ABSTRACT Objective The present study aimed to investigate the expression and biological behaviour of the six‐transmembrane epithelial antigen of the prostate 1 (STEAP1) in oral squamous cell carcinoma (OSCC), and to further analyse its underlying mechanisms. Material and Methods Western blot and immunohistochemistry were used to detect protein expression. After overexpression of STEAP1 in OSCC cells by plasmid transfection, cell proliferation, migration, and invasion abilities were assessed using CCK‐8, scratch, and Transwell assays, respectively, and ROS levels were detected using the corresponding kits. Finally, the expression changes of EMT and Wnt/β‐catenin pathway‐related proteins were analysed by Western blot. Result Western blot (WB) and immunohistochemical (IHC) analyses showed that STEAP1 was significantly underexpressed (p < 0.0001) in oral squamous cell carcinoma (OSCC) tissues and cell lines (SAS, Tca‐8113, SCC15) compared to normal controls. Functional experiments showed that overexpression of STEAP1 effectively inhibited the proliferation (p < 0.001), migration (p < 0.0001), and invasion (p < 0.001) abilities of OSCC cells (SAS, Tca‐8113) and reduced intracellular ROS levels (p < 0.0001). Molecularly, STEAP1 overexpression up‐regulated E‐cadherin (p < 0.01) and down‐regulated N‐cadherin (p < 0.05), inhibiting the EMT process; meanwhile, it decreased the protein levels of β‐catenin (p < 0.05), Axin2 (p < 0.05), and c‐Myc (p < 0.05), as well as the protein levels of the p‐ GSK3β/T‐GSK3β ratio (p < 0.05), but there was no significant change in total GSK3β protein, suggesting inhibition of the Wnt/β‐catenin pathway. Conclusion STEAP1 is downregulated in OSCC and suppresses malignant phenotypes of OSCC cells in vitro, with effects associated with EMT‐related changes and attenuation of Wnt/β‐catenin‐associated signalling.

4148 Background: Immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1 have demonstrated efficacy in aHCC. Despite improved outcomes with PD-1/PD-L1 inhibitor-based regimens, prognosis remains poor and there is a continued unmet need for alternative therapies with long-term survival benefits. This study aimed to evaluate the effectiveness and safety of IBI310 (anti-CTLA-4 antibody) combined with sintilimab (anti-PD-1 antibody) in the first-line treatment of aHCC. Methods: Pts were randomized in a 2:1 ratio to IBI310+sintilimab group or sorafenib group. The experimental group received IBI310 3mg/kg intravenously (IV) and sintilimab 200 mg IV on day 1 of every 3 weeks. The control group received sorafenib 400 mg orally twice daily (BID) continuously until disease progression, intolerable toxicity, death or other protocol-specified discontinuation criteria. During the study, the IBI310 dose was adjusted to 1 mg/kg every 6 weeks. Primary end points included overall survival (OS) and objective response rate (ORR)assessed by the independent radiology review committee (IRRC) per RECIST v1.1. Secondary endpoint included progression-free survival (PFS), disease control rate (DCR), safety, etc. Results: As of August 2022, 344 patients were enrolled and allocated to Group 1 (G1, IBI310 3mg/kg + sintilimab, n=84), Group 2 (G2, modified-dose IBI310 1mg/kg + sintilimab, n=145) and Group 3 (G3, sorafenib, n=115). Overall, PFS and ORR improved with IBI310+sintilimab vs Sorafenib. The median OS in the primary endpoint was 44.0 months(G1), 36.1 months(G2) and 22.9 months(G3), respectively. Confirmed ORRs were significantly higher in the combination therapy groups (G1: 41.7%; G2: 22.1%) versus the control group (2.6%). Median PFS of three groups were 13.5 months(G1), 6.1 months(G2) and 2.8 months(G3), respectively. Grade ≥3 treatment-related adverse events (TRAEs) occurred in 60.7% (G1), 34.7% (G2), and 35.1% (G3) of patients. Conclusions: Compared with sorafenib group, combination treatment of IBI310 + sintilimab as first-line treatment demonstrated survival benefits and a manageable safety profile in aHCC. Clinical trial information: NCT04720716 . Survival data. IBI310(3mg/kg)+Sintilimab(N=84) IBI310(1mg/kg)+Sintilimab(N=145) Sorafenib(N=115) mOS, m 44.0 36.1 22.9 Confirmed ORR, n(%) 35(41.7) 32(22.1) 3(2.6) mPFS, m 13.5 6.1 2.8

