ABSTRACT
Immune checkpoint inhibitors (ICIs) have robust therapeutic efficacy, offering sustained clinical benefit in various malignancies. However, the optimal duration of treatment remains under investigation. This review summarizes recent trends in long-term ICI therapy, with particular focus on hepatocellular carcinoma (HCC). The conventional 2-year treatment limitation, initially based on data from non-small cell lung cancer trials (e.g., KEYNOTE-010, Check-Mate-017), has been adopted broadly across tumor types. Follow-up data suggest that many patients maintain remission even after discontinuation of treatment, prompting reevaluation of prolonged therapy necessity. In HCC, atezolizumab plus bevacizumab has become the firstline standard treatment, but questions persist regarding continuation beyond two years and post-progression management. Emerging data indicate that salvage therapies—including tyrosine kinase inhibitors like sorafenib or lenvatinib—remain viable options after ICI failure. Furthermore, recent studies from European cohorts and Asian populations have provided insights into long-term survival, treatment sequencing. This review aims to provide a clinical and practical overview of these evolving paradigms to guide personalized, evidence-based decisions in immune-oncology.
-
KEYWORDS: Hepatocellular carcinoma; Immunotherapy; Treatment; Immune checkpoint inhibitors; Treatment outcome
INTRODUCTION
Immune checkpoint inhibitors (ICIs) have redefined the therapeutic landscape of cancer treatment over the past decade. By targeting inhibitory pathways such as PD-1 programmed cell death protein-1 (PD-1)/programmed death-ligand (PD-L1) and cytotoxic T-lymphocyte–associated protein 4, ICIs unleash anti-tumor immunity and have demonstrated durable clinical responses across a wide range of malignancies. Among liver cancers, hepatocellular carcinoma (HCC) has historically been associated with limited systemic treatment options and poor prognosis. The advent of immunotherapy, particularly the combination of atezolizumab and bevacizumab (Atezo/Bev), has significantly improved patient outcomes. The IMbrave150 trial established Atezo/Bev as the preferred first-line therapy for unresectable HCC, showing a notable improvement in overall survival (OS) and progression-free survival (PFS) compared to sorafenib [
1].
Despite the clinical success of ICIs, several critical questions remain unanswered—chief among them is the optimal duration of therapy. In pivotal trials for non-small cell lung cancer (NSCLC), such as KEYNOTE-010 and CheckMate-017/057, the treatment duration for pembrolizumab and nivolumab was capped at two years [
2,
3]. Long-term follow-up data showed that many patients who discontinued treatment after two years continued to maintain disease control, leading to the hypothesis that prolonged therapy may not be necessary in all cases [
4]. These findings laid the foundation for the current practice of limiting ICI duration to 24 months in many clinical guidelines and reimbursement systems.
However, the direct extrapolation of these principles to HCC may be problematic. Unlike NSCLC, HCC often arises in the setting of chronic liver disease or cirrhosis, where hepatic reserve, portal hypertension, and bleeding risk must all be carefully considered. Moreover, the biological behavior of HCC and its tumor-immune microenvironment differ substantially from other solid tumors. Despite this, the two-year treatment cap is often applied uniformly across cancer types, including HCC, without robust supporting data [
5].
Recent retrospective studies and real-world evidence are beginning to shed light on the consequences of treatment discontinuation, rechallenge (the reintroduction of the same or a different immune checkpoint inhibitor after prior discontinuation) strategies, and outcomes after progression. Some patients exhibit durable complete or partial responses even after early cessation, while others may require reintroduction of ICIs or transition to salvage therapies such as tyrosine kinase inhibitors (TKIs) like sorafenib, lenvatinib, or cabozantinib [
6,
7]. Furthermore, evolving staging systems, biomarker profiles such as alpha-fetoprotein (AFP), albumin bilirubin (ALBI) grade, and emerging trial results are influencing individualized treatment planning in clinical practice [
8].
This review aims to critically evaluate the recent trends in long-term immunotherapy for HCC, focusing on duration of treatment, outcomes beyond progression, and the integration of sequential and salvage strategies to guide optimized care.
