Patients with uHCC and Child-Pugh B8/9 also benefit from a combination of antiangiogenic agents and PD-1 inhibitors: a multicenter real-world study

Patients with uHCC and Child-Pugh B8/9 also benefit from a combination of antiangiogenic agents and PD-1 inhibitors: a multicenter real-world study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Patients with uHCC and Child-Pugh B8/9 also benefit from a combination of antiangiogenic agents and PD-1 inhibitors: a multicenter real-world study Xiaoyan Ding, Xue Yin, Linlin Zheng, Lin Zhou, Junke Hu, Wei Sun, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4467107/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Unresectable hepatocellular carcinoma (uHCC) patients with Child-Pugh grade B have limited treatment options and poor outcomes. Methods: Patients with uHCC and Child-pugh B who received lenvatinib plus PD-1 inhibitors or sorafenib plus PD-1 inhibitors at one of three centers were retrospectively reviewed. These patients were divided into two subgroups: one with Child-pugh B7 (Group A, n =106) and another with Child-pugh B/9 (Group B, n = 73). Overall survival (OS) was defined as the primary endpoint. Secondary endpoints included time to progression (TTP), the objective response rate (ORR), and safety. Prognostic factors were evaluated using multivariate Cox proportional hazards models, while nomograms were constructed to predict 12-month survival. Results: Between December 31, 2020 and March 30, 2023, a total of 179 patients were enrolled. The objective response and disease control rates of patients in the Child–pugh groups B and A were 26.0% and 76.7%, and 33.0% and 83.0%, respectively. There was no difference in median TTP (6.3 vs. 7.8 months, P = 0.28) or OS (14.0 vs. 17.8months, P = 0.20) between Group B and Group A. However, while the safety profiles were comparable between the two groups, patients with Child-pugh B8/9 had a significantly higher frequency of dose reductions and discontinuations (P = 0.04 and P < 0.001), compared to those with Child-pugh B7. According to the results of multivariate analysis，we constructed a nomogram to predict 12-month survival rates，considering tumor size, BCLC stage, tumor response , drug resistance. The nomogram-related receiver operating characteristics (ROC) curves indicated that the area under the curve (AUC) values were 0.752. Furthermore, the calibration curves revealed good agreement between real measurements and nomogram predictions. Conclusions: A combination of multi-kinase inhibitors (lenvatinib or sorafenib) plus PD-1 inhibitors was safe, well-tolerated, and especially it can also benefit patients with uHCC and Child-pugh B8/9. Hepatocellular carcinoma Lenvatinib Sorafenib Immune checkpoint inhibitors Child-Pugh B Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction Hepatocellular carcinoma (HCC) accounts for 90% of primary liver tumors and is the third leading cause of cancer-related deaths worldwide ( 1 , 2 ). HCC develops after chronic liver injury and/or cirrhosis, which impacts treatment options. The severity of cirrhosis can be categorized into subgroups A, B, and C using the Child-Pugh score, which is based on laboratory values and clinical assessments. Because HCC often has an occult onset and atypical symptoms, 60–70% of cases are initially diagnosed as unresectable, and systemic therapy is recommended as the standard first-line regimen ( 2 ). However, more than 70% of patients with unresectable hepatocellular carcinoma (uHCC) have concurrent cirrhosis, and up to 30% of these patients have grade B liver function ( 3 – 7 ). Although many anti-angiogenic tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) have been used in clinical practice for uHCC since 2007, the median overall survival (mOS) has been relatively unchanged in patients with uHCC and Child-Pugh B, ranging from 4.0 to 9.0 months ( 3 – 7 ). In addition, given that patients with Child-Pugh B have been excluded from large-scale, multicenter, phase III, randomized controlled clinical trials such as REFLECT( 8 ), ORIENT-32 ( 9 ), and IMbrave 150, systemic treatment options for these patients remain limited ( 10 ). To date, NCCN guidelines have only recommended sorafenib (GIDEON) and nivolumab (CheckMate-040) for advanced HCC with Child-Pugh B graded liver function ( 3 , 4 , 7 ). In a large retrospective study of 510 patients with advanced HCC and Child-Pugh B liver function, the mOS was 4.0 months for sorafenib and 5.0 months for first-line nivolumab ( 5 ). Lenvatinib is another first-line TKI that was studied in phase III global multicenter REFELECT study. The lenvatinib arm showed significant improvements in median time to progression (mTTP) and objective response rate (ORR) compared to the sorafenib arm (mTTP 11.0 months vs. 3.7 months; ORR 21.5% vs. 8.3%) ( 8 ). Although no statistical difference was found in OS, in the subgroup analysis of Chinese patients, the mOS in the lenvatinib group was 15.0 months compared to 10.2 months in the sorafenib group ( 8 ). In a meta-analysis, lenvatinib was shown to be significantly more effective than sorafenib in treating hepatitis B virus (HBV) -positive HCC patients (HR = 0.82) ( 11 ). However, HCC patients with grade B liver function were not included in the REFLECT study ( 8 ). In a retrospective study of 181 patients with advanced HCC who received lenvatinib as a first-line regimen (126 grade A; 55 grade B), the ORR in HCC with liver function grade A5 was significantly higher than that in HCC with grade A6 or grade B7 and 8 (44.0%, 25.5%, 22.2%, and 5.3%, respectively [P = 0.002]) ( 6 ). Another large-scale study enrolled 343 patients with advanced HCC, including 67 patients with Child-Pugh B, and found a median OS of 9 months. The discontinuation rate was 70.1% in grade B compared with 69.2% in grade A ( 12 ). uHCC patients with Child-Pugh B liver functions continue to have low ORRs and poor prognoses, suggesting an urgent need to explore new treatment options. Increasing numbers of preclinical studies and clinical reports have demonstrated synergy in angiogenesis by targeting VEGF/VEGFR plus PD-1/PD-L1 inhibitors( 13 , 14 ). Combination regimens have been the primary and preferred choice for uHCC, and the combination of sorafenib plus PD-1 inhibitors or lenvatinib plus PD-1 inhibitors were administered to patients with uHCC and Child-Pugh A liver function. However, it is not recommended in the guidelines for uHCC with Child-Pugh B liver function, and data on dual regimens in uHCC with Child-Pugh B is limited. Thus, we performed this multicenter retrospective study to explore the action of combination regimen of TKIs with PD-1 inhibitors for uHCC with Child-Pugh B liver function, especially for patients with Child-pugh B8/9. Methods Study design and patients This multicenter retrospective study was conducted at three separate centers in China (Captial Medical University Affiliated Beijing Ditan Hospital, The Fifth Medical Cancer, Chinese PLA General Hospital, and Capital Medical University Affiliated Beijing You’an Hospital). We included patients diagnosed with uHCC and Child-Pugh B liver function between December 31, 2020 and March 30, 2023. According to Child-Pugh scores, the enrolled patients were divided into two groups, Child-pugh B7 (Group A) and Child-Pugh B/9 (Group B). And 173 patients received treatment with either lenvatinib plus PD-1 inhibitors or sorafenib plus PD-1 inhibitors, 6 patients received treatment with other TKIs (regorafenib or donafenib) plus PD-1 inhibitors. Eligible patients had ≥ 1 typically enhancing measurable target lesion ≥ 1 cm based on the modified Response Evaluation Criteria in Solid Tumors (mRECIST) ( 15 ), a Child-Pugh score ≥ 7–9, were older than 18 years, histologically or clinically confirmed diagnosis of HCC ( 16 ), a life expectancy ≥ 3 months, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, normal renal function, and no prior systemic therapy. Additional inclusion criteria included Barcelona Clinic Liver Cancer (BCLC) stage B/C disease and postoperative disease recurrence. Patients received at least one cycle of systemic therapy (one dose of PD-1 inhibitor and sorafenib or one dose of PD-1 inhibitor and lenvatinib). Patients with extrahepatic tumor spread or portal vein tumor thrombus (PVTT) were permitted except for those with symptomatic brain metastases. Patients were excluded if they had complete obstruction invasion of the primary branch of the biliary tract or had received any prior systemic therapy. In addition, patients were excluded if they had received any local treatment for HCC or radiotherapy for intrahepatic lesions for four weeks or three months, respectively, before giving informed consent. Patients with serious comorbidities, incomplete data, or who were lost to follow-up were also excluded. The study was conducted in accordance with Good Clinical Practice, the principles outlined in the Declaration of Helsinki, and local laws. All participants provided written informed consent before enrollment. The study has been approved by the Ethics Committee of the Capital Medical University affiliated Beijing Ditan Hospital (Ethical approval number: JDLKZ-2021-041-01). Treatments Systemic drugs Sorafenib (Bayer, Leverkusen, Germany, Sor) was initially administered orally at 200 mg twice daily. Lenvatinib (Lenvima ®; Eisai Co., Ltd., Tokyo, Japan, Len) was administered orally daily according to body weight: Patients weighing < 60 kg received 4mg of lenvatinib once daily; patients weighing ≥ 60 kg received 8 mg of lenvatinib once daily. Patients received 200 mg of sintilimab, camrelizumab, or tislelizumab intravenously on day one of a 21-day cycle following the first dose of lenvatinib or sorafenib. These agents were managed according to local regulations with dose reductions or treatment interruptions in the event of disease progression or unacceptable toxicity. Any drug interruptions and dose reductions were recorded, as well as the reasons for these events. Study Endpoints The primary endpoint was OS, defined as the time from the date of enrollment to death due to any cause. Secondary endpoints included TTP, tumor response, the objective response rate (ORR), and safety. TTP was defined as the interval from the date of enrollment to the date of radiographic progression. Tumor responses were assessed using contrast-enhanced dynamic CT or MRI and by mRECIST. The best overall response was considered to be the final response. Final responses were documented as either complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD). The percentage of patients achieving a complete or partial response (CR/PR) was defined as ORR ( 15 ). PVTT was considered a non-target lesion. In both groups, tumor responses to the entire treatment regimen were evaluated every 8–12 weeks after enrollment. Adverse events (AEs) were graded and recorded using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.18( 17 ). Statistical Analyses Statistical analysis was performed using R software (4.0.5). Categorical variables were presented as numbers (percentages), which were compared by Pearson 's χ2 test. And continuous variables with skewed distributions were presented as medians [interquartile range], which were compared by t test. Fischer exact test was used to compare baseline categorical characteristics, treatment response and AEs between groups. TTP and OS were estimated using the Kaplan–Meier method, and the differences were compared using the log-rank test. Univariate and multivariate Cox proportional hazards models were used to analyze prognostic factors for OS. And the nomogram-based prediction models were constructed by applied for forward and backward stepwise regression in multivariate Cox analysis. In addition, the ROC and calibration curve were plotted separately to demonstrate the model's performance, and the predictive value was exhibited by calculating the area under the ROC curve (AUC). Results Patient Baseline Characteristics A total of 191 HCCs with Child-Pugh B graded liver function who were diagnosed between December 31, 2020 and March 30, 2023 at one of the three included hospital sites were initially recruited. Subsequently, 12 patients withdraw their consent, leaving 179 patients included in the final analysis (Fig. 1) . Based on their Child-Pugh scores, patients were divided into two Group: Group A (106 patients; Child-Pugh B7) and Group B (73 patients; Child-Pugh B8/9). The median age was 61 (inter-quartile range: 53–68), with the majority being male (84.9%). Additionally, a total of 153 patients (85.5%) had hepatitis B-virus (HBV). Among them, 110 patients (61.5%) presented with type I-IV PVTT, and 47.5% (85 patients) of the cohort had extrahepatic metastasis. Treatment-wise, 24.6% of the cohort received sorafenib plus PD-1 inhibitors, while 72.1% received lenvatinib plus PD-1 inhibitors. Regarding tumor treatment history, 10 (5.6%), 37 (20.7%), and 28 (15.6%) patients had previously undergone hepatectomy, TACE, and ablation, respectively. Furthermore, 94 (52.5%) patients had alpha-feto protein (AFP) levels ≥ 400ng/ml. Moreover, 163 (91.1%) patients presented with ALBI grade 1–2, with the percentage significantly higher in Group A (98.1%) than in Group B (80.8%). Also, 88 (49.2%) patients presented with ECOG 1, with the percentage significantly higher in Group B (75.3%) than in Group A (31.1%). ( Table 1 ) . Table 1 Baseline patient demographic and disease characteristics Characteristics Child-Pugh B7 (n = 106) Child-Pugh B8/9 (n = 73) P value Age (median, IQR) (61 [53–68]) 59 [52–68] 62 [55–68] 0.70 Sex (Male/Female, 151/28) 93(87.7%)/13(12.3%) 58(79.5%)/15(20.5%) 0.13 ECOG PS score (n, %) 0 (91, 50.8%) 1 (88, 49.2%) 73 (68.9%) 33 (31.1%) 18 (24.7%) 55 (75.3%) < 0.001 Hepatitis virus status (n,%) HBV (153, 85.5%) HCV (17, 9.5%) non-HBV or HCV (9, 5.0%) 92 (86.8%) 11 (10.4%) 3 (2.8%) 61 (83.6%) 6 (8.2%) 6 (8.2%) 0.25 Extrahepatic metastasis (n, %) Yes (85, 47.5%) No (94, 52.5%) 58 (54.7%) 48 (45.3%) 36 (49.3%) 37 (50.7%) 0.48 With PVTT (n, %) Yes (110, 61.5%) No (69, 38.5%) 61 (57.5%) 45 (42.5%) 49 (67.1%) 24 (32.9%) 0.20 Treatment SOR + PD-1 (44, 24.6%) LEN + PD-1 (129, 72.1%) 27 (25.5%) 75 (70.8%) 17 (23.3%) 54 (74.1%) 0.87 Others (6, 3.4%) 4 (3.8%) 2 (2.7%) Number of liver tumors (n, %) 1–2 (71, 39.7%) ≥ 3 (108, 60.3%) 40 (37.7%) 66 (62.3%) 31 (42.5%) 42 (57.5%) 0.53 AFP (ng/mL)* n (%) ≥ 400 ng/mL (94, 52.5%) < 400ng/ml (85, 47.5%) 47 (44.3%) 59 (55.7%) 38(52.1%) 35 (47.9%) 0.31 ALBI (n, %) Grade 1–2 (163, 91.1%) 104 (98.1%) 59 (80.8%) < 0.001 Grade 3 (16, 8.9%) 9 (1.9%) 14 (19.2%) BCLC Stage B (28, 15.6%) Stage C (151, 84.4%) Tumor treatment history Hepatectomy (10, 5.6%) TACE (37, 20.7%) Albation (28, 15.6%) 19 (17.9%) 87 (82.1%) 6 (5.7%) 21 (19.8%) 18 (17.0%) 9 (12.3%) 64 (87.7%) 4 (5.5%) 16 (21.9%) 10 (13.7%) 0.31 0.96 0.73 0.55 IQR: inter-quartile range; PVTT: portal vein tumor thrombus; ECOG PS: Eastern Cooperative Oncology Group Performance Status; AFP: Alpha-Feto Protein; HBV:Hepatitis B virus; HCV: Hepatitis C virus; TACE: Transcatheter Arterial Chemoembolization; BCLC: Barcelona Clinic Liver Cancer Efficacy Median TTP and OS for the whole cohort were 7.3 months (95% CI: 6.3–8.3) and 16 months (95% CI: 12.9–19.1), respectively. Until the last follow-up, 84 patients died, with 77 cases dying of disease progression. Additionally, 4 patients experienced mortality due to gastrointestinal hemorrhage (one with Child-Pugh B7 and three with Child-Pugh B8/9), one patient with Child-Pugh B8/9 died from liver failure, one with Child-Pugh B7 suffered from immune hemolytic anemia, and one with Child-Pugh B8/9 succumbed to Corona Virus Disease 2019 (COVID-19). Median TTP (7.8 vs 6.3 months, P = 0.28) and OS (17.8 vs 14.0 months, P = 0.20) did not differ significantly between Group A and B (Fig. 2) . Moreover, there were no significant differences in mTTP (7.8 vs. 6.2 months, P = 0.18) or mOS (14.6 vs. 16.4 months, P = 0.50) between patients treated with sorafenib plus PD-1 inhibitors and those treated with lenvatinib plus PD-1 inhibitors (P = 0.35) (Fig. 3) . Furthermore, no significant differences were found in mTTP (7.8 vs. 6.2 months, P = 0.18) or mOS (14.6 vs. 16.4 months, P = 0.50) between patients with ALBI grade 1/2 compared to those with ALBI grade 3. With a median follow-up of 13.8 months, no significant difference was found in the ORR between Group A and Group B (33.0% vs 26.0%, P = 0.32) ( Table 2 ) . Among the 106 patients in the Child-Pugh B7 group, 0.6% (n = 1) achieved a complete response, 34% (n = 32.1) achieved a partial response, 50.0% (n = 53) had stable disease, and 17.0% (n = 18) had progressive disease. In comparison, 27.4% (n = 20) of the 73 patients in Child-Pugh B8/9 group had a partial response, 49.3% (n = 36) had stable disease, and 23.3% (n = 17) had progressive disease. In total,126 patients developed disease progression till the last follow-up. Table 2 Therapeutic response to sorafenib or lenvatinib in combination with PD- 1 inhibitor for HCC with Child-Pugh B Efficacy Child-Pugh B7 (n = 106) Child-Pugh B8/9 (n = 73) P value Complete response (n,%) 1 (0.6%) 0 NS 0.51 NS 0.30 Partial response (n,%) 34 (32.1%) 20 (27.4%) Stable disease (n,%) 53 (50.0%) 36 (49.3%) Progression disease (n,%) 18 (17.0%) 17 (23.3%) Objective response rate (n,%) 35 (33.0%) 19(26.0%) 0.32 Disease control rate (n,%) 88 (83.0%) 56 (76.7%) 0.30 Safety Treatment-related AEs are presented in Table 3 . In this study, the majority of patients (92.2%, n = 165) experienced AEs, with 45.8% (n = 82) reporting treatment-related AEs ≥ grade 3. In Group B, the incidences of AEs of any grade and those of grade ≥ 3 were 93.2% and 49.3%, respectively. Safety profiles were comparable between Group B and Group A. Common adverse events in Group B included hypertension, fatigue, and diarrhoea, while rash, fatigue, and hypertension were common in Group A. In addition, approximately 30.2% (n = 54) of patients developed immune-related adverse events (irAEs), with immune thrombocytopenia, hepatotoxicity, and hypothyroidism being the most common. About half of these patients required steroids. The incidence of gastrointestinal hemorrhage was 8.2% (n = 6) in Group B and 7.5% (n = 8) in Group A, respectively (P = 0.87). Reported dose reductions (31.3% vs. 46.6%) or discontinuations (27.4% vs. 53.4%) for TKIs plus Table 3 Adverse events B7 (n = 106) B8/9 (n = 73) P-value Total treatment-emergent AEs Total treatment-related treatment-emergent AEs 99 (92.5%) 97 (91.5%) 68 (93.2%) 68 (93.2%) 0.42 0.69 Treatment-emergent AEs (grade ≥ 3) Treatment-related treatment-emergent AEs (grade ≥ 3) 49 (46.2%) 46 (43.4%) 37(50.7%) 36 (49.3%) 0.56 0.44 Serious treatment-emergent AEs Serious treatment-related treatment-emergent AEs SAEs (grade 5) 8 (6GI Hemorrhage,2ALT/AST elevation) 8(6GI Hemorrhage; 2ALT/AST elevation) 2(2 GI Hemorrhage) 6(5GI H, 1 immune hemolytic anemia) 6(5GI H, 1 immune hemolytic anemia) 2(1GI H, 1 immune hemolytic anemia) IrAE Grade 3–4 Grade 5 37 (34.9%) 6*(5.7%) 0 17 (31.5%) 1** (1.4%) 1***(1.4%) 0.67 0.24 0.41 Treatment-emergent adverse events occurring in ≥ 25% of patients in either group Anorexia Any grade Grade ≥ 3 35 (33.0%) 0 24 (32.9%) 0 0.98 -- Increased blood bilirubin Any grade Grade ≥ 3 40 (43.4%) 11 (10.4%) 28 (39.7%) 6 (8.2%) 0.63 0.63 Decreased serum albumin Any grade Grade ≥ 3 36 (34%) 6 (5.7%) 21 (28.8%) 4 (5.5%) 0.46 1 Hypertension Any grade Grade ≥ 3 48 (45.3%) 6 (5.7%) 26 (35.6%) 6 (8.2%) 0.20 0.55 Diarrhea Any grade Grade ≥ 3 32 (30.2%) 5 (4.7%) 29 (39.7%) 4 (5.5%) 0.19 1 Ascites Any grade Grade ≥ 3 40 (37.7%) 5 (4.7%) 36 (49.3%) 5 (6.8%) 0.12 0.74 ALT or AST elevation Any grade Grade ≥ 3 41(38.7%) 4(3.8%) 19(26.0%) 3(4.1%) 0.08 0.91 Fatigue Any grade Grade ≥ 3 33 (34.4%) 2 (1.9%) 25 (34.2%) 1 (1.4%) 1 1 Hypothyroidism Any grade Grade ≥ 3 32 (30.2%) 0 18 (25.0%) 0 0.45 -- Hepatic encephalopathy Any grade Grade ≥ 3 11 (10.4%) 4 (3.8%) 6 (8.2%) 2 (2.7%) 0.63 1 Dose reduction† for TKIs Proteinuria Diarrhea Fatigue Ascites Hepatic encephalopathy Grade 3 increased blood bilirubin Decreased platelet count Grade 4 ALT/AST elevation Grade 3 hypertension 33 (31.3%) 5 2 2 4 8 5 2 2 3 34 (46.6%) 7 5 2 4 5 4 1 3 3 0.04 Discontinuation‡ for TKIs Proteinuria Diarrhea Fatigue Ascites Hepatic encephalopathy Grade 3 increased blood bilirubin Hemorrhage, upper GI Grade 3 hypertension Anemia Decreased platelet count 29 (27.4%) 3 2 1 3 5 6 6 2 0 1 39 (53.4%) 6 5 2 5 5 7。 5 3 0 1 < 0.001 ALT = alanine aminotransferase; AST = aspartate aminotransferase; GI = gastrointestinal; AE = adverse events; SOR = sorafenib; LEN = Lenvatinib; TKIs = tyrosine kinase inhibitors including lenvatinib and sorafenib. *: 1 case had hypophysitis, 2 case reported grade 3–4 ALT/AST elevation, 2 case had immune-related rash, and 1 case reported decreased platelet count. **. One case reported immune-related rash. ***: One case reported grade 5 immune hemolytic anemia. PD-1 inhibitor significantly differed between groups. Although 46.9% (n = 84) of patients died at the time of the last follow-up, no deaths were associated with the combination sorafenib-PD-1 inhibitor or the lenvatinib-PD-1 treatments. Prediction models with survival In univariate analysis, factors associated with OS included ECOG PS score, tumor size, BCLC stage, tumor response and drug resistance ( Table 4 ) . Subsequently, the stepwise regression was applied for multivariate Cox analysis to identify the prognostic model of patient survival with exceptional performance. This model with excellent performance but minimum number of variables was obtained, where the screened variables included tumor size [hazard ratio (HR) = 1.58; 95% CI: 0.99–2.54; P = 0.06], BCLC stage (HR = 0.6; 95% CI: 0.34–1.07; P = 0.08), tumor response (HR = 0.28; 95% CI: 0.15–0.51; P < 0.001), and drug resistance (HR = 1.9; 95% CI: 121 − 2.99; P = 0.01). The Harrell's C-index of this prognostic model was calculated as 0.719, indicating its robust discriminatory ability. Furthermore, nomograms were plotted to predict the probability of patient survival at 12 months (Fig. 5A) . Calibration curves showed good agreement between the model-predicted 12-month survival of patients and actual observations (Fig. 5B) . The discrimination of this model in the ROC curve was fair, with an AUC value of 0.752 (95% CI, 0.66–0.84) (Fig. 5C) . Table 4 Univariate and multivariate analyses of the variables associated with survival of patients with uHCC and Child-Pugh B Characteristic Univariate Cox Multivariate Cox HR (95% CI) P value HR (95% CI) P value Group SOR + PD-1 LEN + PD-1 Others + PD-1 Reference 0.52 (0.15–1.75) 0.50 (0.16–1.63) - 0.29 0.25 - - - - - - Sex (Male vs Female) 0.77(0.42–1.39) 0.39 - - Age (≥ 60 years vs <60 years) 1.30(0.74–2.29) 0.36 - - ECOG PS score (1 vs 0) 1.63(1.04–2.57) 0.03 - - Number of liver tumors (≥ 3 vs 1–2) 0.74(0.48–1.14) 0.18 - - Diameter of target tumor (≥ 9cm vs <9cm) 1.48(0.96–2.28) 0.08 1.58(0.99–2.54) 0.06 With PVTT (yes vs no) 1.08(0.76–1.56) 0.64 - - Extrahepatic metastasis (yes vs no) 0.76(0.49–1.18) 0.22 - - AFP (≥ 400ng/ml vs <400ng/ml) 1.30(0.74–2.29) 0.36 - - Child-Pugh (B8/9 vs B7) 0.90(0.58–1.41) 0.65 - - BCLC (Stage C vs Stage B) 0.63 (0.37–1.06) 0.08 0.6(0.34–1.07) 0.08 ALBI (Grade 3 vs Grade 1–2) 0.97(0.52–1.81) 0.93 - - Tumor response 0.001 - - PD reference - - - CR - - - - PR 0.22(0.11–0.44) - 0.28(0.15–0.51) < 0.001 SD 0.49(0.27–0.89) - 0.48(0.27–0.83) 0.01 Drug resistance 1.87 (1.21–2.88) 0.01 1.9(1.21–2.99) 0.01 (yes or no) PVTT: portal vein tumor thrombus; ECOG PS: Eastern Cooperative Oncology Group Performance Status; AFP: Alpha-Feto Protein; HBV: Hepatitis B virus; HCV: Hepatitis C virus; TACE: Transcatheter Arterial Chemoembolization; BCLC: Barcelona Clinic Liver Cancer; LEN: Lenvatinib; SOR: Sorafenib. Discussion Patients in the real world have diverse clinical presentations, but those with Child -Pugh B graded liver functions tend to be excluded from clinical trials. In fact, the prognosis of advanced HCC is determined not only by tumor burden but also by liver function ( 18 , 19 ). Previous studies have reported a median survival was 2–5 months for untreated patients with Child-Pugh B HCC ( 20 , 21 ). The PRODIGE 21 marked the first randomized trial completed in HCC patients with Child-Pugh B, focused on mono-TKIs( 22 ). The multi-center retrospective study focused on HCCs with limited treatment options to explore the feasibility of a combination of anti-angiogenic agent and PD-1 inhibitor treatment in patients with HCC and Child-pugh B. Our findings reveal no significant prognostic differences between patients with Child-Pugh B7 and B8/9 treated with TKIs plus PD-1 inhibitors. Similarly, no significant disparity was observed in OS and TTP between patients receiving lenvatinib plus ICI or sorafenib plus ICI treatment. Stratification based on ALBI grade showed similar OS and TTP between ALBI grade 1/2 and grade 3 patients. Taken together, these results suggest that the combination of anti-angiogenic agent and PD-1 inhibitor treatment can bring survival benefits among HCC patients with Child-pugh B8/9, irrespective of the specific TKI and PD-1 