Hepatotoxicity of immune checkpoint inhibitor plus targeted therapy versus tyrosine kinase inhibitor monotherapy in unresectable hepatocellular carcinoma: a systematic review and meta-analysis

Introduction

Hepatocellular carcinoma (HCC), the predominant histological subtype of primary liver cancer, ranks as the third leading cause of cancer-related mortality globally (1). Chronic hepatitis B virus (HBV) infection is the dominant etiological factor, especially in highly endemic regions such as China, where HCC cases and related deaths account for an increasing proportion of the global total (2). For decades, treatment options for unresectable HCC were severely limited, resulting in persistently dismal long-term survival (3,4). The development of vascular endothelial growth factor (VEGF)-targeted tyrosine kinase inhibitors (TKIs; e.g., lenvatinib, sorafenib) represented a major breakthrough, establishing these agents as guideline-endorsed first-line treatments (5,6). Despite this progress, clinical benefits remain modest, with 5-year overall survival rates remaining below 10%. Furthermore, long-term TKI exposure is frequently complicated by substantial toxicities including hypertension, proteinuria, bleeding diatheses, and hand-foot skin reaction, all of which impair quality of life and limit treatment persistence (7).

In recent years, tumor cells have been shown to evade host immune surveillance by exploiting immune checkpoint pathways to suppress T-cell activity (8). The advent of immune checkpoint inhibitors (ICIs) has established these agents as a cornerstone of treatment for unresectable HCC (9), but response rates to single-agent ICI therapy remain suboptimal, providing a strong rationale for combination strategies to enhance antitumor activity. As ICI-containing regimens are increasingly integrated into routine HCC care, immune-related adverse events have become a major focus of oncologic safety research. Among these, drug-induced liver injury and exacerbation of pre-existing hepatic dysfunction represent critical safety concerns in HCC, where underlying liver disease is ubiquitous (10). Moreover, VEGF-targeted TKIs are independently associated with hepatotoxicity, suggesting that ICI plus targeted therapy may impose additive or synergistic liver injury risk (11). Patients with HCC are inherently predisposed to liver enzyme abnormalities due to underlying tumor burden and chronic HBV infection, so clinical management must balance antitumor efficacy with vigilant mitigation of drug-related hepatotoxicity (12).

Clinical data directly comparing hepatotoxicity-related serious adverse events (SAEs) and fatal adverse events (FAEs) between ICI-based combination therapy and TKI monotherapy in HCC remain extremely scarce. These patients are at heightened risk of severe complications, including acute-on-chronic liver failure, progressive hepatic dysfunction, and death. Accordingly, we performed this meta-analysis to compare the hepatotoxicity profiles of ICI-based combination therapies versus standard TKI monotherapy in patients with unresectable HCC. We present this article in accordance with the PRISMA reporting checklist (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2026-1-0342/rc).

Methods

Search strategy

A comprehensive literature search was performed across the Cochrane Library, Embase, and PubMed databases from inception to March 2026. Search terms included “Programmed cell death protein-ligand 1 (PD-L1) inhibitors”, “Programmed cell death protein-1 (PD-1) inhibitors”, “HCC”, “anti-angiogenic therapy”, and related synonyms. The search was restricted to published, English-language randomized controlled trials (RCTs).

Inclusion and exclusion criteria for the literature

We enrolled only studies meeting the inclusion criteria: (I) subjects: patients with unresectable HCC; (II) intervention: combination therapy of PD-1/PD-L1 inhibitors with anti-angiogenic agents; (III) control group: monotherapy with TKI; (IV) results: all studies reported at least one safety outcome, including data on one prespecified hepatic safety endpoint (hepatotoxicity-related SAE or FAE). Exclusion criteria include non-original research (for instance, case reports, reviews, consensus documents and letters to the editor), non-randomized studies (like animal studies, preclinical studies, retrospective studies), conference abstracts, and studies with incomplete data or fewer than 10 patients.

