Updates in Treatment of Unresectable Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is the sixth-leading cause of cancer-related death in the United States, with an estimated 41,630 new diagnoses and 29,840 deaths in 2024.¹ Globally, HCC ranks as the sixth most common cancer and third in cancer-related mortality.² The median age at diagnosis is 67 years, and incidence rates for males are 2 to 3 times greater than for females due to an imbalance in risk factors.³ In the United States, the overall incidence has declined since 2011, and mortality plateaued in 2013, likely due to advances in prevention and treatment.⁴ However, the 5-year relative survival rate remains low, at 21.7%, highlighting the aggressive nature of HCC and the need for improvements in treatment.³ To this end, systemic therapies such as immunotherapy and anti-VEGF monoclonal antibodies have dramatically transformed the treatment landscape in the past 5 years. 

Risk Factors and Diagnosis

Cirrhosis is a leading risk factor for HCC, with an annual incidence of approximately 2% in affected patients. Persistent liver injury from cirrhosis, often due to viral hepatitis (B or C), promotes inflammation, DNA damage, and abnormal cell growth, increasing the risk of malignant transformation of liver cells into HCC. Other causes of cirrhosis include alcohol use and metabolic dysfunction–associated steatotic liver disease.⁴

HCC can be diagnosed with noninvasive imaging (ie, multiphase computed tomography or magnetic resonance imaging), which differs from most cancers requiring histologic confirmation via biopsy. The Barcelona Clinic Liver Cancer (BCLC) staging system, used by the American Association for the Study of Liver Diseases (AASLD) and the European Society of Medical Oncology (ESMO), stratifies patients into prognostic groups to guide treatment. Earlier stages of HCC (BCLC stage 0 through stage A) are managed with locoregional treatments, including liver transplantation, ablation, or resection. Intermediate-stage HCC (BCLC stage B) may involve liver transplantation, resection, or transarterial therapies. Systemic therapies are utilized in more advanced stages of HCC (BCLC stages B and C) that are classified as locally advanced, unresectable, or metastatic disease.^4,5

Until recently, oral tyrosine kinase inhibitors (TKIs) were the standard systemic treatment for more advanced stages of HCC. Over the past 5 years, the treatment landscape has evolved with the introduction of immunotherapy, used either alone or in combination with anti-VEGF therapy. As emerging research investigates these therapeutic drug classes in novel combinations at various stages of care, pharmacists play a vital role in applying the latest evidence to meaningful patient outcomes. This review will provide guidance for pharmacists caring for patients with locally advanced, unresectable, or metastatic HCC by summarizing the latest data, comparing available therapy options, and examining pharmacological and safety profiles of treatment alongside patient-specific considerations.

First-Line Systemic Treatment

The Era of TKIs

Before the introduction of sorafenib (Nexavar; Bayer HealthCare Pharmaceuticals), there was no established standard of care for treating advanced HCC. The approval of sorafenib in 2007 and lenvatinib (Lenvima; Eisai) in 2018 marked the beginning of the TKI era in the treatment of HCC.^6,7 The SHARP (NCT00105443) trial demonstrated prolonged median overall survival (OS) of sorafenib by 3 months compared with placebo, establishing sorafenib as the standard of care in advanced HCC for over a decade.⁸ After the approval of sorafenib, numerous other TKIs were evaluated but failed to demonstrate noninferiority until the REFLECT (NCT01761266) trial determined that lenvatinib was noninferior in median OS compared with sorafenib (13.6 vs 12.3 months) with a higher overall response rate (ORR) (24.1% vs 9.2%).^9,10 Additional efficacy data are summarized in Table 1.

Compared with sorafenib, lenvatinib has a higher incidence of hypertension and proteinuria but fewer symptomatic adverse events (AEs) such as hand-foot syndrome, diarrhea, and alopecia, as demonstrated in Table 2. The REFLECT trial established lenvatinib as an alternative to sorafenib among patients with Child-Turcotte-Pugh (CTP) class A liver function, and agent selection is often influenced by safety profile, dosing frequency, and insurance coverage. Among patients with CTP class B liver function, there are data to support the safety of sorafenib, with no significant pharmacokinetic differences between CTP class A and CTP class B patients.¹¹ In patients with impaired liver and/or renal dysfunction, a pharmacokinetic study provides alternative empiric sorafenib dosing considerations.¹² Data on the use of lenvatinib in CTP class B liver function remains limited; thus, CTP status may be an additional factor to consider between the 2 agents.¹³ Although TKIs provide OS benefits, newer agents aim to extend OS, improve ORR, and decrease AEs that significantly impact quality of life.⁸

The Shift to Immunotherapy

The liver naturally maintains a balance between immunosuppressive cells, such as regulatory T cells (Tregs), and immune-activating cells, such as cluster of differentiation 8+ (CD8+) cytotoxic T cells, to prevent excessive immune responses while maintaining the ability to mount an antitumor defense. In HCC, this balance is disrupted. Chronic inflammation from viral infections (eg, hepatitis B or C) exhausts CD8+ cytotoxic T cells, while alcoholic steatohepatitis suppresses CD8+ cytotoxic T cells, weakening the ability to mount an effective antitumor response. As a result, the weakened antitumor response permits tumor progression, making immune dysregulation a key driver of HCC development.¹⁴

Over the past decade, extensive clinical trial efforts have explored how immunotherapy can restore immune balance by reactivating exhausted or suppressed CD8+ cytotoxic T cells and overcoming immunosuppression to improve outcomes in HCC. Since 2020, the first-line treatment landscape for advanced HCC has shifted toward immunotherapy-based regimens. For patients who are ineligible for immunotherapy, TKIs such as sorafenib or lenvatinib remain first-line options.^4,5,15