inhibitor combination or ALBI grade status. Systemic treatment modalities are complicated by tumor heterogeneity and the immune microenvironment ( 23 , 24 ). The immune environment is suppressed in cirrhosis, but ICI can overcome this and provoke immune responses ( 25 , 26 ). Anti-angiogenic therapy can induce hypoxia, while the combination of immunotherapy can reverse hypoxia-induced suppressive immune microenvironments( 9 , 10 , 27 ). Sorafenib was the most widely used agent in patients with Child–Pugh B HCC ( 22 ). However, most of the HCC patients in our study cohort also had HBV infections. Lenvatinib has been shown to have more pronounced benefits in HBV-related HCC than sorafenib ( 8 , 11 ), as well as higher immunotherapy efficacy for viral hepatitis-related HCC ( 28 ). Considering these findings, a regimen of lenvatinib combined with PD-1 inhibitors may be appropriate in areas with high incidences of HBV-related HCC with liver function impairment, but more clinical trials are required for validation. Management of patients with HCC is challenging in those with impaired liver function ( 29 ). Median TTP and median OS in this study cohort were 7.3 months and 16.0 months, respectively, higher than sorafenib alone and nivolumab alone in HCC with Child-Pugh B ( 3 , 7 , 30 – 32 ). Despite the poor prognosis of uHCC with Child-Pugh B, 54 (30.2%) patients had sustained radiographic responses, similar to ORRs reported in previous clinical trials for PD-1 inhibitors combined with anti-vascular agents ( 9 , 10 , 33 ). A meta-analysis reported that patients with uHCC and Child-pugh B receiving ICIs had an ORR of 14% (95% CI, 11%-17%), with a mOS of 5.49 months and a mPFS of 2.68 months ( 34 ), and the adverse outcomes suggest the limitation of mono-ICIs for these patients. Regarding safety outcomes, the incidences of any AEs was comparable between HCCs with Child-pugh B7 and those with Child-pugh B8/9 in our study. These findings were similar to those from other studies that have also included patients with Child-Pugh B ( 2 – 4 , 7 , 32 ). Interestingly, higher incidences of TKI dose reductions and drug discontinuations were reported in Child-pugh B8/9 Group, potentially attributed to the compromised liver function and increased susceptibility to medication-related adverse effects in this patient subset. In our study, we also had a relatively high incidence of gastrointestinal hemorrhage (9.7%, 16/179). And gastrointestinal bleeding was the primary reason for treatment discontinuation, which was associated with the use of the sorafenib or lenvatinib. Despite these findings, however, no new safety signals emerged from our study compared with prior clinical trials for sorafenib, lenvatinib, sintilimab, or camrelizumab( 8 , 9 , 33 , 35 ), and we found only one treatment-related death caused by irAE. Another important safety concern is that patients with decompensated cirrhosis are more likely to have impaired liver function, upper gastrointestinal bleeding, and thrombocytopenia. Thus, liver function and symptoms of upper gastrointestinal bleeding should be monitored closely in this population. Identification of prognostic biomarkers is crucial for clinical treatment decisions. Child-Pugh B, a heterogeneous classification, implies worse prognoses with higher scores ( 3 ). However, we found no significant differences in survival outcomes between patients with advanced Child-Pugh B7 and Child-Pugh B8/9 who received combination therapy. Our findings differ from the results from the CheckMate 040 study, as its Child-Pugh B cohort included only Child- Pugh B7/8 ( 7 ). To date, there has been a scarcity of predictive models developed specifically for the entire spectrum of Child-Pugh B patients, and our research fills this gap. Our model not only considers patients' status (BCLC stage) but also integrates tumor characteristics (tumor size), efficacy (tumor response), and resistance profiles (drug resistance), thereby improving predictions of survival rates for the entire Child-Pugh B cohort treated with TKIs and PD-1 inhibitors. The established prediction model performed well in predicting relapse at 12 months with an AUC value of 0.752 (95% CI, 0.66–0.84). Calibration curves of the model built for predicting survival probability of 12 months indicated a good consistency between the predicted and observed results. We believe this tool holds utility for both patients and clinical practitioners alike. To our knowledge, our nomogram is the first linked to survival for Child-Pugh B patients undergoing TKIs plus ICIs for HCC. The limitations of this study are partly associated with its retrospective study design. Firstly, inherent bias in patient selection may have occurred, the ratio of ECOG 1 was significantly in group B than that in Group A, but ECOG was not adverse prognostic factor in multivariate analyses, potentially limiting the generalizability of our cohort to the broader HCC population. Secondly, we used two PD-1 inhibitors, and drug heterogeneity may have affected data analysis. Third, we did not have a Child-Pugh A control group with which to compare any safety differences. Besides, despite the nomogram's promising performance, limitations persist, primarily stemming from the relatively modest sample size in our study. The model warrants further internal and external validation to fortify its reliability and applicability. Despite these limitations, our study was more inclusive of patients with advanced liver disease than most clinical trials. Conclusion Combination TKI-ICI treatment showed high clinical activity with manageable toxicity in a cohort of HCC patients with Child-Pugh B graded liver functioning. And patients with Child-Pugh B8/9 can also benefit from this combined treatment approach. However, there is a lack of prospective data for these patients, and it is worth evaluating the safety and efficacy of the combination regimens we examined here in comprehensive clinical trials. Statement of Ethics The study protocol, any amendments, and informed consent were approved by central or independent Institutional Review Board/Ethics Committee at participating sites. The study was conducted in accordance with the principles of the Declaration of Helsinki, Good Clinical Practice guidelines, and local applicable regulatory requirements. All participants provided written informed consent. Declarations F unding information : This study was funded by the Capital’s Funds for Health Improvement and Research (SF202222175). Conflicts of Interest: All ofthe authors declare no conflict of interest. Author contributions: Chen J. and Liu M. had helped the conception and design of this article. Ding X. and Yin X. had contributed by providing study patients. Ding X. and Yin X. had contributed to this manuscript by collection and assembling data. Zheng L., Zhou L., Teng Y., Xu Y., Hu J. and Sun W. had contributed to this manuscript by providing data analysis and interpretation. Ding X., Yin X.,Zhou L., Sun L., Shen Y. and Li W. had contributed to the writing of the manuscript. Chen J., Liu M, Ding X., Yin X., Zheng L., Zhou L., Hu J., Sun W., Sun L., Teng Y., Xu Y., Shen Y. and Li W. had given their final approval to submit this version of the manuscript to Journal of Cancer Research and Clinical Oncology . Data accessibility statement: The source data for this study are available from the corresponding author upon reasonable request. Acknowledgments: The authors thank all members of the study group. We also thank the Capital’s Funds for Health Improvement and Research for their funding. References Mittal S, El-Serag HB, Sada YH, Kanwal F, Duan Z, Temple S et al (2016) Hepatocellular Carcinoma in the Absence of Cirrhosis in United States Veterans is Associated With Nonalcoholic Fatty Liver Disease. Clin Gastroenterol Hepatol 14(1):124–31e1 Chapin WJ, Hwang WT, Karasic TB, McCarthy AM, Kaplan DE (2023) Comparison of nivolumab and sorafenib for first systemic therapy in patients with hepatocellular carcinoma and Child-Pugh B cirrhosis. Cancer Med 12(1):189–199 Marrero JA, Kudo M, Venook AP, Ye SL, Bronowicki JP, Chen XP et al (2016) Observational registry of sorafenib use in clinical practice across Child-Pugh subgroups: The GIDEON study. J Hepatol 65(6):1140–1147 McNamara MG, Slagter AE, Nuttall C, Frizziero M, Pihlak R, Lamarca A et al (2018) Sorafenib as first-line therapy in patients with advanced Child-Pugh B hepatocellular carcinoma-a meta-analysis. Eur J Cancer 105:1–9 Choi WM, Lee D, Shim JH, Kim KM, Lim YS, Lee HC et al (2020) Effectiveness and Safety of Nivolumab in Child-Pugh B Patients with Hepatocellular Carcinoma: A Real-World Cohort Study. Cancers (Basel). ;12(7): 1968 Ogushi K, Chuma M, Uojima H, Hidaka H, Numata K, Kobayashi S et al (2020) Safety and Efficacy of Lenvatinib Treatment in Child-Pugh A and B Patients with Unresectable Hepatocellular Carcinoma in Clinical Practice: A Multicenter Analysis. Clin Exp Gastroenterol 13:385–396 Kudo M, Matilla A, Santoro A, Melero I, Gracián AC, Acosta-Rivera M et al (2021) CheckMate 040 cohort 5: A phase I/II study of nivolumab in patients with advanced hepatocellular carcinoma and Child-Pugh B cirrhosis. J Hepatol 75(3):600–609 Kudo M, Finn RS, Qin S, Han KH, Ikeda K, Piscaglia F et al (2018) Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. 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Cancers (Basel) 13(11):2608 Kimura T, Kato Y, Ozawa Y, Kodama K, Ito J, Ichikawa K et al (2018) Immunomodulatory activity of lenvatinib contributes to antitumor activity in the Hepa1-6 hepatocellular carcinoma model. Cancer Sci 109(12):3993–4002 Kato Y, Tabata K, Kimura T, Yachie-Kinoshita A, Ozawa Y, Yamada K et al (2019) Lenvatinib plus anti-PD-1 antibody combination treatment activates CD8 + T cells through reduction of tumor-associated macrophage and activation of the interferon pathway. PLoS ONE 14(2):e0212513 Lencioni R, Montal R, Torres F, Park JW, Decaens T, Raoul JL et al (2017) Objective response by mRECIST as a predictor and potential surrogate end-point of overall survival in advanced HCC. J Hepatol 66(6):1166–1172 [Guidelines for diagnosis and treatment of primary liver cancer in China (2020) (2019 edition)]. Zhonghua Gan Zang Bing Za Zhi 28(2):112–128 NCI Common Terminology Criteria for Adverse Events v4.0 (CTCAE) 2009 [ http://ctep.cancer.gov/forms/CTCAE Cabibbo G, Petta S, Barbara M, Attardo S, Bucci L, Farinati F et al (2017) Hepatic decompensation is the major driver of death in HCV-infected cirrhotic patients with successfully treated early hepatocellular carcinoma. J Hepatol 67(1):65–71 Iavarone M, Cabibbo G, Biolato M, Della Corte C, Maida M, Barbara M et al (2015) Predictors of survival in patients with advanced hepatocellular carcinoma who permanently discontinued sorafenib. Hepatology 62(3):784–791 Giannini EG, Farinati F, Ciccarese F, Pecorelli A, Rapaccini GL, Di Marco M et al (2015) Prognosis of untreated hepatocellular carcinoma. Hepatology 61(1):184–190 Jeon D, Song GW, Lee HC, Shim JH (2022) Treatment patterns for hepatocellular carcinoma in patients with Child-Pugh class B and their impact on survival: A Korean nationwide registry study. Liver Int 42(12):2830–2842 Labeur TA, Achterbergh R, Takkenberg B, Van Delden O, Mathôt R, Klümpen HJ (2020) Sorafenib for Patients with Hepatocellular Carcinoma and Child-Pugh B Liver Cirrhosis: Lessons Learned from a Terminated Study. Oncologist 25(9):e1274–e9 Kuo HY, Chiang NJ, Chuang CH, Chen CY, Wu IC, Chang TT et al (2020) Impact of Immune Checkpoint Inhibitors with or without a Combination of Tyrosine Kinase Inhibitors on Organ-Specific Efficacy and Macrovascular Invasion in Advanced Hepatocellular Carcinoma. Oncol Res Treat 43(5):211–220 Huang C, Zhu XD, Shen YH, Wu D, Ji Y, Ge NL et al (2021) Organ specific responses to first-line lenvatinib plus anti-PD-1 antibodies in patients with unresectable hepatocellular carcinoma: a retrospective analysis. Biomark Res 9(1):19 Ringelhan M, Pfister D, O'Connor T, Pikarsky E, Heikenwalder M (2018) The immunology of hepatocellular carcinoma. Nat Immunol 19(3):222–232 Llovet JM, Castet F, Heikenwalder M, Maini MK, Mazzaferro V, Pinato DJ et al (2022) Immunotherapies for hepatocellular carcinoma. Nat Rev Clin Oncol 19(3):151–172 Jain RK (2014) Antiangiogenesis strategies revisited: from starving tumors to alleviating hypoxia. Cancer Cell 26(5):605–622 Qin S, Ren Z, Feng YH, Yau T, Wang B, Zhao H et al (2021) Atezolizumab plus Bevacizumab versus Sorafenib in the Chinese Subpopulation with Unresectable Hepatocellular Carcinoma: Phase 3 Randomized, Open-Label