Data extraction

Two independent investigators (S.W. and Y.H.) screened citations and extracted data using a standardized electronic form. A third independent researcher (Y.W.) resolved disputes and validated the final dataset. Study identifiers (year, authors, title), design, treatment specifics (regimen, dosage), patient characteristics (number, stage, age, gender), and safety results (FAEs, SAEs) were among the extracted data. Grade ≥3 adverse events were classified as SAEs. FAEs were classified as grade 5 adverse events (treatment-related deaths).

Risk of bias and quality assessment

To assess the risk of bias in the chosen studies, two independent researchers (F.C. and S.W.) used the Cochrane Systematic Review Risk of Bias Assessment Tool (13). Random sequence creation, blinding of outcome assessment, allocation concealment, selective reporting, insufficient outcome data, as well as other biases were among the domains in which the risk of bias was evaluated. A third researcher (M.L.) was consulted in order to settle any disputes that came up throughout the evaluation.

Statistical analysis

All statistical analyses were performed using Review Manager (RevMan) version 5.4. A random-effects model was applied to account for anticipated interstudy heterogeneity. Pooled effects were reported as odds ratios (ORs) with 95% confidence intervals (CIs). Statistical significance was defined as a two-sided P<0.05. Heterogeneity was quantified using the I² statistic and Cochran’s Q test; I²>50% was considered indicative of substantial heterogeneity. Sensitivity analyses were conducted by sequentially omitting individual trials to assess the robustness of pooled estimates when significant heterogeneity was detected.

Results

Search results and literature characteristics

The initial database search identified 5,749 articles. After screening and deduplication, 8 RCTs were included for analysis, involving 4,379 patients with unresectable HCC who had not received prior systemic treatment (Figure 1). Experimental regimens comprised 6 PD-1 + VEGF inhibitor combinations [camrelizumab plus rivoceranib (14), sintilimab plus bevacizumab (15), pembrolizumab plus lenvatinib (16), penpulimab plus anlotinib (17), toripalimab plus bevacizumab (18) and finotonlimab plus bevacizumab (19)] and 2 PD-L1 + VEGF inhibitor combinations [atezolizumab plus bevacizumab (20) and atezolizumab plus cabozantinib (21)]. Six trials were phase 3, and two were phase 2–3, published between 2021 and 2025. Detailed baseline characteristics are summarized in Table 1.

Figure 1 Flow diagram representing the selection process.

SAEs

The incidence of SAEs was 13.3% in the TKI group (n=1,739) and 20.0% in the ICI combination group (n=2,640). Meta-analysis showed a significantly higher SAE risk in the ICI combination group (OR, 1.71; 95% CI: 1.11–2.63; P=0.02; I²=82%, P<0.00001; Figure 2). Sensitivity analysis identified the COSMIC-312 study as the primary source of heterogeneity (Table S1).

Figure 2 Meta-analysis of overall hepatotoxicity-related SAEs: ICI plus targeted therapy versus TKI monotherapy in unresectable HCC. CI, confidence interval; HCC, hepatocellular carcinoma; ICI, immune checkpoint inhibitor; SAE, serious adverse event; TKI, tyrosine kinase inhibitor.

Combination therapy was associated with a significantly higher risk of elevated total bilirubin (OR, 2.05; 95% CI: 1.34–3.13; P=0.0009; I²=12%, P=0.34). No significant between-group differences were observed for elevated aspartate aminotransferase (AST), alanine aminotransferase (ALT), ascites, conjugated bilirubin, aberrant liver function, high blood alkaline phosphatase (ALP) or γ-glutamyl transferase (GGT) (Figures 3,4). Sensitivity analyses confirmed stable pooled estimates after omitting individual studies.

Figure 3 Forest plots of hepatocellular injury markers between ICI combination therapy and TKI monotherapy. (A) Forest plot for total bilirubin. (B) Forest plot for ALT. (C) Forest plot for AST. (D) Forest plot for GGT. ALT, alanine aminotransferase; AST, aspartate aminotransferase; CI, confidence interval; GGT, γ-glutamyl transferase; ICI, immune checkpoint inhibitor; TKI, tyrosine kinase inhibitor.