MAIN BODY
Rationale for the 2-Year Treatment Limit in Immune Checkpoint Inhibitor Therapy
The decision to limit ICI therapy to a duration of two years originated from pivotal clinical trials conducted in NSCLC, notably KEYNOTE-010 and CheckMate-017/057. In these studies, pembrolizumab and nivolumab were administered for a maximum of 24 months, regardless of response status, based on early assumptions that sustained antitumor immunity might persist after discontinuation [
2,
3].
The KEYNOTE-001 trial further reinforced this approach by demonstrating that a considerable proportion of patients with NSCLC maintained long-term remission after completing two years of pembrolizumab therapy [
4]. Specifically, five-year overall survival among patients who responded to treatment was markedly high, suggesting that extended therapy beyond two years might not be necessary for all individuals. These results contributed to the development of a “stop at 2 years” paradigm in several clinical guidelines and reimbursement systems.
This practice model was later adopted across various tumor types, including HCC, despite substantial differences in tumor biology, host immunity, and hepatic reserve. For HCC, the IMbrave150 trial established Atezo/Bev as the new standard first-line therapy based on superior OS and PFS compared to sorafenib [
1]. However, the trial did not explicitly define an optimal treatment duration, and subsequent real-world studies have shown diverse treatment timelines depending on patient response, liver function, and institutional practice [
6].
The rationale for a two-year treatment limit in ICI therapy stems from NSCLC trials, where discontinuation after 24 months was associated with durable responses and reduced risk of cumulative immune-related toxicity. This model offers clear advantages, such as minimizing overtreatment, limiting long-term toxicity, and reducing the substantial financial and quality-of-life burden of indefinite immunotherapy. However, in HCC the applicability of this “stop at 2 years” paradigm is less certain. Unlike NSCLC, HCC arises in the context of chronic liver disease, with distinct tumor biology and variable hepatic reserve, making the durability of antitumor immunity after fixed-duration therapy unclear. Real-world data show heterogeneous treatment courses, with some patients benefitting from extended therapy, while others discontinue earlier due to liver decompensation or toxicity. Thus, while the two-year model provides regulatory simplicity and potential benefits, its universal application to HCC risks both undertreatment and overtreatment. Tumor-specific studies are required to determine whether fixed-duration therapy or individualized continuation strategies best balance efficacy, toxicity, cost, and patient quality of life in advanced HCC.
In summary, the two-year treatment limit is a legacy of lung cancer immunotherapy trials, supported by long-term survival data. However, its universal application to HCC remains an assumption rather than an evidence-based standard. These findings underscore the need for HCC-specific studies to define optimal ICI duration, considering its unique clinical complexity.
Long-Term Outcomes After 2 Years of Atezo/Bev Therapy in HCC
As Atezo/Bev becomes the standard first-line therapy for unresectable HCC, attention has shifted toward the long-term outcomes beyond the two-year treatment period. Although initial trials, including IMbrave150, demonstrated improved survival and response rates over sorafenib, the long-term post-treatment result has not been fully clarified [
1].
Several retrospective cohort studies and early follow-up analyses have attempted to characterize patients who remained progression-free after two years of Atezo/Bev therapy. In a Taiwanese multicenter cohort, the 60-month OS rate for all patients receiving Atezo/Bev was approximately 19.6%, while those who achieved partial or complete responses had a significantly improved 5-year OS of 47.4% [
9]. These findings suggest that durable responders may derive long-term benefit even without continued therapy.
A separate European registry study found that more than 60% of patients who had shown a sustained response after two years of Atezo/Bev treatment were able to maintain disease control for 6 to 12 months even after stopping therapy. During this treatment-free period, there was no meaningful decline in either quality of life or liver function [
10]. These results suggest that, for carefully selected patients, discontinuing immunotherapy after two years may be a safe and effective strategy.
However, a smaller Japanese cohort highlighted the heterogeneity in long-term outcomes. While some patients discontinued Atezo/Bev after two years due to sustained remission, others experienced late progression within 6 months of treatment cessation [
11]. This suggests that complete responders may benefit from longer surveillance intervals, whereas partial responders or those with residual tumor burden might require closer monitoring or even continuation of therapy.
