Immune Checkpoint Inhibitors for Child-Pugh Class B Advanced Hepatocellular Carcinoma

Key Points Question What are the efficacy and tolerability of immune checkpoint inhibitors (ICIs) for patients with advanced hepatocellular carcinoma (HCC) with Child-Pugh B liver function? Findings In this systematic review and meta-analysis of 22 studies involving 699 patients with Child-Pugh B and 2114 patients with Child-Pugh A advanced HCC, ICI therapy in the Child-Pugh B group appeared to be safe and showed a significant number of radiologic responses, but survival outcomes were inferior compared with the Child-Pugh A group. Meaning These findings suggest that although the overall prognosis is still poor for patients with HCC, a proportion of patients with Child-Pugh B liver function might benefit from ICI therapy.


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iver cancer is the third leading cause of cancer-related deaths, is sixth in global incidence for cancers, 1 and has been increasing in many regions of the world. 2 Hepatocellular carcinoma (HCC) accounts for approximately 90% of primary liver cancer. 3Due to late-stage diagnosis, most patients with HCC are not eligible for surgical or locoregional treatment, making systemic treatment the mainstay treatment option. 4However, varying degrees of hepatic dysfunction resulting from underlying liver disease are associated with the prognosis and efficacy of systemic treatment. 5orafenib was the standard first-line treatment for advanced HCC, 6 but its therapeutic effect in patients with impaired liver function is poor.[9][10] Hence, treatment should be individualized for patients with Child-Pugh B cirrhosis. 11he emergence of immune checkpoint inhibitors (ICIs) has shown promising results in trials of advanced HCC. 12,13 Compared with sorafenib, nivolumab treatment has been associated with improved OS and better tolerability in patients with Child-Pugh B HCC . 14Subgroup analysis of cohort 5 of the prospective Check-Mate 040 study, which included 49 patients with Child-Pugh B cirrhosis, showed similar radiologic response and safety but worse survival compared with patients with Child-Pugh A cirrhosis.Some patients with Child-Pugh B cirrhosis, particularly responders, even showed an improvement in liver function. 15espite the considerable knowledge gap, the majority of patients participating in clinical trials assessing ICI treatment typically are required to have Child-Pugh A liver function, although many patients with advanced HCC actually present with impaired liver function and higher Child-Pugh classes.Therefore, we performed a systematic review and metaanalysis with original data collected from the primary studies to evaluate the efficacy and safety of ICI therapy in patients with Child-Pugh B advanced HCC.

Search Strategy and Selection Criteria
This systematic review and meta-analysis was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline 16 (eAppendix 3 in Supplement 1), and its protocol was registered with PROSPERO (CRD42022379407).We searched PubMed, Embase, Web of Science, and Cochrane Library from inception to June 15, 2022, without language restrictions.References in eligible articles were also searched when necessary.The search strategy is detailed in eAppendix 1 in Supplement 1. Two reviewers (E.X. and Y.Z.) independently completed the title and abstract screening for eligibility using a preplanned list of inclusion and exclusion criteria (eAppendix 2 in Supplement 1), with discrepancies resolved by consensus or discussion with either Y.H.Y. or F.J. The institutional review board of the Second Affiliated Hospital of Xi'an Jiaotong University waived the need for review and informed consent because the study did not involve direct interaction with human participants or the collection of new data.

Data Extraction and Quality Assessment
Two reviewers (E.X. and Y.Z.) independently extracted data from each study, including the first author's name, study characteristics, therapeutic method, patient demographic characteristics, HCC etiology, liver function, Barcelona Clinic Liver Cancer stage, duration of follow-up, and relevant outcomes.We collected but did not analyze data on sex due to unavailability of detailed subgroup data.Data on race and ethnicity were not collected due to heterogeneity in data availability and classification methods.When necessary, original authors were contacted to supplement missing or unclear information.The 2 reviewers independently assessed study quality, resolving disagreements through consensus or consultation with authors Y.H.Y. or F.J. The Newcastle-Ottawa Scale was used for observational studies, 17 designating those scoring 7 or higher as high quality and those scoring 4 to 6 as fair quality.For singlegroup studies, an Institute of Health Economics (IHE) case series studies quality appraisal tool was used, 18 with those meeting 70% or more of the 20 criteria deemed acceptable.

