BACKGROUND & AIMS:In patients with variceal hemorrhage, nonselective beta-blockers plus endoscopic variceal ligation are recommended to prevent rebleeding when pre-emptive transjugular intrahepatic portosystemic shunt is not indicated or placed. The aim of this study was to determine whether decompensating events occurring before variceal hemorrhage are associated with worse outcomes in patients treated with nonselective beta-blockers plus endoscopic variceal ligation to prevent recurrent variceal hemorrhage. METHODS:This was a systematic review and individual participant data meta-analysis of studies including patients with cirrhosis and variceal hemorrhage not eligible for pre-emptive transjugular intrahepatic portosystemic shunt in patients with Child-Pugh class A-B and receiving nonselective beta-blockers plus endoscopic variceal ligation to prevent recurrent bleeding. All-cause mortality and new or worsening decompensation were analyzed using cause-specific Cox models and random-effects individual participant data meta-analysis. RESULTS:Thirteen studies (5 randomized controlled trials, 8 observational) contributed 1659 patients (Child-Pugh class A, 805; class B, 853); 606 had had prior decompensation, 121 had ascites, 154 had encephalopathy (alone or combined), 106 had ascites plus variceal hemorrhage, and 225 had variceal hemorrhage alone. The 2-year mortality was 25.1% with prior decompensation and 13.5% without (P < .0001): specific adjusted hazard ratios were 1.8 (95% confidence interval, 1.2-2.6) for prior ascites, 1.7 (95% confidence interval, 1.3-2.3) for encephalopathy, 0.83 (95% confidence interval, 0.6-1.2) for variceal hemorrhage, and 1.4 (95% confidence interval, 0.92-2.3) for variceal hemorrhage + ascites. Individual patient data meta-analysis showed a pooled adjusted hazard ratio for death of 1.4 (95% confidence interval, 1.1-1.7) with prior decompensation. New or worsening decompensation was also significantly higher with any prior decompensation: pooled adjusted hazard ratio, 1.7 (95% confidence interval, 1.15-2.44). CONCLUSIONS:Among patients with Child-Pugh class A-B cirrhosis who were not candidates for pre-emptive transjugular intrahepatic portosystemic shunt and were treated with nonselective beta-blockers plus endoscopic variceal ligation after variceal hemorrhage, prior decompensation identified a subgroup at increased risk of mortality in whom the potential benefit of transjugular intrahepatic portosystemic shunt warrants further investigation.

Abstract Purpose JS207 is a bispecific antibody targeting PD-1 and VEGF-A. This Phase II study (NCT06954467) aimed to evaluate the safety and efficacy of JS207 in combination with JS007, an antibody targeting CTLA-4, in patients with advanced hepatocellular carcinoma (HCC). Methods This study comprised a dose exploration phase with 3 to 12 patients for selection of the optimal dose of JS007, followed by a randomized expansion phase enrolled 40 to 60 patients. Patients with histologically or cytologically confirmed unresectable or metastatic HCC who had not previously received any systemic anticancer therapy were eligible. In the dose exploration phase, a fixed dose of JS207 at 10 mg/kg was administered every 3 weeks (Q3W) in combination with JS007. In the first dose cohort, patients received a single dose of JS007 at 3 mg/kg on cycle 1 day 1, then 1 mg/kg Q6W beginning at cycle 4. Depending upon the tolerability in this first dose cohort, JS007 was to be escalated to 3 mg/kg Q6W or de-escalated to 1 mg/kg Q3W for the first 4 cycles, followed by JS007 1 mg/kg Q6W beginning at cycle 4 in both the escalated and de-escalated cohorts. Based on the dose exploration phase, the optimal JS007 dose regimen was selected for use in the randomized expansion phase. During the randomized (1:1) expansion phase, patients were assigned to receive either JS207 10 mg/kg Q3W combined with JS007 or JS207 10 mg/kg Q3W as monotherapy. The primary endpoints included safety and investigator-assessed objective response rate (ORR). Results As of December 