333 Background: Docetaxel has demonstrated promising activity in gastric cancer, both as monotherapy and in combination with other agents. Albumin-bound docetaxel (HB1801) is a new kind of taxane and has many advantages compared with docetaxel. Previous phase I study has demonstrated that HB1801 showed preliminary efficacy in patients with gastric cancer. Methods: In this phase II study, eligible patients were aged 18-75 years with histologically confirmed gastric or gastroesophageal junction (G/GEJ) adenocarcinoma, who progressed on at least first line of combined chemotherapy of platinum and fluorouracil. Patients were randomized (1:1) to receive HB1801 (100 mg/m 2 ) or docetaxel (Taxotere, 75 mg/m 2 ) administered every 3 weeks by intravenous infusion. Stratified factors included previous treatment with immunotherapy (yes or no) and ECOG PS (0 or 1). Primary endpoint was progression free survival (PFS). Results: As of June 25, 2024, 128 patients were randomized to the HB1801 group ( n =65) or the docetaxel group ( n =63). The two groups were comparable on baseline characteristics. Overall, the median age was 59.0 (range 27-75) years, 106 (82.8%) patients had ECOG PS of 1. 76 (59.4%) patients had received previous treatment with immunotherapy. 76 (59.4%) patients had ≥ 2 metastatic sites. Median PFS was 4.0 months (95%CI 2.8-4.2) with HB1801 versus 2.7 months (95%CI 1.8-3.0) with docetaxel, HR = 0.81(95%CI 0.53, 1.21). Objective response rate and disease control rate were 21.5% (1CR and 13 PRs, 95%CI 12.3-33.5) and 56.9% (20 SDs, 95%CI 44.0-69.2) in the HB1801 group, compared with 14.3% (1 CR and 8 PRs, 95%CI 6.8-25.4) and 42.9% (17 SDs, 95%CI 30.5-56.0) in the docetaxel group. Median overall survival was 11.3 months with HB1801 versus 7.8 months with docetaxel (HR = 0.59 [95%CI 0.35, 1.01], p=0.025). Treatment-related adverse events (TRAEs) occurred in 93.8% of patients receiving HB1801, and 93.7% of patients receiving docetaxel. Alopecia (46.2% vs. 39.7%), fatigue (43.1% vs 23.8%), anemia (40.0% vs 39.7%), hypoalbuminemia (29.2% vs 12.7%), decreased appetite (21.5% vs 12.7%), peripheral edema (16.9% vs 12.7%) and nausea (15.4% vs 19.0%) were the most common TRAEs in the HB1801 group and the docetaxel group. 20 patients (30.8%) in the HB1801 group and 19 patients (30.2%) in the docetaxel group experienced ≥grade 3 TRAEs, with the most common being anemia and fatigue. 3 patients in the docetaxel group experienced treatment emergent adverse events (TEAEs) leading to death, which one was considered to be treatment-related. No patients in the HB1801 group had TEAEs leading to death. No new safety signal was observed in HB1801 group. Conclusions: Compared with Taxotere, HB1801 results in 41% reduction in risk of death with a manageable safety profile in patients with previously treated advanced G/GEJ cancer. Clinical trial information: NCT05705635 .

With a low autoimmune risk and dedicated induction of type Ⅰ interferon production in immunotherapy, "STING therapy" holds broad prospects in the treatment of aggressive and metastatic cancers such as ovarian cancer (OC). Inducing pyroptosis constitutes a promising approach for activating the anti-tumor immune response. Nevertheless, compared to combination therapies, "single-molecule multitarget" drugs possess the merits of a lower interaction risk, more predictable pharmacokinetics and a lower cost of clinical trials. Therefore, the present study was conducted to construct a structurally stable nanoparticles (TPAQu-Pt@HA NPs) with controlled drug release behavior and active targeting ability based on a self-designed and synthesized photo-platinum compound (TPAQu-Pt) with aggregation-induced emission (AIE) effect without excipients. The NPs attained "single-molecule multitarget" effect via three mechanisms: 1) causing nuclear and mitochondrial DNA damage and cytoplasmic leakage of double-stranded DNA (dsDNA), effectively activating cGAS-STING pathway; 2) inducing pyroptosis benefited from the AIE effect conferring a stronger ROS-generating capacity; 3) photothermal therapy worsened mitochondrial dysfunction and intensified pyroptosis, amplifying activation of cGAS-STING pathway and the subsequent anti-tumor immune response. In conclusion, this study provided a scientific basis for the molecular modification of cisplatin, which was expected to improve the treatment status of OC.

