immunotherapy, the pooled objective response rate (ORR) and disease control rates were 12 and 42 percent, respectively; the pooled median progression-free survival (PFS) and overall survival (OS) were three and six months, respectively. Patients with Child-Pugh class B disease who were treated with immunotherapy generally achieved lower ORRs and shorter OS and PFS than those with Child-Pugh class A disease. However, in some of the included studies, immunotherapy demonstrated prolonged responses and improved liver function within some patients with Child-Pugh class B disease [77,78]. Patients with Child-Pugh class B disease had similar rates of grade ≥3 treatment-related adverse events (12 versus 11 percent) and lower rates of grade ≥3 immune-related adverse events (7 versus 12 percent) compared with Child-Pugh class A disease.
Antiangiogenic agents — For patients with advanced HCC and Child-Pugh class B cirrhosis, single-agent antiangiogenic therapy is an acceptable option for initial therapy. Although these regimens are effective, ORRs are modest and antiangiogenic agents may be difficult to tolerate in these patients who may be quite ill at baseline.
Sorafenib — For patients with Child-Pugh class B cirrhosis, sorafenib as an option for initial therapy is effective, but it can be difficult to tolerate in patients who are already ill due to their disease or other comorbidities.
For patients with Child-Pugh class B cirrhosis, we administer sorafenib at an initial dose of 200 mg twice daily in patients with a total bilirubin 1.5 to 3 times the upper limit of normal (ULN). The daily dose can then be increased in 200 mg increments approximately every five days (or as tolerated) until the target dose of 400 mg twice daily is reached. This approach results in less toxicity and lower rates of drug discontinuation without compromising efficacy [20,21]. We do not administer sorafenib to patients with more severe degrees of hyperbilirubinemia. (See "Hepatotoxicity of molecularly targeted agents for cancer therapy", section on 'Sorafenib'.)
There are limited studies on the efficacy of sorafenib in patients with advanced HCC and Child-Pugh class B cirrhosis [79-82]. Data are as follows:
●In a placebo-controlled phase III trial (SHARP) of patients with advanced HCC (Child-Pugh class A cirrhosis in 95 percent; Child-Pugh class B cirrhosis in 5 percent), sorafenib improved OS. (See 'Sorafenib' above.)
The safety and efficacy of sorafenib in patients with elevated transaminase levels were studied in a subgroup analysis of the SHARP trial [83]. Patients with mild or moderate liver dysfunction (≥1.8 times ULN) did not experience increased hepatic or other toxicity. Although median OS was diminished in patients with moderate liver dysfunction treated with either sorafenib or placebo, median time to tumor progression (TTP) and OS favored the sorafenib group regardless of transaminase levels. The study concluded that sorafenib was safe and effective, even in patients with mild or moderately elevated baseline transaminase levels and that hepatic function remained stable over the course of sorafenib therapy.
●A meta-analysis of 30 studies included 8678 patients with advanced HCC (79 percent with Child-Pugh class A cirrhosis and 19 percent with Child-Pugh class B cirrhosis) treated with first-line sorafenib [82]. Child-Pugh class B cirrhosis was associated with lower OS relative to Child-Pugh class B cirrhosis (median OS 4.6 versus 8.8 months). However, both groups had similar rates of grade 3 or 4 treatment-related toxicity and treatment discontinuation without progression. Similar results for sorafenib have been seen in other observational studies [84].
Other agents — In patients with advanced HCC and Child-Pugh class B disease, other antiangiogenic agents that have been evaluated include regorafenib [85], cabozantinib [86,87], and lenvatinib [88,89]. In this population, these agents have modest efficacy but are associated with increased toxicity.
Chemotherapy — For patients with Child-Pugh class B cirrhosis who progress on or are ineligible for sorafenib, chemotherapy can achieve modest responses with limited survival benefit, but patients must weigh this against the possible toxicities and their predicted life expectancy.
For patients with good performance status and minimal comorbidities, chemotherapy options include gemcitabine plus oxaliplatin (GEMOX) [90-92] and FOLFOX [93].
For less fit patients or those with hyperbilirubinemia, options include fluoropyrimidines (oral capecitabine [94,95], infusional fluorouracil plus leucovorin [96,97]) and mitoxantrone [98,99]. Anthracyclines (doxorubicin [100-108], epirubicin [109,110], pegylated liposomal doxorubicin [111-113]) have also been studied in advanced HCC, but require dose modification in patients with liver dysfunction. (See "Hepatotoxicity of chemotherapy and other cytotoxic agents", section on 'Anthracyclines'.)