IMbrave150 Study. Liver Cancer 10(4):296–308 Cheon J, Kim H, Kim HS, Kim CG, Kim I, Kang B et al (2023) Atezolizumab plus bevacizumab in patients with child-Pugh B advanced hepatocellular carcinoma. Ther Adv Med Oncol 15:17588359221148541 Abou-Alfa GK, Amadori D, Santoro A, Figer A, De Greve J, Lathia C et al (2011) Safety and Efficacy of Sorafenib in Patients with Hepatocellular Carcinoma (HCC) and Child-Pugh A versus B Cirrhosis. Gastrointest Cancer Res 4(2):40–44 Køstner AH, Sorensen M, Olesen RK, Grønbæk H, Lassen U, Ladekarl M (2013) Sorafenib in advanced hepatocellular carcinoma: a nationwide retrospective study of efficacy and tolerability. ScientificWorldJournal 2013:931972 Barroso-Sousa LGDAF, Bento R, Blanco AD, Valente BP, Pfiffer GL (2015) Safety and efficacy of sorafenib in patients with Child-Pugh B advanced hepatocellular carcinoma. Mol Clin Oncol 3(4):793–796 Xu J, Shen J, Gu S, Zhang Y, Wu L, Wu J et al (2021) Camrelizumab in Combination with Apatinib in Patients with Advanced Hepatocellular Carcinoma (RESCUE): A Nonrandomized, Open-label, Phase II Trial. Clin Cancer Res 27(4):1003–1011 Xie E, Yeo YH, Scheiner B, Zhang Y, Hiraoka A, Tantai X et al (2023) Immune Checkpoint Inhibitors for Child-Pugh Class B Advanced Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis. JAMA Oncol 9(10):1423–1431 Sidaway P (2024) Adjuvant sintilimab effective in high-risk HCC. Nat Rev Clin Oncol 21(3):168 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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HCC develops after chronic liver injury and/or cirrhosis, which impacts treatment options. The severity of cirrhosis can be categorized into subgroups A, B, and C using the Child-Pugh score, which is based on laboratory values and clinical assessments. Because HCC often has an occult onset and atypical symptoms, 60\u0026ndash;70% of cases are initially diagnosed as unresectable, and systemic therapy is recommended as the standard first-line regimen (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). However, more than 70% of patients with unresectable hepatocellular carcinoma (uHCC) have concurrent cirrhosis, and up to 30% of these patients have grade B liver function (\u003cspan additionalcitationids=\"CR4 CR5 CR6\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). Although many anti-angiogenic tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) have been used in clinical practice for uHCC since 2007, the median overall survival (mOS) has been relatively unchanged in patients with uHCC and Child-Pugh B, ranging from 4.0 to 9.0 months (\u003cspan additionalcitationids=\"CR4 CR5 CR6\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). In addition, given that patients with Child-Pugh B have been excluded from large-scale, multicenter, phase III, randomized controlled clinical trials such as REFLECT(\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e), ORIENT-32 (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e), and IMbrave 150, systemic treatment options for these patients remain limited (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eTo date, NCCN guidelines have only recommended sorafenib (GIDEON) and nivolumab (CheckMate-040) for advanced HCC with Child-Pugh B graded liver function (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). In a large retrospective study of 510 patients with advanced HCC and Child-Pugh B liver function, the mOS was 4.0 months for sorafenib and 5.0 months for first-line nivolumab (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). Lenvatinib is another first-line TKI that was studied in phase III global multicenter REFELECT study. The lenvatinib arm showed significant improvements in median time to progression (mTTP) and objective response rate (ORR) compared to the sorafenib arm (mTTP 11.0 months vs. 3.7 months; ORR 21.5% vs. 8.3%) (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). Although no statistical difference was found in OS, in the subgroup analysis of Chinese patients, the mOS in the lenvatinib group was 15.0 months compared to 10.2 months in the sorafenib group (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). In a meta-analysis, lenvatinib was shown to be significantly more effective than sorafenib in treating hepatitis B virus (HBV) -positive HCC patients (HR\u0026thinsp;=\u0026thinsp;0.82) (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). However, HCC patients with grade B liver function were not included in the REFLECT study (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). In a retrospective study of 181 patients with advanced HCC who received lenvatinib as a first-line regimen (126 grade A; 55 grade B), the ORR in HCC with liver function grade A5 was significantly higher than that in HCC with grade A6 or grade B7 and 8 (44.0%, 25.5%, 22.2%, and 5.3%, respectively [P\u0026thinsp;=\u0026thinsp;0.002]) (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). Another large-scale study enrolled 343 patients with advanced HCC, including 67 patients with Child-Pugh B, and found a median OS of 9 months. The discontinuation rate was 70.1% in grade B compared with 69.2% in grade A (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). uHCC patients with Child-Pugh B liver functions continue to have low ORRs and poor prognoses, suggesting an urgent need to explore new treatment options.\u003c/p\u003e \u003cp\u003eIncreasing numbers of preclinical studies and clinical reports have demonstrated synergy in angiogenesis by targeting VEGF/VEGFR plus PD-1/PD-L1 inhibitors(\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). Combination regimens have been the primary and preferred choice for uHCC, and the combination of sorafenib plus PD-1 inhibitors or lenvatinib plus PD-1 inhibitors were administered to patients with uHCC and Child-Pugh A liver function. However, it is not recommended in the guidelines for uHCC with Child-Pugh B liver function, and data on dual regimens in uHCC with Child-Pugh B is limited. Thus, we performed this multicenter retrospective study to explore the action of combination regimen of TKIs with PD-1 inhibitors for uHCC with Child-Pugh B liver function, especially for patients with Child-pugh B8/9.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design and patients\u003c/h2\u003e \u003cp\u003eThis multicenter retrospective study was conducted at three separate centers in China (Captial Medical University Affiliated Beijing Ditan Hospital, The Fifth Medical Cancer, Chinese PLA General Hospital, and Capital Medical University Affiliated Beijing You\u0026rsquo;an Hospital). We included patients diagnosed with uHCC and Child-Pugh B liver function between December 31, 2020 and March 30, 2023. According to Child-Pugh scores, the enrolled patients were divided into two groups, Child-pugh B7 (Group A) and Child-Pugh B/9 (Group B). And 173 patients received treatment with either lenvatinib plus PD-1 inhibitors or sorafenib plus PD-1 inhibitors, 6 patients received treatment with other TKIs (regorafenib or donafenib) plus PD-1 inhibitors.\u003c/p\u003e \u003cp\u003eEligible patients had\u0026thinsp;\u0026ge;\u0026thinsp;1 typically enhancing measurable target lesion\u0026thinsp;\u0026ge;\u0026thinsp;1 cm based on the modified Response Evaluation Criteria in Solid Tumors (mRECIST) (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e), a Child-Pugh score\u0026thinsp;\u0026ge;\u0026thinsp;7\u0026ndash;9, were older than 18 years, histologically or clinically confirmed diagnosis of HCC (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e), a life expectancy\u0026thinsp;\u0026ge;\u0026thinsp;3 months, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, normal renal function, and no prior systemic therapy. Additional inclusion criteria included Barcelona Clinic Liver Cancer (BCLC) stage B/C disease and postoperative disease recurrence. Patients received at least one cycle of systemic therapy (one dose of PD-1 inhibitor and sorafenib or one dose of PD-1 inhibitor and lenvatinib). Patients with extrahepatic tumor spread or portal vein tumor thrombus (PVTT) were permitted except for those with symptomatic brain metastases. Patients were excluded if they had complete obstruction invasion of the primary branch of the biliary tract or had received any prior systemic therapy. In addition, patients were excluded if they had received any local treatment for HCC or radiotherapy for intrahepatic lesions for four weeks or three months, respectively, before giving informed consent. Patients with serious comorbidities, incomplete data, or who were lost to follow-up were also excluded.\u003c/p\u003e \u003cp\u003e The study was conducted in accordance with Good Clinical Practice, the principles outlined in the Declaration of Helsinki, and local laws. All participants provided written informed consent before enrollment. The study has been approved by the Ethics Committee of the Capital Medical University affiliated Beijing Ditan Hospital (Ethical approval number: JDLKZ-2021-041-01).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eTreatments\u003c/h2\u003e \u003cdiv id=\"Sec5\" class=\"Section3\"\u003e \u003ch2\u003eSystemic drugs\u003c/h2\u003e \u003cp\u003eSorafenib (Bayer, Leverkusen, Germany, Sor) was initially administered orally at 200 mg twice daily. Lenvatinib (Lenvima \u0026reg;; Eisai Co., Ltd., Tokyo, Japan, Len) was administered orally daily according to body weight: Patients weighing\u0026thinsp;\u0026lt;\u0026thinsp;60 kg received 4mg of lenvatinib once daily; patients weighing\u0026thinsp;\u0026ge;\u0026thinsp;60 kg received 8 mg of lenvatinib once daily.\u003c/p\u003e \u003cp\u003ePatients received 200 mg of sintilimab, camrelizumab, or tislelizumab intravenously on day one of a 21-day cycle following the first dose of lenvatinib or sorafenib.\u003c/p\u003e \u003cp\u003eThese agents were managed according to local regulations with dose reductions or treatment interruptions in the event of disease progression or unacceptable toxicity. Any drug interruptions and dose reductions were recorded, as well as the reasons for these events.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStudy Endpoints\u003c/h2\u003e \u003cp\u003eThe primary endpoint was OS, defined as the time from the date of enrollment to death due to any cause.\u003c/p\u003e \u003cp\u003eSecondary endpoints included TTP, tumor response, the objective response rate (ORR), and safety. TTP was defined as the interval from the date of enrollment to the date of radiographic progression. Tumor responses were assessed using contrast-enhanced dynamic CT or MRI and by mRECIST. The best overall response was considered to be the final response. Final responses were documented as either complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD). The percentage of patients achieving a complete or partial response (CR/PR) was defined as ORR (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). PVTT was considered a non-target lesion. In both groups, tumor responses to the entire treatment regimen were evaluated every 8\u0026ndash;12 weeks after enrollment. Adverse events (AEs) were graded and recorded using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.18(\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analyses\u003c/h2\u003e \u003cp\u003eStatistical analysis was performed using R software (4.0.5). Categorical variables were presented as numbers (percentages), which were compared by Pearson 's χ2 test. And continuous variables with skewed distributions were presented as medians [interquartile range], which were compared by \u003cem\u003et\u003c/em\u003e test. Fischer exact test was used to compare baseline categorical characteristics, treatment response and AEs between groups. TTP and OS were estimated using the Kaplan\u0026ndash;Meier method, and the differences were compared using the log-rank test. Univariate and multivariate Cox proportional hazards models were used to analyze prognostic factors for OS. And the nomogram-based prediction models were constructed by applied for forward and backward stepwise regression in multivariate Cox analysis. In addition, the ROC and calibration curve were plotted separately to demonstrate the model's performance, and the predictive value was exhibited by calculating the area under the ROC curve (AUC).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003ePatient Baseline Characteristics\u003c/h2\u003e \u003cp\u003eA total of 191 HCCs with Child-Pugh B graded liver function who were diagnosed between December 31, 2020 and March 30, 2023 at one of the three included hospital sites were initially recruited. Subsequently, 12 patients withdraw their consent, leaving 179 patients included in the final analysis \u003cb\u003e(Fig.