15, 2025, 10 patients were enrolled in the dose exploration phase. Three patients received JS207 in the initial dose cohort, while 7 patients received JS207 combined with JS007 in the higher dose cohort (3 mg/kg Q6W x 4 cycles, then 1 mg/kg Q6W thereafter). No patients experienced dose-limiting toxicity. The most common treatment-related adverse events (TRAEs) (incidence ≥ 20%) included increased alanine aminotransferase (50.0%), increased aspartate aminotransferase (50.0%), anaemia (50.0%), pyrexia (40.0%), thrombocytopenia (40.0%), hypothyroidism (30.0%), proteinuria (30.0%), rash (30.0%), and infusion related reactions (30.0%). Three patients (30.0%) experienced grade ≥ 3 TRAE; no patients experienced treatment-emergent adverse events leading to death. Among patients who reveived the initialor higher dose of JS007, the ORR were 33.3% (1/3) and 71.4% (5/7), respectively. The disease control rate was 100% (3/3) and 85.7% (6/7), respectively. Conclusion: The combination of JS207 and JS007 demonstrated promising efficacy with an acceptable safety profile as first line treatment of advanced HCC. The randomized expansion phase of this study is ongoing. Citation Format: Jian Zhou, Guoming Shi, Yongsheng Ge, Shuijun Zhang, Xiwen Huang, Shunda Du, Yong Gao, Guohong Han, Xiaoyong Huang, Zhenda Wang, Junliang Li, Jing Xu, Jiazheng Yan, Jianjun Zou, Jia Fan. JS207, a bispecific antibody targeting PD-1 and VEGF-A, combined with JS007 (anti-CTLA4), for patients with advanced hepatocellular carcinoma in a randomized, multicenter, Phase II study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT159.

BACKGROUND:TACE is the standard treatment for intermediate-stage hepatocellular carcinoma but has limited survival benefits. TALENTACE evaluated adding atezolizumab and bevacizumab to on-demand TACE versus on-demand TACE alone in patients with systemically untreated, intermediate-to-high tumour burden unresectable hepatocellular carcinoma. METHODS:In this randomised, open-label, phase 3 study at 40 centres in China and Japan, patients aged 18 years or older with confirmed, unresectable hepatocellular carcinoma and an anticipated life expectancy of 12 months or more were eligible for inclusion. Eligible patients were required to have an Eastern Cooperative Oncology Group performance status of 0-1, Child-Pugh class A liver function, no previous systemic therapy, and a sum of tumour maximum diameter (cm) and lesion number of six or more based on the six-and-twelve score. Patients were randomly assigned (1:1), using a permuted-block method implemented via an interactive voice and web response system, to on-demand TACE plus atezolizumab 1200 mg intravenously and bevacizumab 15 mg/kg intravenously once every 3 weeks (initiated 14 days to 8 weeks after TACE), or on-demand TACE alone, with TACE administered at the investigators' discretion. The randomisation sequence was generated by an independent biostatistician at the system vendor and was concealed from the sponsor study team and investigators until randomisation; allocation was stratified by baseline α-fetoprotein, prior locoregional therapy, and baseline Vp1/2 (and geographic region in earlier protocol versions). Primary endpoints were investigator-assessed TACE progression-free survival (TACE-PFS; time from randomisation to untreatable [unTACEable] progression, TACE failure or refractoriness, or death), and overall survival, both analysed in the intention-to-treat population. Overall survival was assessed under a prespecified adaptive (group sequential) design comprising two interim analyses and one final analysis. Safety was evaluated in the as-treated population, defined as all randomised patients who received any study treatment, analysed according to the treatment received. This study is registered with ClinicalTrials.gov (NCT04712643) and is ongoing. FINDINGS:Between Feb 23, 2021, and August 11, 2023, 342 patients were randomly assigned to TACE plus atezolizumab and bevacizumab (n=171) or on-demand TACE alone (n=171). Median age was 61·0 years (range 