Figure 4 Forest plots of cholestatic and other hepatic adverse parameters in two groups. (A) Forest plot for conjugated bilirubin. (B) Forest plot for ascites. (C) Forest plot for aberrant liver function. (D) Forest plot for ALP. ALP, alkaline phosphatase; CI, confidence interval.

FAEs

All included studies reported FAEs. In the ICI combination group (n=2,640), FAEs included abnormal liver function (3 cases), hepatic failure (2 cases), and liver injury (1 case). In the TKI group (n=1,739), FAEs included hepatic failure (2 cases) and hepatic cirrhosis (1 case). FAE incidence was 0.22% with ICI combinations and 0.17% with TKIs (Table 2). There was no significant difference between the two groups in the incidence of FAEs (OR, 1.00; 95% CI: 0.25–4.01; P>0.99; I²=0%, P=0.99; Figure 5).

Figure 5 Meta-analysis of FAEs of ICI plus targeted therapy versus TKI in unresectable HCC. CI, confidence interval; FAE, fatal adverse event; HCC, hepatocellular carcinoma; ICI, immune checkpoint inhibitor; TKI, tyrosine kinase inhibitor.

Quality assessment of the included studies

The RoB 2.0 tool was used to assess risk of bias (Figure 6). Overall methodological quality was acceptable. Most trials were evaluated as low risk of bias for the randomization process (D1), as adequate random sequence generation and allocation procedures were clearly documented. Domains related to missing outcome data (D3) and outcome measurement (D4) were also determined to be low risk across all included studies. For the selection of reported results (D5), most trials were assessed as low risk, whereas two studies raised certain concerns due to incomplete reporting of some prespecified secondary outcomes. Given that the majority of trials adopted an open-label design, the domain associated with deviations from the intended interventions (D2) was identified as raising certain concerns (Figure S1).

Figure 6 Quality evaluation of the included randomized controlled trials.

Discussion

Over the past decade, immunotherapy has profoundly transformed cancer treatment. ICI combination therapy has demonstrated promising efficacy across multiple solid tumors, including HCC (22-26). With widespread clinical adoption, clinicians have become increasingly vigilant regarding the safety of combination strategies.

Our meta-analysis demonstrates that the risk of grade 3–5 hepatotoxicity-related SAEs is significantly higher in the ICI combination group than in the TKI monotherapy group. Sensitivity analysis further identified the COSMIC-312 trial as the primary source of heterogeneity, likely due to its PD-L1 plus TKI regimen, whereas most included studies adopted PD-1 combined with TKI therapy. A large-scale meta-analysis of phase 3 trials including more than 164,000 ICI-treated patients reported an overall incidence of ICI-related liver injury of 1.72%, with any-grade ALT elevation being the most frequent manifestation (4.73%) and grade 3–5 events occurring in only 0.67% (27). However, toxicity rates vary considerably by regimen: 4% to 7% for PD-1 monotherapy, approximately 4% for cytotoxic T lymphocyte antigen 4 (CTLA-4) monotherapy, and 19–37% for PD-1 plus CTLA-4 combination therapy (28-30). Grade ≥3 hepatotoxicity occurs in 1–3% of patients receiving ICI monotherapy, increasing to 9–19% with PD-1 plus CTLA-4 combination therapy (31). When combined with chemotherapy or TKIs, any-grade hepatic toxicity rises to 27–29%, with grade ≥3 events affecting 13–15% of patients (32,33). These findings confirm that single-agent ICI therapy is relatively safe in unresectable HCC, whereas ICI combination therapy imparts a significantly higher hepatotoxicity risk relative to TKI monotherapy. This elevated risk is particularly notable in Asian populations, where HBV prevalence is high and underlying cirrhosis is nearly universal, rendering patients more susceptible to acute-on-chronic liver failure and progressive hepatic decompensation. A recent comparative study including 375 HCC patients treated with atezolizumab + bevacizumab and 459 patients with other advanced solid tumors treated with anti-PD-(L)1 monotherapy reported that 72% of HCC patients had underlying cirrhosis versus only 1.9% of patients with other malignancies. Any-grade ICI-related hepatotoxicity occurred in 11.4% of HCC patients versus 2.6% of controls (22.1 vs. 2.1 per 100 person-years; P<0.001). Median time to hepatic toxicity onset was 1.4 months in HCC patients versus 4.7 months in non-HCC patients, highlighting the heightened vulnerability of the cirrhotic liver to immune-mediated injury (34). Our analysis detected no significant difference in FAEs incidence between treatment groups, likely due to the small absolute number of fatal hepatic events (6 vs. 3), resulting in limited statistical power. Nonetheless, the low absolute rates of fatal hepatotoxicity in both groups are reassuring, although close clinical monitoring remains warranted.

