Real-world efficacy and prognostic factors of lenvatinib plus PD-1 inhibitors in 378 unresectable hepatocellular carcinoma patients

Real-world efficacy and prognostic factors of lenvatinib plus PD-1 inhibitors in 378 unresectable hepatocellular carcinoma patients | 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 Real-world efficacy and prognostic factors of lenvatinib plus PD-1 inhibitors in 378 unresectable hepatocellular carcinoma patients Xu Yang, Bowen Che, Yanyu Wang, Yunchao Wang, Junyu Long, Nan Zhang, and 24 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-2152996/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 08 Feb, 2023 Read the published version in Hepatology International → Version 1 posted 4 You are reading this latest preprint version Abstract Introduction Combining lenvatinib with a programmed cell death protein-1 (PD-1) inhibitor has been explored for the treatment of unresectable hepatocellular carcinoma (uHCC). This study aimed to investigate the real-world efficacy and prognostic factors of lenvatinib plus PD-1 inhibitor in large cohorts of Asia uHCC patients. Methods Patients with uHCC treated with lenvatinib and PD-1 inhibitors were included. The primary endpoints were overall survival (OS) and progression-free survival (PFS), and the secondary endpoints were the response rate (ORR) and adverse events (AEs). Prognostic factors of survival were also analysed. Results A total of 378 uHCC patients from two medical centres in China were included retrospectively. The median age was 55 years, and 86.5% of patients were male. Hepatitis B virus (HBV) infection (89.9%) was the dominant aetiology. The median OS was 17.8 (95% confidence intervals (CIs) 14.0-21.6) months. The median PFS was 6.9 (95% CI 6.0-7.9) months. The best objective response rate (ORR) and disease control rate (DCR) were 19.6% and 73.5%, respectively. In multivariate analysis, Child-Pugh score, Barcelona Clinic Liver Cancer stage, Eastern Cooperative Oncology Group performance status score, involved organs, tumour burden score, and combination with local therapy were independent prognostic factors for OS. 100% and 57.9% patients experienced all grade and grade 3/4 treatment-emergent AEs. Conclusion This real-world study of lenvatinib plus PD-1 inhibitors demonstrated long survival and considerable ORRs and DCRs for uHCC patients in China. The tolerability of combination therapy was acceptable but still be monitored closely. Hepatocellular carcinoma Unresectable Lenvatinib PD-1 inhibitor Pembrolizumab Nivolumab Adverse effects Hepatitis B virus Figures Figure 1 Figure 2 Figure 3 Introduction Hepatocellular carcinoma (HCC) has a high incidence and mortality. Most cases are unresectable HCC (uHCC) [ 1 , 2 ]. Patients with uHCC exhibit a median overall survival (OS) of only 11.8–21.2 months for systematic therapy in phase III studies [ 3 – 10 ] and real-world studies [ 11 – 14 ]. Recently, phase 1b studies of lenvatinib plus a PD-1 inhibitor (pembrolizumab or nivolumab) for the treatment of uHCC patients showed promising efficacy in European and American [ 15 ] and Japanese cohorts [ 16 ]. Even recently LEAP-002 study found lenvatinib plus pembrolizumab don’t significant increase OS (21.2 vs. 19.0 months, HR = 0.840, P = 0.0227 < 0.0185) than lenvatinib but still showed the longest OS in patients with uHCC [ 10 ]. In East Asia, especially China, where chronic hepatitis B infection is an important aetiological factor and where the disease is different from other areas [ 1 , 17 ], the efficacy of lenvatinib plus PD-1 inhibitor combination therapy is unclear. Many PD-1 inhibitors for patients with uHCC are approved for use in China [ 18 – 20 ], However, there are still lacking large Chinese uHCC cohorts to evaluate this combination therapy. Moreover, it remains unclear whether such patients could achieve better survival with lenvatinib plus PD-1 inhibitor combination therapy. Therefore, in this study, we intended to observe the effect of lenvatinib plus PD-1 inhibitor combination therapy in a large, retrospective uHCC cohort and explore its prognostic factors for survival. Patients And Methods Study design and patients We retrospectively collected data on consecutive patients treated with lenvatinib plus PD-1 inhibitors for uHCC from Oct 2017 to Nov 2021, in 2 tertiary care hospitals (Peking Union Medical College Hospital (PUMCH) and the Fifth Medical Center of the People's Liberation Army General Hospital (PLAGH). Patients were eligible for this study if they met the following criteria. Patients were pathologically confirmed to have HCC or confirmed by imaging to have HCC [ 21 – 23 ]; patients exhibited at least one measurable lesion pre Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1; patients exhibited unresectable HCC not eligible for curative treatment; patients were at least 18 years old; Child-Pugh classification A-B, and patients exhibited Eastern Cooperative Oncology Group (ECOG) performance status (PS) scores of 0–2. Exclusion criteria included the presence of end-stage HCC; history of organ transplant; received prior lenvatinib or PD-1 inhibitor, discontinued use of combination therapy after less than 2 cycles of treatment. This study was compliant with the principles of the Declaration of Helsinki and was also approved by the Institutional Review Board and Ethics Committee of PUMCH (IRB No. JS-1391) and the Fifth Medical Center of PLAGH (IRB No. KY-2022-4-24-1). Written informed consent was collected from all patients before the application of medication. This study has already been registered at NCT03892577. Treatment Patients were treated with the devo combination of lenvatinib and a PD-1 inhibitor. The dose of lenvatinib was dependent on patient weight ( > = 60 kg: 12 mg; <60 kg: 8 mg). For PD-1 inhibitors, pembrolizumab or nivolumab, camrelizumab, sintilimab, toripalimab, or tislelizumab were allowed, and 200 mg (toripalimab: 240 mg) every three weeks was administered intravenously. Endpoints and assessments The primary endpoints were OS and progression-free survival (PFS), and the secondary endpoints were objective response rate (ORR) and safety. OS was defined as the time elapsed from the start of combination therapy until death (all causes). Surviving patients were censored at the last follow-up date. Tumour response was evaluated by the RECIST v1.1 guidelines [ 24 ]. PFS was defined as the time elapsed from the start of combination therapy until the date of progression or death (all causes), whichever occurred first. Durable clinical benefit (DCB) was defined as complete response (CR), partial response (PR), or stable disease (SD) for ≥ 24 weeks [ 25 ], which was evaluated by professional radiologists at our centre who were blinded to the therapeutic outcomes and clinicopathological features. Grades of AEs were assessed by physical examination and laboratory and imaging tests performed at the time of treatment based on the National Cancer Institute’s Common Toxicity Criteria (CTCAE), version 5.0. Statistical analyses Survival curves were estimated by using the Kaplan-Meier method and compared with the log-rank test. Univariate and multivariate Cox proportional hazard regression models were used to estimate the possible risk factors influencing PFS and OS, expressed as hazard ratios (HRs) and 95% confidence intervals (CIs). All variables potentially associated with OS or PFS and having a univariate p value of < 0.1 were included in multivariate analyses. Results with two-tailed p values of < 0.05 were considered statistically significant. Statistical analyses were performed using R version 4.1.2 and Statistical Package for the Social Sciences (version 25; IBM Corp., Armonk, NY). Results Patient characteristics 598 patients with hepatocellular carcinoma from Oct 2017 to Nov 2021 were screened from two hospitals, and 220 patients were excluded. Then a total of 378 consecutively eligible uHCC patients who treated with lenvatinib plus PD-1 inhibitors were evaluated (Fig. 1 ). Their baseline demographic and clinical characteristics are summarized in Table 1 . Table 1 Baseline demographic and clinical characteristics of Chinese unresectable hepatocellular carcinoma (uHCC) patients and LEAP-002 study receiving lenvatinib plus PD-1 inhibitors Present study LEAP-002 study Variable Lenvatinib plus PD-1 inhibitors (N = 378) Lenvatinib plus pembrolizumab (N = 395) Lenvatinib plus placebo (N = 399) Median age (range) 55 (18–89) 66 (19–88) 66 (20–88) Sex — no. (%) Male 327 (86.5) 317 (80.3) 327 (82.0) Female 51 (13.5) 78 (19.7) 72 (18.0) ECOG performance status — no. (%) 0 165 (43.7) 268 (67.8) 273 (68.4) 1 164 (43.4) 127 (32.2) 126 (31.6) 2 49 (13.0) 0 (0) 0 (0) Child-Pugh Grade — no. (%) A 293 (77.5) 393 (99.5) 397 (99.5) B 85 (22.5) 2 (0.5) 2 (0.5) BCLC Stage — no. (%) B 48 (12.7) 85 (21.5) 95 (23.8) C 330 (87.3) 310 (78.5) 302 (75.7) Etiology — no. (%) HBV 340 (89.9) 192 (48.6) 193 (48.4) HCV 11 (2.9) 94 (23.8) 87 (21.8) HBV & HCV 1 (0.3) 0 (0) 0 (0) others 26 (6.9) 109 (27.6) 119 (29.8) MVI — no. (%) Yes 198 (52.4) 71 (18.0) 62 (15.5) No 180 (47.6) 324 (82.0) 337 (84.5) EHS metastasis — no. (%) Yes 173 (45.8) 249 (63.0) 243 (60.9) No 205 (54.2) 146 (37.0) 156 (39.1) MVI or EHS — no. (%) 297 (78.6) 268 (67.8) 262 (65.7) AFP level — no. (%) =400 ng/mL 179 (47.8) 276 (69.9) 267 (66.9) No. of involved organs — no. (%) 1 217 (57.4) - - 2 123 (32.5) - - >=3 38 (10.1) - - Tumour burden score (TBS) — no. (%) =8 179 (47.4) - - Tumor largest size — no. (%) =7 cm 183 (48.4) - - Number of prior systemic therapies— no. (%) 0 310 (82.0) - - 1 60 (15.9) - - >=2 8 (2.1) - - Combined with local therapy — no. (%) Yes 206 (54.5) - - No 172 (45.5) - - Abbreviations: AFP, alpha-fetoprotein; BCLC, Barcelona Clinic Liver Cancer; ECOG, Eastern Cooperative Oncology Group; EHS, extra-hepatic spread; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, chronic hepatitis C virus; MVI, macrovascular invasion Of 378 patients, the median age was 55 years, and the majority (86.5%) of patients were male. The percentages of patients with ECOG-PS values of 0, 1 and 2 were 43.7%, 43.4% and 13.0%, respectively. Chronic hepatitis B virus (HBV) infection (89.9%) was the dominant aetiology. At baseline, 198 (52.4%) patients exhibited macrovascular invasion (MVI) by the tumour, whereas 173 (45.8%) exhibited extra-hepatic spread (EHS) of the tumour. The tumour burden score (TBS) was calculated by the maximum tumour size and number of tumours in the liver [ 26 , 27 ]. Using the cut-off of 8 [ 26 , 27 ], 47.4% of patients were classified as the high TBS score group. Most uHCC patients were systematic therapy naïve (82.0%). During the treatment, 54.5% of patients also received local therapy (transarterial chemoembolization (TACE), radiofrequency ablation (RFA) or radiation therapy (RT)) before and after two months of this combination therapy. There were many kinds of PD-1 inhibitors used in our cohorts. The proportions of patients using pembrolizumab, nivolumab, sintilimab, camrelizumab, toripalimab, and tislelizumab were 