21·0-90·0), 66 (19%) of 342 participants were female, 276 (81%) were male, 308 (90%) were Chinese, and 34 (10%) were Japanese. The mean size of the largest target lesion per RECIST 1.1 was 7·7 cm (SD 4·3) in both arms. In the TACE plus atezolizumab and bevacizumab group, 36 (21%) of 171 patients were Barcelona Clinic Liver Cancer stage A, 100 (58%) were stage B, and 35 (20%) were stage C; in the TACE alone group, 42 (25%) of 171 patients were Barcelona Clinic Liver Cancer stage A, 105 (61%) were stage B, and 24 (14%) were stage C. At data cutoff (Feb 28, 2025; median follow-up 26·25 months [IQR 21·16-33·74]), median TACE-PFS was 11·30 months (95% CI 7·52-15·01) with TACE plus atezolizumab and bevacizumab versus 7·03 months (95% CI 5·32-8·41) with TACE alone (hazard ratio [HR] 0·71 [95% CI 0·55-0·92]; two-sided stratified log-rank p=0·0089). Overall survival remains immature and was assessed at the first of the prespecified interim analyses; median overall survival was 34·53 months (99·62% CI 24·80-not evaluable) in the TACE plus atezolizumab and bevacizumab group compared with 35·38 months (99·62% CI 24·74-not evaluable) in the TACE alone group (HR 0·96 [99·62% CI 0·58-1·58]). The most common grade 3-4 adverse events in the TACE plus atezolizumab and bevacizumab group were decreased platelet count (23 [14%] of 166), hypertension (23 [14%]), and post-embolisation syndrome (21 [13%]); in the TACE alone group, the most common were post-embolisation syndrome (23 [13%] of 173), decreased platelet count (12 [7%]), and increased aspartate aminotransferase (12 [7%]). The most common serious adverse event was ascites (eight [5%]) in the TACE plus atezolizumab and bevacizumab group and post-embolisation syndrome (six [3%]) in the TACE alone group. Treatment-related deaths occurred in five patients in the TACE plus atezolizumab and bevacizumab group (gastrointestinal haemorrhage, liver abscess, haemolytic anaemia, hypertension, and unknown death) and three patients in the TACE alone group (post-procedural haemorrhage, ascites, and unknown death). No new safety signals were identified. INTERPRETATION:On-demand TACE plus atezolizumab and bevacizumab significantly improved TACE-PFS versus on-demand TACE alone. Overall survival follow-up is ongoing. FUNDING:Shanghai Roche Pharmaceuticals.

Lenvatinib stands out as a first-line therapy for individuals with advanced hepatocellular carcinoma (HCC). Concurrently, hepatic arterial infusion chemotherapy comprising oxaliplatin, fluorouracil, and leucovorin (FOLFOX-HAIC) has emerged as a potential option for those with advanced HCC. It is necessary to investigate the efficacy and safety of lenvatinib plus FOLFOX-HAIC (lenvaHAIC) for advanced HCC in real-world situations. In this retrospective analysis, 127 consecutive patients underwent lenvaHAIC, while 184 patients received lenvatinib alone as first-line treatment at six Chinese academic centers between January 2019 and June 2022. Following 1:1 propensity score matching, we established paired cohorts (113 patients in each group) for evaluating survival. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and safety profiles were compared between the two groups. The lenvaHAIC group exhibited significantly prolonged median PFS and OS than the lenvatinib group (PFS: 12.3 vs. 6.2 months; OS: 25.6 vs. 12.3 months; P < .001 for each). In the propensity score-matched cohorts (113 pairs), both PFS and OS were notably extended in the lenvaHAIC group compared with those in the lenvatinib group (P < .001). Multivariate analysis identified lenvaHAIC treatment as an independent factor for improved PFS (hazard ratio [HR] 0.45; P < .001) and OS (HR 0.38; P < .001). Grade 3–4 adverse events, including nausea, vomiting, diarrhea, thrombocytopenia, and neutropenia, were more prevalent in the lenvaHAIC group. In this real-world study, lenvaHAIC, compared with lenvatinib monotherapy, was associated with significantly prolonged PFS and OS and a higher ORR, while demonstrating a manageable safety profile in patients with advanced HCC.