In terms of treatment-related toxicity, long-term administration of ICIs has been associated with delayed-onset immune-related adverse events (irAEs), including autoimmune hepatitis and endocrinopathies [
12]. Therefore, minimizing unnecessary exposure beyond two years may reduce cumulative risk.
Overall, these findings highlight the need to individualize treatment. Instead of applying a fixed 2-year limit to everyone, decisions should be based on response strength, liver function, tumor characteristics, and patient values.
Management Beyond Progression: Salvage and Rechallenge Strategies
Despite the success of ICIs such as Atezo/Bev in HCC, many patients will eventually experience disease progression. Managing these patients effectively requires thoughtful integration of salvage and rechallenge strategies based on disease kinetics, prior response, and overall hepatic function.
1. Salvage therapy after progression on Atezo/Bev
For patients who progress on Atezo/Bev, salvage options typically involve multi-kinase inhibitors (TKIs) such as sorafenib, lenvatinib, cabozantinib, or ramucirumab. Retrospective data suggest that both sorafenib and lenvatinib retain clinical activity in patients previously treated with ICIs, although the optimal sequencing remains uncertain [
13]. A multicenter Japanese study reported median OS of 10.2 months and 7.6 months for lenvatinib and sorafenib, respectively, after progression on Atezo/Bev [
14].
Cabozantinib has also shown promise as a second- or third-line option, particularly in patients with extrahepatic spread or macrovascular invasion. In the CELESTIAL trial, which included patients previously treated with sorafenib, cabozantinib demonstrated a significant survival benefit and may retain efficacy post-ICI exposure [
15].
2. Rechallenge strategies: Is there a role for re-treatment with ICIs?
Rechallenge with ICIs after prior exposure is an emerging area of interest. In selected patients who had previously responded to Atezo/Bev and discontinued therapy due to irAEs or stable disease, reintroduction of the same or alternative ICI regimens has led to renewed responses in some cases [
16].
However, the evidence remains limited and largely anecdotal. A recent observational cohort from Korea showed that ICI rechallenge in patients who had initial partial or complete response could re-induce tumor control in approximately 30% of cases, though with a slightly higher risk of irAEs [
17]. This suggests that ICI rechallenge may be a viable option, particularly for those with prior clinical benefit, good performance status, and no severe previous toxicity.
3. Clinical considerations in sequencing and personalization
Selecting the optimal post-progression strategy depends on multiple factors, including liver function (Child-Pugh and ALBI grade), tumor burden, performance status, and AFP level. Importantly, hepatic reserve often dictates whether a patient can tolerate TKIs or further immunotherapy. In patients with impaired liver function, best supportive care or enrollment in clinical trials may be more appropriate.
Additionally, ongoing trials are evaluating novel combinations or sequencing strategies that may redefine post-ICI treatment standards in the near future. Until then, clinicians must balance oncologic efficacy with tolerability and patient preference in guiding salvage therapy (a treatment administered after the failure of standard therapy, often involving tyrosine kinase inhibitors or alternative systemic agents).
Predictive Factors Influencing Long-Term Benefit
While ICIs such as Atezo/Bev have shown meaningful survival benefits in HCC, not all patients experience sustained clinical benefit. Identifying reliable predictive factors is essential for optimizing patient selection, minimizing overtreatment, and guiding long-term treatment planning.
1. Tumor response depth and radiologic criteria
One of the most consistent predictors of long-term benefit is the depth of tumor response. Patients who achieve complete response (CR) or partial response (PR) by RECIST (response evaluation criteria in solid tumors) or modified RECIST (mRECIST) criteria show markedly improved PFS and OS compared to those with stable disease (SD) or progressive disease (PD) [
18]. In particular, Complete responders often sustain disease control post-treatment, indicating radiologic response may reflect immune memory [
19].
2. AFP as a biomarker
AFP, long used as a prognostic marker in HCC, also appears to have predictive value in the context of immunotherapy. Post-treatment AFP decline, particularly a ≥50% reduction within the first 6–8 weeks, has been associated with higher objective response rates and longer OS [
20]. Conversely, patients with high baseline AFP levels and no subsequent decrease may be less likely to benefit from ICI-based therapy.