\u0026nbsp;1)\u003c/b\u003e. Based on their Child-Pugh scores, patients were divided into two Group: Group A (106 patients; Child-Pugh B7) and Group B (73 patients; Child-Pugh B8/9). The median age was 61 (inter-quartile range: 53\u0026ndash;68), with the majority being male (84.9%). Additionally, a total of 153 patients (85.5%) had hepatitis B-virus (HBV). Among them, 110 patients (61.5%) presented with type I-IV PVTT, and 47.5% (85 patients) of the cohort had extrahepatic metastasis. Treatment-wise, 24.6% of the cohort received sorafenib plus PD-1 inhibitors, while 72.1% received lenvatinib plus PD-1 inhibitors. Regarding tumor treatment history, 10 (5.6%), 37 (20.7%), and 28 (15.6%) patients had previously undergone hepatectomy, TACE, and ablation, respectively. Furthermore, 94 (52.5%) patients had alpha-feto protein (AFP) levels\u0026thinsp;\u0026ge;\u0026thinsp;400ng/ml. Moreover, 163 (91.1%) patients presented with ALBI grade 1\u0026ndash;2, with the percentage significantly higher in Group A (98.1%) than in Group B (80.8%). Also, 88 (49.2%) patients presented with ECOG 1, with the percentage significantly higher in Group B (75.3%) than in Group A (31.1%). \u003cb\u003e(\u003c/b\u003eTable\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e\u003cb\u003e)\u003c/b\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline patient demographic and disease characteristics\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eChild-Pugh B7 (n\u0026thinsp;=\u0026thinsp;106)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eChild-Pugh B8/9 (n\u0026thinsp;=\u0026thinsp;73)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (median, IQR) (61 [53\u0026ndash;68])\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e59 [52\u0026ndash;68]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e62 [55\u0026ndash;68]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.70\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex (Male/Female, 151/28)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e93(87.7%)/13(12.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e58(79.5%)/15(20.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.13\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eECOG PS score (n, %)\u003c/p\u003e \u003cp\u003e0 (91, 50.8%)\u003c/p\u003e \u003cp\u003e1 (88, 49.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e73 (68.9%)\u003c/p\u003e \u003cp\u003e33 (31.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18 (24.7%)\u003c/p\u003e \u003cp\u003e55 (75.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHepatitis virus status (n,%)\u003c/p\u003e \u003cp\u003eHBV (153, 85.5%)\u003c/p\u003e \u003cp\u003eHCV (17, 9.5%)\u003c/p\u003e \u003cp\u003enon-HBV or HCV (9, 5.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e92 (86.8%)\u003c/p\u003e \u003cp\u003e11 (10.4%)\u003c/p\u003e \u003cp\u003e3 (2.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e61 (83.6%)\u003c/p\u003e \u003cp\u003e6 (8.2%)\u003c/p\u003e \u003cp\u003e6 (8.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.25\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eExtrahepatic metastasis (n, %)\u003c/p\u003e \u003cp\u003eYes (85, 47.5%)\u003c/p\u003e \u003cp\u003eNo (94, 52.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e58 (54.7%)\u003c/p\u003e \u003cp\u003e48 (45.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e36 (49.3%)\u003c/p\u003e \u003cp\u003e37 (50.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.48\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWith PVTT (n, %)\u003c/p\u003e \u003cp\u003eYes (110, 61.5%)\u003c/p\u003e \u003cp\u003eNo (69, 38.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e61 (57.5%)\u003c/p\u003e \u003cp\u003e45 (42.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e49 (67.1%)\u003c/p\u003e \u003cp\u003e24 (32.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.20\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTreatment\u003c/p\u003e \u003cp\u003eSOR\u0026thinsp;+\u0026thinsp;PD-1 (44, 24.6%)\u003c/p\u003e \u003cp\u003eLEN\u0026thinsp;+\u0026thinsp;PD-1 (129, 72.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e27 (25.5%)\u003c/p\u003e \u003cp\u003e75 (70.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17 (23.3%)\u003c/p\u003e \u003cp\u003e54 (74.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.87\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOthers (6, 3.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (3.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (2.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of liver tumors (n, %)\u003c/p\u003e \u003cp\u003e1\u0026ndash;2 (71, 39.7%)\u003c/p\u003e \u003cp\u003e\u0026ge;\u0026thinsp;3 (108, 60.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e40 (37.7%)\u003c/p\u003e \u003cp\u003e66 (62.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31 (42.5%)\u003c/p\u003e \u003cp\u003e42 (57.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.53\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAFP (ng/mL)* n (%)\u003c/p\u003e \u003cp\u003e\u0026ge;\u0026thinsp;400 ng/mL (94, 52.5%)\u003c/p\u003e \u003cp\u003e\u0026lt;\u0026thinsp;400ng/ml (85, 47.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e47 (44.3%)\u003c/p\u003e \u003cp\u003e59 (55.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e38(52.1%)\u003c/p\u003e \u003cp\u003e35 (47.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.31\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eALBI (n, %)\u003c/p\u003e \u003cp\u003eGrade 1\u0026ndash;2 (163, 91.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e104 (98.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e59 (80.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGrade 3 (16, 8.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (1.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14 (19.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBCLC\u003c/p\u003e \u003cp\u003eStage B (28, 15.6%)\u003c/p\u003e \u003cp\u003eStage C (151, 84.4%)\u003c/p\u003e \u003cp\u003eTumor treatment history\u003c/p\u003e \u003cp\u003eHepatectomy (10, 5.6%)\u003c/p\u003e \u003cp\u003eTACE (37, 20.7%)\u003c/p\u003e \u003cp\u003eAlbation (28, 15.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e19 (17.9%)\u003c/p\u003e \u003cp\u003e87 (82.1%)\u003c/p\u003e \u003cp\u003e6 (5.7%)\u003c/p\u003e \u003cp\u003e21 (19.8%)\u003c/p\u003e \u003cp\u003e18 (17.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (12.3%)\u003c/p\u003e \u003cp\u003e64 (87.7%)\u003c/p\u003e \u003cp\u003e4 (5.5%)\u003c/p\u003e \u003cp\u003e16 (21.9%)\u003c/p\u003e \u003cp\u003e10 (13.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.31\u003c/p\u003e \u003cp\u003e0.96\u003c/p\u003e \u003cp\u003e0.73\u003c/p\u003e \u003cp\u003e0.55\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eIQR: inter-quartile range; PVTT: portal vein tumor thrombus; ECOG PS: Eastern Cooperative Oncology Group Performance Status; AFP: Alpha-Feto Protein; HBV:Hepatitis B virus; HCV: Hepatitis C virus; TACE: Transcatheter Arterial Chemoembolization; BCLC: Barcelona Clinic Liver Cancer\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eEfficacy\u003c/h2\u003e \u003cp\u003eMedian TTP and OS for the whole cohort were 7.3 months (95% CI: 6.3\u0026ndash;8.3) and 16 months (95% CI: 12.9\u0026ndash;19.1), respectively. Until the last follow-up, 84 patients died, with 77 cases dying of disease progression. Additionally, 4 patients experienced mortality due to gastrointestinal hemorrhage (one with Child-Pugh B7 and three with Child-Pugh B8/9), one patient with Child-Pugh B8/9 died from liver failure, one with Child-Pugh B7 suffered from immune hemolytic anemia, and one with Child-Pugh B8/9 succumbed to Corona Virus Disease 2019 (COVID-19). Median TTP (7.8 vs 6.3 months, P\u0026thinsp;=\u0026thinsp;0.28) and OS (17.8 vs 14.0 months, P\u0026thinsp;=\u0026thinsp;0.20) did not differ significantly between Group A and B \u003cb\u003e(Fig.\u0026nbsp;2)\u003c/b\u003e. Moreover, there were no significant differences in mTTP (7.8 vs. 6.2 months, P\u0026thinsp;=\u0026thinsp;0.18) or mOS (14.6 vs. 16.4 months, P\u0026thinsp;=\u0026thinsp;0.50) between patients treated with sorafenib plus PD-1 inhibitors and those treated with lenvatinib plus PD-1 inhibitors (P\u0026thinsp;=\u0026thinsp;0.35) \u003cb\u003e(Fig.\u0026nbsp;3)\u003c/b\u003e. Furthermore, no significant differences were found in mTTP (7.8 vs. 6.2 months, P\u0026thinsp;=\u0026thinsp;0.18) or mOS (14.6 vs. 16.4 months, P\u0026thinsp;=\u0026thinsp;0.50) between patients with ALBI grade 1/2 compared to those with ALBI grade 3.\u003c/p\u003e \u003cp\u003eWith a median follow-up of 13.8 months, no significant difference was found in the ORR between Group A and Group B (33.0% vs 26.0%, P\u0026thinsp;=\u0026thinsp;0.32) \u003cb\u003e(\u003c/b\u003eTable\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e\u003cb\u003e)\u003c/b\u003e. Among the 106 patients in the Child-Pugh B7 group, 0.6% (n\u0026thinsp;=\u0026thinsp;1) achieved a complete response, 34% (n\u0026thinsp;=\u0026thinsp;32.1) achieved a partial response, 50.0% (n\u0026thinsp;=\u0026thinsp;53) had stable disease, and 17.0% (n\u0026thinsp;=\u0026thinsp;18) had progressive disease. In comparison, 27.4% (n\u0026thinsp;=\u0026thinsp;20) of the 73 patients in Child-Pugh B8/9 group had a partial response, 49.3% (n\u0026thinsp;=\u0026thinsp;36) had stable disease, and 23.3% (n\u0026thinsp;=\u0026thinsp;17) had progressive disease. In total,126 patients developed disease progression till the last follow-up.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eTherapeutic response to sorafenib or lenvatinib in combination with PD- 1 inhibitor for HCC with Child-Pugh B\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEfficacy\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eChild-Pugh B7 (n\u0026thinsp;=\u0026thinsp;106)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003eChild-Pugh B8/9 (n\u0026thinsp;=\u0026thinsp;73)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eComplete response (n,%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e1 (0.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\" morerows=\"3\" rowspan=\"4\"\u003e \u003cp\u003eNS\u003c/p\u003e \u003cp\u003e0.51\u003c/p\u003e \u003cp\u003eNS\u003c/p\u003e \u003cp\u003e0.30\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePartial response (n,%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e34 (32.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e20 (27.4%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStable disease (n,%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e53 (50.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e36 (49.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProgression disease (n,%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e18 (17.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e17 (23.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eObjective response rate (n,%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e35 (33.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e19(26.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.32\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDisease control rate (n,%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e88 (83.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e56 (76.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.30\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eSafety\u003c/h2\u003e \u003cp\u003eTreatment-related AEs are presented in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. In this study, the majority of patients (92.2%, n\u0026thinsp;=\u0026thinsp;165) experienced AEs, with 45.8% (n\u0026thinsp;=\u0026thinsp;82) reporting treatment-related AEs\u0026thinsp;\u0026ge;\u0026thinsp;grade 3. In Group B, the incidences of AEs of any grade and those of grade\u0026thinsp;\u0026ge;\u0026thinsp;3 were 93.2% and 49.3%, respectively. Safety profiles were comparable between Group B and Group A. Common adverse events in Group B included hypertension, fatigue, and diarrhoea, while rash, fatigue, and hypertension were common in Group A. In addition, approximately 30.2% (n\u0026thinsp;=\u0026thinsp;54) of patients developed immune-related adverse events (irAEs), with immune thrombocytopenia, hepatotoxicity, and hypothyroidism being the most common. About half of these patients required steroids. The incidence of gastrointestinal hemorrhage was 8.2% (n\u0026thinsp;=\u0026thinsp;6) in Group B and 7.5% (n\u0026thinsp;=\u0026thinsp;8) in Group A, respectively (P\u0026thinsp;=\u0026thinsp;0.87). Reported dose reductions (31.3% vs. 46.6%) or discontinuations (27.4% vs. 53.4%) for TKIs plus\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eAdverse events\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eB7 (n\u0026thinsp;=\u0026thinsp;106)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003eB8/9 (n\u0026thinsp;=\u0026thinsp;73)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal treatment-emergent AEs\u003c/p\u003e \u003cp\u003eTotal treatment-related treatment-emergent AEs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e99 (92.5%)\u003c/p\u003e \u003cp\u003e97 (91.