Immune Checkpoint Inhibitor Plus VEGF Inhibitor

Research into the immunological pathogenesis of HCC has driven the investigation of immune checkpoint inhibitors (ICIs) and VEGF inhibitors as therapeutic strategies. Beyond its role in angiogenesis and tumor growth, VEGF overexpression also promotes intratumoral accumulation of immunosuppressive cells (eg, Tregs), impairs T cell differentiation, and drives exhaustion of CD8+ cytotoxic T cells—all of which contribute to an immunosuppressive tumor microenvironment.^16,17 The combination of ICIs and VEGF inhibitors synergistically targets HCC by addressing both immune suppression and abnormal tumor vasculature. ICIs activate CD8+ cytotoxic T cells to promote tumor-killing effects, while VEGF inhibitors normalize tumor vasculature to improve drug delivery and counteract VEGF-driven immune suppression, thereby enhancing ICI efficacy.¹⁴

With this synergy in mind, the IMbrave150 (NCT03434379) trial showed that the combination of atezolizumab (Tecentriq; Genentech) plus bevacizumab (Avastin; Genentech) significantly improved median OS compared with sorafenib (19.2 vs 13.4 months), resulting in a 34% reduction in risk of death. With significantly improved survival benefits and a different toxicity profile from sorafenib, as outlined in Table 1, IMbrave150 has reshaped the treatment landscape for unresectable HCC and established atezolizumab plus bevacizumab as a preferred first-line treatment option in the National Comprehensive Cancer Network (NCCN) guidelines.^15,17,18

Since IMbrave150 demonstrated improved OS with the combination of immune checkpoint and anti-VEGF monoclonal antibodies, newer studies have examined the combination of ICI with oral TKIs. Following a similar synergistic principle, multikinase inhibitors target several pathways, including VEGF, with immunomodulatory activity that aims to enhance the effect of ICI on the immunogenic HCC tumor.^14,19,20

The LEAP-002 (NCT0371.93) trial aimed to harness this synergistic mechanism but resulted in no significant difference in outcomes with the combination of pembrolizumab (Keytruda; Merck & Co) and lenvatinib compared with lenvatinib alone (median OS, 21.2 vs 19 months; median progression-free survival [PFS], 8.2 vs 8 months). While there were no significant differences in toxicities, the lack of prolonged PFS with the addition of pembrolizumab to lenvatinib did not support any changes to first-line therapy recommendations.²⁰ Similarly, COSMIC-312 (NCT03755791) did not find any difference in median OS with atezolizumab plus cabozantinib (Cabometyx; Exelixis, Inc) compared with sorafenib alone (16.5 vs 15.5 months).¹⁹ To date, the combination of immunotherapy plus oral TKIs has not been incorporated into the NCCN guidelines.

The CARES-310 (NCT03764293) trial demonstrated that the combination of camrelizumab (Jiangsu HengRui Medicine Co), a humanized immunoglobulin (Ig)G4 monoclonal antibody targeting PD-1, plus rivoceranib (Elevar Therapeutics, Inc), an oral TKI with a high affinity for VEGFR2, significantly improved median OS compared with sorafenib (22.1 vs 15.2 months), resulting in a 38% reduction in risk of death.²¹ Notably, the majority of patients were from East Asia, and most had a viral etiology, which has been noted to be more responsive to immunotherapy than nonviral etiology HCC in previous meta-analyses²²; consequently, the population difference may partly explain the numerically longer median OS seen in CARES-310. To date, this is the only trial combining immunotherapy and an oral TKI with positive results, establishing the regimen as a first-line treatment option in the 2025 ESMO guidelines on HCC.⁵ However, camrelizumab and rivoceranib are currently not approved by the FDA nor listed in the NCCN guidelines, making adoption of the combination therapy as a therapeutic first-line option in the United States unlikely.

Dual Immune Checkpoint Inhibitors

Because HCC is an immunogenic tumor that responds to immunotherapy, trials consisting of dual ICI regimens were conducted to explore the benefit of targeting 2 distinct checkpoint blockade pathways.¹⁷PD-1 and PD-L1 inhibition attenuates previously activated T cells during the later stages of an immune response, while another pathway, involving cytotoxic T lymphocyte–associated antigen 4 (CTLA-4), regulates T-cell activation and proliferation in the early stages of an immune response.^17,23,24 The HIMALAYA (NCT03298451) trial demonstrated that the STRIDE regimen, comprising a single priming dose of tremelimumab (Imjudo; AstraZeneca) plus durvalumab (Imfinzi; AstraZeneca) followed by durvalumab alone improved median OS compared with sorafenib (16.43 vs 13.77 months), achieving a 22% reduction in the risk of death. A third cohort examined durvalumab monotherapy and demonstrated noninferiority to sorafenib, with a median OS of 16.56 months and a 14% reduction in the risk of death.^25,26 The STRIDE regimen has been incorporated as a preferred, first-line treatment option in the NCCN guidelines for unresectable HCC due to improved survival outcomes and distinct toxicity profile compared with sorafenib, as demonstrated in Table 1.¹⁵

Since the advent of the STRIDE regimen, both the NCCN and AASLD guidelines list 2 first-line options for patients with unresectable HCC.^4,15 While head-to-head data comparing atezolizumab/bevacizumab and the STRIDE regimen are lacking, certain patient characteristics may influence clinicians to select 1 regimen over the other. Notably, the IMbrave150 trial excluded patients with untreated or incompletely treated esophageal or gastric varices due to concerns over bleeding.¹⁷ Additional patient-related factors that may preclude the use of an anti-VEGF monoclonal antibody include history of hemorrhage, uncontrolled hypertension, pre-existing renal disease with proteinuria, or recent surgical procedures with concerns for delay in wound healing.²⁷ Conversely, atezolizumab/bevacizumab may be preferred over STRIDE in patients with a higher tumor burden, given the higher ORR observed in IMbrave150 (27.3%) compared with HIMALAYA (20.1%).^17,25,28