3. Liver function reserve: ALBI and Child-Pugh score
Liver function is a crucial determinant of immunotherapy outcomes in HCC. Patients with well-preserved hepatic reserve—typically ALBI grade 1 or Child-Pugh A status—show better tolerance to therapy and improved survival [
21]. Even within the Child-Pugh A group, ALBI grading can provide finer risk stratification. Those with ALBI grade 2 or compensated cirrhosis still benefit from Atezo/Bev, but often with shorter durations of response or greater susceptibility to toxicity [
22].
4. Inflammatory markers and systemic immune status
Emerging evidence suggests that systemic inflammation influences immunotherapy outcomes. High neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, or elevated C-reactive protein levels have been linked to poorer responses and survival in HCC patients receiving ICIs [
23]. These markers may reflect a tumor-promoting microenvironment that suppresses effective immune activation.
5. Genetic and molecular predictors (future direction)
Although not yet part of routine clinical practice, several molecular markers—including PD-L1 expression, WNT/β-catenin pathway mutations, and T-cell infiltration patterns—are under investigation for their predictive value in HCC immunotherapy [
24]. Advances in tumor genomics and liquid biopsy may allow for personalized predictions of long-term benefit in the near future.
While pivotal clinical trials such as IMbrave150 provide the foundational evidence for using Atezo/Bev in HCC, their findings are often derived from highly selected patient populations. In real-world clinical settings, significant variability exists across geographic regions, healthcare systems, and patient characteristics, which can influence treatment duration, sequencing, and overall outcomes.
1. Differences in baseline patient profiles
Studies from Asian countries, particularly Taiwan, and Korea, have highlighted that real-world patients often present with higher rates of hepatitis B virus-related HCC, smaller tumor burden at diagnosis, and better preserved liver function compared to Western populations [
25]. This is largely due to well-established surveillance programs in these countries, allowing hepatocellular carcinoma to be detected at an earlier stage when liver function remains relatively preserved. In contrast, European and North American cohorts tend to have a higher proportion of patients with alcohol-related or non-alcoholic steatohepatitis-related HCC and more advanced liver dysfunction at the time of systemic therapy initiation [
26].
These differences in disease etiology and hepatic reserve significantly affect the tolerability and efficacy of immunotherapy. For example, the same Atezo/Bev regimen may be administered for longer durations in Japanese cohorts, where liver function is more preserved and surveillance programs allow earlier detection [
27].
2. Variability in treatment duration and discontinuation practice
In Western practice, adherence to the 2-year treatment cap has been relatively common due to protocol guidance from NSCLC studies and payer regulations [
3,
4]. However, in many Asian centers, treatment beyond 2 years is occasionally pursued in patients showing continued benefit and tolerability. A Korean multicenter study reported that approximately 17% of patients remained on Atezo/Bev beyond 24 months, and some continued treatment until radiographic or biochemical progression occurred [
28].
Conversely, early discontinuation is more common in lower-resource settings due to financial constraints, limited insurance coverage, or drug availability. These factors may lead to premature cessation of immunotherapy despite clinical benefit, thereby affecting long-term survival outcomes [
29].
3. Impact of national guidelines and reimbursement policies
National HCC guidelines also influence how long patients remain on therapy. In Japan and Korea, where national insurance partially covers immunotherapy, treatment decisions often reflect both clinical judgment and economic considerations. In some European countries, continuation beyond 2 years may require case-by-case approval or trial enrollment [
30].
Furthermore, differing interpretations of radiologic response criteria (e.g., RECIST vs. mRECIST) across institutions can influence decisions about continuation or discontinuation, adding another layer of variability to real-world outcomes.
Future Directions: Toward Personalized Long-Term Immunotherapy
As ICIs become central to the treatment of HCC, the need to move beyond a fixed treatment duration model has become increasingly clear. Current practices—such as the two-year cap adapted from lung cancer protocols—do not adequately account for the biological diversity of HCC or patient-specific factors. A more personalized, adaptive approach to long-term immunotherapy is both necessary and imminent.