Statistical Analysis
The primary outcomes of this meta-analysis were objective response rate (ORR), OS, and treatment-related adverse events (trAEs) among patients with Child-Pugh B advanced HCC treated with ICIs and how these compared with patients with Child-Pugh A advanced HCC.The secondary outcomes were disease control rate (DCR), progression-free survival (PFS), and immunotherapy-related adverse events (irAEs) in patients with Child-Pugh B vs those with Child-Pugh A. For dichotomous data, we calculated odds ratios (ORs) and 95% CIs as summary statistics.Hazard ratios (HRs) were used as a measure of the prognostic value to analyze PFS and OS.Unadjusted or adjusted HRs and 95% CIs were extracted from studies and then pooled separately.Considering that some studies did not report HRs and 95% CIs, the methods described by Liu et al 19 were used to obtain the survival data from the reported Kaplan-Meier (K-M) curves.In the single-group study that only included patients with Child-Pugh B HCC, outcomes including ORR, DCR, PFS, OS, and incidence of trAEs or irAEs were pooled with the same variable derived from the randomized clinical trials or cohort studies with both Child-Pugh A and B groups.
A generalized linear mixed model was used for the metaanalysis of single proportions.Heterogeneity across included studies was assessed using the Cochran Q and I 2 statistics.If the I 2 statistic was less than 50% or the P value greater than .10, the heterogeneity was considered to be low, and the fixedeffect model was applied.Otherwise, the random-effects model was applied.We also performed meta-regression analyses to explore potential sources of heterogeneity among the studies.The following study characteristics were included for analytic purposes: year of publication, study design (retrospective or prospective), sample size, proportion of nonviral etiology, proportion of Barcelona Clinic Liver Cancer C/D stage, median follow-up, ICI regimens (monotherapy, combined with targeted therapy, with or without other therapy), and median age.Publication bias was evaluated using the Begg test and funnel plot.The survival, ggplot2, IPDfromKM, and meta packages in R, version 4.1.3software (R Project for Statistical Computing) were used for statistical analyses.The threshold of statistical significance was set at a 2-sided P < .05.
Because of the limited number of studies, we only performed subgroup analyses of unadjusted HRs of OS based on ICI regimens.Regardless of ICI regimens, patients with Child-Pugh B advanced HCC had a poorer prognosis than those with Child-Pugh A (eFigure 6 in Supplement 1).Notably, we did not observe any differences in OS (HR, 1.08; 95% CI, 0.73-1.60;P = .69)and PFS (HR, 1.19; 95% CI, 0.66-2.13;P = .57)between patients with CTP8/9 and CTP7 (eFigure 4D and E in Supplement 1).

Meta-Regression Analyses
We conducted meta-regression analyses on primary outcomes with high heterogeneity (eTables 4 and 5 in Supple-ment 1).We found no significant associations among the pooled incidence of trAEs in patients with Child-Pugh B vs Child-Pugh A advanced HCC, pooled median OS in the Child-Pugh B group, and the variables of interest.

Sensitivity Analysis and Publication Bias
To assess whether any single study had a dominant effect on the meta-analysis, we excluded 1 study at a time and analyzed its effect on the main summary estimate.In this analysis, no single study significantly affected the outcome or the heterogeneity (eFigure 7 in Supplement 1).In addition, there was no evidence of publication bias based on the Begg test (eFigure 8 in Supplement 1).

