Abstract Background Patients with hepatocellular carcinoma (HCC) have an unmet need for new therapies that improve survival. This phase II trial investigated the efficacy and safety of ociperlimab and tislelizumab plus BAT1706 (a bevacizumab biosimilar) in patients with first-line HCC. Methods In this phase II, multicenter, randomized, multi-arm, open-label trial, patients with advanced HCC received ociperlimab and tislelizumab plus BAT1706 (Arm A) or tislelizumab plus BAT1706 (Arm B). The primary objective was to evaluate efficacy using objective response rate (ORR) assessed by the investigator per RESIST v1.1 for Arms A and B. Results 94 patients were randomized to Arm A (N = 62) and Arm B (N = 32). Confirmed ORR (95% confidence interval) was 37.1% (25.2–50.3) for Arm A and 40.6% (23.7–59.4) for Arm B. In Arms A and B, respectively, 90.3% and 80.6% of patients experienced treatment-related treatment-emergent adverse events (TEAEs), 59.7% and 32.3% experienced Grade ≥ 3 treatment-related TEAEs and 22.6% and 9.7% experienced treatment-related TEAEs leading to treatment discontinuation. Immune-mediated adverse events were reported in 50.0% of patients in Arm A and 45.2% of patients in Arm B. Infusion-related reactions occurred in a single patient in Arm A. Conclusion In patients with advanced HCC, tislelizumab plus BAT1706 demonstrated promising ORR, while adding ociperlimab was not associated with improved efficacy. The safety profile of ociperlimab and tislelizumab plus BAT1706 was tolerable and manageable, with no new safety signals identified. Trial registration ClinicalTrials.gov: NCT04948697 (September 20, 2021).

2508 Background: Advanced hepatocellular carcinoma (HCC) remains a high unmet-medical-need malignancy with limited therapeutic options. Ori-C101 is a novel, armored, autologous GPC3-directed CAR-T cell therapy. Following promising results from early-phase trials (ChiCTR190028121; NCT05652920, BEACON study), we shall herein update outcomes from the BEACON study with focusing on long-term safety, durability of response, and survival after more than 2 years of follow-up. Methods: This is an open-label, multi-center, phase Ib dose-escalation and expansion study enrolled patients (pts) with GPC3 + advanced HCC who had progressed on ≥2 prior lines of systemic therapy (including ICIs and TKIs). A single dose of Ori-C101 was administered via hepatic arterial infusion to enhance regional cell delivery. Integrated analyses assessed safety, tolerability, PK, and efficacy (per RECIST v1.1)，aiming to determine the RP2D. Results: As of Dec 24, 2025, 19 pts received Ori-C101 infusion across 4 dose levels (DLs). All pts had BCLC stage B/C disease and 31.6% (6/19) had extrahepatic metastases. Pts were previously treated with a median of 3 lines (range 2–8) therapies. Safety: Safety remained manageable; no late-onset nor cumulative toxicities were observed through the extended follow-up period. The most common ≥G3 TEAEs (≥10.0%) were transient hematologic toxicities and hepatic laboratory abnormalities. CRS occurred in 100.0% (19/19) of pts; while ≥G3 CRS observed in 42.1% (8/19). No ICANS occurred. One pt at DL4 experienced a DLT of G4 CRS complicated by secondary DIC. Efficacy: In 18 efficacy-evaluable pts, Ori-C101 demonstrated a robust dose-dependent response. Confirmed ORR was 50.0% (9/18); DCR was 77.8% (14/18). At RP2D (DL3), the confirmed ORR and DCR were 66.7% (6/9) and 88.9% (8/9), respectively. Critically, responses were not only rapid but also remarkably durable. 88.9% (8/9) of responders achieved objective response within 1.1 months; at M3, 83.3% (5/6) of responders at the RP2D remained PR. Notably, 1 pt at DL4 achieved CR with a duration exceeding 20 months. Preliminary overall survival data indicate a substantial long-term survival benefit with a median OS of 14.4 months (range 2.6–22.0). In addition, Dose-Exposure-Responses analysis showed dose-dependent CAR-T cells expansion, pharmacodynamic effects and improved tumor response. Conclusions: Ori-C101 demonstrates a manageable safety profile and compelling, durable anti-tumor activity in GPC3 + advanced HCC. The combination of high ORR and prolonged survival benefit distinguishes Ori-C101 as a potential paradigm-shifting therapy for patients who have failed standard-of-care treatments. A phase II/III study is currently underway to further confirm the efficacy and asses the safety of Ori-C101. Clinical trial information: NCT05652920 .