Background & Aims:We performed a meta-analysis of data from the KEYNOTE-240 and KEYNOTE-394 studies to obtain a more precise estimate of the pembrolizumab treatment effect in participants with previously treated advanced hepatocellular carcinoma (HCC). Methods:Participants with confirmed HCC and disease progression after treatment with or intolerance of sorafenib or oxaliplatin-based chemotherapy (KEYNOTE-394 only), Barcelona Clinic Liver Cancer stage C or B disease not amenable to or refractory to locoregional therapy, and one or more measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 were randomly assigned 2:1 to receive pembrolizumab or placebo for ≤35 cycles. Data from the KEYNOTE-240 and KEYNOTE-394 intention-to-treat populations were pooled, and the treatment effect was evaluated for pembrolizumab and placebo separately. Results:In total, 578 and 288 participants who received pembrolizumab and placebo, respectively, were included in this analysis. Compared with placebo, pembrolizumab improved overall survival (hazard ratio 0.79, 95% CI 0.67-0.93), progression-free survival (per RECIST v1.1 by blinded independent central review [BICR]; hazard ratio 0.76, 95% CI 0.64-0.89), and objective response rate (per RECIST v1.1 by BICR; 15.4% vs. 2.8%, for an estimated treatment difference of 12.5%; 95% CI 8.8-16.2). Subgroup analyses showed that the treatment effect of pembrolizumab was generally similar across baseline participant characteristics, including viral status, Barcelona Clinic Liver Cancer stage, and geographic region. Conclusions:Meta-analysis of KEYNOTE-240 and KEYNOTE-394 showed that pembrolizumab provides clinically meaningful improvement in overall survival, progression-free survival, and objective response rate. This analysis expands on findings from each study individually and provides further evidence of the global benefit of pembrolizumab as second-line therapy for advanced HCC after prior sorafenib- or oxaliplatin-based therapy. Impact and implications:To obtain a more precise estimate of the pembrolizumab treatment effect in participants with previously treated advanced hepatocellular carcinoma, we performed a meta-analysis of efficacy using pooled participant data from the phase III KEYNOTE-240 and KEYNOTE-394 studies. Subgroup analyses showed that the treatment effect of pembrolizumab was generally similar across baseline characteristics, including viral status, Barcelona Clinic Liver Cancer stage, and geographic region. This meta-analysis provides further evidence of the global benefit of pembrolizumab as second-line therapy for advanced hepatocellular carcinoma. Clinical Trials Registration:Registered at ClinicalTrials.gov NCT02702401 (KEYNOTE-240) and NCT03062358 (KEYNOTE-394).

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 & Aims: We performed a meta-analysis of data from the KEYNOTE-240 and KEYNOTE-394 studies to obtain a more precise estimate of the pembrolizumab treatment effect in participants with previously treated advanced hepatocellular carcinoma (HCC). Methods: Participants with confirmed HCC and disease progression after treatment with or intolerance of sorafenib or oxaliplatin-based chemotherapy (KEYNOTE-394 only), Barcelona Clinic Liver Cancer stage C or B disease not amenable to or refractory to locoregional therapy, and one or more measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 were randomly assigned 2:1 to receive pembrolizumab or placebo for <= 35 cycles. Data from the KEYNOTE-240 and KEYNOTE-394 intention-to-treat populations were pooled, and the treatment effect was evaluated for pembrolizumab and placebo separately. Results: In total, 578 and 288 participants who received pembrolizumab and placebo, respectively, were included in this analysis. Compared with placebo, pembrolizumab improved overall survival (hazard ratio 0.79, 95% CI 0.67-0.93), progression-free survival (per RECIST v1.1 by blinded independent central review [BICR]; hazard ratio 0.76, 95% CI 0.64-0.89), and objective response rate (per RECIST v1.1 by BICR; 15.4% vs. 2.8%, for an estimated treatment difference of 12.5%; 95% CI 8.8-16.2). Subgroup analyses showed that the treatment effect of pembrolizumab was generally similar across baseline participant characteristics, including viral status, Barcelona Clinic Liver Cancer stage, and geographic region. Conclusions: Meta-analysis of KEYNOTE-240 and KEYNOTE-394 showed that pembrolizumab provides clinically meaningful improvement in overall survival, progression-free survival, and objective response rate. This analysis expands on findings from each study individually and provides further evidence of the global benefit of pembrolizumab as second-line therapy for advanced HCC after prior sorafenib- or oxaliplatin-based therapy.