In addition to STRIDE, the CheckMate 9DW (NCT04039607) trial evaluated nivolumab (Opdivo; Bristol Myers Squibb) in combination with ipilimumab (Yervoy; Bristol Myers Squibb) as another emerging first-line regimen featuring dual immunotherapy that demonstrated improved median OS compared with an oral TKI (lenvatinib or sorafenib; 23.7 vs 20.6 months), representing a 21% reduction in risk of death. Additionally, the combination regimen yielded one of the highest ORRs seen thus far in first-line unresectable HCC at 36% compared with 13% with the TKIs.²⁹ As of April 2025, the FDA has approved the combination treatment with nivolumab plus ipilimumab in the first-line setting for HCC, and the NCCN guidelines, updated before the FDA approval, currently have the regimen incorporated as another recommended first-line option.^15,30

The favorable results of CheckMate 9DW elicit a discussion on selection between the 2 dual ICI regimens. The nivolumab plus ipilimumab regimen has yielded one of the highest ORRs, but there were also high rates of AEs reported. While data from the HIMALAYA and CheckMate 9DW cannot be directly compared, the STRIDE regimen appeared to have numerically lower rates of all-grade (75.8% vs 83%) and grade 3 to 4 treatment-related AEs (25.8% vs 41%) as well as lower discontinuation rates (8.2% vs 18%).^25,29 One potential explanation for the lower rates of AEs is the difference in frequency with which the CTLA-4 inhibitors are administered. Tremelimumab is administered once in the STRIDE regimen, whereas ipilimumab is given every 3 weeks for up to 4 cycles, combined with nivolumab and ipilimumab, which increases cumulative exposure and the risk of toxicity from CTLA-4 inhibition. Another potential reason is the different immunoglobulin isotypes. Tremelimumab is an IgG2 antibody that has reduced Fc-dependent effector functions compared with ipilimumab, an IgG1 antibody that more robustly triggers effector mechanisms, resulting in stronger immune responses but more immune-related AEs.^31,32

Single-Agent Immune Checkpoint Inhibitor

While the preferred first-line NCCN regimens for HCC include either ICI plus VEGF inhibitor or dual ICI, there is evidence to support the utility of single-agent ICI. The RATIONALE-301 (NCT03412773) trial demonstrated that tislelizumab-jsgr (Tevimbra; BeiGene) was noninferior in median OS to sorafenib (15.9 vs 14.1 months) with relatively tolerable AEs.³³ Although tislelizumab is a recommended first-line option per the NCCN guidelines, it is currently not FDA approved for use in HCC.³⁴ Single-agent immunotherapy has also been shown to be noninferior to sorafenib, as demonstrated by the durvalumab monotherapy arm in the HIMALAYA trial.²⁵ Clinicians may consider single-agent ICI in patients who have poor performance status (PS) and are not able to tolerate higher rates of AEs associated with dual immune checkpoint inhibition.

Subsequent-Line Systemic Treatment

In HCC, tumor progression often occurs within the liver, potentially further impairing hepatic function and limiting subsequent options for systemic therapy.³⁵ Several retrospective analyses have reported that the proportion of patients advancing to second-line therapy ranges from 19% to 55%, with the remainder receiving best supportive care.^35-38 Among patients who progress on or discontinue first-line therapy due to intolerance and remain eligible for subsequent-line treatment, these observational cohort studies indicate that TKIs, particularly sorafenib and lenvatinib, are the most commonly prescribed agents.^35-38 Notably, 2 studies reported median OS with numerically longer OS with lenvatinib (7.7 to 8 months) compared with sorafenib (4.8 to 6.3 months) in the second-line setting.^35,36 

For patients who receive first-line immunotherapy-based regimens, sorafenib and lenvatinib are reasonable subsequent-line options recommended in the guidelines.^5,15,39 Indeed, the NCCN guidelines state that regimens with first-line data are reasonable to consider for subsequent-line treatment given the lack of randomized trials dictating optimal second-line treatment after failure of frontline ICI therapy.⁴⁰

Among immunotherapy-eligible patients who progress after receiving first-line atezolizumab plus bevacizumab, it is unclear whether switching to a dual immunotherapy regimen with the addition of an anti-CTLA4 agent provides a benefit. Only a handful of small retrospective studies have examined the safety and efficacy of salvage nivolumab plus ipilimumab after initial anti–PD-1/PD-L1 therapy in unresectable HCC. Among these studies, ORRs ranged from 22% to 30%, with median PFS ranging from 2.9 to 5.4 months. Additionally, there were no new safety signals, suggesting that the combination of nivolumab plus ipilimumab following atezolizumab plus bevacizumab may be a viable option to extend PFS.^41-43

Single-Agent Tyrosine Kinase Inhibitors

Among patients previously treated with sorafenib who have progressed, evidence supports the use of other single-agent TKIs as subsequent-line treatment. The CELESTIAL (NCT01908426) trial demonstrated superior median OS by 2.2 months and PFS by 3.3 months with cabozantinib vs placebo and had a manageable AE profile.⁴⁴ Similarly, the RESORCE (NCT01774344) trial demonstrated superior median OS by 2.8 months with regorafenib (Stivarga; Bayer) compared with placebo and had similar grade 3 or higher AEs as in CELESTIAL.⁴⁵ Both CELESTIAL and RESORCE provide sequencing evidence for the utility of cabozantinib and regorafenib, respectively, among patients who had been previously exposed to sorafenib. While both trials were conducted before the immunotherapy era, the data are extrapolated and applied as subsequent-line options often after sorafenib or lenvatinib, which are preceded by immunotherapy-based regimens in immunotherapy-eligible patients.^4,5,15,39 

Other single-agent TKIs recommended in the NCCN guidelines include repotrectinib (Augtyro; Bristol Myers Squibb) for NTRK gene fusion–positive tumors and selpercatinib (Retevmo; Eli Lilly and Company) for RET gene fusion–positive tumors. Both have tumor-agnostic indications for their respective gene fusion proteins.^46,47