Pancreatic ductal adenocarcinoma (PDAC) is a highly mortal cancer whose only potentially curative treatment is surgical resection. Intraoperative assessment of its surgical margins is vital for patient survival. Frozen section biopsy is routinely performed for this purpose. However, its heavy reliance on pathologists' expertise often leads to diagnostic discrepancies. The inherent invasiveness of PDAC also leads to sampling errors. This study developed an intelligent molecular cytology approach that improves diagnostic objectivity and broadens sampling coverage. Our method, Multi-Instance Cytology with LEArned Raman-embedding (MICLEAR), leverages compositional information from label-free Raman imaging. First, 4085 cells were brushed off from the pancreases of 41 patients and imaged using stimulated Raman scattering microscopy. Then, a contrastive learning-based cell embedding model was developed to compress each cell's morphological and compositional information into a compact cell vector. Finally, a multi-instance learning-based diagnostic model using cell vectors was employed to predict the likelihood that a patient's margin is positive. MICLEAR achieved 80% sensitivity, 100% specificity, and an area under the receiver operating characteristic curve of 0.86 in 27 patients for validation, comprising 10 with positive margins and 17 with negative margins, in approximately 8 minutes per patient. It may hold promise for more efficient and accurate intraoperative assessment of PDAC surgical margins.

Background/Aim: Protein tyrosine phosphatase kappa (PTPRK), a recognized tumor suppressor, has been implicated in cancer progression of certain solid tumors. This study investigated the role of PTPRK in the progression of pancreatic cancer. Materials and Methods: PTPRK transcripts were determined in a pancreatic cancer cohort using real-time PCR. The functional impact of PTPRK was evaluated in pancreatic cancer cells with PTPRK knockdown, followed by an assessment of its implications in disease progression. Results: Elevated PTPRK expression was observed in pancreatic cancer and was positively correlated with tumor T stage. Knockdown of PTPRK led to reduced cellular proliferation and decreased expression of cyclin-dependent kinase 6 (CDK6). Additionally, an increase in VEGFC expression was noted in PTPRK knockdown cells. Conclusion: Up-regulation of PTPRK in pancreatic cancer is associated with disease progression and poor prognosis. PTPRK facilitates cancer cell proliferation through CDK6, highlighting the potential for therapeutic strategies targeting PTPRK and CDK6 in pancreatic cancer treatment.

Current imaging techniques inadequately delineate surgical margins of well-differentiated liposarcoma (WDLS), increasing risks of incomplete resection or overtreatment. MDM2, a p53-inhibiting oncoprotein amplified in WDLS, represents a dual diagnostic and therapeutic target. Therefore, we developed two radionuclide probes utilizing the MDM2-targeting stapled peptide with high binding affinity to evaluate their suitability for tumor-specific diagnostic purposes, which named [68Ga]Ga-DOTA-7041 and [68Ga]Ga-DOTA-P53-8 to conduct a head-to-head comparative study. Among these, [68Ga]Ga-DOTA-7041 showed superior MDM2-binding affinity (6.7 nM). In vivo imagery in ccRCC tumor-bearing PDX models showed significant and rapid uptake for both radiotracers, with specific radioactive accumulation beginning at 10 min and persisting over time. In contrast, the SW872 liposarcoma mouse model demonstrated slower and lower uptake, visible at 4 h in PET/CT scans. The further Clinical PET/CT in a WDLS patient using the superior probe [68Ga]Ga-DOTA-7041 showed heterogeneous tumor uptake, correlating with postoperative MDM2 immunohistochemistry. In this study, [68Ga]Ga-DOTA-7041 demonstrated diagnostic potential in both animal models and patients with liposarcoma as first-in-human PET tracer targeting MDM2. The disparate tumor uptake observed, compared to the high uptake in renal cancer models, may provide valuable insights into the challenges of targeting MDM2/MDMX with therapeutic agents in liposarcoma treatments.