Background Aspirin is a simple, globally available medication that has been shown to reduce the incidence of colorectal cancer. We aimed to evaluate the safety and efficacy of aspirin in the secondary prevention of colorectal cancer. Methods This phase 3, randomised, double-blind, placebo-controlled trial was conducted at 66 centres across 11 countries and territories (ten in Asia-Pacific; one in the Middle East). The trial included patients aged 18 years and older with Dukes' C or high-risk Dukes' B colon cancer or Dukes' B or C rectal cancer who had undergone resection and had completed standard adjuvant therapy (at least 3 months of chemotherapy). Patients with contraindications to aspirin, familial syndromes of colorectal cancer, recent other cancers, and clinically significant history of cardiovascular disease or stroke were excluded. Patients were randomly assigned (1:1) to aspirin 200 mg daily or placebo for 3 years, and were followed up for 5 years. Randomisation was stratified by study centre, tumour site and stage, and inclusion of oxaliplatin in adjuvant chemotherapy. The patients, study team, and sponsor were masked to treatment assignment. The primary endpoint was disease-free survival. The primary analysis used a stratified Cox model in those commencing study treatment (modified intention-to-treat population), analysing all events to March 31, 2023. Safety was analysed in the same population. This trial is registered at ClinicalTrials.gov (NCT00565708). The primary analysis has been completed, but translational studies of putative aspirin sensitivity biomarkers are ongoing. Findings Between Feb 25, 2009, and June 30, 2021, 1587 patients underwent randomisation, of whom 1550 were included in the modified intention-to-treat analysis: 791 (51%) in the aspirin group and 759 (49%) in the placebo group. Of these patients, the median age was 57 years (IQR 48-65); 897 (58%) were male and 653 (42%) female; 271 (17%) had Dukes' B colon cancer, 770 (50%) Dukes' C colon cancer, and 509 (33%) rectal cancer. Median follow-up at data cutoff was 592 months (IQR 367-600). 5-year disease-free survival was 770% (95% CI 736-800) in the aspirin group and 748% (713-779) in the placebo group (hazard ratio of 091 [95% CI 073-113]; p=038). Any-grade adverse events were reported in 390 (49%) of 791 patients in the aspirin group versus 386 (51%) of 759 in the placebo group. Serious adverse events were reported in 95 (12%) patients in the aspirin group versus 107 (14%) in the placebo group. There were no treatment-related deaths in either group. Among adverse events of special interest, there were no cases of acute myocardial infarction in the aspirin group versus two in the placebo group; no ischaemic cerebrovascular events in the aspirin group versus two in the placebo group; and three major gastrointestinal bleeds in the aspirin group versus one in the placebo group. Interpretation In patients with colorectal cancer, aspirin 200 mg daily for 3 years after completion of standard adjuvant therapy was well tolerated but did not significantly improve disease-free survival. Copyright (c) 2025 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.