Introduction:Patients with advanced hepatocellular carcinoma (HCC) face an extremely poor prognosis. Sorafenib, a multikinase inhibitor, remains an essential treatment for advanced HCC in certain clinical settings where immunotherapy is either contraindicated or unavailable. However, the survival benefit of transarterial chemoembolization (TACE) plus sorafenib remains under investigation. Methods:The SELECT trial was a multicenter, randomized, controlled study conducted across twelve centers in China. From September 7, 2013, to December 4, 2019, 199 patients with advanced-stage HCC were randomly assigned in a 1:1 ratio to receive either TACE plus sorafenib or sorafenib monotherapy. Results:The median age of the study population was 55 years (IQR 46-63), with hepatic virus infection being the predominant cause of HCC. In the intention-to-treat (ITT) population, the overall survival (OS) analysis did not show a statistically significant difference between the combination and sorafenib monotherapy groups (14.9 months [95% CI: 10.5-19.3] vs. 11.9 months [95% CI: 9.0-14.8], HR 0.862, p = 0.312). However, the combination therapy group demonstrated significantly improved time to progression (TTP) (10.0 months [95% CI: 6.4-13.6] vs. 5.9 months [95% CI: 3.1-8.7]; p = 0.016) and post hoc progression-free survival (PFS) (8.5 months [95% CI: 6.7-10.3] vs. 5.6 months [95% CI: 4.1-7.1]; p = 0.034). In predefined per-protocol analysis, the combination therapy group showed a significantly longer median OS compared to the monotherapy group (14.6 months [11.3-17.9] vs. 7.4 months [95% CI: 4.3-10.5], HR 0.539, p = 0.001). Conclusion:Although the combination of TACE and sorafenib did not demonstrate a significant improvement in OS in the ITT analysis, it met the secondary endpoints, including TTP and post hoc PFS. These findings provide valuable insights for the design of future trials and highlight the importance of integrating locoregional interventions with systemic therapies in the management of advanced-stage HCC.

BACKGROUND & AIMS:Large-scale cohort studies on interventional radiological treatments for Budd-Chiari syndrome (BCS), including percutaneous angioplasty (PTA) with or without routine stenting and transjugular intrahepatic portosystemic shunt (TIPS), are lacking. We aimed to evaluate the long-term outcomes of these treatments in Chinese BCS patients. METHODS:Consecutive patients diagnosed with BCS in 6 Chinese tertiary centers were retrospectively screened for eligibility between January 2010 and May 2019. The roles of the treatment modalities, as well as their associated clinical outcomes, were assessed. RESULTS:Overall, 997 patients were enrolled, with obstruction types classified as inferior vena cava (15.7%), hepatic vein (16.2%), and combined (68.1%). The majority (93.5%) presented with moderate-to-severe symptoms, with 60.7% (n = 607) showing a disease course exceeding 6 months. All patients received anticoagulation, among them, 117 (11.7%) patients underwent medical therapy alone, including 65 asymptomatic or mildly symptomatic patients, and 52 with failed, unfeasible, or declined recanalization; 834 (83.7%) patients successfully recanalized through PTA alone (n = 566) or PTA with routine stenting (n = 268); 90 (9.0%) patients received TIPS placement (comprising 46 initial and 44 converted procedures); and no patients underwent liver transplantation. With a median follow-up of 57.3 months, 103 (10.5%) deaths occurred, primarily from liver failure. The 5-year rates for overall, TIPS-free, stenting-TIPS-free, and intervention-free survival were 90.2% (95% confidence interval [CI]: 88.2%-92.3%), 83.0% (95% CI: 80.5%-85.6%), 59.3% (95% CI: 56.2%-62.6%), and 10.6% (95% CI: 8.8%-12.7%), respectively (P < .001), with consistent outcomes across BCS subtypes. CONCLUSIONS:With predominantly inferior vena cava obstruction presented and recanalization used, interventional radiological treatment could achieve a good long-term outcome in Chinese patients with BCS.