Apart from overall severe toxicity, we also focused on liver-related SAEs. Bilirubin elevation was significantly more common in the combination therapy group, with minimal interstudy heterogeneity. ICI-related hepatotoxicity typically presents with a mixed hepatocellular and cholestatic phenotype, ranging from asymptomatic transaminitis to severe jaundice, cholangitis, autoimmune hepatitis, and acute liver failure (35-37). Currently, several meta-analyses have reported ICI-associated hepatotoxicity rates ranging from 2% to 30% (35,37,38). A meta-analysis of 117 clinical trials (including 7 HCC-specific studies) found that the most common hepatotoxicity manifestations were ALT and AST elevations, with any-grade incidences of 5.29% and 5.88%, respectively; for anti-PD-L1 agents, rates were 3.72%/3.60% (grade ≥3: 1.08%/1.03%). In HCC cohorts, any-grade AST/ALT elevations reached 14.2%/13.3% vs. 4.92%/5.38% in non-HCC solid tumors (P<0.001) (39). While ALT and AST elevations represent early indicators of hepatocellular injury, bilirubin is a critical biomarker of hepatic synthetic and excretory function. Significant hyperbilirubinemia indicates severe hepatocellular or cholestatic damage and is strongly associated with treatment interruption, dose modification, and treatment-related mortality. ICI-related hepatotoxicity typically manifests within days to months after initiation, with a median onset of 3–9 weeks (40). A meta-analysis of 30 trials (12,921 patients) reported grade ≥3 all-cause AE rates were 67% for combination therapy, similar to TKI monotherapy (69%) and substantially higher than single-agent ICI therapy (35%), while hepatotoxicity-related AE rates were 36%, 28% and 21%, respectively (41). Our analysis confirmed that ICI combinations did not increase grade ≥3 ALT/AST elevation but significantly raised grade ≥3 bilirubin elevation, consistent with prior literature and emphasizing the need for routine bilirubin monitoring.

Several mechanisms may underlie the increased hepatotoxicity of ICI-based combinations. Reactivation of hepatitis viruses, particularly HBV, constitutes a serious and potentially life-threatening complication during combination therapy with ICIs and TKIs. In chronic HBV infection, viral persistence is facilitated by the functional exhaustion of virus-specific CD8⁺ T cells, a mechanism that maintains a dynamic equilibrium between the virus and the host immune response (42); given that restoring anti-tumor immunity and reversing T-cell exhaustion are the core objectives of ICIs, breaking immune tolerance via ICIs can enhance HBV-specific T-cell activity, and the subsequent immune-mediated destruction of infected hepatocytes clinically presents as HBV reactivation and a sharp elevation in serum transaminases. Secondly, ICI therapies can induce liver injury mimicking autoimmune hepatitis: by blocking checkpoint molecules (e.g., CTLA-4, PD-1/PD-L1), ICIs abrogate inhibitory signals on T cells, leading to their dysregulated activation, and these activated T cells may directly attack hepatocytes or secrete excessive pro-inflammatory cytokines, thereby creating a localized inflammatory microenvironment that recruits and further activates other immune cells, initiating a self-perpetuating cycle of progressive liver damage (43). The synergistic hepatotoxicity observed in ICI-TKI combinations can be attributed to convergent pathways of vascular injury: ICI-activated T cells trigger inflammatory damage to liver endothelial cells, while concurrent TKI therapy impairs endothelial repair capacity by inhibiting VEGF-related signaling pathways, resulting in a marked loss of vascular integrity that amplifies the initial immune-mediated insult (44). Furthermore, both drug classes can directly damage hepatocytes, sinusoidal endothelial cells, and bile duct epithelia, leading to a significant cumulative risk of hepatotoxicity. To mitigate this risk, a comprehensive pretreatment evaluation should be performed prior to the initiation of combination therapy, including HBV serological testing, assessment of hepatic reserve function, and evaluation of potential drug-drug interactions.