Background & Aims We performed a meta-analysis of data from the KEYNOTE-240 and KEYNOTE-394 studies to obtain a more precise estimate of the pembrolizumab treatment effect in participants with previously treated advanced hepatocellular carcinoma (HCC). Methods Participants with confirmed HCC and disease progression after treatment with or intolerance of sorafenib or oxaliplatin-based chemotherapy (KEYNOTE-394 only), Barcelona Clinic Liver Cancer (BCLC) stage C or B disease not amenable to or refractory to locoregional therapy, and ≥1 measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 were randomly assigned 2:1 to receive pembrolizumab or placebo for ≤35 cycles. Data from the KEYNOTE-240 and KEYNOTE-394 intention-to-treat populations were pooled, and the treatment effect was evaluated for pembrolizumab and placebo separately. Results In total, 578 and 288 participants who received pembrolizumab and placebo, respectively, were included in this analysis. Compared with placebo, pembrolizumab improved overall survival (OS; hazard ratio [HR], 0.79; 95% confidence interval [CI], 0.67–0.93), progression-free survival (PFS; per RECIST 1.1 by blinded independent central review [BICR]; HR, 0.76; 95% CI, 0.64–0.89), and objective response rate (ORR; per RECIST 1.1 by BICR; 15.4% vs 2.8%, for an estimated treatment difference of 12.5%; 95% CI, 8.8–16.2). Subgroup analyses showed that the treatment effect of pembrolizumab was generally similar across baseline participant characteristics, including viral status, BCLC stage, and geographic region. Conclusions Meta-analysis of KEYNOTE-240 and KEYNOTE-394 showed that pembrolizumab provides clinically meaningful improvement in OS, PFS, and ORR. This analysis expands on findings from each study individually and provides further evidence of the global benefit of pembrolizumab as second-line therapy for advanced HCC after prior sorafenib- or oxaliplatin-based therapy. Impact and Implications To obtain a more precise estimate of the pembrolizumab treatment effect in participants with previously treated advanced HCC, we performed a meta-analysis of efficacy using pooled participant data from the phase 3 KEYNOTE-240 and KEYNOTE-394 studies. Subgroup analyses showed that the treatment effect of pembrolizumab was generally similar across baseline characteristics, including viral status, BCLC stage, and geographic region. This meta-analysis provides further evidence of the global benefit of pembrolizumab as second-line therapy for advanced HCC. Clinical trial numbers ClinicalTrials.gov NCT02702401 (KEYNOTE-240) and NCT03062358 (KEYNOTE-394).

Background: The development of novel targeted therapies for gastric cancer (GC) has been significantly hindered by our limited understanding of the molecular mechanisms underlying its progression. As SIN3 transcription regulator family member A (SIN3A) and synaptopodin-2 (SYNPO2) may influence GC progression, this study aimed to investigate the impact of SIN3A-mediated regulation of SYNPO2 on GC progression. Methods: The expression levels of SYNPO2 and its binding interaction with SIN3A in GC were analyzed using bioinformatics tools. The binding sites between SIN3A and SYNPO2 were validated through a dual-luciferase reporter assay. Furthermore, the biological function of SIN3A in regulating SYNPO2 was investigated in GC cells using gene silencing and overexpression approaches. Cell proliferation, colony formation, apoptosis, migration, and invasion were assessed using cell counting, colony formation assay, flow cytometry, wound healing, Transwell, and molecular analyses. Results: GC cells presented significantly reduced SYNPO2 expression (p < 0.01). SYNPO2 overexpression inhibited GC cell viability, colony formation, migration, and invasion, while promoting apoptosis (p < 0.01). SYNPO2 was found to bind to SIN3A and mediate its transcriptional repression. SIN3A overexpression enhanced GC cell viability, colony formation, migration, and invasion, inhibited apoptosis, upregulated B-cell lymphoma 2 (Bcl-2), and downregulated Bcl-2-associated X protein (Bax) and cleaved caspase-3 expression, whereas SIN3A knockdown produced the opposite effects (p < 0.05). The effects of SIN3A knockdown were reversed by SYNPO2 silencing in GC cells (p < 0.05). Conclusion: SIN3A knockdown-mediated upregulation of SYNPO2 suppresses GC malignancy processes, offering insights into a novel strategy for developing targeted therapies for gastric cancer.