Anti-VEGF Monoclonal Antibody

Similar to bevacizumab, ramucirumab (Cyramza; Eli Lilly and Company) acts on VEGF but specifically binds VEGF receptor 2 (VEGFR-2), blocking VEGF ligand binding and subsequently inhibiting angiogenesis.⁴⁸ Unlike bevacizumab, ramucirumab has been studied only as a single agent in the subsequent-line setting. The REACH-2 (NCT02435433) trial demonstrated median OS benefits with ramucirumab compared with placebo (8.5 vs. 7.3 months) in patients who previously received sorafenib as first-line therapy. Notably, the trial included only patients with α-fetoprotein (AFP) levels greater than or equal to400 ng/mL, which has been associated with increased VEGF receptor expression, increased angiogenesis, and a poorer prognosis in previous trials.^15,49 Better median PFS (2.8 months vs 1.6 months) was observed in patients with AFP greater than or equal to400 ng/mL. Consequently, the NCCN guidelines list single-agent ramucirumab as a subsequent-line systemic therapy option when AFP is greater than or equal to400 ng/mL.¹⁵

Since the approval of ramucirumab as a subsequent-line therapy, bevacizumab in combination with atezolizumab has become a frontline option for unresectable HCC, targeting the same VEGF/VEGFR pathway. It is unclear if there is a benefit in utilizing ramucirumab following progression on atezolizumab plus bevacizumab. Several small, retrospective, single-center studies have evaluated the efficacy and safety of ramucirumab following atezolizumab plus bevacizumab among patients with unresectable HCC and AFP levels greater than or equal to 400 ng/mL. In these studies, ORR ranged from 15.4% to 33.3% with a median PFS of 3 to 4 months and no new safety signals.^50,51 While limited by retrospective study designs and small sample sizes, these findings suggest that ramucirumab may still provide clinical benefit in subsequent-line settings following prior exposure to atezolizumab plus bevacizumab.

Single-Agent Immune Checkpoint Inhibitor

In the CheckMate 459 (NCT02576509) trial, nivolumab monotherapy did not meet the primary outcome of improved OS compared with sorafenib. Despite not meeting the primary outcome, there were more grade 3 or higher AEs with sorafenib compared with nivolumab single agent (50% vs 23%).⁵² While nivolumab did not provide a survival advantage compared with first-line sorafenib, the use of single-agent nivolumab may be reasonable among patients who are unlikely to tolerate sorafenib-related AEs. Of note, the NCCN guidelines currently list only single-agent nivolumab as a potential option in the subsequent-line setting for patients not previously treated with an ICI.¹⁵

Pembrolizumab is another single-agent ICI established as a subsequent-line therapeutic option for patients who experience disease progression or intolerance following treatment with sorafenib, as evidenced by the phase 2 KEYNOTE-224 (NCT02702414) trial.^53,54 Notably, the confirmatory phase 3 KEYNOTE-240 (NCT02702401) trial among previously treated patients with sorafenib evaluating pembrolizumab plus best supportive care (BSC) vs placebo plus BSC did not meet the primary end points of OS and PFS on the basis of the trial’s prespecified statistical criteria.⁵⁵ However, there was a significant improvement in ORR (18.3% vs 4.4%) in which the FDA has retained the indication for HCC only in the subsequent-line setting, specifically among patients who have not previously had a PD-1/PD-L1 agent.^55,56 As a result, clinicians may prefer to use pembrolizumab in patients who were started on sorafenib but progressed or developed intolerance to the medication. Additionally, KEYNOTE-224 had a second cohort consisting of 51 patients with previously untreated, advanced HCC that demonstrated a median OS of 17 months,⁵⁷ which is comparable with other single-agent ICIs used in the first-line setting.^25,33 However, due to the lack of a comparator arm in this trial, NCCN lists pembrolizumab first-line therapy as a category 2B recommendation.¹⁵

Finally, dostarlimab-gxly (Jemperli; GlaxoSmithKline) is another notable single-agent ICI outlined in the NCCN guidelines as a subsequent-line therapy option for HCC.¹⁵ Dostarlimab-gxly has received accelerated FDA approval for the treatment of patients with mismatch repair– deficient tumors that have progressed on prior lines of therapy.⁵⁸

Practical Considerations

Despite the introduction of immunotherapy-based regimens, the armamentarium for unresectable HCC remains limited to a handful of agents. Close management of toxicities that may arise from these systemic therapies is essential to optimizing clinical benefits while reducing the risk of treatment discontinuation.

ICIs are associated with a unique set of immune-mediated toxicities that may involve any organ or system at any point during or after treatment, with a median onset of 2 to 16 weeks from initiating treatment.⁵⁹ In general, patients with mild immune-related AEs (irAEs) may continue ICI therapy with close monitoring. In contrast, moderate to severe irAEs warrant prompt initiation of immunosuppressive therapy, often with corticosteroids, and interruption or permanent discontinuation of ICI treatment. Several guidelines for the diagnosis and management of irAEs have been developed.^60-63

TKIs are associated with a different range of on- and off-target toxicities due to the multitude of pathways targeted.⁶⁴ Depending on the severity of AE as graded by the Common Terminology Criteria for Adverse Events, management of the TKI may involve an interruption, dose reduction, or cessation of therapy. Referral to the specific TKI package insert can provide additional guidance to support clinical judgment in the most appropriate course of action.