18.3%, 5.6%, 33.9%, 27.5%, 11.6% and 3.2%, respectively. Efficacy outcomes and prognostic factors and subgroup analyses for survival At the time of analysis, the median follow-up was 10.4 (interquartile range (IQR), 6.2–15.8) months. The median OS was 17.8 months (95% confidence intervals (CIs), 14.0-21.6) (Fig. 2 A), and the 1-year and 1.5-year OS rates were 43.7% (95% CI, 38.7–48.7) and 18.3% (95% CI, 14.4–22.1), respectively (Table 2 ). Eight potentially prognostic variables for OS were selected by univariate Cox analysis, namely, Child-Pugh score, Barcelona Clinic Liver Cancer (BCLC) stage, ECOG PS, a-fetoprotein (AFP) level, involved organs, TBS, MVI, and combination with local therapy (Table 3 ). In multivariate analysis, Child-Pugh grade (B vs. A: HR, 1.675; 95% CI, 1.171–2.396, P = 0.005; 10.5 vs. 22.6 months; Fig. 3 A), ECOG PS (1–2 vs. 0: HR, 2.209; 95% CI, 1.538–3.173, P < 0.001; 11.5 vs. 26.7 months; Fig. 3 B), involved organs (< 3 vs. ≥ 3: HR, 1.716; 95% CI, 1.073–2.744, P = 0.024; 10.3 vs. 19.4 months; Fig. 3 C) and TBS (high vs. low: HR, 1.543; 95% CI, 1.093–2.177,, P = 0.014; 13.7 vs. 24.5 months; Fig. 3 D), were independently associated with significantly shorter OS. Conversely, BCLC stage (B vs. C: HR, 0.297; 95% CI, 0.115–0.767, P = 0.012; not be evaluated (NE) vs. 15.5 months; Fig. 3 E) and combination with local therapy (Yes vs. no: HR, 0.665; 95% CI, 0.485–0.911, P = 0.011; 22.6 vs. 13.9 months; Fig. 3 F) were associated with significantly longer OS. (Table 3 ). Table 2 Efficacy outcomes in Chinese unresectable hepatocellular carcinoma (uHCC) patients and LEAP-002 study receiving lenvatinib plus PD-1 inhibitors Parameter Present study LEAP-002 study Lenvatinib plus PD-1 inhibitors (N = 378) Lenvatinib plus pembrolizumab (N = 395) Lenvatinib plus placebo (N = 399) ORR, % (95 CI) 19.6 (15.6–23.6) 26.1% 17.5% Best overall response CR, no. (%) 0 (0) - - PR, no. (%) 74 (19.6) - - SD, no. (%) 221 (58.5) - - PD, no. (%) 57 (15.1) - - Unknown/not evaluable, no. (%) 26 (6.9) - - DCR, % (95 CI) 78.0 (73.9–82.2) 81.3% 78.4% CBR, % (95 CI) 50.0 (45.0–55.0) - - DOR, % (95 CI) 10.8 (7.5–14.0) 16.6 (range: 2.0 + − 33.6+) 10.4 (range: 1.9–35.1+) Median PFS, months (95%CI) 6.9 (6.0-7.9) 8.2 (6.4–8.4) 8.0 (6.3–8.2) 6 months, % (95 CI) 44.0 (38.9–49.2) - - 12 months, % (95 CI) 15.0 (11.3–18.6) 34.1% 29.3% Median OS, months, months (95%CI) 17.8 (14.0-21.6) 21.2 (19.0-23.6) 19.0 (17.2–21.7) 6 months, % (95 CI) 75.4 (71.1–79.7) - - 12 months, % (95 CI) 43.7 (38.7–48.7) - - 18 months, % (95 CI) 18.3 (14.4–22.1) - - Median follow-up, month (IQR) 10.4 (6.2–15.8) 32.1 (range: 25.8–41.1) Abbreviations: CI, confidence interval; CR, complete response; DCR, disease control rate; DCB, Durable clinical benefit; DOR, duration of response; IQR, interquartile range; ORR, objective response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease. Table 3 Univariate and multivariate analyses of prognostic factors for progression-free survival (PFS) and overall survival (OS) Variates Univariate analysis for PFS Multivariate analysis Univariate analysis for OS Multivariate analysis P value P value HR (95% CI) P value P value HR (95% CI) Age (< 65 vs. ≥ 65) 0.116 0.552 Sex (Female vs. Male) 0.979 0.710 HBV (No vs. Yes) 0.793 0.854 HCV (No vs. Yes) 0.454 0.829 Child–Pugh score (B vs. A) 0.050 0.565 1.100 (0.795–1.523) < 0.001 0.005 1.675 (1.171–2.396) BCLC stage (B vs. C) 0.001 0.544 0.859 (0.525–1.404) < 0.001 0.012 0.297 (0.115–0.767) ECOG PS (1–2 vs. 0) < 0.001 < 0.001 1.832 (1.363–2.461) < 0.001 < 0.001 2.209 (1.538–3.173) AFP level (≥ 400 vs. <400) 0.059 0.488 1.098 (0.843–1.431) 0.014 0.474 1.122 (0.819–1.536) Involve organs (≥ 3 vs. <3) 0.113 0.005 0.024 1.716 (1.073–2.744) TBS (≥ 8 vs. <8) 0.001 0.047 1.348 (1.005–1.809) < 0.001 0.014 1.543 (1.093–2.177) MVI (Yes vs. No) 0.004 0.239 1.203 (0.885–1.636) 0.001 0.431 1.162 (0.800-1.689) EHS (Yes vs. No) 0.367 0.153 First line (No vs. Yes) 0.495 0.848 Combination with local therapy (Yes vs. N0) 0.005 0.008 0.701 (0.539–0.912) 0.004 0.011 0.665 (0.485–0.911) PD-1 inhibitor (Others vs. Pembrolizumab) 0.451 0.332 Abbreviations: AFP, alpha-fetoprotein; BCLC, Barcelona Clinic Liver Cancer; CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; EHS, extra-hepatic spread; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, chronic hepatitis C virus; HR, hazard radio; MVI, macrovascular invasion; OS, overall survival; PFS, progression-free survival; TBS, tumour burden score. For PFS analysis, 361 patients could be analysed. The median PFS was 6.9 months (95% CI, 6.0-7.9) (Fig. 2 B), and the 0.5-year and 1-year PFS rates were 44.0% (95% CI, 38.9–49.2) and 15.0% (95% CI, 11.3–18.6), respectively. By multivariate analysis, ECOG PS (1–2 vs. 0: HR, 1.832; 95% CI, 1.363–2.461, P < 0.001; 5.1 vs. 10.1 months; Figure S1A) and TBS (high vs. low: HR, 1.348; 95% CI, 1.005–1.809, P = 0.047; 5.4 vs. 8.2 months, P = 0.001; Figure S1B) was associated with significantly shorter PFS. (Table 3 ). However, combination with local therapy (yes vs. no: HR, 0.701; 95% CI, 0.539–0.912, P = 0.008; 7.8 vs. 5.5 months; Figure S1C) were independent predictors of longer PFS. In the intent-to-treat analysis of 378 patients by RECIST v1.1 criteria, objective responses were observed in 74 patients (19.6%, 95% CI: 15.6–23.6), and disease control was observed in 295 patients (78.0%, 95% CI: 73.9–82.2). If the tumour achieved a response, the median duration of response (DOR) was 10.8 (95% CI: 7.5–14.0) months. Half (50%) of the patients reached the CBR from lenvatinib plus PD-1 inhibitor therapy. Safety All patients were able to be assessed for drug safety. The overall incidence of treatment-emergent adverse events (TEAEs) was 100% (Table 4 ). However, TEAEs were grade 3/4 in 219 (57.9%) patients. The most frequent grade 3 to 4 TEAEs (> 5%) were hypertension (15.1%), increased blood bilirubin levels (8.5%), fatigue (7.7%), proteinuria (7.1%), decreased platelet count (6.9%), decreased appetite (6.3%), hypokalaemia (6.3%), and diarrhoea (5.8%). Grade 5 fatal adverse events occurred in 5 patients (1.3%) and included upper gastrointestinal bleeding (four patients) and cerebral haemorrhage (one patient). Table 4 Most common treatment-emergent adverse events in 378 Chinese unresectable hepatocellular carcinoma (uHCC) patients receiving lenvatinib plus PD-1 inhibitors Adverse events, n (%) Any grade Grade 3–4 Grade 5 Treatment-emergent adverse events 378 (100.0) 219 (57.9) 5 (1.3)* Hypertension 185 (48.9) 57 (15.1) Increased blood bilirubin 162 (42.9) 32 (8.5) Fatigue 241 (63.7) 29 (7.7) Proteinuria 89 (23.5) 27 (7.1) Decreased platelet count 139 (36.8) 26 (6.9) Decreased appetite 299 (79.1) 24 (6.3) Hypokalaemia 89 (23.5) 24 (6.3) Diarrhoea 87 (23) 22 (5.8) Elevated aspartate aminotransferase 154 (40.7) 18 (4.8) Upper gastrointestinal bleeding 52 (13.8) 18 (4.8) 4 (1.1) Hyponatremia 97 (25.7) 12 (3.2) Decreased leukocytes 99 (26.2) 11 (2.9) Rash 202 (53.4) 10 (2.6) Elevated alanine aminotransferase 160(42.3) 8 (2.1) Decreased weight 86 (22.8) 8 (2.1) Palmar-plantar erythrodysaesthesia 60 (15.9) 7 (1.9) Pneumonia 19 (5.0) 7 (1.9) Hypoalbuminemia 198 (52.4) 6 (1.6) Pain 68 (18) 4 (1.1) Nausea 51 (13.5) 3 (0.8) Vomiting 40 (10.6) 2 (0.5) Dysphonia 30 (7.9) 2 (0.5) Pruritus 23 (6.1) 2 (0.5) Hypothyroidism 126 (33.3) 1 (0.3) Abdominal pain 82 (21.7) 1 (0.3) Fever 65 (17.2) 1 (0.3) Edema limbs 33 (8.7) 1 (0.3) Oral mucositis 32 (8.5) 1 (0.3) Periodontal disease 30 (7.9) 1 (0.3) Constipation 25 (6.6) 1 (0.3) Abdominal distension 49 (13.0) 0 (0.0) Epistaxis 13 (3.4) 0 (0.0) *including cerebral haemorrhage (N = 1) Discussion To our knowledge, this is the largest real-world study of the use of lenvatinib plus PD-1 inhibitors for uHCC patients. We found that the median OS was 17.8 months and the median PFS was 6.9 months. The ORR and DCR were 19.6% and 73.5%, respectively. We also found Child-Pugh score, BCLC, ECOG, involved organs, TBS, and combination with local therapy were independent prognostic factors for OS. Many other cohort studies have also reported the efficacy of lenvatinib plus PD-1 inhibitors in uHCC patients. The phase I Keynote-524 study, the most representative study, found that lenvatinib plus the PD-1 inhibitor pembrolizumab for 100 uHCC patients could reach an ORR of 36.0%. Moreover, the median PFS and median OS were 8.6 months and 22.0 months, respectively [ 15 ]. However phage 3 LEAP-002 study found lenvatinib plus pembrolizumab don’t significant increase OS (21.2 vs. 19.0 months, HR, 0.840, P = 0.0227 < 0.0185) than lenvatinib plus placebo in patients with uHCC [ 10 ]. The negative LEAP-002 study found that OS in the lenvatinib plus placebo arm (19.0 months) was longer than in the lenvatinib arm (13.6 months) in 2018 REFLECT study [ 4 ] due to higher rates (22.8%) and efficacy of sequential immunotherapy [ 10 ]. The efficacy of the combination therapy in our real-world cohort was lower than that achieved in the Keynote-524 study [ 15 ] and LEAP-002 [ 10 ] because important baseline characteristics (Child-Pugh score, BCLC stage, ECOG PS scores, MVI) were better in these two studies than in our present study. However such parameters may be also more realistic in real-world practice. In clinical practice, the main concern is selecting patients who would benefit from the therapy[ 28 ]. We found that worse ECOG PS (1–2 vs. 0) was a negative prognostic factor for OS (HR = 2.209, p < 0.001) and PFS (HR = 1.832, p 0.05) in multivariate analysis. Many studies also found that ECOG and Child-Pugh scores were prognostic factors for patients with uHCC who were administered lenvatinib and/or PD-1 inhibitors [ 29 – 31 ]. Wu et al found in multivariate analyses that Child-Pugh class (Class B vs. A, HR = 2.646, P = 0.039) but not ECOG of ≥ 1 (HR = 1.889, P = 0.162) was a poor prognostic factor of survival for uHCC patients treated with lenvatinib plus pembrolizumab [ 30 ]. Choi et al studied 203 Korean patients with uHCC treated with nivolumab and found that the Child-Pugh B group had shorter mOS (2.8 vs. 10.7 months; HR = 2.10; p < 0.001) but not mPFS (HR = 1.17, P = 0.430) [ 32 ]. Patients with worse ECOG PS or worse liver function might benefit less from lenvatinib plus PD-1 inhibitors, so the application of drugs should be done with caution. Tumour characteristics are very important for survival for patients with uHCC [ 33 ]. We found that the involved organs and TBS may influence PFS and OS. In a post-analysis of the REFLECT study for patients with uHCC treated with lenvatinib or sorafenib, the number of tumour sites at baseline was a very important prognostic factor (P < 0.001) for OS in multivariate analysis [ 34 ]. Moreover, we found that combination locoregional therapy was an independent factor for both better PFS and OS. This result was consistent with the results of previous studies that found that adding locoregional therapy to a lenvatinib plus a PD-1 inhibitor or lenvatinib monotherapy therapeutic regimen could lead to a high response and long survival [ 9 , 35 – 39 ]. Regarding