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e68 (93.2%)\u003c/p\u003e \u003cp\u003e68 (93.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.42\u003c/p\u003e \u003cp\u003e0.69\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTreatment-emergent AEs (grade\u0026thinsp;\u0026ge;\u0026thinsp;3)\u003c/p\u003e \u003cp\u003eTreatment-related treatment-emergent AEs (grade\u0026thinsp;\u0026ge;\u0026thinsp;3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e49 (46.2%)\u003c/p\u003e \u003cp\u003e46 (43.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e37(50.7%)\u003c/p\u003e \u003cp\u003e36 (49.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.56\u003c/p\u003e \u003cp\u003e0.44\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSerious treatment-emergent AEs\u003c/p\u003e \u003cp\u003eSerious treatment-related treatment-emergent AEs\u003c/p\u003e \u003cp\u003eSAEs (grade 5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (6GI Hemorrhage,2ALT/AST elevation)\u003c/p\u003e \u003cp\u003e8(6GI Hemorrhage; 2ALT/AST elevation)\u003c/p\u003e \u003cp\u003e2(2 GI Hemorrhage)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e6(5GI H, 1 immune hemolytic anemia)\u003c/p\u003e \u003cp\u003e6(5GI H, 1 immune hemolytic anemia)\u003c/p\u003e \u003cp\u003e2(1GI H, 1 immune hemolytic anemia)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIrAE\u003c/p\u003e \u003cp\u003eGrade 3\u0026ndash;4\u003c/p\u003e \u003cp\u003eGrade 5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e37 (34.9%)\u003c/p\u003e \u003cp\u003e6*(5.7%)\u003c/p\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e17 (31.5%)\u003c/p\u003e \u003cp\u003e1** (1.4%)\u003c/p\u003e \u003cp\u003e1***(1.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.67\u003c/p\u003e \u003cp\u003e0.24\u003c/p\u003e \u003cp\u003e0.41\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e \u003cp\u003eTreatment-emergent adverse events occurring in \u0026ge;\u0026thinsp;25% of patients in either group\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnorexia\u003c/p\u003e \u003cp\u003eAny grade\u003c/p\u003e \u003cp\u003eGrade\u0026thinsp;\u0026ge;\u0026thinsp;3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e35 (33.0%)\u003c/p\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e24 (32.9%)\u003c/p\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.98\u003c/p\u003e \u003cp\u003e--\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIncreased blood bilirubin\u003c/p\u003e \u003cp\u003eAny grade\u003c/p\u003e \u003cp\u003eGrade\u0026thinsp;\u0026ge;\u0026thinsp;3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e40 (43.4%)\u003c/p\u003e \u003cp\u003e11 (10.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e28 (39.7%)\u003c/p\u003e \u003cp\u003e6 (8.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.63\u003c/p\u003e \u003cp\u003e0.63\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDecreased serum albumin\u003c/p\u003e \u003cp\u003eAny grade\u003c/p\u003e \u003cp\u003eGrade\u0026thinsp;\u0026ge;\u0026thinsp;3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e36 (34%)\u003c/p\u003e \u003cp\u003e6 (5.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e21 (28.8%)\u003c/p\u003e \u003cp\u003e4 (5.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.46\u003c/p\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypertension\u003c/p\u003e \u003cp\u003eAny grade\u003c/p\u003e \u003cp\u003eGrade\u0026thinsp;\u0026ge;\u0026thinsp;3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e48 (45.3%)\u003c/p\u003e \u003cp\u003e6 (5.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e26 (35.6%)\u003c/p\u003e \u003cp\u003e6 (8.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e0.20\u003c/p\u003e \u003cp\u003e0.55\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiarrhea\u003c/p\u003e \u003cp\u003eAny grade\u003c/p\u003e \u003cp\u003eGrade\u0026thinsp;\u0026ge;\u0026thinsp;3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e32 (30.2%)\u003c/p\u003e \u003cp\u003e5 (4.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e29 (39.7%)\u003c/p\u003e \u003cp\u003e4 (5.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e0.19\u003c/p\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAscites\u003c/p\u003e \u003cp\u003eAny grade\u003c/p\u003e \u003cp\u003eGrade\u0026thinsp;\u0026ge;\u0026thinsp;3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e40 (37.7%)\u003c/p\u003e \u003cp\u003e5 (4.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e36 (49.3%)\u003c/p\u003e \u003cp\u003e5 (6.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e0.12\u003c/p\u003e \u003cp\u003e0.74\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eALT or AST elevation\u003c/p\u003e \u003cp\u003eAny grade\u003c/p\u003e \u003cp\u003eGrade\u0026thinsp;\u0026ge;\u0026thinsp;3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e41(38.7%)\u003c/p\u003e \u003cp\u003e4(3.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19(26.0%)\u003c/p\u003e \u003cp\u003e3(4.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e0.08\u003c/p\u003e \u003cp\u003e0.91\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFatigue\u003c/p\u003e \u003cp\u003eAny grade\u003c/p\u003e \u003cp\u003eGrade\u0026thinsp;\u0026ge;\u0026thinsp;3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e33 (34.4%)\u003c/p\u003e \u003cp\u003e2 (1.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25 (34.2%)\u003c/p\u003e \u003cp\u003e1 (1.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypothyroidism\u003c/p\u003e \u003cp\u003eAny grade\u003c/p\u003e \u003cp\u003eGrade\u0026thinsp;\u0026ge;\u0026thinsp;3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e32 (30.2%)\u003c/p\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18 (25.0%)\u003c/p\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e0.45\u003c/p\u003e \u003cp\u003e--\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHepatic encephalopathy\u003c/p\u003e \u003cp\u003eAny grade\u003c/p\u003e \u003cp\u003eGrade\u0026thinsp;\u0026ge;\u0026thinsp;3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11 (10.4%)\u003c/p\u003e \u003cp\u003e4 (3.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (8.2%)\u003c/p\u003e \u003cp\u003e2 (2.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e0.63\u003c/p\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDose reduction\u0026dagger; for TKIs\u003c/p\u003e \u003cp\u003eProteinuria\u003c/p\u003e \u003cp\u003eDiarrhea\u003c/p\u003e \u003cp\u003eFatigue\u003c/p\u003e \u003cp\u003eAscites\u003c/p\u003e \u003cp\u003eHepatic encephalopathy\u003c/p\u003e \u003cp\u003eGrade 3 increased blood bilirubin\u003c/p\u003e \u003cp\u003eDecreased platelet count\u003c/p\u003e \u003cp\u003eGrade 4 ALT/AST elevation\u003c/p\u003e \u003cp\u003eGrade 3 hypertension\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e33 (31.3%)\u003c/p\u003e \u003cp\u003e5\u003c/p\u003e \u003cp\u003e2\u003c/p\u003e \u003cp\u003e2\u003c/p\u003e \u003cp\u003e4\u003c/p\u003e \u003cp\u003e8\u003c/p\u003e \u003cp\u003e5\u003c/p\u003e \u003cp\u003e2\u003c/p\u003e \u003cp\u003e2\u003c/p\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e34 (46.6%)\u003c/p\u003e \u003cp\u003e7\u003c/p\u003e \u003cp\u003e5\u003c/p\u003e \u003cp\u003e2\u003c/p\u003e \u003cp\u003e4\u003c/p\u003e \u003cp\u003e5\u003c/p\u003e \u003cp\u003e4\u003c/p\u003e \u003cp\u003e1\u003c/p\u003e \u003cp\u003e3\u003c/p\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e0.04\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiscontinuation\u0026Dagger; for TKIs\u003c/p\u003e \u003cp\u003eProteinuria\u003c/p\u003e \u003cp\u003eDiarrhea\u003c/p\u003e \u003cp\u003eFatigue\u003c/p\u003e \u003cp\u003eAscites\u003c/p\u003e \u003cp\u003eHepatic encephalopathy\u003c/p\u003e \u003cp\u003eGrade 3 increased blood bilirubin\u003c/p\u003e \u003cp\u003eHemorrhage, upper GI\u003c/p\u003e \u003cp\u003eGrade 3 hypertension\u003c/p\u003e \u003cp\u003eAnemia\u003c/p\u003e \u003cp\u003eDecreased platelet count\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e29 (27.4%)\u003c/p\u003e \u003cp\u003e3\u003c/p\u003e \u003cp\u003e2\u003c/p\u003e \u003cp\u003e1\u003c/p\u003e \u003cp\u003e3\u003c/p\u003e \u003cp\u003e5\u003c/p\u003e \u003cp\u003e6\u003c/p\u003e \u003cp\u003e6\u003c/p\u003e \u003cp\u003e2\u003c/p\u003e \u003cp\u003e0\u003c/p\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e39 (53.4%)\u003c/p\u003e \u003cp\u003e6\u003c/p\u003e \u003cp\u003e5\u003c/p\u003e \u003cp\u003e2\u003c/p\u003e \u003cp\u003e5\u003c/p\u003e \u003cp\u003e5\u003c/p\u003e \u003cp\u003e7。\u003c/p\u003e \u003cp\u003e5\u003c/p\u003e \u003cp\u003e3\u003c/p\u003e \u003cp\u003e0\u003c/p\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eALT\u0026thinsp;=\u0026thinsp;alanine aminotransferase; AST\u0026thinsp;=\u0026thinsp;aspartate aminotransferase; GI\u0026thinsp;=\u0026thinsp;gastrointestinal; AE\u0026thinsp;=\u0026thinsp;adverse events; SOR\u0026thinsp;=\u0026thinsp;sorafenib; LEN\u0026thinsp;=\u0026thinsp;Lenvatinib; TKIs\u0026thinsp;=\u0026thinsp;tyrosine kinase inhibitors including lenvatinib and sorafenib.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e*: 1 case had hypophysitis, 2 case reported grade 3\u0026ndash;4 ALT/AST elevation, 2 case had immune-related rash, and 1 case reported decreased platelet count.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e**. One case reported immune-related rash. ***: One case reported grade 5 immune hemolytic anemia.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003ePD-1 inhibitor significantly differed between groups. Although 46.9% (n\u0026thinsp;=\u0026thinsp;84) of patients died at the time of the last follow-up, no deaths were associated with the combination sorafenib-PD-1 inhibitor or the lenvatinib-PD-1 treatments.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003ePrediction models with survival\u003c/h2\u003e \u003cp\u003eIn univariate analysis, factors associated with OS included ECOG PS score, tumor size, BCLC stage, tumor response and drug resistance \u003cb\u003e(\u003c/b\u003eTable\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e\u003cb\u003e)\u003c/b\u003e. Subsequently, the stepwise regression was applied for multivariate Cox analysis to identify the prognostic model of patient survival with exceptional performance. This model with excellent performance but minimum number of variables was obtained, where the screened variables included tumor size [hazard ratio (HR)\u0026thinsp;=\u0026thinsp;1.58; 95% CI: 0.99\u0026ndash;2.54; P\u0026thinsp;=\u0026thinsp;0.06], BCLC stage (HR\u0026thinsp;=\u0026thinsp;0.6; 95% CI: 0.34\u0026ndash;1.07; P\u0026thinsp;=\u0026thinsp;0.08), tumor response (HR\u0026thinsp;=\u0026thinsp;0.28; 95% CI: 0.15\u0026ndash;0.51; P\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and drug resistance (HR\u0026thinsp;=\u0026thinsp;1.9; 95% CI: 121\u0026thinsp;\u0026minus;\u0026thinsp;2.99; P\u0026thinsp;=\u0026thinsp;0.01). The Harrell's C-index of this prognostic model was calculated as 0.719, indicating its robust discriminatory ability. Furthermore, nomograms were plotted to predict the probability of patient survival at 12 months \u003cb\u003e(Fig.\u0026nbsp;5A)\u003c/b\u003e. Calibration curves showed good agreement between the model-predicted 12-month survival of patients and actual observations \u003cb\u003e(Fig.\u0026nbsp;5B)\u003c/b\u003e. The discrimination of this model in the ROC curve was fair, with an AUC value of 0.752 (95% CI, 0.66\u0026ndash;0.84) \u003cb\u003e(Fig.