Background: A significant portion of primary liver cancer patients in China are diagnosed at intermediate-to-advanced stages, often making them ineligible for curative surgery. Furthermore, high postoperative recurrence rates, reaching up to 70%, pose a major challenge for long-term survival. The emergence of novel systemic treatments, such as immune checkpoint inhibitor combinations, and advancements in locoregional therapies have created new opportunities for conversion and perioperative strategies. This updated consensus aims to standardize the clinical application of these therapies based on the latest evidence, with the objective of improving patient prognosis. Methods: A multidisciplinary committee of 97 experts was convened to revise previous guidelines. The process involved a comprehensive search of medical databases and conference proceedings, with evidence graded according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. Consensus statements were finalized through a formal electronic voting process, requiring at least 80% agreement for approval, resulting in 18 updated statements. Results: The consensus provides refined definitions for conversion and perioperative therapy. It recommends various strategies for oncological conversion, including systemic therapy with anti-angiogenic drugs plus immunotherapy, and locoregional approaches like precision transarterial chemoembolization (TACE) and hepatic artery infusion chemotherapy (HAIC). The document strongly affirms surgical resection as a crucial step for achieving long-term survival after successful conversion and offers guidance on surgical timing and adjuvant therapy. For resectable patients with high-risk features, neoadjuvant and adjuvant treatments are outlined to mitigate recurrence. The consensus also advocates for using dynamic enhanced magnetic resonance imaging ( MRI) and the modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria for efficacy assessment and underscores the essential role of a multidisciplinary team in management. Conclusions: This updated consensus offers standardized, evidence-based guidance for clinicians on implementing conversion and perioperative strategies to optimize patient-centered care and highlights the need for continued research to further refine these promising approaches.

Hepatocellular carcinoma (HCC), which accounts for approximately 75–85% of primary liver cancers, ranks 4th in newly diagnosed cases among various types of cancer in China, and is the 2nd leading cause of cancer-related mortality, thereby posing a significant threat to the life and health of the Chinese population. Since the publication of the “Guidelines for Diagnosis and Treatment of Primary Liver Cancer in China” in June 2017, which were updated by the China’s National Health Commission in December 2019 and December 2021, additional high-quality evidence from researchers worldwide regarding the diagnosis, staging, and treatment of HCC has emerged, necessitating another update to the guidelines. The new edition (2024 Edition) was written by more than 120 multidisciplinary experts in the field of HCC in China, which not only reflects the real-world situation in China but also may reshape the nationwide diagnosis and treatment of HCC. The new guideline aims to encourage the implementation of evidence-based practice and improve the national average 5-year survival rate for patients with HCC, as proposed in the “Healthy China 2030: A Vision for Health Care.”

BACKGROUND & AIMS:Spontaneous portosystemic shunt (SPSS) embolization represents a promising intervention for refractory hepatic encephalopathy (HE). This systematic review and meta-analysis evaluate the efficacy and safety of SPSS embolization in cirrhotic patients without transjugular intrahepatic portosystemic shunts (TIPS). METHODS:We systematically searched PubMed, Web of Science, Embase, and the Cochrane Library through June 12, 2024 to identify studies investigating SPSS embolization for HE. Meta-analysis was performed using fixed-effect or random-effects models to calculate clinical success (defined as HE remission), procedural success rates, and complication frequencies. RESULTS:Analysis of 10 retrospective studies encompassing 289 cirrhotic patients yielded the following pooled outcomes: hepatic encephalopathy remission rate of 83.1% (95% CI: 70.4%-93.1%), procedural success rate of 99.8% (95% CI: 98.3%-100%), and long-term adverse event rate of 42.9% (95% CI: 34.7%-51.4%). The predominant long-term complications included ascites (51.6% of complications), variceal progression (23.4%), and thrombosis (8.0%), while primary procedure-related adverse reactions were infection (37%) and fever (29%). Subgroup analyses demonstrated no statistically significant effect of etiology (p=0.788) or shunt type (p=0.271) on disease remission rates, but revealed significant differences between surgical approaches (p<0.001), with balloon-occluded retrograde transvenous obliteration (BRTO) showing the highest efficacy (97.4%-100%). CONCLUSION:SPSS embolization demonstrates both high efficacy for refractory hepatic encephalopathy (83.1% remission rate) and exceptional procedural success (99.8%). Despite substantial long-term complications (42.9%, predominantly portal hypertension sequelae), current evidence from predominantly retrospective studies supports its consideration as a therapeutic option. Technique selection should be individualized pending further validation of BRTO's superiority.