Background:In most patients with advanced perihilar cholangiocarcinoma (pCCA), multi-branch biliary involvement results in inadequate jaundice relief despite biliary drainage. Together with recurrent cholangitis, persistent fever, impaired liver function, and poor performance status, these factors often preclude standard systemic treatment. We conducted a prospective, multicentre, non-randomised controlled study to evaluate whether a treatment pathway incorporating hepatic arterial infusion chemotherapy (HAIC) after biliary drainage was associated with clinical outcomes in this treatment-limited population. Methods:This prospective, multicentre, non-randomised controlled study enrolled systemic-treatment-naïve participants with pathologically confirmed advanced pCCA at five tertiary centres in China between November 1, 2021, and July 5, 2024. Key eligibility criteria included absence of distant metastases or N2 disease, Eastern Cooperative Oncology Group (ECOG) performance status 0-1, and Child-Pugh score ≤7; key exclusion criteria included prior systemic treatment, uncontrolled infection, and severe organ dysfunction. Participants received biliary drainage followed by HAIC (BD + HAIC) or biliary drainage plus best supportive care (BD + BSC). HAIC consisted of oxaliplatin 40 mg/m2 (0-2 h) and 5-fluorouracil 800 mg/m2 (2-24 h) on days 1-3, with intravenous leucovorin 200 mg/m2, repeated every 4 weeks. The primary outcome was overall survival (OS) in the intention-to-treat population, assessed throughout follow-up. Secondary endpoints included jaundice remission rate, duration of jaundice remission (DJR), and safety; safety was assessed in the per-protocol population. The trial is registered at ClinicalTrials.gov (NCT05024513) on Aug 23, 2021. Findings:A total of 127 participants were enrolled (63 BD + HAIC; 64 BD + BSC). Median OS was 17.63 months in the BD + HAIC group and 6.10 months in the BD + BSC group (P < 0.0001). Jaundice remission occurred in 93.7% versus 46.9% of participants (P < 0.0001). Median DJR was 12.67 months versus 4.50 months (P < 0.0001). Adverse events were generally manageable; haematological and gastrointestinal events were more frequent with BD + HAIC, whereas elevated total bilirubin was more frequent with BD + BSC. Grade 3-4 events were uncommon, and no treatment-related deaths were observed. Interpretation:Biliary drainage followed by HAIC was associated with longer survival and more durable jaundice remission than biliary drainage plus best supportive care in a treatment-limited population with advanced pCCA. Given the non-randomised design, lack of a contemporary systemic-therapy control arm, and risk of selection bias and unmeasured confounding, these findings should be considered hypothesis-generating only and not evidence of a causal treatment effect. Randomised studies comparing BD + HAIC with appropriate contemporary systemic therapy are required to determine its clinical benefit in this setting. Funding:This study was supported by the Beijing Natural Science Foundation, and the National Natural Science Foundation of China.

This consensus by the CSCO Pancreatic Cancer Expert Committee establishes evidence-based guidelines for molecular testing in pancreatic ductal adenocarcinoma. It details recommendations for biomarkers (e.g., KRAS, BRCA, MSI), liquid biopsy, and precision imaging to direct targeted therapies and immunotherapy, aiming to standardize diagnosis and optimize individualized patient care. Pancreatic ductal adenocarcinoma (PDAC) is the most common pathological type of primary pancreatic malignancy, accounting for ~95% of cases and generally referred to as pancreatic cancer [1]. Its prognosis is extremely poor and its incidence continues to rise [2]. According to the most recent global cancer statistics, the incidence of pancreatic cancer ranks 12th among all cancers, and its mortality ranks 6th, making it one of the deadliest malignancies worldwide [3]. Approximately 57% of patients have metastatic disease at diagnosis and require systemic therapy, for which chemotherapy remains the standard first-line option [1]. However, the overall response rate to currently available systemic regimens is low, and the 5-year survival rate for patients with metastatic disease remains below 5% [3]. Although most pancreatic cancers harbor canonical driver mutations, they exhibit marked heterogeneity at the molecular level. Whole-genome sequencing (WGS) and integrative genomic analyses have identified molecular subtypes of PDAC with potential clinical relevance [4-9]. With the increasing implementation of precision oncology, the Chinese Society of Clinical Oncology (CSCO) Guidelines for the Diagnosis and Treatment of Pancreatic Cancer give a level 1 recommendation to perform genetic and other molecular testing on tissue or cytologic specimens as part of the pathological diagnostic work-up, in order to guide individualized treatment, including targeted therapy and immunotherapy [10]. To further promote the use of genetic and molecular testing in the precision treatment of pancreatic cancer, the CSCO Pancreatic Cancer Expert Committee convened a multidisciplinary panel to develop the present Chinese Expert Consensus on Precision Testing and Molecular Diagnosis of Pancreatic Cancer (2025), aiming to provide clinicians with an authoritative reference for precision diagnostics and treatment decision-making.