PATIENTS WITH CHILD-PUGH CLASS C CIRRHOSIS —
Supportive care alone is appropriate for patients with Child-Pugh class C cirrhosis (table 2), a poor functional status (Eastern Cooperative Oncology Group [ECOG] 3 to 4) (table 1), and/or significant comorbidities. Most patients with Child-Pugh class C cirrhosis have liver function that is insufficient to tolerate systemic therapy. In addition, systemic therapy is unlikely to benefit them because of their limited overall survival (OS) [79,114].
Sorafenib is unlikely to benefit patients with Child-Pugh class C cirrhosis. As an example, in a retrospective study of 59 patients with HCC, median OS with sorafenib therapy for those with Child-Pugh class A, B, and C cirrhosis was eight, four, and two months, respectively [80].
SOCIETY GUIDELINE LINKS —
Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hepatocellular carcinoma".)
INFORMATION FOR PATIENTS —
UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Liver cancer (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Indications for systemic therapy – Systemic therapy is an appropriate option for patients with advanced unresectable or metastatic hepatocellular carcinoma (HCC) not amenable to curative or locoregional therapy, adequate performance status (table 1), and appropriate underlying liver function (table 2). Patients who are candidates for systemic therapy have any of the following clinical scenarios (see 'Indications for systemic therapy' above):
•Extrahepatic metastatic disease
•Tumors confined to the liver that progress after locoregional therapies
•Tumors with extensive vascular invasion (figure 1)
•Large intrahepatic tumor burden (ie, diffuse and/or bilateral lobar involvement) unsuitable for locoregional approaches (algorithm 1)
●Initial therapy for patients with Child-Pugh class A cirrhosis
•No prior liver transplantation – For most patients with an Eastern Cooperative Oncology Group (ECOG) performance status less than 2 (table 1), no worse than Child-Pugh class A cirrhosis, and no prior history of liver transplantation, we suggest either atezolizumab plus bevacizumab or tremelimumab plus durvalumab rather than an antiangiogenic agent alone or a single-agent immune checkpoint inhibitor (Grade 2C). Both regimens improved overall survival (OS) relative to antiangiogenic agents in separate phase III trials. (See 'Initial therapy for patients with Child-Pugh class A cirrhosis' above.)
Selection of therapy is based on patient symptoms, comorbidities, performance status, rate of tumor progression, and clinician preference. (See 'Selection of therapy' above.)
-For patients whose disease is severely symptomatic or rapidly progressive, we offer atezolizumab plus bevacizumab due to the solid objective response rates (ORRs; up to 30 percent) seen with this regimen. (See 'Atezolizumab plus bevacizumab' above.)
-For patients with a higher risk of bleeding, a recent arterial thrombotic event, active wounds, gastrointestinal perforation, or an absolute contraindication to bevacizumab, we offer tremelimumab plus durvalumab. One exception is a patient with treated esophageal varices within the past six months, for whom atezolizumab plus bevacizumab is also an option. (See 'Tremelimumab plus durvalumab' above.)
•Ineligible for combination therapy – For those who are ineligible for (or are anticipated to poorly tolerate) initial combination immunotherapy-based regimens, appropriate alternatives include an antiangiogenic tyrosine kinase inhibitor (TKI) or single-agent immunotherapy. (See 'Ineligible for combination therapy' above.)
-Antiangiogenic agents – For patients who select an antiangiogenic TKI, we suggest lenvatinib rather than sorafenib (Grade 2B), which is better tolerated and demonstrates higher ORRs with similar OS. (See 'Lenvatinib' above.)
-Single-agent immunotherapy – For patients who select immunotherapy, options include durvalumab, tislelizumab, and pembrolizumab. Any of these agents are appropriate as they have not been directly compared in randomized trials. (See 'Single-agent immunotherapy' above.)
•Prior liver transplantation – For patients who recur with advanced unresectable or metastatic HCC after orthotopic liver transplantation, we suggest initial therapy with an antiangiogenic TKI rather than other systemic agents (Grade 2C). Options include lenvatinib or sorafenib. We do not offer regimens that contain immunotherapy following liver transplantation because of the high rate of allograft rejection. Patients interested in immunotherapy should be treated in the context of a clinical trial and with transplant hepatology support. (See 'Prior liver transplantation' above.)