safety, ≥grade 3 TEAEs need to be closely monitored. In the Keynote-524 study, grade 3 TEAEs were hypertension (18%), increased AST levels (14%), increased lipase levels (11%), diarrhoea (7%), increased blood bilirubin levels (6% at level 3 and 2% at level 4), fatigue (6%), asthenia (6%), increased ALT levels (6%), decreased weight (5%) and proteinuria (5%) [ 15 ]. In the LEAP-002 study, 96.5% and 61.5% uHCC patients underwent all grade treatment-related adverse events [ 10 ], which is similar to our study. In our cohort, notably, fatigue, decreased appetite, and gastrointestinal bleeding may need closer monitoring and good management. Fatigue and decreased appetite may lead to low quality of life, while gastrointestinal bleeding is always life-threatening, especially in patients with chronic liver disease [ 40 ]. There are several limitations in our study. First, potential bias could not easily be avoided due to the nature of the retrospective design. Second, there are multiple kinds of PD-1 inhibitors that exhibit heterogeneous effects; however, we did not find a significant difference when comparing the use of other PD-1 inhibitors with the use of pembrolizumab. Third, our cohort was predominantly HBV-infected uHCC patients, and the applicability of these findings to non-HBV-infected uHCC patients remains to be further validated in real-world practice. Conclusions In conclusion, a real-world study found that lenvatinib plus PD-1 inhibitors achieved long survival and considerable response for uHCC patients in China. The tolerability of combination therapy was acceptable but should still be monitored closely in real-world practice. Abbreviations AFP, alpha-fetoprotein; ALT, elevated alanine aminotransferase; AST, aspartate aminotransferase; BCLC, Barcelona Clinic Liver Cancer; CI, confidence interval; CR, complete response; CTCAE, Common Terminology Criteria for Adverse Events; DCR, disease control rate; DCB, Durable clinical benefit; DOR, duration of response; ECOG, Eastern Cooperative Oncology Group; EHS, extra-hepatic spread; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, chronic hepatitis C virus; HAIC, hepatic arterial infusion chemotherapy; IQR, interquartile range; MVI, macrovascular invasion; ORR, objective response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PD-1, programmed death 1; PR, partial response; RECIST, Response Evaluation Criteria in Solid Tumors; PLAGH, People's Liberation Army General Hospital; PS, performance status; PUMCH, Peking Union Medical College Hospital; SD, stable disease. TBS, tumor burden score; TACE, transarterial chemoembolization; TEAE, treatment-emergent adverse event; VEGF, vascular endothelial growth factor. Declarations Funding This work was supported by CAMS Innovation Fund for Medical Sciences (CIFMS) (2021-I2M-1-061 and 2021-1-I2M-003), CAMS Clinical and Translational Medicine Research Funds (2019XK320006), CSCO-hengrui Cancer Research Fund (Y-HR2019-0239, Y-HR2020MS-0414 and Y-HR2020QN-0415), CSCO-MSD Cancer Research Fund (Y-MSDZD2021-0213), and National Ten-thousand Talent Program. The funders had no role in the study design, data collection and analysis, decision to publish or preparation of the manuscript. Ethical Statement This study was performed in accordance with the Declaration of Helsinki, and it has been approved by the Institutional Review Board at the PUMCH (IRB No. JS-1391) and the Fifth Medical Center of PLAGH (IRB No. KY-2022-4-24-1). Written informed consent was collected from all patients before the application of medication. Conflict of Interest The authors declare no conflict of interest. Author contributions HZ, YL, XY, BC, YW, and YW contributed to the conception and design of the study. HZ, YL, XY, BC, YW, and YW performed the data collection and analysis. HZ, YL, XY, BC, YW, YW, JL, NZ, JX, ZX, LZ, JC, JL, JL, FX, DW,YL, HS, JP, KH, MG, LH, JS, LY, LZ, JZ, ZL, XY, YM, and XS provided study materials or patients. HZ, YL, XY, BC, YW, YW contributed to data collection. HZ, YL, XY, BC, YW, and YW contributed to data analysis and interpretation. All authors contributed to the writing of the manuscript and approved the final version. Permission to reproduce material from other sources Not applicable. References Llovet JM, Kelley RK, Villanueva A, Singal AG, Pikarsky E, Roayaie S, et al. Hepatocellular carcinoma. Nat Rev Dis Primers. 2021;7:6. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. 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Tsuchiya K, Kurosaki M, Sakamoto A, Marusawa H, Kojima Y, Hasebe C, et al. The Real-World Data in Japanese Patients with Unresectable Hepatocellular Carcinoma Treated with Lenvatinib from a Nationwide Multicenter Study. Cancers. 2021;13:2608. Wu CJ, Lee PC, Hung YW, Lee CJ, Chi CT, Lee IC, et al. Lenvatinib plus pembrolizumab for systemic therapy-naïve and -experienced unresectable hepatocellular carcinoma. Cancer Immunol Immunother 2022. Kuo HY, Chiang NJ, Chuang CH, Chen CY, Wu IC, Chang TT, et al. 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. 2020;43:211–20. Choi W-M, Lee D, Shim JH, Kim KM, Lim Y-S, Lee HC, et al. Effectiveness and Safety of Nivolumab in Child–Pugh B Patients with Hepatocellular Carcinoma: A Real-World Cohort Study. Cancers 2020;12:1968. Kim HS, Kim CG, Hong JY, Kim I-h, Kang B, Jung S, et al. The presence and size of intrahepatic tumors determine the therapeutic efficacy of nivolumab in advanced hepatocellular carcinoma. Ther Adv Med Oncol. 2022;14:17588359221113266. Kudo M, Finn RS, Qin S, Han K-H, Ikeda K, Cheng A-L, et al. Overall survival and objective response in advanced unresectable hepatocellular carcinoma: A subanalysis of the REFLECT study. J Hepatol 2022. Cai M, Huang W, Huang J, Shi W, Guo Y, Liang L, et al. Transarterial Chemoembolization Combined With Lenvatinib Plus PD-1 Inhibitor for Advanced Hepatocellular Carcinoma: A Retrospective Cohort Study. Front Immunol. 2022;13:848387. Cao F, Yang Y, Si T, Luo J, Zeng H, Zhang Z, et al. The Efficacy of TACE Combined With Lenvatinib Plus Sintilimab in Unresectable Hepatocellular Carcinoma: A Multicenter Retrospective Study. Front Oncol. 2021;11:783480. Wu JY, Yin ZY, Bai YN, Chen YF, Zhou SQ, Wang SJ, et al. Lenvatinib Combined with Anti-PD-1 Antibodies Plus Transcatheter Arterial Chemoembolization for Unresectable Hepatocellular Carcinoma: A Multicenter Retrospective Study. J Hepatocell Carcinoma. 2021;8:1233–40. He MK, Liang RB, Zhao Y, Xu YJ, Chen HW, Zhou YM, et al. Lenvatinib, toripalimab, plus hepatic arterial infusion chemotherapy versus lenvatinib alone for advanced hepatocellular carcinoma. Ther Adv Med Oncol. 2021;13:17588359211002720. Xiang YJ, Wang K, Yu HM, Li XW, Cheng YQ, Wang WJ, et al. Transarterial chemoembolization plus a PD-1 inhibitor with or without lenvatinib for intermediate-stage hepatocellular carcinoma. Hepatol Res. 2022;52:721–9. Rapposelli IG, Tada T, Shimose S, Burgio V, Kumada T, Iwamoto H, et al. Adverse events as potential predictive factors of activity in patients with advanced hepatocellular carcinoma treated with lenvatinib. Liver Int. 2021;41:2997–3008. Supplementary Files FigureS1.pdf Figure S1. Kaplan-Meier curves for progression-free survival stratified by Eastern Cooperative Oncology Group (ECOG) performance status (PS) score (A), tumour burden score (B), and combination with local therapy (C) subgroups. Cite Share Download PDF Status: Published Journal Publication published 08 Feb, 2023 Read the published version in Hepatology International → Version 1 posted Reviewers invited by journal 30 Oct, 2022 Reviewers agreed at journal 14 Oct, 2022 Editor assigned by journal 11 Oct, 2022 First submitted to journal 10 Oct, 2022 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. 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subgroups\u003c/p\u003e","description":"","filename":"Figure3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-2152996/v1/ae44b9d23974e1d1806071b3.jpg"},{"id":44719229,"identity":"ea70c20f-bede-4495-afb9-b43952626721","added_by":"auto","created_at":"2023-10-16 18:53:59","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":943502,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2152996/v1/70a45bd7-8f56-40d9-b999-27f2e274665e.pdf"},{"id":27938223,"identity":"18597152-7fc3-4cb6-aa7b-923a0fae6a49","added_by":"auto","created_at":"2022-10-18 15:21:57","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":856030,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFigure S1.\u003c/strong\u003e Kaplan-Meier curves for progression-free survival stratified by Eastern Cooperative Oncology Group (ECOG) performance status (PS) score (A), tumour burden score (B), and combination with local therapy (C) subgroups.\u003c/p\u003e","description":"","filename":"FigureS1.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2152996/v1/fd90cb02ee8a7d40939c25ed.pdf"}],"financialInterests":"","formattedTitle":"Real-world efficacy and prognostic factors of lenvatinib plus PD-1 inhibitors in 378 unresectable hepatocellular carcinoma patients","fulltext":[{"header":"Introduction","content":"\u003cp\u003eHepatocellular carcinoma (HCC) has a high incidence and mortality. Most cases are unresectable HCC (uHCC) [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Patients with uHCC exhibit a median overall survival (OS) of only 11.8\u0026ndash;21.2 months for systematic therapy in phase III studies [\u003cspan additionalcitationids=\"CR4 CR5 CR6 CR7 CR8 CR9\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] and real-world studies [\u003cspan additionalcitationids=\"CR12 CR13\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eRecently, phase 1b studies of lenvatinib plus a PD-1 inhibitor (pembrolizumab or nivolumab) for the treatment of uHCC patients showed promising efficacy in European and American [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e] and Japanese cohorts [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Even recently LEAP-002 study found lenvatinib plus pembrolizumab don\u0026rsquo;t significant increase OS (21.2 vs. 19.0 months, HR\u0026thinsp;=\u0026thinsp;0.840, P\u0026thinsp;=\u0026thinsp;0.0227\u0026thinsp;\u0026lt;\u0026thinsp;0.0185) than lenvatinib but still showed the longest OS in patients with uHCC [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. In East Asia, especially China, where chronic hepatitis B infection is an important aetiological factor and where the disease is different from other areas [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], the efficacy of lenvatinib plus PD-1 inhibitor combination therapy is unclear.\u003c/p\u003e \u003cp\u003eMany PD-1 inhibitors for patients with uHCC are approved for use in China [\u003cspan additionalcitationids=\"CR19\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e], However, there are still lacking large Chinese uHCC cohorts to evaluate this combination therapy. Moreover, it remains unclear whether such patients could achieve better survival with lenvatinib plus PD-1 inhibitor combination therapy. Therefore, in this study, we intended to observe the effect of lenvatinib plus PD-1 inhibitor combination therapy in a large, retrospective uHCC cohort and explore its prognostic factors for survival.