1. Shift toward combining immune checkpoint inhibitors with targeted agents or TACE in intermediate-stage HCC
A number of ongoing phase III trials are exploring the integration of systemic immunotherapy into the treatment paradigm for BCLC B stage HCC. These studies investigate combinations of immune checkpoint inhibitors with targeted agents or transarterial chemoembolization (TACE), aiming to enhance outcomes beyond what TACE alone can achieve. Collectively, they represent a decisive shift toward establishing systemic therapy as a frontline component in intermediate-stage disease, with the ultimate goal of improving progression-free and overall survival (
Table 1).
2. Individualized treatment duration based on biomarkers and response
Future clinical strategies will likely incorporate dynamic biomarkers to guide treatment duration. Longitudinal monitoring of AFP kinetics, radiologic response (CR/PR/SD), and immune-related markers such as circulating T-cell profiles or cytokine levels could allow clinicians to tailor treatment length to patient response [
31]. For instance, patients who show deep and sustained responses may be candidates for early discontinuation, while others with partial responses or high-risk features may benefit from extended therapy.
3. Integration of molecular and genomic profiling
Advances in genomics may soon enable more precise patient selection. Mutations in the WNT/β-catenin pathway, for example, have been associated with poor response to ICIs, while tumors with high T-cell infiltration may predict durable benefit [
32]. Liquid biopsies and circulating tumor DNA analysis could allow real-time assessment of tumor evolution and immune escape, providing actionable information to adjust immunotherapy plans accordingly [
33].
4. Adaptive trial designs and response-guided protocols
To move toward personalization, future trials must adopt adaptive designs (clinical trial structure that allows pre-specified modifications based on interim results) that stratify patients not only by tumor stage but also by biological markers and response trajectories. Trials such as STOP-HCC and RESTART-HCC are exploring response-guided discontinuation or rechallenge protocols, which may ultimately provide a framework for individualized duration strategies.
5. Balancing efficacy, toxicity, and cost
From a practical perspective, prolonged ICI therapy comes with increased risk of immune-related adverse events, financial toxicity, and patient fatigue. Personalized duration models could optimize outcomes by maintaining efficacy while minimizing harm and resource burden [
34]. This is particularly relevant in resource-limited settings where prolonged therapy is often unsustainable.
6. Multidisciplinary and global collaboration
Finally, to realize the goal of personalized immunotherapy, collaboration across disciplines—oncology, hepatology, immunology, radiology—as well as across regions is critical. Harmonizing data from real-world cohorts, global registries, and clinical trials will enable the development of evidence-based, individualized immunotherapy algorithms.
CONCLUSION
The advent of immune checkpoint inhibitors, particularly the combination of atezolizumab and bevacizumab, has transformed the treatment landscape for unresectable hepatocellular carcinoma. While randomized trials established their efficacy, many critical questions remain regarding long-term management, particularly treatment duration beyond two years and post-progression strategies.
Evidence from NSCLC trials provided the initial rationale for the 2-year treatment model, but its universal application to HCC lacks robust tumor-specific validation. Real-world data suggest that a subset of patients—particularly those who achieve deep responses—may safely discontinue treatment after two years, while others might benefit from continued therapy or transition to salvage regimens such as tyrosine kinase inhibitors. Moreover, rechallenge with ICIs may be feasible in select cases with prior benefit and tolerability.
Predictive factors such as AFP dynamics, radiologic response, liver function scores, and emerging molecular markers can help refine long-term therapeutic decisions. Regional differences in disease etiology, practice patterns, and access to care further emphasize the need for individualized approaches.
Looking forward, the future of immunotherapy in HCC lies in personalization. Adaptive trial designs, biomarker-guided strategies, and collaborative real-world data collection will be crucial in moving beyond one-size-fits-all protocols. Ultimately, tailoring treatment duration and sequencing based on individual patient and tumor biology may improve long-term outcomes while minimizing unnecessary toxicity and cost.
NOTES
-
ACKNOWLEDGEMENTS
None.
-
FUND
None.
-
ETHICS STATEMENT
Approval was obtained from the local Ethical Review Board, for this review article. The consent for publication is not required as the submission does not include any images or information that may identify the person.
-
CONFLICTS OF INTEREST
No potential conflict of interest relevant to this article was reported.