In addition to management of AEs, pharmacists are well positioned to screen for drug-drug interactions (DDIs) with HCC treatment. With immunotherapy and anti-VEGF monoclonal antibodies, there are no clinically relevant DDIs to note. However, since many of the oral TKIs used in HCC treatment are metabolized via cytochrome P450 (CYP) 3A4, concomitant agents (including herbal supplements and grapefruit) that modulate CYP3A4 activity should be used cautiously with close monitoring or avoided based on clinical judgment.⁶⁴ Refer to Table 2 for additional DDI considerations with each specific agent. Additionally, patients with advanced HCC often have impaired hepatic function that may alter drug metabolism. Pharmacists should consult the package insert, review clinical pharmacokinetic data, and apply clinical judgment to determine whether dose adjustments are warranted for anticancer therapy or concomitant medications.⁶⁴

Future Directions

While there have been improvements in median OS and ORR with newer first-line therapies for unresectable HCC in the last 5 years compared with the TKI era, there are still opportunities to prolong OS and obtain higher ORR. There are several notable phase 3 trials on the horizon for the treatment of unresectable HCC.

IMbrave152/SKYSCRAPER-14 (NCT05904886) will evaluate the addition of tiragolumab to first-line atezolizumab plus bevacizumab compared with placebo plus atezolizumab plus bevacizumab. Similar to the PD-1/PD-L1 interaction, T-cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT) is expressed on a variety of tumor surfaces and interacts with CD155 to inhibit the T-cell immune response. Tiragolumab is an investigational monoclonal antibody that binds to TIGIT and prevents this interaction, thereby restoring the immune response against the tumor.⁶⁵ The current estimated study completion date is September 2026.⁶⁶ 

The SIERRA (NCT05883644) trial will be a phase 3b, single-arm, multicenter study that will assess the safety and efficacy of the STRIDE regimen in a broader patient population with unresectable HCC and a poorer prognosis, such as those with CTP class B, a higher PS score, or patients with portal vein thrombosis. Such populations have previously been excluded from major trials, with most existing phase 3 studies including only patients who were CTP class A and had a PS of 0 or 1.⁶⁷ Estimated study completion is December 2025.⁶⁸ 

LIVERATION (NCT05201404) is a phase 3, double-blind, placebo-controlled trial randomly assigning patients with advanced HCC and CTP class B7 cirrhosis who have progressed on at least first-line therapy to namodenoson or placebo.⁶⁹ A3 adenosine receptors (A3ARs) are overexpressed in different types of solid tumors, including HCC. Namodenoson is an A3AR agonist that deregulates the NF-kB and Wnt signaling pathways, leading to an increase in pro-apoptotic proteins and Fas ligand that result in inhibition of tumor growth.⁷⁰ The phase 3 trial was estimated to be completed in October 2025.⁶⁹

Conclusion

The treatment landscape for locally advanced, unresectable, or metastatic HCC has significantly transformed with the introduction of immunotherapy and targeted therapies. The IMbrave150 and HIMALAYA landmark trials demonstrated that atezolizumab plus bevacizumab and tremelimumab plus durvalumab, respectively, improved OS compared with sorafenib, the historical standard of care. These findings establish atezolizumab plus bevacizumab and tremelimumab plus durvalumab as the new, preferred, first-line therapies for immunotherapy-eligible patients with HCC.

Despite promising improvements in the HCC treatment landscape thus far, ongoing clinical trials are needed to explore further enhancement of HCC regimens while also investigating novel agents with the hope that outcomes for patients continue to improve. In the coming years, research in advanced HCC is expected to expand upon immunotherapy strategies, refining target selection and therapeutic combinations. Additional research will need to focus on optimizing treatment sequencing as prolonged response durations to first-line therapy emerge. This review strives to guide oncology pharmacists on multidisciplinary teams who are uniquely positioned to optimize patient care through understanding the evolving treatment landscape of HCC, key considerations in therapy selection, and notable treatment adverse events.

REFERENCES

1.Siegel RL, Giaquinto AN, Jemal A. Cancer statistics, 2024. CA Cancer J Clin. 2024;74(1):12-49. doi:10.3322/caac.21820

2.Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024;74(3):229-263. doi:10.3322/caac.21834

3.Cancer stat facts: liver and intrahepatic bile duct cancer. National Cancer Institute, National Institutes of Health. https://seer.cancer.gov/statfacts/html/livibd.html

4.Singal AG, Llovet JM, Yarchoan M, et al. AASLD Practice Guidance on prevention, diagnosis, and treatment of hepatocellular carcinoma. Hepatology. 2023;78(6):1922-1965. doi:10.1097/HEP.0000000000000466

5.Vogel A, Chan SL, Dawson LA, et al. Hepatocellular carcinoma: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2025;36(5):491-506. doi:10.1016/j.annonc.2025.02.006

6.Nexavar. Prescribing information. Bayer HealthCare Pharmaceuticals Inc; 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/021923s020lbl.pdf

7.Lenvima. Prescribing information. Eisai Inc; 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/206947s021lbl.pdf

8.Llovet JM, Hilgard P, de Oliveira AC, et al. Sorafenib in Advanced Hepatocellular Carcinoma. N Engl J Med. 2008;359(4):378-390. doi:10.1056/NEJMoa0708857

9.Lazzaro A, Hartshorn KL. A comprehensive narrative review on the history, current landscape, and future directions of hepatocellular carcinoma (HCC) systemic therapy. Cancers (Basel). 2023;15(9):2506. doi:10.3390/cancers15092506

10.Kudo M, Finn RS, Qin S, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. The Lancet. 2018;391(10126):1163-1173. doi:10.1016/S0140-6736(18)30207-1

11.Abou-Alfa GK, Schwartz L, Ricci S, et al. Phase II study of sorafenib in patients with advanced hepatocellular carcinoma. J Clin Oncol. 2006;24(26):4293-4300. doi:10.1200/JCO.2005.01.3441

12.Miller AA, Murry DJ, Owzar K, et al. Phase I and pharmacokinetic study of sorafenib in patients with hepatic or renal dysfunction: CALGB 60301. J Clin Oncol. 2009;27(11):1800-1805. doi:10.1200/JCO.2008.20.0931

13.Huynh J, Cho MT, Kim EJ, Ren M, Ramji Z, Vogel A. Lenvatinib in patients with unresectable hepatocellular carcinoma who progressed to Child-Pugh B liver function. Ther Adv Med Oncol. 2022;14:17588359221116608. doi:10.1177/17588359221116608

14.Llovet JM, Castet F, Heikenwalder M, et al. Immunotherapies for hepatocellular carcinoma. Nat Rev Clin Oncol. 2022;19(3):151-172. doi:10.1038/s41571-021-00573-2

15.National Comprehensive Cancer Network (NCCN). NCCN clinical practice guidelines in oncology. Hepatocellular carcinoma, v1.2025.