This study has several limitations. First, the included ICI combination regimens for unresectable HCC were restricted to PD-1/PD-L1 inhibitors plus VEGF inhibitors, with regimens combining CTLA-4 and PD-1 inhibitors not incorporated, thus precluding subgroup analysis to explore the disparate impacts of different ICI combination strategies on SAEs. Second, all data were extracted from published literature, with only routinely reported adverse events recorded, which may result in underreporting of ICI-related hepatotoxicity and introduce potential publication bias. Third, although all included trials adopted comparable grading criteria, heterogeneity existed in the categorized types and severity of hepatotoxicity across studies; only a few common treatment-related hepatic adverse events were eligible for meta-analysis, whereas critical indicators (including acute liver injury and coagulation function) lacked consistent reporting and were therefore not pooled, which may further contribute to between-study heterogeneity. Nevertheless, the present findings still provide practical references and valuable implications for the safety evaluation of ICI-based combination immunotherapy in patients with unresectable HCC. Finally, this meta-analysis was conducted based on aggregated published data rather than individual patient-level data, an inherent limitation of such meta-analytic studies.

Conclusions

This meta-analysis demonstrates that ICI plus targeted therapy was more likely to cause an increase in hepatotoxicity, especially elevated bilirubin levels. These results highlight the need for rigorous liver function monitoring, particularly bilirubin, in clinical practice.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2026-1-0342/rc