BACKGROUND:Although several PD-1 or PD-L1 inhibitors combined with antiangiogenic agents have been approved as first-line treatment of advanced hepatocellular carcinoma, treatment needs remain unmet given the high incidence and mortality of hepatocellular carcinoma and due to factors such as regional approval status, medical insurance restrictions, and cost considerations. In this phase 3 HEPATORCH study, we aimed to compare the efficacy and safety of toripalimab plus bevacizumab versus sorafenib in patients with previously untreated advanced hepatocellular carcinoma. METHODS:We did a randomised, open-label, phase 3 study in 57 hospitals across mainland China, Taiwan, and Singapore. Using a central interactive web response system, eligible patients aged 18-75 years with unresectable or metastatic hepatocellular carcinoma were randomly assigned (1:1) through a stratified block randomisation method to receive 240 mg toripalimab (intravenously, once every 3 weeks) plus 15 mg/kg bevacizumab (intravenously, once every 3 weeks) or 400 mg sorafenib (oral, twice daily). Randomisation was stratified by macrovascular invasion or extrahepatic spread (presence vs absence), ECOG performance status score (0 vs 1), and history of locoregional therapy (yes vs no). The co-primary endpoints were progression-free survival (assessed by the Independent Review Committee per Response Evaluation Criteria in Solid Tumors, version 1.1) and overall survival. Efficacy analysis was performed in the intention-to-treat population (ie, all patients randomly assigned to a treatment group). Safety was assessed in all patients who received at least one dose of study treatment. The study is registered with ClinicalTrials.gov, NCT04723004, and is completed. FINDINGS:Between Nov 23, 2020, and Jan 21, 2022, 545 patients were screened for study inclusion, of whom 219 did not meet the screening criteria. 326 patients were randomly assigned to receive an intervention: 162 patients were assigned to the toripalimab plus bevacizumab group and 164 were assigned to the sorafenib group, with median age 58·0 years (IQR 50·0-66·0) and 56·0 years (49·0-61·0) years, respectively. All 326 patients were included in the intention-to-treat population and the safety population. 282 (87%) patients were male and 44 (14%) were female. At the primary analysis of progression-free survival (data cutoff Aug 10, 2022), median follow-up was 9·4 months (IQR 7·0-12·0). Toripalimab plus bevacizumab significantly prolonged progression-free survival compared with sorafenib (median 5·8 months [95% CI 4·6-7·2] vs 4·0 months [2·8-4·2]; hazard ratio [HR] 0·69 [95% CI 0·53-0·91; p=0·0086). At the final analysis of overall survival (May 31, 2024), median follow-up was 16·4 months (IQR 7·1-29·5). Toripalimab plus bevacizumab significantly improved overall survival compared with sorafenib (median 20·0 months [95% CI 15·3-23·4] vs 14·5 months [11·4-18·8]; HR 0·76 [95% CI 0·58-0·99; p=0·039). Grade 3 or higher adverse events occurred in 102 (63%) patients in the toripalimab plus bevacizumab group compared with 100 (61%) in the sorafenib group, and led to discontinuation of treatment in 21 (13·0%) participants in the toripalimab plus bevacizumab group and 20 (12%) participants in the sorafenib group. The incidence of treatment-related fatal adverse events (two [1%] vs one [1%]) was similar between the toripalimab plus bevacizumab and sorafenib groups. The most common (incidence ≥5% in the toripalimab plus bevacizumab group) grade 3-4 adverse events were hypertension (26 [16%] in the toripalimab plus bevacizumab group vs 19 [12%] in the sorafenib group), thrombocytopenia (16 [10%] vs four [2%]), upper gastrointestinal haemorrhage (ten [6%] vs one [1%]), anaemia (nine [6%] vs seven [4%]), and abnormal hepatic function (nine [6%] vs five [3%]). The most common (incidence ≥2% in the toripalimab plus bevacizumab group) serious adverse events were upper gastrointestinal haemorrhage (12 [7%] vs one [1%]), abnormal hepatic function (eight [5%] vs five [3%]), ascites (six [4%] vs three [2%]), and gastrointestinal haemorrhage (four [2%] vs three [2%]). INTERPRETATION:Among patients with previously untreated advanced hepatocellular carcinoma, toripalimab plus bevacizumab resulted in significantly longer progression-free survival and overall survival than did sorafenib, with an acceptable safety profile. Based on these results, the regimen has been approved for use in China by the National Medical Products Administration. FUNDING:Shanghai Junshi Biosciences. TRANSLATION:For the Chinese translation of the abstract see Supplementary Materials section.