16.Ribatti D. Immunosuppressive effects of vascular endothelial growth factor. Oncol Lett. 2022;24(4):369. doi:10.3892/ol.2022.13489

17.Finn RS, Qin S, Ikeda M, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med. 2020;382(20):1894-1905. doi:10.1056/NEJMoa1915745

18.Cheng AL, Qin S, Ikeda M, et al. Updated efficacy and safety data from IMbrave150: atezolizumab plus bevacizumab vs. sorafenib for unresectable hepatocellular carcinoma. J Hepatol. 2022;76(4):862-873. doi:10.1016/j.jhep.2021.11.030

19.Kelley RK, Rimassa L, Cheng AL, et al. Cabozantinib plus atezolizumab versus sorafenib for advanced hepatocellular carcinoma (COSMIC-312): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2022;23(8):995-1008. doi:10.1016/S1470-2045(22)00326-6

20.Llovet JM, Kudo M, Merle P, et al. Lenvatinib plus pembrolizumab versus lenvatinib plus placebo for advanced hepatocellular carcinoma (LEAP-002): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2023;24(12):1399-1410. doi:10.1016/S1470-2045(23)00469-2

21.Qin S, Chan SL, Gu S, et al. Camrelizumab plus rivoceranib versus sorafenib as first-line therapy for unresectable hepatocellular carcinoma (CARES-310): a randomised, open-label, international phase 3 study. The Lancet. 2023;402(10408):1133-1146. doi:10.1016/S0140-6736(23)00961-3

22.Pinter M, Pinato DJ, Ramadori P, Heikenwalder M. NASH and hepatocellular carcinoma: immunology and immunotherapy. Clin Cancer Res. 2023;29(3):513-520. doi:10.1158/1078-0432.CCR-21-1258

23.Buchbinder EI, Desai A. CTLA-4 and PD-1 pathways: similarities, differences, and implications of their inhibition. Am J Clin Oncol. 2016;39(1):98-106. doi:10.1097/COC.0000000000000239

24.Carloni R, Sabbioni S, Rizzo A, et al. Immune-based combination therapies for advanced hepatocellular carcinoma. J Hepatocell Carcinoma. 2023;10:1445-1463. doi:10.2147/JHC.S390963

25.Abou-Alfa GK, Lau G, Kudo M, et al. Tremelimumab plus durvalumab in unresectable hepatocellular carcinoma. NEJM Evid. 2022;1(8):EVIDoa2100070. doi:10.1056/EVIDoa2100070

26.Sangro B, Chan SL, Kelley RK, et al. Four-year overall survival update from the phase III HIMALAYA study of tremelimumab plus durvalumab in unresectable hepatocellular carcinoma. Ann Oncol. 2024;35(5):448-457. doi:10.1016/j.annonc.2024.02.005

27.Avastin. Prescribing information. Genentech, Inc; 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/125085s0169lbl.pdf

28.Hatanaka T, Naganuma A, Yata Y, Kakizaki S. Atezolizumab plus bevacizumab and tremelimumab plus durvalumab: how should we choose these two immunotherapy regimens for advanced hepatocellular carcinoma?. Hepatobiliary Surg Nutr. 2022;11(6):927-930. doi:10.21037/hbsn-22-510

29.Yau T, Galle PR, Decaens T, et al. Nivolumab plus ipilimumab versus lenvatinib or sorafenib as first-line treatment for unresectable hepatocellular carcinoma (CheckMate 9DW): an open-label, randomised, phase 3 trial. Lancet. 2025;405(10492):1851-1864. doi:10.1016/S0140-6736(25)00403-9

30.FDA approves nivolumab with ipilimumab for unresectable or metastatic hepatocellular carcinoma. FDA. April 11, 2025. Accessed August 8, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-nivolumab-ipilimumab-unresectable-or-metastatic-hepatocellular-carcinoma

31.Vidarsson G, Dekkers G, Rispens T. IgG subclasses and allotypes: from structure to effector functions. Front Immunol. 2014;5:520. doi:10.3389/fimmu.2014.00520

32.Hong MMY, Maleki Vareki S. Addressing the elephant in the immunotherapy room: effector T-cell priming versus depletion of regulatory T-cells by anti-CTLA-4 therapy. Cancers (Basel). 2022;14(6):1580. doi:10.3390/cancers14061580

33.Qin S, Kudo M, Meyer T, et al. Tislelizumab vs sorafenib as first-line treatment for unresectable hepatocellular carcinoma: a phase 3 randomized clinical trial. JAMA Oncol. 2023;9(12):1651-1659. doi:10.1001/jamaoncol.2023.4003

34.Tevimbra. Prescribing information. BeiGene; 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/761417s000lbl.pdf

35.Ben Khaled N, Zarka V, Hobeika B, et al. Therapeutic sequences of systemic therapy after atezolizumab plus bevacizumab for hepatocellular carcinoma: real‐world analysis of the IMMUreal cohort. Aliment Pharmacol Ther. 2025;61(11):1755-1766. doi:10.1111/apt.70090

36.Lee CK, Yoo C, Hong JY, et al. Real-world study of systemic treatment after first-line atezolizumab plus bevacizumab for hepatocellular carcinoma in Asia-Pacific countries. Liver Cancer. 2024;14(2):127-141. doi:10.1159/000540969