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2026-1-0342/prf

Funding: This work was supported by grants from the Self-Raised Scientifc Research Fund of the Ministry of Health of Guangxi Province (No. Z-A20241022) and Guangxi Key Technologies R&D Program (No. Guike AB24010163).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2026-1-0342/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Pol S. Hepatocellular carcinoma (HCC). Med Trop Sante Int 2024;4:mtsi.v4i4.2024.614.
2. Han B, Zheng R, Zeng H, et al. Cancer incidence and mortality in China, 2022. J Natl Cancer Cent 2024;4:47-53. [Crossref] [PubMed]
3. Cheng AL, Kang YK, Lin DY, et al. Sunitinib versus sorafenib in advanced hepatocellular cancer: results of a randomized phase III trial. J Clin Oncol 2013;31:4067-75. [Crossref] [PubMed]
4. Cainap C, Qin S, Huang WT, et al. Linifanib versus Sorafenib in patients with advanced hepatocellular carcinoma: results of a randomized phase III trial. J Clin Oncol 2015;33:172-9. [Crossref] [PubMed]
5. Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008;359:378-90. [Crossref] [PubMed]
6. 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. Lancet 2018;391:1163-73. [Crossref] [PubMed]
7. Yamashita T, Kudo M, Ikeda K, et al. REFLECT-a phase 3 trial comparing efficacy and safety of lenvatinib to sorafenib for the treatment of unresectable hepatocellular carcinoma: an analysis of Japanese subset. J Gastroenterol 2020;55:113-22. [Crossref] [PubMed]
8. Li Q, Han J, Yang Y, et al. PD-1/PD-L1 checkpoint inhibitors in advanced hepatocellular carcinoma immunotherapy. Front Immunol 2022;13:1070961. [Crossref] [PubMed]
9. 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;38:193-202. [Crossref] [PubMed]
10. Sangro B, Chan SL, Meyer T, et al. Diagnosis and management of toxicities of immune checkpoint inhibitors in hepatocellular carcinoma. J Hepatol 2020;72:320-41. [Crossref] [PubMed]
11. Houron C, Danielou M, Mir O, et al. Multikinase inhibitor-induced liver injury in patients with cancer: A review for clinicians. Crit Rev Oncol Hematol 2021;157:103127. [Crossref] [PubMed]
12. Cunningham M, Iafolla M, Kanjanapan Y, et al. Evaluation of liver enzyme elevations and hepatotoxicity in patients treated with checkpoint inhibitor immunotherapy. PLoS One 2021;16:e0253070. [Crossref] [PubMed]
13. Higgins JP, Altman DG, Gøtzsche PC, et al. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ 2011;343:d5928. [Crossref] [PubMed]
14. 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. Lancet 2023;402:1133-46. [Crossref] [PubMed]
15. Ren Z, Xu J, Bai Y, et al. Sintilimab plus a bevacizumab biosimilar (IBI305) versus sorafenib in unresectable hepatocellular carcinoma (ORIENT-32): a randomised, open-label, phase 2-3 study. Lancet Oncol 2021;22:977-90. [Crossref] [PubMed]
16. 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;24:1399-410. [Crossref] [PubMed]
17. Zhou J, Bai L, Luo J, et al. Anlotinib plus penpulimab versus sorafenib in the first-line treatment of unresectable hepatocellular carcinoma (APOLLO): a randomised, controlled, phase 3 trial. Lancet Oncol 2025;26:719-31. [Crossref] [PubMed]
18. Shi Y, Han G, Zhou J, et al. Toripalimab plus bevacizumab versus sorafenib as first-line treatment for advanced hepatocellular carcinoma (HEPATORCH): a randomised, open-label, phase 3 trial. Lancet Gastroenterol Hepatol 2025;10:658-70. [Crossref] [PubMed]
19. Zhao C, Zhang Y, Wang G, et al. Finotonlimab (PD-1 inhibitor) plus bevacizumab (bevacizumab biosimilar) as first-tier therapy for late-stage hepatocellular carcinoma: a randomized phase 2/3 trial. Signal Transduct Target Ther 2025;10:249. [Crossref] [PubMed]
20. 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;76:862-73.
21. 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;23:995-1008. [Crossref] [PubMed]
22. Motzer RJ, Powles T, Atkins MB, et al. Final Overall Survival and Molecular Analysis in IMmotion151, a Phase 3 Trial Comparing Atezolizumab Plus Bevacizumab vs Sunitinib in Patients With Previously Untreated Metastatic Renal Cell Carcinoma. JAMA Oncol 2022;8:275-80. [Crossref] [PubMed]
23. Ferrara R, Imbimbo M, Malouf R, et al. Single or combined immune checkpoint inhibitors compared to first-line platinum-based chemotherapy with or without bevacizumab for people with advanced non-small cell lung cancer. Cochrane Database Syst Rev 2021;4:CD013257. [Crossref] [PubMed]