Discussion
In this systematic review and meta-analysis of data from 22 studies 14,15,[20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39] including 699 patients with Child-Pugh B and 2114 with Child-Pugh A advanced HCC, we found very low heterogeneity across the majority of primary outcome measures analyzed.We obtained original data from 7 main studies 23,24,26,27,30,33,35 and found that the ORR and DCR of patients with Child-Pugh B advanced HCC treated with ICIs were 14% and 46%, respectively, with a median OS of 5.49 months and a median PFS of 2.68 months.The incidence rate of any grade trAEs was 40%, including 12% for grade 3 or higher.Furthermore, the incidence rate of any grade irAEs was 31%, including 7% for grade 3 or higher.Although patients with Child-Pugh B HCC achieved lower ORRs and DCRs and had shorter OS and PFS than those with Child-Pugh A HCC, ICI treatment was not associated with a significantly higher risk of or severe trAEs, and a subset of patients even experienced prolonged responses and improvement in Child-Pugh score in some cases. 15,23Notably, the pooled risk of irAEs was lower in the Child-Pugh B group, although this could be attributed to the shorter duration of therapy.
A recent meta-analysis assessed immunotherapy outcomes for patients with HCC and liver dysfunction but lacked the breadth of our systematic literature search and omitted studies involving immunotherapy plus locoregional treatments or tyrosine kinase inhibitors. 40Our study extends this work by Tanaka et al, 35    acquiring patient data from 7 primary studies, 23,24,26,27,30,33,35 which enabled comprehensive subgroup analyses that consider efficacy outcomes (ie, ORR, DCR, OS, and PFS) and safety profiles, screening more potential studies, and excluding overlapping cohorts.
A meta-analysis of sorafenib use in patients with Child-Pugh B advanced HCC showed a 4.2% response rate. 10However, recent investigations into ICIs, either alone or combined with tyrosine kinase inhibitors, showed promising clinical efficacy, manageable toxic effects, and favorable safety in patients with advanced HCC and Child-Pugh B liver function. 26,32,35Although indirect comparisons should be interpreted with caution, the response rate observed in our study was 14%, suggesting a potential therapeutic benefit from ICI therapy in a relevant proportion of these patients.
Additionally, the median OS reported for sorafenib therapy in the previous meta-analysis was 4.6 months for patients with Child-Pugh B HCC, 10 and in some retrospective or prospective studies, the median OS was approximately 3 to 5 months. 8,41,42otably, our research revealed that with ICI treatment, the median OS was 5.5 months.Although a median OS of less than 6 months still requires much work to improve the efficacy of our treatment options, this finding denotes an improvement over the median OS following sorafenib therapy.However, our findings suggest that in patients with advanced HCC and Child-Pugh B liver function, the efficacy of immunotherapy may be lower compared with Child-Pugh A despite competing comorbidity and a much higher risk of death from liver failure and other cirrhosis-related complications independent of cancer.Results were similar between ICI monotherapy and combination treatments (ie, ICIs combined with targeted therapy) separately.
Advanced liver dysfunction was postulated to polarize the liver microenvironment toward a more profound immunosuppression, 43 implying reduced responsiveness to ICIs.Combination therapy, such as transcatheter arterial chemoembolization, radiofrequency ablation, and radiation therapy, was used in some studies. 15,20,25,29,36Since better liver function is an important factor for maximizing the therapeutic outcome of systemic therapy, 44 the synergistic effect of ICIs combined with other therapies may be more pronounced in patients with Child-Pugh A liver function, which may have contributed to the significant difference in ORR and DCR between the 2 groups in our overall meta-analysis.Additionally, the smaller number of patients in the Child-Pugh B group, shorter follow-up and survival times, and different baseline characteristics between the Child-Pugh B and A groups may have contributed to the observed differences in response rates.
Regarding OS and PFS outcomes, among the 6 studies in the meta-analysis reporting a multivariable comparison of the Child-Pugh status, 21,26-28,37,39 the pooled adjusted HR showed that Child-Pugh B liver function was associated with significantly worse OS.The unadjusted HR also indicated a reduced PFS for Child-Pugh B. Overall, ICI therapy was associated with a worse prognosis in patients with Child-Pugh B vs Child-Pugh A advanced HCC.Similar results were observed in subgroups of patients treated with ICI monotherapy and in combination with targeted therapies.However, because of the lack of an untreated Child-Pugh B control group, solid conclusions regard-ing a potential benefit of ICIs cannot be made.In fact, the prognosis of advanced HCC is determined not only by tumor burden but also by liver function. 45,46Our results confirm that liver function is associated with survival of patients with advanced HCC treated with ICIs.In patients with HCC, liver function is, in most cases, compromised due to the underlying liver fibrosis or cirrhosis but occasionally may also be impaired due to a high tumor burden.In patients with high tumor burden, response to treatment may stabilize or even improve liver function.Indeed, approximately 10% of patients enrolled in cohort 5 of the CheckMate 040 study experienced a significant improvement in liver function that lasted 6 months or longer. 15ur study also affirmed the safety of ICIs in patients with Child-Pugh B advanced HCC, revealing no significant differences in incidence of trAEs between the Child-Pugh A and B groups.This finding aligns with prior studies, including CheckMate 040, 15 Ng et al, 20 and Fessas et al, 26 that have shown comparable safety between the groups.Interestingly, we observed a lower risk of irAEs for patients with Child-Pugh B, possibly due to their shorter exposure to ICIs because of shorter survival.Overall, our study suggests that ICIs, even in patients with advanced HCC with poor liver function, present manageable adverse effects and are safe.Notably, further subgroup analyses did not reveal any significant differences in radiologic response, survival, or incidence of trAEs between patients with CTP7 and CTP8/9 scores.However, due to the limited sample size (fewer than 100 cases with CTP8/9 across 6 studies 23,24,26,27,33,35 ), further multicenter prospective cohort studies are needed to evaluate the association of CTP score with the efficacy and tolerability of ICI treatment in these patients.