\u003c/p\u003e"},{"header":"Patients And Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design and patients\u003c/h2\u003e \u003cp\u003e We retrospectively collected data on consecutive patients treated with lenvatinib plus PD-1 inhibitors for uHCC from Oct 2017 to Nov 2021, in 2 tertiary care hospitals (Peking Union Medical College Hospital (PUMCH) and the Fifth Medical Center of the People's Liberation Army General Hospital (PLAGH).\u003c/p\u003e \u003cp\u003ePatients were eligible for this study if they met the following criteria. Patients were pathologically confirmed to have HCC or confirmed by imaging to have HCC [\u003cspan additionalcitationids=\"CR22\" citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]; patients exhibited at least one measurable lesion pre Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1; patients exhibited unresectable HCC not eligible for curative treatment; patients were at least 18 years old; Child-Pugh classification A-B, and patients exhibited Eastern Cooperative Oncology Group (ECOG) performance status (PS) scores of 0\u0026ndash;2. Exclusion criteria included the presence of end-stage HCC; history of organ transplant; received prior lenvatinib or PD-1 inhibitor, discontinued use of combination therapy after less than 2 cycles of treatment.\u003c/p\u003e \u003cp\u003e This study was compliant with the principles of the Declaration of Helsinki and was also approved by the Institutional Review Board and Ethics Committee of PUMCH (IRB No. JS-1391) and the Fifth Medical Center of PLAGH (IRB No. KY-2022-4-24-1). Written informed consent was collected from all patients before the application of medication. This study has already been registered at NCT03892577.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eTreatment\u003c/h2\u003e \u003cp\u003ePatients were treated with the devo combination of lenvatinib and a PD-1 inhibitor. The dose of lenvatinib was dependent on patient weight (\u0026thinsp;\u0026gt;\u0026thinsp;=\u0026thinsp;60 kg: 12 mg; \u0026lt;60 kg: 8 mg). For PD-1 inhibitors, pembrolizumab or nivolumab, camrelizumab, sintilimab, toripalimab, or tislelizumab were allowed, and 200 mg (toripalimab: 240 mg) every three weeks was administered intravenously.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eEndpoints and assessments\u003c/h2\u003e \u003cp\u003eThe primary endpoints were OS and progression-free survival (PFS), and the secondary endpoints were objective response rate (ORR) and safety. OS was defined as the time elapsed from the start of combination therapy until death (all causes). Surviving patients were censored at the last follow-up date. Tumour response was evaluated by the RECIST v1.1 guidelines [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. PFS was defined as the time elapsed from the start of combination therapy until the date of progression or death (all causes), whichever occurred first. Durable clinical benefit (DCB) was defined as complete response (CR), partial response (PR), or stable disease (SD) for \u0026ge;\u0026thinsp;24 weeks [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e], which was evaluated by professional radiologists at our centre who were blinded to the therapeutic outcomes and clinicopathological features. Grades of AEs were assessed by physical examination and laboratory and imaging tests performed at the time of treatment based on the National Cancer Institute\u0026rsquo;s Common Toxicity Criteria (CTCAE), version 5.0.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analyses\u003c/h2\u003e \u003cp\u003eSurvival curves were estimated by using the Kaplan-Meier method and compared with the log-rank test. Univariate and multivariate Cox proportional hazard regression models were used to estimate the possible risk factors influencing PFS and OS, expressed as hazard ratios (HRs) and 95% confidence intervals (CIs). All variables potentially associated with OS or PFS and having a univariate p value of \u0026lt;\u0026thinsp;0.1 were included in multivariate analyses. Results with two-tailed p values of \u0026lt;\u0026thinsp;0.05 were considered statistically significant. Statistical analyses were performed using R version 4.1.2 and Statistical Package for the Social Sciences (version 25; IBM Corp., Armonk, NY).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv class=\"Section2\" id=\"Sec8\"\u003e\n \u003ch2\u003ePatient characteristics\u003c/h2\u003e\n \u003cp\u003e598 patients with hepatocellular carcinoma from Oct 2017 to Nov 2021 were screened from two hospitals, and 220 patients were excluded. Then a total of 378 consecutively eligible uHCC patients who treated with lenvatinib plus PD-1 inhibitors were evaluated (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). Their baseline demographic and clinical characteristics are summarized in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\n \u003ctable border=\"1\" id=\"Tab1\"\u003e\n \u003ccaption\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eBaseline demographic and clinical characteristics of Chinese unresectable hepatocellular carcinoma (uHCC) patients and LEAP-002 study receiving lenvatinib plus PD-1 inhibitors\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ePresent study\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eLEAP-002 study\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eVariable\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eLenvatinib plus PD-1 inhibitors\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(N\u0026thinsp;=\u0026thinsp;378)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eLenvatinib plus pembrolizumab\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(N\u0026thinsp;=\u0026thinsp;395)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eLenvatinib plus placebo\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(N\u0026thinsp;=\u0026thinsp;399)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMedian age (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e55 (18\u0026ndash;89)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e66 (19\u0026ndash;88)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e66 (20\u0026ndash;88)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSex \u0026mdash; no. (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e327 (86.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e317 (80.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e327 (82.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e51 (13.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e78 (19.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e72 (18.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eECOG performance status \u0026mdash; no. (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e165 (43.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e268 (67.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e273 (68.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e164 (43.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e127 (32.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e126 (31.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e49 (13.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eChild-Pugh Grade \u0026mdash; no. (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e293 (77.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e393 (99.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e397 (99.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e85 (22.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (0.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (0.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBCLC Stage \u0026mdash; no. (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e48 (12.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e85 (21.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e95 (23.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e330 (87.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e310 (78.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e302 (75.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEtiology \u0026mdash; no. (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHBV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e340 (89.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e192 (48.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e193 (48.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHCV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11 (2.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e94 (23.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e87 (21.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHBV \u0026amp; HCV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (0.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eothers\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e26 (6.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e109 (27.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e119 (29.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMVI \u0026mdash; no. (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e198 (52.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e71 (18.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e62 (15.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e180 (47.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e324 (82.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e337 (84.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEHS metastasis \u0026mdash; no. (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e173 (45.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e249 (63.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e243 (60.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e205 (54.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e146 (37.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e156 (39.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMVI or EHS \u0026mdash; no. (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e297 (78.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e268 (67.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e262 (65.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAFP level \u0026mdash; no. (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;400 ng/mL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e199 (52.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e119 (30.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e132 (33.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026gt;=400 ng/mL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e179 (47.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e276 (69.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e267 (66.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo. of involved organs \u0026mdash; no. (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e217 (57.