37.Singal AG, Özgürdal K, Fan X, et al. Real-world systemic treatment patterns after atezolizumab and bevacizumab in patients with hepatocellular carcinoma in the United States. Cancers (Basel). 2023;15(23):5532. doi:10.3390/cancers15235532

38.Wu M, Fulgenzi CAM, D’Alessio A, et al. Second-line treatment patterns and outcomes in advanced HCC after progression on atezolizumab/bevacizumab. JHEP Rep. 2024;7(2):101232. doi:10.1016/j.jhepr.2024.101232

39.Gordan JD, Kennedy EB, Abou-Alfa GK, et al. Systemic therapy for advanced hepatocellular carcinoma: ASCO Guideline Update. J Clin Oncol. 2024;42(15):1830-1850. doi:10.1200/JCO.23.02745

40.Hwang SY, Lee SL, Liu H, Lee SS. Second-line treatment after failure of immune checkpoint inhibitors in hepatocellular carcinoma: tyrosine kinase inhibitor, retrial of immunotherapy, or locoregional therapy? Liver Cancer. 2023;13(3):246-255. doi:10.1159/000534303

41.Roessler D, Öcal O, Philipp AB, et al. Ipilimumab and nivolumab in advanced hepatocellular carcinoma after failure of prior immune checkpoint inhibitor-based combination therapies: a multicenter retrospective study. J Cancer Res Clin Oncol. 2023;149(7):3065-3073. doi:10.1007/s00432-022-04206-8

42.Alden SL, Lim M, Kao C, et al. Salvage ipilimumab plus nivolumab after anti-PD-1/PD-L1 therapy in advanced hepatocellular carcinoma. Cancer Res Commun. 2023;3(7):1312-1317. doi:10.1158/2767-9764.CRC-23-0072

43.Scheiner B, Roessler D, Phen S, et al. Efficacy and safety of immune checkpoint inhibitor rechallenge in individuals with hepatocellular carcinoma. JHEP Rep. 2022;5(1):100620. doi:10.1016/j.jhepr.2022.100620

44.Abou-Alfa GK, Meyer T, Cheng AL, et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Engl J Med. 2018;379(1):54-63. doi:10.1056/NEJMoa1717002

45.Bruix J, Qin S, Merle P, et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;389(10064):56-66. doi:10.1016/S0140-6736(16)32453-9

46.Augtyro. Prescribing information. Bristol Myers Squibb; 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/218213s001lbl.pdf

47.Retevmo. Prescribing information. Eli Lilly and Company; 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/213246s011s013lbl.pdf

48.Cyramza. Prescribing information. Eli Lilly and Company; 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/125477s002lbl.pdf

49.Zhu AX, Kang YK, Yen CJ, et al. Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019;20(2):282-296. doi:10.1016/S1470-2045(18)30937-9

50.Kuzuya T, Kawabe N, Hashimoto S, et al. Clinical outcomes of ramucirumab as post-treatment following atezolizumab/bevacizumab combination therapy in advanced hepatocellular carcinoma. Anticancer Res. 2022;42(4):1905-1910. doi:10.21873/anticanres.15667

51.Shimose S, Sugimoto R, Hiraoka A, et al. Significance of ramucirumab following atezolizumab plus bevacizumab therapy for hepatocellular carcinoma using real‐world data. Hepatol Res. 2023;53(2):116-126. doi:10.1111/hepr.13852

52.Yau T, Park JW, Finn RS, et al. Nivolumab versus sorafenib in advanced hepatocellular carcinoma (CheckMate 459): a randomised, multicentre, open-label, phase 3 trial. Lancet Oncol. 2022;23(1):77-90. doi:10.1016/S1470-2045(21)00604-5

53.Kudo M, Finn RS, Edeline J, et al. Updated efficacy and safety of KEYNOTE-224: a phase II study of pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib. Eur J Cancer. 2022;167:1-12. doi:10.1016/j.ejca.2022.02.009

54.Zhu AX, Finn RS, Edeline J, et al. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial. Lancet Oncol. 2018;19(7):940-952. doi:10.1016/S1470-2045(18)30351-6

55.Finn RS, Ryoo BY, Merle P, et al. Pembrolizumab as second-line therapy in patients with advanced hepatocellular carcinoma in KEYNOTE-240: a randomized, double-blind, phase III trial. J Clin Oncol. 2020;38(3):193-202. doi:10.1200/JCO.19.01307

56.Keytruda. Prescribing information. Merck & Co., Inc; 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/125514s096lbl.pdf

57.Verset G, Borbath I, Karwal M, et al. Pembrolizumab monotherapy for previously untreated advanced hepatocellular carcinoma: data from the open-label, phase II KEYNOTE-224 Trial. Clin Cancer Res. 2022;28(12):2547-2554. doi:10.1158/1078-0432.CCR-21-3807

58.Jemperli. Prescribing information. GlaxoSmithKline; 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761174s000lbl.pdf

59.Ramos-Casals M, Brahmer JR, Callahan MK, et al. Immune-related adverse events of checkpoint inhibitors. Nat Rev Dis Primer. 2020;6(1):38. doi:10.1038/s41572-020-0160-6

60.Schneider BJ, Naidoo J, Santomasso BD, et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: ASCO Guideline Update. J Clin Oncol. 2021;39(36):4073-4126. doi:10.1200/JCO.21.01440

61.Brahmer JR, Abu-Sbeih H, Ascierto PA, et al. Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immune checkpoint inhibitor-related adverse events. J Immunother Cancer. 2021;9(6):e002435. doi:10.1136/jitc-2021-002435

62.Haanen J, Obeid M, Spain L, et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2022;33(12):1217-1238. doi:10.1016/j.annonc.2022.10.001

63.NCCN Clinical Practice Guidelines in Oncology. Management of immunotherapy-related toxicities, v1.2025. December 20, 2024. Accessed August 9, 2025. https://www.nccn.org/professionals/physician_gls/pdf/immunotherapy.pdf