In the global phase 3 KEYNOTE-966 study (NCT04003636), pembrolizumab plus gemcitabine and cisplatin (pembrolizumab group) showed a statistically significant, clinically meaningful improvement in overall survival (OS) versus placebo plus gemcitabine and cisplatin (placebo group) without any new safety signals in participants with advanced biliary tract cancer (BTC). This analysis focused on the subgroup of participants from KEYNOTE-966 enrolled in China. Adults with previously untreated advanced BTC were randomly assigned (1:1) to receive pembrolizumab 200 mg or placebo intravenously every 3 weeks plus gemcitabine 1000 mg/m2 and cisplatin 25 mg/m2 intravenously on days 1 and 8 of every 3-week cycle. Primary endpoint was OS. Secondary endpoints were progression-free survival (PFS), objective response rate (ORR), and duration of response (DOR), all per RECIST v1.1 by blinded independent central review, and safety. One hundred fifty-eight participants were enrolled in China (75, pembrolizumab group; 83, placebo group). Median time from randomization to data cutoff (December 15, 2022) was 20.5 (range, 15.0–28.8) months. Median OS was 14.1 (95

BACKGROUND:Patient-derived xenografts (PDX) models have been regarded as an important tool for preclinical research. The aim of this study was to establish a Chinese PDX library from gastrointestinal cancers, especially esophageal squamous cell carcinoma (ESCC), esophagogastric junction adenocarcinoma (EGJAC), and gastric adenocarcinoma (GAC). METHODS:1001 surgical tissues or endoscopic biopsy tissues of gastrointestinal cancers were subcutaneously implanted into NOD/SCID mice between January 2013 and August 2015. Engraftment rates, latency period of xenograft formation, patients' clinicopathological characteristics and survival associated with xenografts for ESCC, EGJAC and GAC were assessed. RESULTS:208 PDX models were established (20.8%, 208/1001), among which 82 were from ESCC (21.2%, 82/386), 31 from EGJAC (16.9%, 31/183), and 29 from GAC (10.9%, 29/266). The average latency period of xenograft formation of ESCC, EGJAC, and GAC was 76.2, 90.5, and 85.2 days, respectively, for the first passage, and decreased to 52.5, 54.8, and 52.6 days, respectively for the second passage. For ESCC, gender, specimen type and differentiation were associated with engraftment; and for GAC, the factors associated with engraftment were age, specimen type, differentiation, and Lauren classification. The median follow-up of patients with ESCC, EGJAC and GAC was 46, 64 and 64 months, respectively. For GAC, the survival time of patients from whom the tumor tissues achieved successful engraftment was significantly shorter than that without xenograft formation. CONCLUSIONS:We established a Chinese PDX library from gastrointestinal cancers, especially ESCC, a characteristic tumor type in China, providing a platform for drug development and individualized therapy.

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.

Background: Retroperitoneal liposarcoma (RLPS) is a rare malignancy with no effective treatment beyond surgical intervention. Identifying novel therapeutic targets and prognostic markers is critical to improving outcomes. Fibroblast growth factor receptor substrate 2 (FRS2), located near MDM2 on chromosome 12q13-15, has a biological role and prognostic value in liposarcoma, which remain to be fully explored. Methods: Bioinformatics tools were used to analyze the differential expression of FRS2 across various malignancies using public databases, such as GTEx, TCGA, and cBioPortal. In sarcomas (SARC), clinicopathological features, prognostic outcomes, co-expressed genes, levels of tumor-infiltrating immune cells, immunostimulators, major histocompatibility complex (MHC) molecules, and immunochemokines were extracted from multiple public databases. Tumor specimens from 82 RLPS patients at our sarcoma center were collected, and FRS2 expression was assessed through immunohistochemistry. Results: FRS2 was found to be upregulated and amplified in most cancers. GEPIA 2 analysis showed significant variation in FRS2 mRNA expression across cancer types, especially in sarcomas (SARC). Lower FRS2 expression in SARC was correlated with improved overall survival (OS) and disease-free survival (DFS). FRS2 may affect the tumor immune microenvironment, inhibiting immune cell infiltration and promoting immune evasion. In our RLPS cohort, FRS2 overexpression was observed in 58.53% (48/82) of cases and was correlated with age (P = 0.009). High FRS2 expression was associated with poorer OS and DFS (P = 0.049 and P < 0.001, respectively), and multivariate analysis confirmed FRS2 as an independent prognostic factor. Conclusion: FRS2 may serve as a potential prognostic biomarker and therapeutic oncogene target. Additionally, FRS2 could play a role in immune cell infiltration in SARC and represents a promising immunotherapeutic target for cancer treatment.