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e123 (32.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026gt;=3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e38 (10.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTumour burden score (TBS) \u0026mdash; no. (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e199 (52.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026gt;=8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e179 (47.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTumor largest size \u0026mdash; no. (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;7 cm\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e195 (51.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026gt;=7 cm\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e183 (48.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNumber of prior systemic\u003c/p\u003e\n \u003cp\u003etherapies\u0026mdash; no. (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e310 (82.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e60 (15.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026gt;=2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8 (2.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCombined with local therapy \u0026mdash; no. (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e206 (54.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e172 (45.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\"\u003eAbbreviations: AFP, alpha-fetoprotein; BCLC, Barcelona Clinic Liver Cancer; ECOG, Eastern Cooperative Oncology Group; EHS, extra-hepatic spread; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, chronic hepatitis C virus; MVI, macrovascular invasion\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003c/div\u003e\n \u003cp\u003eOf 378 patients, the median age was 55 years, and the majority (86.5%) of patients were male. The percentages of patients with ECOG-PS values of 0, 1 and 2 were 43.7%, 43.4% and 13.0%, respectively. Chronic hepatitis B virus (HBV) infection (89.9%) was the dominant aetiology. At baseline, 198 (52.4%) patients exhibited macrovascular invasion (MVI) by the tumour, whereas 173 (45.8%) exhibited extra-hepatic spread (EHS) of the tumour. The tumour burden score (TBS) was calculated by the maximum tumour size and number of tumours in the liver [\u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e]. Using the cut-off of 8 [\u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e], 47.4% of patients were classified as the high TBS score group. Most uHCC patients were systematic therapy na\u0026iuml;ve (82.0%). During the treatment, 54.5% of patients also received local therapy (transarterial chemoembolization (TACE), radiofrequency ablation (RFA) or radiation therapy (RT)) before and after two months of this combination therapy. There were many kinds of PD-1 inhibitors used in our cohorts. The proportions of patients using pembrolizumab, nivolumab, sintilimab, camrelizumab, toripalimab, and tislelizumab were 18.3%, 5.6%, 33.9%, 27.5%, 11.6% and 3.2%, respectively.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv class=\"Section2\" id=\"Sec9\"\u003e\n \u003ch2\u003eEfficacy outcomes and prognostic factors and subgroup analyses for survival\u003c/h2\u003e\n \u003cp\u003eAt the time of analysis, the median follow-up was 10.4 (interquartile range (IQR), 6.2\u0026ndash;15.8) months. The median OS was 17.8 months (95% confidence intervals (CIs), 14.0-21.6) (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eA), and the 1-year and 1.5-year OS rates were 43.7% (95% CI, 38.7\u0026ndash;48.7) and 18.3% (95% CI, 14.4\u0026ndash;22.1), respectively (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). Eight potentially prognostic variables for OS were selected by univariate Cox analysis, namely, Child-Pugh score, Barcelona Clinic Liver Cancer (BCLC) stage, ECOG PS, a-fetoprotein (AFP) level, involved organs, TBS, MVI, and combination with local therapy (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e). In multivariate analysis, Child-Pugh grade (B vs. A: HR, 1.675; 95% CI, 1.171\u0026ndash;2.396, P\u0026thinsp;=\u0026thinsp;0.005; 10.5 vs. 22.6 months; Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003eA), ECOG PS (1\u0026ndash;2 vs. 0: HR, 2.209; 95% CI, 1.538\u0026ndash;3.173, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001; 11.5 vs. 26.7 months; Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003eB), involved organs (\u0026lt;\u0026thinsp;3 vs. \u0026ge; 3: HR, 1.716; 95% CI, 1.073\u0026ndash;2.744, P\u0026thinsp;=\u0026thinsp;0.024; 10.3 vs. 19.4 months; Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003eC) and TBS (high vs. low: HR, 1.543; 95% CI, 1.093\u0026ndash;2.177,, P\u0026thinsp;=\u0026thinsp;0.014; 13.7 vs. 24.5 months; Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003eD), were independently associated with significantly shorter OS. Conversely, BCLC stage (B vs. C: HR, 0.297; 95% CI, 0.115\u0026ndash;0.767, P\u0026thinsp;=\u0026thinsp;0.012; not be evaluated (NE) vs. 15.5 months; Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003eE) and combination with local therapy (Yes vs. no: HR, 0.665; 95% CI, 0.485\u0026ndash;0.911, P\u0026thinsp;=\u0026thinsp;0.011; 22.6 vs. 13.9 months; Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003eF) were associated with significantly longer OS. (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\n \u003ctable border=\"1\" id=\"Tab2\"\u003e\n \u003ccaption\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eEfficacy outcomes in Chinese unresectable hepatocellular carcinoma (uHCC) patients and LEAP-002 study receiving lenvatinib plus PD-1 inhibitors\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eParameter\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ePresent study\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eLEAP-002 study\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eLenvatinib plus PD-1 inhibitors\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(N\u0026thinsp;=\u0026thinsp;378)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eLenvatinib plus pembrolizumab\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(N\u0026thinsp;=\u0026thinsp;395)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eLenvatinib plus placebo\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(N\u0026thinsp;=\u0026thinsp;399)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eORR, % (95 CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e19.6 (15.6\u0026ndash;23.6)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e26.1%\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e17.5%\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eBest overall response\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCR, no. (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e0 (0)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e-\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e-\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePR, no. (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e74 (19.6)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e-\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e-\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSD, no. (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e221 (58.5)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e-\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e-\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePD, no. (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e57 (15.1)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e-\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e-\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eUnknown/not evaluable, no. (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e26 (6.9)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e-\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e-\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eDCR, % (95 CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e78.0 (73.9\u0026ndash;82.2)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e81.3%\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e78.4%\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eCBR, % (95 CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e50.0 (45.0\u0026ndash;55.0)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e-\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e-\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eDOR, % (95 CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e10.8 (7.5\u0026ndash;14.0)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e16.6 (range: 2.0\u0026thinsp;+\u0026thinsp;\u0026minus;\u0026thinsp;33.6+)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e10.4 (range: 1.9\u0026ndash;35.1+)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eMedian PFS, months (95%CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e6.9 (6.0-7.9)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e8.2 (6.4\u0026ndash;8.4)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e8.0 (6.3\u0026ndash;8.2)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6 months, % (95 CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e44.0 (38.9\u0026ndash;49.2)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e-\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e-\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12 months, % (95 CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e15.0 (11.3\u0026ndash;18.6)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e34.1%\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e29.3%\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eMedian OS, months, months (95%CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e17.8 (14.0-21.6)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e21.2 (19.0-23.6)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e19.0 (17.2\u0026ndash;21.7)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6 months, % (95 CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e75.4 (71.1\u0026ndash;79.7)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e-\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e-\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12 months, % (95 CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e43.7 (38.7\u0026ndash;48.7)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e-\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e-\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e18 months, % (95 CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e18.3 (14.4\u0026ndash;22.1)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e-\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e-\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eMedian follow-up, month (IQR)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e10.4 (6.2\u0026ndash;15.8)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003e32.1 (range: 25.8\u0026ndash;41.1)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\"\u003eAbbreviations: CI, confidence interval; CR, complete response; DCR, disease control rate; DCB, Durable clinical benefit; DOR, duration of response; IQR, interquartile range; ORR, objective response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease.\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/div\u003e\n \u003cdiv class=\"gridtable\"\u003e\n \u003ctable border=\"1\" id=\"Tab3\"\u003e\n \u003ccaption\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eUnivariate and multivariate analyses of prognostic factors for progression-free survival (PFS) and overall survival (OS)\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eVariates\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eUnivariate analysis for PFS\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eMultivariate analysis\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eUnivariate analysis for OS\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eMultivariate analysis\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eP value\u003c/strong\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eP value\u003c/strong\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eHR (95% CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eP value\u003c/strong\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eP value\u003c/strong\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eHR (95% CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAge (\u0026lt;\u0026thinsp;65 vs. \u0026ge; 65)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.116\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.552\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSex (Female vs. Male)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.979\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.710\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHBV (No vs. Yes)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.793\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.854\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHCV (No vs. Yes)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.454\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.829\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eChild\u0026ndash;Pugh score (B vs. A)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.050\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.565\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.100 (0.795\u0026ndash;1.523)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.005\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.675 (1.171\u0026ndash;2.396)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBCLC stage (B vs. C)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.544\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.859 (0.525\u0026ndash;1.404)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.012\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.297 (0.115\u0026ndash;0.767)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eECOG PS (1\u0026ndash;2 vs. 0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.832 (1.363\u0026ndash;2.461)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.209 (1.538\u0026ndash;3.173)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAFP level (\u0026ge;\u0026thinsp;400 vs. \u0026lt;400)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.059\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.488\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.098 (0.843\u0026ndash;1.431)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.014\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.474\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.122 (0.819\u0026ndash;1.536)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eInvolve organs (\u0026ge;\u0026thinsp;3 vs. \u0026lt;3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.113\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.005\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.024\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.716 (1.073\u0026ndash;2.744)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTBS (\u0026ge;\u0026thinsp;8 vs. \u0026lt;8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.047\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.348 (1.005\u0026ndash;1.809)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.014\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.543 (1.093\u0026ndash;2.177)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMVI (Yes vs. No)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.004\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.239\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.203 (0.885\u0026ndash;1.636)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.431\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.162 (0.800-1.689)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEHS (Yes vs. No)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.367\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.153\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFirst line (No vs. Yes)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.495\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.848\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCombination with local therapy (Yes vs. N0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.005\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.008\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.701 (0.539\u0026ndash;0.912)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.004\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.011\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.665 (0.485\u0026ndash;0.911)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePD-1 inhibitor (Others vs. Pembrolizumab)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.451\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.332\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"7\"\u003eAbbreviations: AFP, alpha-fetoprotein; BCLC, Barcelona Clinic Liver Cancer; CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; EHS, extra-hepatic spread; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, chronic hepatitis C virus; HR, hazard radio; MVI, macrovascular invasion; OS, overall survival; PFS, progression-free survival; TBS, tumour burden score.\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eFor PFS analysis, 361 patients could be analysed. The median PFS was 6.9 months (95% CI, 6.0-7.9) (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eB), and the 0.5-year and 1-year PFS rates were 44.0% (95% CI, 38.9\u0026ndash;49.2) and 15.0% (95% CI, 11.3\u0026ndash;18.6), respectively. By multivariate analysis, ECOG PS (1\u0026ndash;2 vs. 0: HR, 1.832; 95% CI, 1.363\u0026ndash;2.461, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001; 5.1 vs. 10.1 months; Figure S1A) and TBS (high vs. low: HR, 1.348; 95% CI, 1.005\u0026ndash;1.809, P\u0026thinsp;=\u0026thinsp;0.047; 5.4 vs. 8.2 months, P\u0026thinsp;=\u0026thinsp;0.001; Figure S1B) was associated with significantly shorter PFS. (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e). However, combination with local therapy (yes vs. no: HR, 0.701; 95% CI, 0.539\u0026ndash;0.912, P\u0026thinsp;=\u0026thinsp;0.008; 7.8 vs. 5.5 months; Figure S1C) were independent predictors of longer PFS.\u003c/p\u003e\n \u003cp\u003eIn the intent-to-treat analysis of 378 patients by RECIST v1.1 criteria, objective responses were observed in 74 patients (19.6%, 95% CI: 15.6\u0026ndash;23.6), and disease control was observed in 295 patients (78.0%, 95% CI: 73.9\u0026ndash;82.2). If the tumour achieved a response, the median duration of response (DOR) was 10.8 (95% CI: 7.5\u0026ndash;14.0) months. Half (50%) of the patients reached the CBR from lenvatinib plus PD-1 inhibitor therapy.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv class=\"Section2\" id=\"Sec10\"\u003e\n \u003ch2\u003eSafety\u003c/h2\u003e\n \u003cp\u003eAll patients were able to be assessed for drug safety. The overall incidence of treatment-emergent adverse events (TEAEs) was 100% (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e). However, TEAEs were grade 3/4 in 219 (57.9%) patients. The most frequent grade 3 to 4 TEAEs (\u0026gt;\u0026thinsp;5%) were hypertension (15.1%), increased blood bilirubin levels (8.5%), fatigue (7.7%), proteinuria (7.1%), decreased platelet count (6.9%), decreased appetite (6.3%), hypokalaemia (6.3%), and diarrhoea (5.8%). Grade 5 fatal adverse events occurred in 5 patients (1.3%) and included upper gastrointestinal bleeding (four patients) and cerebral haemorrhage (one patient).\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\n \u003ctable border=\"1\" id=\"Tab4\"\u003e\n \u003ccaption\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eMost common treatment-emergent adverse events in 378 Chinese unresectable hepatocellular carcinoma (uHCC) patients receiving lenvatinib plus PD-1 inhibitors\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eAdverse events, n (%)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eAny grade\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eGrade 3\u0026ndash;4\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eGrade 5\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTreatment-emergent adverse events\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e378 (100.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e219 (57.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5 (1.3)*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHypertension\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e185 (48.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e57 (15.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIncreased blood bilirubin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e162 (42.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e32 (8.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFatigue\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e241 (63.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e29 (7.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eProteinuria\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e89 (23.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e27 (7.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDecreased platelet count\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e139 (36.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e26 (6.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDecreased appetite\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e299 (79.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e24 (6.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHypokalaemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e89 (23.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e24 (6.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDiarrhoea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e87 (23)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e22 (5.