BACKGROUND:Transarterial chemoembolisation (TACE) is standard care for unresectable, non-metastatic hepatocellular carcinoma. We aimed to evaluate the addition of lenvatinib and pembrolizumab to TACE versus dual placebo plus TACE in patients with unresectable, non-metastatic hepatocellular carcinoma. METHODS:In this multicentre, randomised, double-blind, phase 3 study (LEAP-012), patients were recruited from 137 global sites in 33 countries or regions. Eligible patients were age 18 years or older with unresectable, non-metastatic hepatocellular carcinoma not amenable to curative treatment, but with tumours amenable to TACE, Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and Child-Pugh class A disease. Eligible participants were randomly assigned (1:1), stratified by study site, α-fetoprotein level, ECOG performance status, albumin-bilirubin grade, and tumour burden, by a central interactive response system, to receive TACE and either oral lenvatinib (bodyweight ≥60 kg: 12 mg; bodyweight <60 kg: 8 mg; once daily) plus intravenous pembrolizumab (400 mg once every 6 weeks for up to 2 years) or matched dual placebo (oral and intravenous). Primary endpoints were progression-free survival (threshold one-sided p=0·025), per Response Evaluation Criteria in Solid Tumours version 1.1 (modified for the current study to allow for up to five target tumours in the liver and requiring new intrahepatic tumours to meet LI-RADS 5 criteria to be considered progressive disease) by blinded independent central review, and overall survival (threshold one-sided p=0·0012) in the intention-to-treat (ITT) population (ie, all participants randomly assigned to treatment). Safety was assessed in the as-treated population (ie, all participants who were randomly assigned and received at least one dose of any study treatment). Here, we report results from the first interim analysis (final analysis for progression-free survival). This study is registered with ClinicalTrials.gov, NCT04246177, and is active but not recruiting. FINDINGS:Between May 22, 2020, and Jan 11, 2023, 847 patients were screened, of whom 480 (57%) were enrolled and randomly assigned to receive TACE plus lenvatinib plus pembrolizumab (n=237) or TACE plus dual placebo (n=243; ITT population). Median age was 66 years (IQR 58-73), 82 (17%) of 480 participants were female, 398 (83%) were male, 98 (20%) were White, 347 (72%) were Asian, four (1%) were Black or African American, and five (1%) were American Indian or Alaska Native. Median follow-up as of data cutoff (Jan 30, 2024) was 25·6 months (IQR 19·5-32·4). Median progression-free survival was 14·6 months (95% CI 12·6-16·7; 132 events [20 deaths and 112 progressions]) with lenvatinib plus pembrolizumab and 10·0 months (8·1-12·2; 154 events [eight deaths and 146 progressions]) with placebo (hazard ratio [HR] 0·66 [95% CI 0·51-0·84]; one-sided p=0·0002). 69 (29%) of 237 in the lenvatinib plus pembrolizumab group and 82 (34%) of 243 from the placebo group died, with a 24-month overall survival rate of 75% (95% CI 68-80) in the lenvatinib plus pembrolizumab group and 69% (62-74) in the placebo group (HR 0·80 [95% CI 0·57-1·11]; one-sided p=0·087). Grade 3 or worse treatment-related adverse events occurred in 169 (71%) of 237 participants in the lenvatinib plus pembrolizumab group and in 76 (32%) of 241 in the placebo group, the most common of which were hypertension (57 [24%] vs 18 [7%]) and platelet count decreased (27 [11%] vs 15 [6%]). Deaths due to treatment-related adverse events occurred in four (2%) participants in the lenvatinib plus pembrolizumab group (n=1 each due to hepatic failure, gastrointestinal haemorrhage, myositis, and immune-mediated hepatitis) and one (<1%) in the placebo group (due to brain stem haemorrhage). INTERPRETATION:TACE plus lenvatinib plus pembrolizumab showed significant, clinically meaningful improvement in progression-free survival in patients with unresectable, non-metastatic hepatocellular carcinoma compared with TACE plus placebo. The numerical improvement in overall survival is encouraging, but longer follow-up is necessary. FUNDING:Merck Sharp & Dohme, a subsidiary of Merck & Co, Inc, Rahway, NJ, USA, and Eisai, Nutley, NJ, USA.