Background:Chemotherapy combined with immune checkpoint inhibitor have prolonged survival of patients with advanced biliary tract cancers (BTCs), and the previous studies showed the synergistic anti-tumor effect of chemotherapy, anti-angiogenesis therapy, and immunotherapy. Hepatic arterial infusion chemotherapy (HAIC) achieved a higher tumor response and survival benefit in previous phase II studies for advanced BTCs. Thus, we conducted this phase II trial to evaluate the efficacy and safety of HAIC combined with bevacizumab and toripalimab for advanced BTCs. Methods:Treatment-naïve participants with advanced BTCs were recruited for this phase II trial. Combination therapy, comprising HAIC with bevacizumab (300 mg, day 1), oxaliplatin (40 mg/m2, 2 h, days 1-3), and 5-fluorouracil (800 mg/m2, 22 h, days 1-3) plus intravenous toripalimab (240 mg, day 1 before HAIC), was repeated every 4 weeks for a maximum of six consecutive cycles. Intravenous toripalimab (240 mg) and bevacizumab (300 mg) were administered every 4 weeks as maintenance treatment. The primary endpoint was objective response rate (ORR) according to Immune-Modified Response Evaluation Criteria in Solid Tumors criteria, and the secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. Olink proximity extension assay with a Target 96 Immuno-Oncology panel was exploratory investigated. Results:Between July 2020 and January 2022, 32 participants were enrolled. The ORR was 84.38%, and the disease control rate was 96.88%. Median PFS and OS were 13.20 months [95% confidence interval (CI): 8.93-17.47] and 19.0 months (95% CI: 12.22-25.78), respectively. Grade 3 or higher adverse events (AEs) were observed in 10 participants (31.25%), and the most frequent grade 3 or higher AEs were elevated ALT/AST (4/32, 12.50%), elevated total bilirubin (3/32, 9.38%), and neutropenia (3/32, 9.38%). In exploratory analysis, Child-Pugh B [hazard ratio (HR): 22.65, 95% CI: 3.66-140.08, P=0.001] and high level of macrophage metalloproteinase-12 (HR: 5.99, 95% CI: 1.60-22.37, P=0.008) were indicated as the risk factors related to worse PFS. Conclusions:HAIC combined with bevacizumab and toripalimab may serve as an improved first-line treatment for advanced BTCs, which require a randomized control trial for verification. Trial Registration:This trial is registered at ClinicalTrail.gov (NCT04217954).

Pancreatic ductal adenocarcinoma (PDAC) is highly malignant, with a five-year survival rate of only 12 %. Exact diagnosis and intervention are critical for improving patient prognosis. Core fucosylation (CF) of proteins plays a vital role in the progression of various cancers, including PDAC. In this study, we analysed differences in site-specific CF glycopeptides and corresponding glycoproteins between paired tumour tissues (Ts) and normal adjacent tissues (NATs) from patients with PDAC via a specific enrichment and cleavage strategy. We identified 1447 CF glycoproteins with 2654 CF glycopeptides and revealed that CF glycoproteins are involved in various biological processes. A panel of candidate biomarkers was determined via nested cross-validation and receiver operating characteristic (ROC) analysis with bootstrap resampling and further validated in an independent cohort. This work revealed that several CF glycopeptides from Decay-accelerating factor (CD55), Versican (VCAN), Carboxypeptidase Z (CPZ)and Mucin 16 (MUC16) have the potential to distinguish PDAC NATs from Ts, with an area under the curve (AUC) of 1 in the validation cohort. These data demonstrate that CF glycoproteins may associated with PDAC development and progression and have potential as candidate biomarkers for clinical decision-making.

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.