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eElevated aspartate aminotransferase\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e154 (40.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e18 (4.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eUpper gastrointestinal bleeding\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e52 (13.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e18 (4.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4 (1.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHyponatremia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e97 (25.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12 (3.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDecreased leukocytes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e99 (26.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11 (2.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRash\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e202 (53.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10 (2.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eElevated alanine aminotransferase\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e160(42.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8 (2.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDecreased weight\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e86 (22.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8 (2.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePalmar-plantar erythrodysaesthesia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e60 (15.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7 (1.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePneumonia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e19 (5.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7 (1.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHypoalbuminemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e198 (52.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6 (1.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e68 (18)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4 (1.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNausea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e51 (13.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 (0.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eVomiting\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e40 (10.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (0.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDysphonia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e30 (7.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (0.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePruritus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e23 (6.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (0.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHypothyroidism\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e126 (33.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (0.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAbdominal pain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e82 (21.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (0.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFever\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e65 (17.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (0.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEdema limbs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e33 (8.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (0.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOral mucositis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e32 (8.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (0.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePeriodontal disease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e30 (7.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (0.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eConstipation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e25 (6.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (0.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAbdominal distension\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e49 (13.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEpistaxis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e13 (3.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\"\u003e*including cerebral haemorrhage (N\u0026thinsp;=\u0026thinsp;1)\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eTo our knowledge, this is the largest real-world study of the use of lenvatinib plus PD-1 inhibitors for uHCC patients. We found that the median OS was 17.8 months and the median PFS was 6.9 months. The ORR and DCR were 19.6% and 73.5%, respectively. We also found Child-Pugh score, BCLC, ECOG, involved organs, TBS, and combination with local therapy were independent prognostic factors for OS.\u003c/p\u003e \u003cp\u003eMany other cohort studies have also reported the efficacy of lenvatinib plus PD-1 inhibitors in uHCC patients. The phase I Keynote-524 study, the most representative study, found that lenvatinib plus the PD-1 inhibitor pembrolizumab for 100 uHCC patients could reach an ORR of 36.0%. Moreover, the median PFS and median OS were 8.6 months and 22.0 months, respectively [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. However phage 3 LEAP-002 study found lenvatinib plus pembrolizumab don\u0026rsquo;t significant increase OS (21.2 vs. 19.0 months, HR, 0.840, P\u0026thinsp;=\u0026thinsp;0.0227\u0026thinsp;\u0026lt;\u0026thinsp;0.0185) than lenvatinib plus placebo in patients with uHCC [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. The negative LEAP-002 study found that OS in the lenvatinib plus placebo arm (19.0 months) was longer than in the lenvatinib arm (13.6 months) in 2018 REFLECT study [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e] due to higher rates (22.8%) and efficacy of sequential immunotherapy [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. The efficacy of the combination therapy in our real-world cohort was lower than that achieved in the Keynote-524 study [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e] and LEAP-002 [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] because important baseline characteristics (Child-Pugh score, BCLC stage, ECOG PS scores, MVI) were better in these two studies than in our present study. However such parameters may be also more realistic in real-world practice.\u003c/p\u003e \u003cp\u003eIn clinical practice, the main concern is selecting patients who would benefit from the therapy[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. We found that worse ECOG PS (1\u0026ndash;2 vs. 0) was a negative prognostic factor for OS (HR\u0026thinsp;=\u0026thinsp;2.209, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and PFS (HR\u0026thinsp;=\u0026thinsp;1.832, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Patients with worse Child-Pugh scores (B vs. A) had shorter OS (HR\u0026thinsp;=\u0026thinsp;1.675, P\u0026thinsp;=\u0026thinsp;0.005) but not PFS (P\u0026thinsp;\u0026gt;\u0026thinsp;0.05) in multivariate analysis. Many studies also found that ECOG and Child-Pugh scores were prognostic factors for patients with uHCC who were administered lenvatinib and/or PD-1 inhibitors [\u003cspan additionalcitationids=\"CR30\" citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. Wu et al found in multivariate analyses that Child-Pugh class (Class B vs. A, HR\u0026thinsp;=\u0026thinsp;2.646, P\u0026thinsp;=\u0026thinsp;0.039) but not ECOG of \u0026ge;\u0026thinsp;1 (HR\u0026thinsp;=\u0026thinsp;1.889, P\u0026thinsp;=\u0026thinsp;0.162) was a poor prognostic factor of survival for uHCC patients treated with lenvatinib plus pembrolizumab [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Choi et al studied 203 Korean patients with uHCC treated with nivolumab and found that the Child-Pugh B group had shorter mOS (2.8 vs. 10.7 months; HR\u0026thinsp;=\u0026thinsp;2.10; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) but not mPFS (HR\u0026thinsp;=\u0026thinsp;1.17, P\u0026thinsp;=\u0026thinsp;0.430) [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. Patients with worse ECOG PS or worse liver function might benefit less from lenvatinib plus PD-1 inhibitors, so the application of drugs should be done with caution.\u003c/p\u003e \u003cp\u003eTumour characteristics are very important for survival for patients with uHCC [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. We found that the involved organs and TBS may influence PFS and OS. In a post-analysis of the REFLECT study for patients with uHCC treated with lenvatinib or sorafenib, the number of tumour sites at baseline was a very important prognostic factor (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001) for OS in multivariate analysis [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. Moreover, we found that combination locoregional therapy was an independent factor for both better PFS and OS. This result was consistent with the results of previous studies that found that adding locoregional therapy to a lenvatinib plus a PD-1 inhibitor or lenvatinib monotherapy therapeutic regimen could lead to a high response and long survival [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan additionalcitationids=\"CR36 CR37 CR38\" citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eRegarding safety, \u0026ge;grade 3 TEAEs need to be closely monitored. In the Keynote-524 study, grade 3 TEAEs were hypertension (18%), increased AST levels (14%), increased lipase levels (11%), diarrhoea (7%), increased blood bilirubin levels (6% at level 3 and 2% at level 4), fatigue (6%), asthenia (6%), increased ALT levels (6%), decreased weight (5%) and proteinuria (5%) [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. In the LEAP-002 study, 96.5% and 61.5% uHCC patients underwent all grade treatment-related adverse events [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], which is similar to our study. In our cohort, notably, fatigue, decreased appetite, and gastrointestinal bleeding may need closer monitoring and good management. Fatigue and decreased appetite may lead to low quality of life, while gastrointestinal bleeding is always life-threatening, especially in patients with chronic liver disease [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThere are several limitations in our study. First, potential bias could not easily be avoided due to the nature of the retrospective design. Second, there are multiple kinds of PD-1 inhibitors that exhibit heterogeneous effects; however, we did not find a significant difference when comparing the use of other PD-1 inhibitors with the use of pembrolizumab. Third, our cohort was predominantly HBV-infected uHCC patients, and the applicability of these findings to non-HBV-infected uHCC patients remains to be further validated in real-world practice.