64.Rimassa L, Danesi R, Pressiani T, Merle P. Management of adverse events associated with tyrosine kinase inhibitors: improving outcomes for patients with hepatocellular carcinoma. Cancer Treat Rev. 2019;77:20-28. doi:10.1016/j.ctrv.2019.05.004

65.Badhrinarayanan S, Cotter C, Zhu H, Lin YC, Kudo M, Li D. IMbrave152/SKYSCRAPER-14: a phase III study of atezolizumab, bevacizumab and tiragolumab in advanced hepatocellular carcinoma. Future Oncol. 2024;20(28):2049-2057. doi:10.1080/14796694.2024.2355863

66.A study evaluating atezolizumab and bevacizumab, with or without tiragolumab, in participants with untreated locally advanced or metastatic hepatocellular carcinoma (IMbrave152) (SKYSCRAPER-14). Updated November 13, 2025. Accessed November 24, 2024. https://clinicaltrials.gov/study/NCT05904886

67.Chan, Stephan. 206TiP - SIERRA. Accessed November 24, 2024. https://oncologypro.esmo.org/meeting-resources/esmo-asia-congress-2023/sierra-a-phase-iiib-single-arm-multicentre-study-of-tremelimumab-plus-durvalumab-for-first-line-treatment-of-advanced-unresectable-hepatocellular

68.Durvalumab and tremelimumab as first line treatment in participants with advanced hepatocellular carcinoma (HCC) (SIERRA). Updated June 19, 2025. Accessed November 24, 2024. https://clinicaltrials.gov/study/NCT05883644?cond=Advanced%20Hepatocellular%20Carcinoma&aggFilters=phase:3,status:not%20rec&rank=3

69.Namodenoson in the treatment of advanced hepatocellular carcinoma in patients with Child-Pugh class B7 cirrhosis (LIVERATION). Updated April 29, 2025. Accessed November 24, 2024. https://clinicaltrials.gov/study/NCT05201404

70.Stemmer SM, Manojlovic NS, Marinca MV, et al. Namodenoson in advanced hepatocellular carcinoma and Child–Pugh B cirrhosis: randomized placebo-controlled clinical trial. Cancers (Basel). 2021;13(2):187. doi:10.3390/cancers13020187

71.Santorsola M, Capuozzo M, Nasti G, et al. Exploring the spectrum of VEGF inhibitors’ toxicities from systemic to intra-vitreal usage in medical practice. Cancers (Basel). 2024;16(2):350. doi:10.3390/cancers16020350

72.Reidy DL, Chung KY, Timoney JP, et al. Bevacizumab 5 mg/kg can be infused safely over 10 minutes. J Clin Oncol. 2007;25(19):2691-2695. doi:10.1200/JCO.2006.09.3351

73.Shah SR, Gressett Ussery SM, Dowell JE, et al. Shorter bevacizumab infusions do not increase the incidence of proteinuria and hypertension. Ann Oncol. 2013;24(4):960-965. doi:10.1093/annonc/mds593

74.Tecentriq. Prescribing information. Genentech, Inc; 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/761034s018lbl.pdf

75.Cortellini A, Tucci M, Adamo V, et al. Integrated analysis of concomitant medications and oncological outcomes from PD-1/PD-L1 checkpoint inhibitors in clinical practice. J Immunother Cancer. 2020;8(2):e001361. doi:10.1136/jitc-2020-001361

76.Bessede A, Marabelle A, Guégan JP, et al. Impact of acetaminophen on the efficacy of immunotherapy in cancer patients. Ann Oncol. 2022;33(9):909-915. doi:10.1016/j.annonc.2022.05.010

77.Lopes S, Pabst L, Dory A, et al. Do proton pump inhibitors alter the response to immune checkpoint inhibitors in cancer patients?. a meta-analysis. Front Immunol. 2023;14:1070076. doi:10.3389/fimmu.2023.1070076

78.Kostine M, Mauric E, Tison A, et al. Baseline co-medications may alter the anti-tumoural effect of checkpoint inhibitors as well as the risk of immune-related adverse events. Eur J Cancer. 2021;157:474-484. doi:10.1016/j.ejca.2021.08.036

79.Bar-Sela G, Cohen I, Campisi-Pinto S, et al. Cannabis consumption used by cancer patients during immunotherapy correlates with poor clinical outcome. Cancers (Basel). 2020;12(9):2447. doi:10.3390/cancers12092447

80.Braun IM, Bohlke K, Abrams DI, et al. Cannabis and cannabinoids in adults with cancer: ASCO Guideline. J Clin Oncol. 2024;42(13):1575-1593. doi:10.1200/JCO.23.02596

81.To J, Davis M, Sbrana A, et al. MASCC guideline: cannabis for cancer-related pain and risk of harms and adverse events. Support Care Cancer. 2023;31(4):202. doi:10.1007/s00520-023-07662-1

82.Martins F, Sofiya L, Sykiotis GP, et al. Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance. Nat Rev Clin Oncol. 2019;16(9):563-580. doi:10.1038/s41571-019-0218-0

83.Imfinzi. Prescribing information. AstraZeneca; 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/761069s050lbl.pdf

84.Opdivo. Prescribing information. Bristol Myers Squibb; 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/125554s058lbl.pdf

85.Imjudo. Prescribing information. AstraZeneca; 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/761270s000lbl.pdf

86.Yervoy. Prescribing information. Bristol Myers Squibb; 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/125377s110lbl.pdf

87.Shyam Sunder S, Sharma UC, Pokharel S. Adverse effects of tyrosine kinase inhibitors in cancer therapy: pathophysiology, mechanisms and clinical management. Signal Transduct Target Ther. 2023;8(1):262. doi:10.1038/s41392-023-01469-6

88.Cabometyx. Prescribing information. Exelixis, Inc; 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/208692s010lbl.pdf

89.Stivarga. Prescribing information. Bayer HealthCare Pharmaceuticals Inc; 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203085lbl.pdf