Table 1.Ongoing clinical trials of systemic therapy for BCLC B stage HCC as initial therapy
Table 1.
|
Trial name |
Phase |
Experimental arm |
Primary endpoint |
Registration number |
|
EMERALD-1 |
Ph3 |
Durvalumab + Bevacizumab + TACE vs Durvalumab + TACE |
PFS |
NCT03778957 |
|
LEAP-012 |
Ph3 |
Lenvatinib + Pembrolizumab + TACE |
PFS, OS |
NCT04246177 |
|
CheckMate 74W |
Ph3 |
Nivolumab + Ipilimumab + TACE vs Nivolumab + TACE |
Time to TACE progression, OS |
NCT04340193 |
|
ML42612 |
Ph3 |
Atezolizumab + Bevacizumab + TACE |
PFS, OS |
NCT04712643 |
|
ABC-HCC |
Ph3 |
Atezolizumab + Bevacizumab |
Time to failure of treatment strategy |
NCT04803994 |
|
RENOTACE |
Ph3 |
Regorafenib + Nivolumab |
PFS |
NCT04777851 |
REFERENCES
- 1. Finn RS, Qin S, Ikeda M, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med 2020;382:1894-1905.
- 2. Herbst RS, Baas P, Kim DW, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet 2016;387:1540-1550.
- 3. Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med 2015;373:123-135.
- 4. Garon EB, Hellmann MD, Rizvi NA, et al. Five-year overall survival for patients with advanced NSCLC treated with pembrolizumab: results from the KEYNOTE-001 study. J Clin Oncol 2019;37:2518-2527.
- 5. Reig M, Forner A, Rimola J, et al. BCLC strategy for prognosis prediction and treatment recommendation: the 2022 update. J Hepatol 2022;76:681-693.
- 6. Kudo M, Motomura K, Wada Y, et al. Real-world outcomes of atezolizumab plus bevacizumab for unresectable hepatocellular carcinoma: multicenter analysis in Japan. Liver Cancer 2022;11:156-170.
- 7. Rimassa L, Pressiani T, Merle P. Systemic treatment options in hepatocellular carcinoma: where do we stand? J Hepatol 2021;74:1363-1374.
- 8. Shao YY, Hsu CH, Cheng AL. Predictive biomarkers for immune checkpoint inhibitor therapy in hepatocellular carcinoma: where do we stand? J Hepatocell Carcinoma 2021;8:227-238.
- 9. Chen CT, Feng YH, Yen CJ, Chen SC, Hsu CH, Shao YY. Long-term survival outcomes of atezolizumab plus bevacizumab treatment in patients with advanced hepatocellular carcinoma. J Clin Oncol 2025;4 suppl:600.
- 10. Meyer T, Palmer DH, Sangro B, et al. Real-world outcomes in European HCC patients treated with immunotherapy: post-treatment durability and safety. Liver Int 2023;43:2255-2264.
- 11. Hayakawa Y, Tsuchiya K, Kurosaki M, et al. Early experience of atezolizumab plus bevacizumab therapy in Japanese patients with unresectable hepatocellular carcinoma in real-world practice. Invest New Drugs 2022;40:392-402.
- 12. Wang Y, Zhou S, Yang F, et al. Treatment-related adverse events of PD-1 and PD-L1 inhibitors in clinical trials: a systematic review and meta-analysis. JAMA Oncol 2019;5:1008-1019.
- 13. Hiraoka A, Kumada T, Kariyama K, et al. Therapeutic efficacy of lenvatinib or sorafenib as salvage treatment after failure of atezolizumab plus bevacizumab in patients with unresectable hepatocellular carcinoma. Cancers (Basel) 2022;14:2278.
- 14. Ogushi K, Iwamoto H, Shinkawa H, et al. Clinical outcomes of tyrosine kinase inhibitors after failure of atezolizumab plus bevacizumab in patients with advanced hepatocellular carcinoma. Hepatol Res 2023;53:121-130.
- 15. Abou-Alfa GK, Meyer T, Cheng AL, et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Engl J Med 2018;379:54-63.