ABSTRACT Background Hepatocellular carcinoma (HCC) is the second leading cause of cancer‐related death in China. The rapid progress in systemic therapies has led to the approval of many therapeutic methods that have quickly changed clinical guidelines and practices. Because of the high heterogeneity of HCC, there are still some gaps between the guidelines and real‐world clinical practice. The present study surveyed experts in China to investigate the current treatment concepts and clinical practice regarding HCC. Methods A questionnaire survey on the treatment concepts and clinical practice of HCC was administered to 310 experts with senior professional titles in 2020 and 312 experts in 2021. The results were analyzed and compared. Results For treating patients with resectable HCC, 28% of hepatobiliary surgeons indicated neoadjuvant therapy, and 7% chose systemic therapy ± locoregional therapy as 1 L therapy in 2021 compared with 20% and 1% in 2020. More experts chose adjuvant treatment within 1 month in 2021 compared with 2020, and 6 months and 12 months were the leading choices for the duration of adjuvant treatment. In 2021, 79% of surgeons and 19% of interventionalists were willing to conduct downstaging/conversion therapy for patients with potentially resectable HCC, and 78% chose tyrosine kinase inhibitors (TKI) + immunotherapy (IO) + locoregional therapy for cases in which R0 resection could not be achieved. For completely unresectable HCC, more experts preferred TKI + IO‐based therapy as 1 L therapy in 2021 compared with 2020 (78% vs. 55%). The proportion of experts who indicated TKI + IO‐based therapy as 2 L therapy increased from 32% in 2020 to 40% in 2021. Conclusion The survey results indicated that in 2021, compared with 2020, more experts opted to administer IO + TKI for the treatment of liver cancer, and more experts and patients were willing to participate in clinical research.

LBA4005 Background: To date, no phase 3 clinical trial has demonstrated an overall survival (OS) benefit in patients with locally advanced pancreatic adenocarcinoma (LA-PAC). TTFields are electric fields that disrupt cancer cell division. TTFields therapy is approved for glioblastoma, pleural mesothelioma, and metastatic non-small cell lung cancer. A phase 2 trial in PAC demonstrated the safety and preliminary efficacy of TTFields therapy with gemcitabine with or without nab-paclitaxel. We report final data from PANOVA-3 (NCT03377491), the largest global, phase 3, randomized, open-label trial in LA-PAC to date. Methods: Adult patients with newly diagnosed unresectable LA-PAC were randomized 1:1 to receive TTFields therapy (150 kHz) with gemcitabine/nab-paclitaxel (GnP) or GnP. The primary endpoint was OS. Secondary endpoints included progression-free survival (PFS), local PFS, objective response rate (ORR), and pain-free survival. Distant PFS (metastases beyond the pancreas and regional lymph nodes) was assessed post hoc. Survival data were compared using the Kaplan-Meier method and a log-rank test. Results: 571 patients were randomized. Baseline characteristics were generally well balanced between the study arms. OS was significantly longer with TTFields/GnP than with GnP (median 16.2 [95% CI: 15.0, 18.0] vs 14.2 months [95% CI: 12.8, 15.4]; HR 0.82 [95% CI: 0.68, 0.99], p=0.039). One-year survival rate was also significantly improved with TTFields/GnP vs GnP (68.1% [95% CI: 62.0-73.5] vs 60.2% [95% CI: 54.2-65.7], p=0.029). There was no significant difference in PFS or local PFS between arms. Pain-free survival was significantly longer with TTFields/GnP vs GnP (median 15.2 [95% CI: 10.3, 22.8] vs 9.1 months [95% CI: 7.4, 12.7]; HR 0.74 [95% CI: 0.56, 0.97], p=0.027). Post-hoc analysis showed significant distant PFS benefit (median 13.9 [95% CI: 12.2, 16.8] vs 11.5 months [95% CI: 10.4, 12.9], HR 0.74 [95% CI: 0.57, 0.96], p=0.022) with TTFields/GnP vs GnP. ORR was similar between arms (36.1% [95% CI: 30.0, 42.4] vs 30.0% [95% CI: 24.3, 36.2], p=0.094). 97.8% and 98.9% of patients who received TTFields/GnP and GnP, respectively, had adverse events (AEs) and 88.6% and 84.3% had grade ≥3 AEs. The most frequent grade ≥3 AEs were neutropenia (47.8% and 47.6%) and anemia (21.9% and 22.3). 81% of patients receiving TTFields/GnP had device-related AEs, mostly grade 1/2 skin AEs, e.g., dermatitis (27.7%), rash (17.5%), and pruritus (15.0%); grade 3 and grade 4 device-related AEs occurred in 9.1% and 0.4% of patients, respectively. Conclusions: PANOVA-3 is the largest phase 3 trial exclusively performed in patients with LA-PAC and the first to show a statistically significant OS benefit. With no additive systemic toxicity and a statistically significant pain-free survival benefit, TTFields therapy is a potential new standard treatment for LA-PAC. Clinical trial information: NCT03377491 .