•NTRK fusion-positive tumor – For the rare patient with a neurotrophic tyrosine receptor kinase (NTRK) fusion-positive advanced or metastatic HCC, we suggest initial treatment with a TRK-inhibitor rather than other systemic agents (Grade 2C) due to the high ORRs and durable treatment responses seen with these agents. Options include larotrectinib, entrectinib, and repotrectinib. (See "TRK fusion-positive cancers and TRK inhibitor therapy".)
●Second-line therapy for patients with Child-Pugh class A cirrhosis – For patients with no worse than Child-Pugh class A cirrhosis, selection of second-line therapy is based on prior treatment received as well as patient performance status and comorbidities. The optimal approach is not established and clinical trial enrollment is encouraged, where available.
•Prior immunotherapy-containing regimen – For patients who progress on initial therapy that contains immunotherapy (eg, atezolizumab plus bevacizumab, durvalumab plus tremelimumab, or single-agent immunotherapy), we suggest second-line therapy with lenvatinib rather than other systemic agents (Grade 2C). Alternative options include cabozantinib, regorafenib, sorafenib, or ramucirumab (for alpha-fetoprotein [AFP] ≥400 ng/mL). (See 'Prior immunotherapy-containing regimen' above and 'Tyrosine kinase inhibitors' above.)
•Prior antiangiogenic TKI – For patients who progress on initial therapy with antiangiogenic TKIs (eg, lenvatinib or sorafenib) and have no prior history of liver transplantation, we suggest second-line therapy with nivolumab plus ipilimumab rather than other immunotherapy options or an alternative antiangiogenic TKI (Grade 2C). Pembrolizumab is an appropriate alternative for those who are anticipated to not tolerate the potential toxicities of nivolumab plus ipilimumab. (See 'Nivolumab plus ipilimumab' above and 'Pembrolizumab' above.)
For those patients who are ineligible for immunotherapy, options include alternative antiangiogenic agents such as regorafenib, cabozantinib, or ramucirumab (for AFP ≥400 ng/mL). (See 'Regorafenib' above and 'Cabozantinib' above and 'Ramucirumab' above.)
●Patients with Child-Pugh class B cirrhosis – For patients with Child-Pugh class B cirrhosis (table 2), ECOG performance status <2 (table 1), and minimal comorbidities, we suggest initial therapy with single-agent immunotherapy (durvalumab, tislelizumab, or pembrolizumab) rather than other systemic agents, which are generally safe and offer modest ORRs and disease control (Grade 2C). Antiangiogenic therapy is an appropriate alternative that is effective, but these agents may be difficult to tolerate in these patients who may be quite ill at baseline. (See 'Patients with Child-Pugh Class B cirrhosis' above.)
●Patients with Child-Pugh class C cirrhosis – For patients with Child-Pugh class C cirrhosis (table 2), a poor functional status (ECOG 3 to 4) (table 1), and/or significant comorbidities, we offer supportive care. (See 'Patients with Child-Pugh class C cirrhosis' above.)
●Assessing treatment response – Patients who are receiving initial systemic therapy for advanced or metastatic HCC should continue treatment until disease progression or intolerance. (See "Assessment of tumor response in patients receiving systemic and nonsurgical locoregional treatment of hepatocellular cancer", section on 'Techniques for assessment of treatment response'.)
•To assess for treatment response, we evaluate the patient's clinical status, obtain imaging studies, and serially measure the tumor marker AFP (if initially elevated).
•Imaging is typically carried out using contrast-enhanced CT or MRI of the abdomen and pelvis after six to eight weeks of therapy and then every two to three months thereafter.
•Patients treated with regimens that contain targeted agents should be assessed for treatment response using modified Response Evaluation Criteria in Solid Tumors (RECIST) for HCC (table 3). Patients treated with immunotherapy plus antiangiogenic agents (eg, atezolizumab plus bevacizumab) may be evaluated with these criteria, but clinicians are advised to discuss the results of such imaging studies with radiology and/or a multidisciplinary tumor board.
•For patients treated with immunotherapy only, regimens should be assessed for treatment response using immunotherapy response criteria. (See "Principles of cancer immunotherapy", section on 'Immunotherapy response criteria'.)