\u0026nbsp;5C)\u003c/b\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eUnivariate and multivariate analyses of the variables associated with survival of patients with uHCC and Child-Pugh B\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"8\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eCharacteristic\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eUnivariate Cox\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e \u003cp\u003eMultivariate Cox\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHR (95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eHR (95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"1\" nameend=\"c8\" namest=\"c8\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGroup\u003c/p\u003e \u003cp\u003eSOR\u0026thinsp;+\u0026thinsp;PD-1\u003c/p\u003e \u003cp\u003eLEN\u0026thinsp;+\u0026thinsp;PD-1\u003c/p\u003e \u003cp\u003eOthers\u0026thinsp;+\u0026thinsp;PD-1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003cp\u003e0.52 (0.15\u0026ndash;1.75)\u003c/p\u003e \u003cp\u003e0.50 (0.16\u0026ndash;1.63)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003cp\u003e0.29\u003c/p\u003e \u003cp\u003e0.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003cp\u003e-\u003c/p\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003cp\u003e-\u003c/p\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c8\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex\u003c/p\u003e \u003cp\u003e(Male vs Female)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.77(0.42\u0026ndash;1.39)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e0.39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c8\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003cp\u003e(\u0026ge;\u0026thinsp;60 years vs \u0026lt;60 years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.30(0.74\u0026ndash;2.29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e0.36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c8\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eECOG PS score\u003c/p\u003e \u003cp\u003e(1 vs 0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.63(1.04\u0026ndash;2.57)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e0.03\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c8\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of liver tumors\u003c/p\u003e \u003cp\u003e(\u0026ge;\u0026thinsp;3 vs 1\u0026ndash;2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.74(0.48\u0026ndash;1.14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e0.18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c8\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiameter of target tumor\u003c/p\u003e \u003cp\u003e(\u0026ge;\u0026thinsp;9cm vs \u0026lt;9cm)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.48(0.96\u0026ndash;2.28)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e0.08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.58(0.99\u0026ndash;2.54)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e0.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c8\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWith PVTT\u003c/p\u003e \u003cp\u003e(yes vs no)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.08(0.76\u0026ndash;1.56)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e0.64\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c8\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eExtrahepatic metastasis\u003c/p\u003e \u003cp\u003e(yes vs no)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.76(0.49\u0026ndash;1.18)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e0.22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c8\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAFP\u003c/p\u003e \u003cp\u003e(\u0026ge;\u0026thinsp;400ng/ml vs \u0026lt;400ng/ml)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.30(0.74\u0026ndash;2.29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e0.36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c8\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChild-Pugh\u003c/p\u003e \u003cp\u003e(B8/9 vs B7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.90(0.58\u0026ndash;1.41)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e0.65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c8\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBCLC\u003c/p\u003e \u003cp\u003e(Stage C vs Stage B)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.63 (0.37\u0026ndash;1.06)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e0.08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.6(0.34\u0026ndash;1.07)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e0.08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c8\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eALBI\u003c/p\u003e \u003cp\u003e(Grade 3 vs Grade 1\u0026ndash;2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.97(0.52\u0026ndash;1.81)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e0.93\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c8\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTumor response\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c8\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ereference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c8\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c8\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.22(0.11\u0026ndash;0.44)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.28(0.15\u0026ndash;0.51)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c8\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.49(0.27\u0026ndash;0.89)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.48(0.27\u0026ndash;0.83)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e0.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c8\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDrug resistance\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.87 (1.21\u0026ndash;2.88)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e0.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.9(1.21\u0026ndash;2.99)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e0.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c8\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e(yes or no)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c8\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"8\"\u003ePVTT: portal vein tumor thrombus; ECOG PS: Eastern Cooperative Oncology Group Performance Status; AFP: Alpha-Feto Protein; HBV: Hepatitis B virus; HCV: Hepatitis C virus; TACE: Transcatheter Arterial Chemoembolization; BCLC: Barcelona Clinic Liver Cancer; LEN: Lenvatinib; SOR: Sorafenib.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003ePatients in the real world have diverse clinical presentations, but those with Child -Pugh B graded liver functions tend to be excluded from clinical trials. In fact, the prognosis of advanced HCC is determined not only by tumor burden but also by liver function (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). Previous studies have reported a median survival was 2\u0026ndash;5 months for untreated patients with Child-Pugh B HCC (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). The PRODIGE 21 marked the first randomized trial completed in HCC patients with Child-Pugh B, focused on mono-TKIs(\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). The multi-center retrospective study focused on HCCs with limited treatment options to explore the feasibility of a combination of anti-angiogenic agent and PD-1 inhibitor treatment in patients with HCC and Child-pugh B. Our findings reveal no significant prognostic differences between patients with Child-Pugh B7 and B8/9 treated with TKIs plus PD-1 inhibitors. Similarly, no significant disparity was observed in OS and TTP between patients receiving lenvatinib plus ICI or sorafenib plus ICI treatment. Stratification based on ALBI grade showed similar OS and TTP between ALBI grade 1/2 and grade 3 patients. Taken together, these results suggest that the combination of anti-angiogenic agent and PD-1 inhibitor treatment can bring survival benefits among HCC patients with Child-pugh B8/9, irrespective of the specific TKI and PD-1 inhibitor combination or ALBI grade status.\u003c/p\u003e \u003cp\u003eSystemic treatment modalities are complicated by tumor heterogeneity and the immune microenvironment (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e). The immune environment is suppressed in cirrhosis, but ICI can overcome this and provoke immune responses (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e). Anti-angiogenic therapy can induce hypoxia, while the combination of immunotherapy can reverse hypoxia-induced suppressive immune microenvironments(\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e). Sorafenib was the most widely used agent in patients with Child\u0026ndash;Pugh B HCC (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). However, most of the HCC patients in our study cohort also had HBV infections. Lenvatinib has been shown to have more pronounced benefits in HBV-related HCC than sorafenib (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e), as well as higher immunotherapy efficacy for viral hepatitis-related HCC (\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e). Considering these findings, a regimen of lenvatinib combined with PD-1 inhibitors may be appropriate in areas with high incidences of HBV-related HCC with liver function impairment, but more clinical trials are required for validation.\u003c/p\u003e \u003cp\u003eManagement of patients with HCC is challenging in those with impaired liver function (\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e). Median TTP and median OS in this study cohort were 7.3 months and 16.0 months, respectively, higher than sorafenib alone and nivolumab alone in HCC with Child-Pugh B (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan additionalcitationids=\"CR31\" citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e). Despite the poor prognosis of uHCC with Child-Pugh B, 54 (30.2%) patients had sustained radiographic responses, similar to ORRs reported in previous clinical trials for PD-1 inhibitors combined with anti-vascular agents (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e). A meta-analysis reported that patients with uHCC and Child-pugh B receiving ICIs had an ORR of 14% (95% CI, 11%-17%), with a mOS of 5.49 months and a mPFS of 2.68 months (\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e), and the adverse outcomes suggest the limitation of mono-ICIs for these patients.\u003c/p\u003e \u003cp\u003eRegarding safety outcomes, the incidences of any AEs was comparable between HCCs with Child-pugh B7 and those with Child-pugh B8/9 in our study. These findings were similar to those from other studies that have also included patients with Child-Pugh B (\u003cspan additionalcitationids=\"CR3\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e). Interestingly, higher incidences of TKI dose reductions and drug discontinuations were reported in Child-pugh B8/9 Group, potentially attributed to the compromised liver function and increased susceptibility to medication-related adverse effects in this patient subset. In our study, we also had a relatively high incidence of gastrointestinal hemorrhage (9.7%, 16/179). And gastrointestinal bleeding was the primary reason for treatment discontinuation, which was associated with the use of the sorafenib or lenvatinib. Despite these findings, however, no new safety signals emerged from our study compared with prior clinical trials for sorafenib, lenvatinib, sintilimab, or camrelizumab(\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e), and we found only one treatment-related death caused by irAE. Another important safety concern is that patients with decompensated cirrhosis are more likely to have impaired liver function, upper gastrointestinal bleeding, and thrombocytopenia. Thus, liver function and symptoms of upper gastrointestinal bleeding should be monitored closely in this population.\u003c/p\u003e \u003cp\u003eIdentification of prognostic biomarkers is crucial for clinical treatment decisions. Child-Pugh B, a heterogeneous classification, implies worse prognoses with higher scores (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). However, we found no significant differences in survival outcomes between patients with advanced Child-Pugh B7 and Child-Pugh B8/9 who received combination therapy. Our findings differ from the results from the CheckMate 040 study, as its Child-Pugh B cohort included only Child- Pugh B7/8 (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). To date, there has been a scarcity of predictive models developed specifically for the entire spectrum of Child-Pugh B patients, and our research fills this gap. Our model not only considers patients' status (BCLC stage) but also integrates tumor characteristics (tumor size), efficacy (tumor response), and resistance profiles (drug resistance), thereby improving predictions of survival rates for the entire Child-Pugh B cohort treated with TKIs and PD-1 inhibitors. The established prediction model performed well in predicting relapse at 12 months with an AUC value of 0.752 (95% CI, 0.66\u0026ndash;0.84). Calibration curves of the model built for predicting survival probability of 12 months indicated a good consistency between the predicted and observed results. We believe this tool holds utility for both patients and clinical practitioners alike. To our knowledge, our nomogram is the first linked to survival for Child-Pugh B patients undergoing TKIs plus ICIs for HCC.