Limitations
Several limitations should be acknowledged.First, the majority of the included studies were retrospective, which may be subject to selection bias, and larger randomized clinical trials are recommended.Second, the smaller number of patients with Child-Pugh B liver function and baseline differences between the Child-Pugh B and A cohorts may represent potential sources of bias.However, the pooled adjusted HR was similar to the pooled unadjusted HR.Third, the confounding factors analyzed in multivariable Cox proportional hazards regression models varied across studies, although the pooled adjusted HR in the overall patient cohort showed low heterogeneity.Fourth, there may be potential underreporting of AEs in some studies, and the lack of an untreated Child-Pugh B cohort prevents definite conclusions regarding a potential survival benefit of ICI therapy in these patients.Fifth, we noticed high heterogeneity in some of our results, particularly in single-arm studies.Our attempts to detect potential sources of heterogeneity through meta-regression analyses did not yield any results.The high heterogeneity observed in the single-group meta-analysis may be attributable to the combination of single-group and comparative research data.Therefore, these results should be interpreted with caution.Sixth, 5 studies did not provide detailed information on the specific ICI agents used, 20,30,[36][37][38] which may limit the relevance of the data from these studies and high- lights the importance of reporting detailed information on the ICI agents used in future studies.

Conclusions
The findings of our systematic review and meta-analysis show that ICI therapy in patients with Child-Pugh B advanced HCC appears to be safe and associated with a significant number of radiologic responses, even though survival is inherently lower than in patients with Child-Pugh A HCC. Our data support the use of immunotherapy in wellselected patients with HCC and Child-Pugh B liver function, but randomized studies are needed to confirm the outcomes of ICI treatment in patients with advanced liver disease.

Figure 1 .A
Figure 1.Immune Checkpoint Inhibitor Treatment in Patients With Advanced Hepatocellular Carcinoma (HCC) and Child-Pugh B Liver Function

Figure
Figure 2.Estimated Overall Survival (OS) and Progression-Free Survival (PFS) in Patients With Advanced Hepatocellular Carcinoma and Child-Pugh B vs A Liver Function

Figure 3 .
Figure 3. Association of Immune Checkpoint Inhibitors With Median Overall Survival (OS) and Progression-Free Survival (PFS) in Patients With Hepatocellular Carcinoma and Child-Pugh B Liver Function 2. Estimated Overall Survival (OS) and Progression-Free Survival (PFS) in Patients With Advanced Hepatocellular Carcinoma and Child-Pugh B vs A Liver Function jamaoncology.com(Reprinted) JAMA Oncology October 2023 Volume 9, Number 10

Table .
Pooled Incidence of Adverse Events Immune Checkpoint Inhibitors for Child-Pugh B Hepatocellular CarcinomaOriginal Investigation Research jamaoncology.com(Reprinted) JAMA Oncology October 2023 Volume 9, Number 10