24. Schmid P, Rugo HS, Adams S, et al. Atezolizumab plus nab-paclitaxel as first-line treatment for unresectable, locally advanced or metastatic triple-negative breast cancer (IMpassion130): updated efficacy results from a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2020;21:44-59. [Crossref] [PubMed]
25. Janjigian YY, Shitara K, Moehler M, et al. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial. Lancet 2021;398:27-40. [Crossref] [PubMed]
26. Garassino MC, Gadgeel S, Speranza G, et al. Pembrolizumab Plus Pemetrexed and Platinum in Nonsquamous Non-Small-Cell Lung Cancer: 5-Year Outcomes From the Phase 3 KEYNOTE-189 Study. J Clin Oncol 2023;41:1992-8. [Crossref] [PubMed]
27. Zheng C, Huang S, Lin M, et al. Hepatotoxicity of immune checkpoint inhibitors: What is Currently Known. Hepatol Commun 2023;7:e0063. [Crossref] [PubMed]
28. Wolchok JD, Chiarion-Sileni V, Gonzalez R, et al. Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. N Engl J Med 2017;377:1345-56. [Crossref] [PubMed]
29. Mok TSK, Wu YL, Kudaba I, et al. Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. Lancet 2019;393:1819-30. [Crossref] [PubMed]
30. Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Five-Year Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. N Engl J Med 2019;381:1535-46. [Crossref] [PubMed]
31. Biewenga M, van der Kooij MK, Wouters MWJM, et al. Checkpoint inhibitor induced hepatitis and the relation with liver metastasis and outcome in advanced melanoma patients. Hepatol Int 2021;15:510-9. [Crossref] [PubMed]
32. Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 2011;364:2517-26. [Crossref] [PubMed]
33. Rini BI, Plimack ER, Stus V, et al. Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med 2019;380:1116-27. [Crossref] [PubMed]
34. Celsa C, Cabibbo G, Fulgenzi CAM, et al. Characteristics and outcomes of immunotherapy-related liver injury in patients with hepatocellular carcinoma versus other advanced solid tumours. J Hepatol 2024;80:431-42. [Crossref] [PubMed]
35. Jennings JJ, Mandaliya R, Nakshabandi A, et al. Hepatotoxicity induced by immune checkpoint inhibitors: a comprehensive review including current and alternative management strategies. Expert Opin Drug Metab Toxicol 2019;15:231-44. [Crossref] [PubMed]
36. Parlati L, Vallet-Pichard A, Batista R, et al. Incidence of grade 3-4 liver injury under immune checkpoints inhibitors: A retrospective study. J Hepatol 2018;69:1396-7. [Crossref] [PubMed]
37. Alessandrino F, Tirumani SH, Krajewski KM, et al. Imaging of hepatic toxicity of systemic therapy in a tertiary cancer centre: chemotherapy, haematopoietic stem cell transplantation, molecular targeted therapies, and immune checkpoint inhibitors. Clin Radiol 2017;72:521-33. [Crossref] [PubMed]
38. Peeraphatdit TB, Wang J, Odenwald MA, et al. Hepatotoxicity From Immune Checkpoint Inhibitors: A Systematic Review and Management Recommendation. Hepatology 2020;72:315-29. [Crossref] [PubMed]
39. Fu J, Li WZ, McGrath NA, et al. Immune Checkpoint Inhibitor Associated Hepatotoxicity in Primary Liver Cancer Versus Other Cancers: A Systematic Review and Meta-Analysis. Front Oncol 2021;11:650292. [Crossref] [PubMed]
40. Martins F, Sofiya L, Sykiotis GP, et al. Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance. Nat Rev Clin Oncol 2019;16:563-80. [Crossref] [PubMed]
41. Griffiths CD, Zhang B, Tywonek K, et al. Toxicity Profiles of Systemic Therapies for Advanced Hepatocellular Carcinoma: A Systematic Review and Meta-analysis. JAMA Netw Open 2022;5:e2222721. [Crossref] [PubMed]
42. Venzin V, Beccaria CG, Perucchini C, et al. CD4(+) T cells license Kupffer cells to reverse CD8(+) T cell dysfunction induced by hepatocellular priming. Nat Immunol 2025;26:1352-66. [Crossref] [PubMed]
43. De Martin E, Michot JM, Rosmorduc O, et al. Liver toxicity as a limiting factor to the increasing use of immune checkpoint inhibitors. JHEP Rep 2020;2:100170. [Crossref] [PubMed]
44. Zhang Q, Chen L, Guo X, et al. Morphology of immune-mediated hepatitis: A comparison between immune checkpoint inhibitor therapy and combined immune checkpoint inhibitor/anti-angiogenic therapy. Ann Diagn Pathol 2024;68:152225. [Crossref] [PubMed]