\u003c/p\u003e \u003cp\u003eThe limitations of this study are partly associated with its retrospective study design. Firstly, inherent bias in patient selection may have occurred, the ratio of ECOG 1 was significantly in group B than that in Group A, but ECOG was not adverse prognostic factor in multivariate analyses, potentially limiting the generalizability of our cohort to the broader HCC population. Secondly, we used two PD-1 inhibitors, and drug heterogeneity may have affected data analysis. Third, we did not have a Child-Pugh A control group with which to compare any safety differences. Besides, despite the nomogram's promising performance, limitations persist, primarily stemming from the relatively modest sample size in our study. The model warrants further internal and external validation to fortify its reliability and applicability. Despite these limitations, our study was more inclusive of patients with advanced liver disease than most clinical trials.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eCombination TKI-ICI treatment showed high clinical activity with manageable toxicity in a cohort of HCC patients with Child-Pugh B graded liver functioning. And patients with Child-Pugh B8/9 can also benefit from this combined treatment approach. However, there is a lack of prospective data for these patients, and it is worth evaluating the safety and efficacy of the combination regimens we examined here in comprehensive clinical trials.\u003c/p\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eStatement of Ethics\u003c/h2\u003e \u003cp\u003eThe study protocol, any amendments, and informed consent were approved by central or independent Institutional Review Board/Ethics Committee at participating sites. The study was conducted in accordance with the principles of the Declaration of Helsinki, Good Clinical Practice guidelines, and local applicable regulatory requirements. All participants provided written informed consent.\u003c/p\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eF\u003c/strong\u003e\u003cstrong\u003eunding information\u003c/strong\u003e:\u0026nbsp;This study was funded by the Capital\u0026rsquo;s Funds for Health Improvement and Research (SF202222175).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of Interest:\u0026nbsp;\u003c/strong\u003eAll ofthe authors declare no conflict of interest.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions:\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eChen J. and Liu M. had helped the conception and design of this article. Ding X. and Yin X. had contributed by providing study patients.\u0026nbsp;Ding X. and Yin X. had contributed to this manuscript by collection and assembling data.\u0026nbsp;Zheng L.,\u0026nbsp;Zhou L., Teng Y., Xu Y., Hu J. and Sun W. had contributed to this manuscript by providing data analysis and interpretation.\u0026nbsp;Ding X., Yin X.,Zhou L., Sun L., Shen Y. and Li W. had contributed to the writing of the manuscript.\u0026nbsp;Chen J., Liu M, Ding X., Yin X.,\u0026nbsp;Zheng L.,\u0026nbsp;Zhou L., Hu J., Sun W., Sun L., Teng Y., Xu Y., Shen Y. and Li W. had given their final approval to submit this version of the manuscript to\u003cstrong\u003e\u003cem\u003eJournal of\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cem\u003e\u0026nbsp;Cancer Research and Clinical Oncology\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cem\u003e.\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData accessibility statement:\u0026nbsp;\u003c/strong\u003eThe source data for this study are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments:\u0026nbsp;\u003c/strong\u003eThe authors thank all members of the study group. We also thank the Capital\u0026rsquo;s Funds for Health Improvement and Research for their funding.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eMittal S, El-Serag HB, Sada YH, Kanwal F, Duan Z, Temple S et al (2016) Hepatocellular Carcinoma in the Absence of Cirrhosis in United States Veterans is Associated With Nonalcoholic Fatty Liver Disease. Clin Gastroenterol Hepatol 14(1):124\u0026ndash;31e1\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChapin WJ, Hwang WT, Karasic TB, McCarthy AM, Kaplan DE (2023) Comparison of nivolumab and sorafenib for first systemic therapy in patients with hepatocellular carcinoma and Child-Pugh B cirrhosis. Cancer Med 12(1):189\u0026ndash;199\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMarrero JA, Kudo M, Venook AP, Ye SL, Bronowicki JP, Chen XP et al (2016) Observational registry of sorafenib use in clinical practice across Child-Pugh subgroups: The GIDEON study. 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Clin Exp Gastroenterol 13:385\u0026ndash;396\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKudo M, Matilla A, Santoro A, Melero I, Graci\u0026aacute;n AC, Acosta-Rivera M et al (2021) CheckMate 040 cohort 5: A phase I/II study of nivolumab in patients with advanced hepatocellular carcinoma and Child-Pugh B cirrhosis. J Hepatol 75(3):600\u0026ndash;609\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKudo M, Finn RS, Qin S, Han KH, Ikeda K, Piscaglia F et al (2018) Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet 391(10126):1163\u0026ndash;1173\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRen Z, Xu J, Bai Y, Xu A, Cang S, Du C et al (2021) Sintilimab plus a bevacizumab biosimilar (IBI305) versus sorafenib in unresectable hepatocellular carcinoma (ORIENT-32): a randomised, open-label, phase 2\u0026ndash;3 study. 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J Hepatol 66(6):1166\u0026ndash;1172\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003e[Guidelines for diagnosis and treatment of primary liver cancer in China (2020) (2019 edition)]. Zhonghua Gan Zang Bing Za Zhi 28(2):112\u0026ndash;128\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNCI Common Terminology Criteria for Adverse Events v4.0 (CTCAE) 2009 [ \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://ctep.cancer.gov/forms/CTCAE\u003c/span\u003e\u003cspan address=\"http://ctep.cancer.gov/forms/CTCAE\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCabibbo G, Petta S, Barbara M, Attardo S, Bucci L, Farinati F et al (2017) Hepatic decompensation is the major driver of death in HCV-infected cirrhotic patients with successfully treated early hepatocellular carcinoma. 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Cancer Cell 26(5):605\u0026ndash;622\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eQin S, Ren Z, Feng YH, Yau T, Wang B, Zhao H et al (2021) Atezolizumab plus Bevacizumab versus Sorafenib in the Chinese Subpopulation with Unresectable Hepatocellular Carcinoma: Phase 3 Randomized, Open-Label IMbrave150 Study. Liver Cancer 10(4):296\u0026ndash;308\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCheon J, Kim H, Kim HS, Kim CG, Kim I, Kang B et al (2023) Atezolizumab plus bevacizumab in patients with child-Pugh B advanced hepatocellular carcinoma. Ther Adv Med Oncol 15:17588359221148541\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAbou-Alfa GK, Amadori D, Santoro A, Figer A, De Greve J, Lathia C et al (2011) Safety and Efficacy of Sorafenib in Patients with Hepatocellular Carcinoma (HCC) and Child-Pugh A versus B Cirrhosis. Gastrointest Cancer Res 4(2):40\u0026ndash;44\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eK\u0026oslash;stner AH, Sorensen M, Olesen RK, Gr\u0026oslash;nb\u0026aelig;k H, Lassen U, Ladekarl M (2013) Sorafenib in advanced hepatocellular carcinoma: a nationwide retrospective study of efficacy and tolerability. ScientificWorldJournal 2013:931972\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBarroso-Sousa LGDAF, Bento R, Blanco AD, Valente BP, Pfiffer GL (2015) Safety and efficacy of sorafenib in patients with Child-Pugh B advanced hepatocellular carcinoma. Mol Clin Oncol 3(4):793\u0026ndash;796\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eXu J, Shen J, Gu S, Zhang Y, Wu L, Wu J et al (2021) Camrelizumab in Combination with Apatinib in Patients with Advanced Hepatocellular Carcinoma (RESCUE): A Nonrandomized, Open-label, Phase II Trial. Clin Cancer Res 27(4):1003\u0026ndash;1011\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eXie E, Yeo YH, Scheiner B, Zhang Y, Hiraoka A, Tantai X et al (2023) Immune Checkpoint Inhibitors for Child-Pugh Class B Advanced Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis. JAMA Oncol 9(10):1423\u0026ndash;1431\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSidaway P (2024) Adjuvant sintilimab effective in high-risk HCC. Nat Rev Clin Oncol 21(3):168\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Hepatocellular carcinoma, Lenvatinib, Sorafenib, Immune checkpoint inhibitors, Child-Pugh B","lastPublishedDoi":"10.21203/rs.3.rs-4467107/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4467107/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eUnresectable hepatocellular carcinoma (uHCC) patients with Child-Pugh grade B have limited treatment options and poor outcomes.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003ePatients with uHCC and Child-pugh B who received lenvatinib plus PD-1 inhibitors or sorafenib plus PD-1 inhibitors at one of three centers were retrospectively reviewed. These patients were divided into two subgroups: one with Child-pugh B7 (Group A, n =106) and another with Child-pugh B/9 (Group B, n = 73). Overall survival (OS) was defined as the primary endpoint. Secondary endpoints included time to progression (TTP), the objective response rate (ORR), and safety. Prognostic factors were evaluated using multivariate Cox proportional hazards models, while nomograms were constructed to predict 12-month survival.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eBetween December 31, 2020 and March 30, 2023, a total of 179 patients were enrolled. The objective response and disease control rates of patients in the Child–pugh groups B and A were 26.0% and 76.7%, and 33.0% and 83.0%, respectively. There was no difference in median TTP (6.3 vs. 7.8 months, P = 0.28) or OS (14.0 vs. 17.8months, P = 0.20) between Group B and Group A. However, while the safety profiles were comparable between the two groups, patients with Child-pugh B8/9 had a significantly higher frequency of dose reductions and discontinuations (P = 0.04 and P \u0026lt; 0.001), compared to those with Child-pugh B7. According to the results of multivariate analysis，we constructed a nomogram to predict 12-month survival rates，considering tumor size, BCLC stage, tumor response , drug resistance. The nomogram-related receiver operating characteristics (ROC) curves indicated that the area under the curve (AUC) values were 0.752. Furthermore, the calibration curves revealed good agreement between real measurements and nomogram predictions.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA combination of multi-kinase inhibitors (lenvatinib or sorafenib) plus PD-1 inhibitors was safe, well-tolerated, and especially it can also benefit patients with uHCC and Child-pugh B8/9.\u003c/p\u003e","manuscriptTitle":"Patients with uHCC and Child-Pugh B8/9 also benefit from a combination of antiangiogenic agents and PD-1 inhibitors: a multicenter real-world study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-06-10 22:32:59","doi":"10.21203/rs.3.rs-4467107/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"8a66b873-ff94-4801-b6e8-4edfca29e5af","owner":[],"postedDate":"June 10th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-06-10T22:33:01+00:00","versionOfRecord":[],"versionCreatedAt":"2024-06-10 22:32:59","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4467107","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4467107","identity":"rs-4467107","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}