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn conclusion, a real-world study found that lenvatinib plus PD-1 inhibitors achieved long survival and considerable response for uHCC patients in China. The tolerability of combination therapy was acceptable but should still be monitored closely in real-world practice.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eAFP, alpha-fetoprotein; ALT, elevated alanine aminotransferase; AST, aspartate aminotransferase; BCLC, Barcelona Clinic Liver Cancer; CI, confidence interval; CR, complete response; CTCAE, Common Terminology Criteria for Adverse Events; DCR, disease control rate; DCB, Durable clinical benefit; DOR, duration of response; ECOG, Eastern Cooperative Oncology Group; EHS, extra-hepatic spread; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, chronic hepatitis C virus; HAIC, hepatic arterial infusion chemotherapy; IQR, interquartile range; MVI, macrovascular invasion; ORR, objective response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PD-1, programmed death 1; PR, partial response; RECIST, Response Evaluation Criteria in Solid Tumors; PLAGH, People\u0026apos;s Liberation Army General Hospital; PS, performance status; PUMCH, Peking Union Medical College Hospital; SD, stable disease. TBS, tumor burden score; TACE, transarterial chemoembolization; TEAE, treatment-emergent adverse event; VEGF, vascular endothelial growth factor.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by CAMS Innovation Fund for Medical Sciences (CIFMS) (2021-I2M-1-061 and 2021-1-I2M-003), CAMS Clinical and Translational Medicine Research Funds (2019XK320006), CSCO-hengrui Cancer Research Fund (Y-HR2019-0239, Y-HR2020MS-0414 and Y-HR2020QN-0415), CSCO-MSD Cancer Research Fund (Y-MSDZD2021-0213), and National Ten-thousand Talent Program. The funders had no role in the study design, data collection and analysis, decision to publish or preparation of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was performed in accordance with the Declaration of Helsinki, and it has been approved by the Institutional Review Board at the PUMCH (IRB No. JS-1391) and the Fifth Medical Center of PLAGH (IRB No. KY-2022-4-24-1). Written informed consent was collected from all patients before the application of medication.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHZ, YL, XY, BC, YW, and YW contributed to the conception and design of the study. HZ, YL, XY, BC, YW, and YW performed the data collection and analysis. HZ, YL, XY, BC, YW, YW, JL, NZ, JX, ZX, LZ, JC, JL, JL, FX, DW,YL, HS, JP, KH, MG, LH, JS, LY, LZ, JZ, ZL, XY, YM, and XS provided study materials or patients. HZ, YL, XY, BC, YW, YW contributed to data collection. HZ, YL, XY, BC, YW, and YW contributed to data analysis and interpretation. All authors contributed to the writing of the manuscript and approved the final version.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePermission to reproduce material from other sources\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eLlovet JM, Kelley RK, Villanueva A, Singal AG, Pikarsky E, Roayaie S, et al. Hepatocellular carcinoma. Nat Rev Dis Primers. 2021;7:6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. 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Machine learning models in the prediction of 1-year mortality in patients with advanced hepatocellular cancer on immunotherapy: a proof-of-concept study. Hepatol Int. 2022;16:879\u0026ndash;91.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTsuchiya K, Kurosaki M, Sakamoto A, Marusawa H, Kojima Y, Hasebe C, et al. The Real-World Data in Japanese Patients with Unresectable Hepatocellular Carcinoma Treated with Lenvatinib from a Nationwide Multicenter Study. Cancers. 2021;13:2608.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWu CJ, Lee PC, Hung YW, Lee CJ, Chi CT, Lee IC, et al. Lenvatinib plus pembrolizumab for systemic therapy-na\u0026iuml;ve and -experienced unresectable hepatocellular carcinoma. Cancer Immunol Immunother 2022.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKuo HY, Chiang NJ, Chuang CH, Chen CY, Wu IC, Chang TT, et al. 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. 2020;43:211\u0026ndash;20.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChoi W-M, Lee D, Shim JH, Kim KM, Lim Y-S, Lee HC, et al. Effectiveness and Safety of Nivolumab in Child\u0026ndash;Pugh B Patients with Hepatocellular Carcinoma: A Real-World Cohort Study. Cancers 2020;12:1968.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKim HS, Kim CG, Hong JY, Kim I-h, Kang B, Jung S, et al. The presence and size of intrahepatic tumors determine the therapeutic efficacy of nivolumab in advanced hepatocellular carcinoma. Ther Adv Med Oncol. 2022;14:17588359221113266.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKudo M, Finn RS, Qin S, Han K-H, Ikeda K, Cheng A-L, et al. Overall survival and objective response in advanced unresectable hepatocellular carcinoma: A subanalysis of the REFLECT study. J Hepatol 2022.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCai M, Huang W, Huang J, Shi W, Guo Y, Liang L, et al. Transarterial Chemoembolization Combined With Lenvatinib Plus PD-1 Inhibitor for Advanced Hepatocellular Carcinoma: A Retrospective Cohort Study. Front Immunol. 2022;13:848387.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCao F, Yang Y, Si T, Luo J, Zeng H, Zhang Z, et al. The Efficacy of TACE Combined With Lenvatinib Plus Sintilimab in Unresectable Hepatocellular Carcinoma: A Multicenter Retrospective Study. Front Oncol. 2021;11:783480.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWu JY, Yin ZY, Bai YN, Chen YF, Zhou SQ, Wang SJ, et al. Lenvatinib Combined with Anti-PD-1 Antibodies Plus Transcatheter Arterial Chemoembolization for Unresectable Hepatocellular Carcinoma: A Multicenter Retrospective Study. J Hepatocell Carcinoma. 2021;8:1233\u0026ndash;40.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHe MK, Liang RB, Zhao Y, Xu YJ, Chen HW, Zhou YM, et al. Lenvatinib, toripalimab, plus hepatic arterial infusion chemotherapy versus lenvatinib alone for advanced hepatocellular carcinoma. Ther Adv Med Oncol. 2021;13:17588359211002720.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eXiang YJ, Wang K, Yu HM, Li XW, Cheng YQ, Wang WJ, et al. Transarterial chemoembolization plus a PD-1 inhibitor with or without lenvatinib for intermediate-stage hepatocellular carcinoma. Hepatol Res. 2022;52:721\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRapposelli IG, Tada T, Shimose S, Burgio V, Kumada T, Iwamoto H, et al. Adverse events as potential predictive factors of activity in patients with advanced hepatocellular carcinoma treated with lenvatinib. Liver Int. 2021;41:2997\u0026ndash;3008.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"hepatology-international","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"hepi","sideBox":"Learn more about [Hepatology International](https://www.springer.com/journal/12072)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/hepi/default.aspx","title":"Hepatology International","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Hepatocellular carcinoma, Unresectable, Lenvatinib, PD-1 inhibitor, Pembrolizumab, Nivolumab, Adverse effects, Hepatitis B virus","lastPublishedDoi":"10.21203/rs.3.rs-2152996/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-2152996/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eIntroduction\u003c/h2\u003e \u003cp\u003eCombining lenvatinib with a programmed cell death protein-1 (PD-1) inhibitor has been explored for the treatment of unresectable hepatocellular carcinoma (uHCC). This study aimed to investigate the real-world efficacy and prognostic factors of lenvatinib plus PD-1 inhibitor in large cohorts of Asia uHCC patients.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003ePatients with uHCC treated with lenvatinib and PD-1 inhibitors were included. The primary endpoints were overall survival (OS) and progression-free survival (PFS), and the secondary endpoints were the response rate (ORR) and adverse events (AEs). Prognostic factors of survival were also analysed.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eA total of 378 uHCC patients from two medical centres in China were included retrospectively. The median age was 55 years, and 86.5% of patients were male. Hepatitis B virus (HBV) infection (89.9%) was the dominant aetiology. The median OS was 17.8 (95% confidence intervals (CIs) 14.0-21.6) months. The median PFS was 6.9 (95% CI 6.0-7.9) months. The best objective response rate (ORR) and disease control rate (DCR) were 19.6% and 73.5%, respectively. In multivariate analysis, Child-Pugh score, Barcelona Clinic Liver Cancer stage, Eastern Cooperative Oncology Group performance status score, involved organs, tumour burden score, and combination with local therapy were independent prognostic factors for OS. 100% and 57.9% patients experienced all grade and grade 3/4 treatment-emergent AEs.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eThis real-world study of lenvatinib plus PD-1 inhibitors demonstrated long survival and considerable ORRs and DCRs for uHCC patients in China. The tolerability of combination therapy was acceptable but still be monitored closely.\u003c/p\u003e","manuscriptTitle":"Real-world efficacy and prognostic factors of lenvatinib plus PD-1 inhibitors in 378 unresectable hepatocellular carcinoma patients","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2022-10-18 15:21:54","doi":"10.21203/rs.3.rs-2152996/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewersInvited","content":"","date":"2022-10-30T04:38:21+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2022-10-15T03:35:09+00:00","index":0,"fulltext":""},{"type":"editorAssigned","content":"","date":"2022-10-11T07:29:02+00:00","index":"","fulltext":""},{"type":"submitted","content":"Hepatology International","date":"2022-10-11T00:09:57+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"hepatology-international","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"hepi","sideBox":"Learn more about [Hepatology International](https://www.springer.com/journal/12072)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/hepi/default.aspx","title":"Hepatology International","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"411aec1b-1de8-470b-a5ea-371124916709","owner":[],"postedDate":"October 18th, 2022","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2023-10-16T18:51:44+00:00","versionOfRecord":{"articleIdentity":"rs-2152996","link":"https://doi.org/10.1007/s12072-022-10480-y","journal":{"identity":"hepatology-international","isVorOnly":false,"title":"Hepatology International"},"publishedOn":"2023-02-08 18:46:08","publishedOnDateReadable":"February 8th, 2023"},"versionCreatedAt":"2022-10-18 15:21:54","video":"","vorDoi":"10.1007/s12072-022-10480-y","vorDoiUrl":"https://doi.org/10.1007/s12072-022-10480-y","workflowStages":[]},"version":"v1","identity":"rs-2152996","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-2152996","identity":"rs-2152996","version":["v1"]},"buildId":"7rjqhiLT3MXkJMwkYKINL","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}