- 16. Lai KC, Chen YH, Hung YP, Chiang NJ, Chen MH, Chen SC. Efficacy and safety of durvalumab rechallenge in advanced hepatocellular carcinoma patients refractory to prior anti-PD-1 therapy. Hepatol Int 2024;18:1804-1814.
- 17. Inno A, Roviello G, Ghidini A, et al. Rechallenge of immune checkpoint inhibitors: A systematic review and meta-analysis. Crit Rev Oncol Hematol 2021;165:103434.
- 18. Kudo M, Izumi N, Kubo S, et al. Response evaluation criteria for immune checkpoint inhibitor-based treatments of hepatocellular carcinoma: a practical review. Liver Cancer 2021;10:349-359.
- 19. Heimbach JK, Kulik LM, Finn RS, et al. AASLD guidelines for the treatment of hepatocellular carcinoma. Hepatology 2018;67:358-380.
- 20. Lee J, Hsu CH, Yu SJ, et al. Early AFP response as a predictor of outcome in patients with advanced hepatocellular carcinoma treated with immunotherapy. Cancer Med 2022;11:1635-1643.
- 21. Johnson PJ, Berhane S, Kagebayashi C, et al. Assessment of liver function in patients with hepatocellular carcinoma: a new evidence-based approach—the ALBI grade. J Clin Oncol 2015;33:550-558.
- 22. Kim BK, Kim SU, Kim KA, et al. Prognostic value of ALBI grade compared to Child-Pugh classification in hepatocellular carcinoma. J Gastroenterol Hepatol 2016;31:1033-1039.
- 23. Pinato DJ, Sharma R, Nicolini F, et al. Inflammation-based prognostic scores in patients with advanced hepatocellular carcinoma. J Hepatol 2012;57:101-108.
- 24. Du J, Zhang E, Huang Z. The predictive value of next generation sequencing for matching advanced hepatocellular carcinoma patients to targeted and immunotherapy. Front Immunol 2024;15:1358306.
- 25. Omata M, Cheng AL, Kokudo N, et al. Asia-Pacific clinical practice guidelines on the management of hepatocellular carcinoma: a 2017 update. Hepatol Int 2017;11:317-370.
- 26. Llovet JM, Kelley RK, Villanueva A, et al. Hepatocellular carcinoma. Nat Rev Dis Primers 2021;7:6.
- 27. Kudo M, Ueshima K, Ikeda M, et al. Real-world efficacy and safety of atezolizumab plus bevacizumab for unresectable HCC in Japan: early post-marketing phase vigilance. Cancers (Basel) 2021;13:552.
- 28. Kim Y, Kim JS, Kang B, et al. Distinct characteristics and changes in liver function of patients with hepatocellular carcinoma treated with atezolizumab plus bevacizumab for more than 1 year. Cancer Res Treat 2024;56:1231-1239.
- 29. Lal LS, Aly A, Le LB, Peckous S, Seal B, Teitelbaum A. Healthcare costs related to adverse events in hepatocellular carcinoma treatment: A retrospective observational claims study. Cancer Rep (Hoboken) 2022;5:e1504.
- 30. Vogel A, Saborowski A, Finn RS, et al. Treatment strategies for HCC: expanding perspectives from Asia to the West. Hepatology 2023;78:1314-1326.
- 31. Yau T, Kang YK, Kim TY, et al. Efficacy and biomarker analysis of camrelizumab plus rivoceranib vs sorafenib in untreated advanced HCC: a randomized phase III trial (CARE-HCC). Lancet 2023;401:1109-1121.
- 32. Harding JJ, Nandakumar S, Armenia J, et al. Prospective genotyping of hepatocellular carcinoma: clinical implications of next-generation sequencing for matching patients to targeted and immune therapies. Clin Cancer Res 2019;25:2116-2126.
- 33. Lee SK, Kim SU, Kim DY, et al. Clinical utility of liquid biopsy in monitoring immunotherapy response in hepatocellular carcinoma. J Hepatol 2023;78:880-893.
- 34. Duffy AG, Greten TF. Immunological off-target effects of immune checkpoint inhibitors in cancer therapy. Nat Rev Clin Oncol 2020;17:509-524.