BACKGROUND:Mismatch repair deficient (dMMR) and microsatellite instability-high (MSI-H) cancers are associated with an increased number of somatic mutations, which can render tumors more susceptible to immune checkpoint blockade. However, a comprehensive evaluation of the efficacy profile of immune checkpoint inhibitors in this patient population across multiple cancer types is lacking. This study aims to address this knowledge gap by synthesizing data from phase I-III clinical trials. METHODS:A systematic search was conducted in PubMed, Embase, the Cochrane Central Register of Controlled Trials, and Google Scholar from inception until June 2024. Eligible studies included randomized controlled trials (RCTs), nonrandomized comparative studies, and single-arm trials investigating immune checkpoint inhibitors in patients with dMMR/MSI-H advanced cancers. The primary outcome was objective response rate (ORR), and the secondary outcomes included disease control rate (DCR), 1-year, 2-year, and 3-year overall survival (OS) and progression-free survival (PFS) rates. Subgroup analyses were conducted for the primary outcome stratified by major study characteristics. RESULTS:Of the 10 802 identified studies, 19 trials in 25 studies totaling 2052 participants met the inclusion criteria and were included in the meta-analysis. The pooled ORR was 41.7% (95% CI, 35.7-47.7%). The pooled DCR was 68.9% (95% CI, 62.2-75.7%). The pooled 12-month, 24-month, and 36-month OS rates were 29.1% (95% CI, 19.9-38.3%), 35.8% (95% CI, 23.6-48.0%), and 35.8% (95% CI, 23.6-48.0%), respectively. The pooled 12-month, 24-month, and 36-month PFS rates were 46.4% (95% CI, 39.1-53.8%), 67.0% (95% CI, 55.2-78.8%), and 63.1% (95% CI, 37.3-88.9%), respectively. CONCLUSIONS:The study establishes the therapeutic potential of immune checkpoint inhibitors in dMMR/MSI-H advanced cancers, highlighting the importance of MSI status in this context. Further, head-to-head comparisons are needed to conclusively determine MSI's predictive power relative to proficient mismatch repair/microsatellite stable (pMMR/MSS) tumors.

BACKGROUND:Triple-negative breast cancer (TNBC) has a poor prognosis with current treatment options. Novel therapeutic strategies are urgently needed to enhance treatment outcomes for TNBC. OBJECTIVE:This study evaluated the efficacy of a three-agent regimen compared to existing treatment regimens in a TNBC mouse model, and elucidated its potential mechanisms of action. METHODS:The TNBC xenograft tumor mouse model was established using a 4T1 cell line in female BALB/c mice. Mice were treated with the three-agent regimen and other comparative treatments. Tumor volume was monitored to assess the anti-tumor effects. Biochemical and pathological evaluations were conducted to examine the impact of the regimen on anti-tumor immunity, anti- tumor angiogenesis, and tumor cell apoptosis. RESULTS:The three-agent regimen consisting of SIN+BEV+PAB demonstrated significant anti-tumor efficacy compared to controls, PAB alone, SIN+PAB, and BEV+PAB groups from day 9 of drug administration. The superior anti-tumor effect of SIN+BEV+PAB was primarily attributed to enhanced anti-tumor immunity, evidenced by increased percentages of CD4+ and CD8+ T cells, elevated IFN-γ levels, and decreased percentages of Tregs, reduced levels of TGF-β, IL-6, and IL-10. Additionally, the regimen showed potent anti-angiogenic effects by reducing VEGF expression and micro vessel density (MVD). Furthermore, it promoted tumor cell apoptosis through upregulation of BAX and cleaved caspase3, while downregulating Bcl2. CONCLUSION:These findings suggest that the novel three-agent combination of SIN+BEV+PAB may prove beneficial in improving treatment outcomes for patients with TNBC. The development of this regimen, which may be eligible for patent protection, could facilitate its introduction as a new therapeutic option for advanced TNBC in clinical practice.

IntroductionGastric cancer (GC) is a highly heterogeneous malignancy with poor prognosis, underscoring the urgent need for reliable biomarkers to guide precise stratification and therapy. Transfer RNA-derived small RNAs (tsRNAs) have emerged as potential key regulators in cancer, yet their systematic role in defining GC subtypes remains unexplored.MethodsWe profiled tsRNA expression in GC using transcriptomic data from TCGA and GEO databases. Unsupervised consensus clustering identified tsRNA-based subtypes. A prognostic model was constructed using machine learning algorithms and validated across multiple cohorts. The functional role of a key tsRNA, tsRNA-Asp-3-0024, was investigated through Pandora-seq, qRT-PCR, and in vitro and organoid-based assays.ResultsThree distinct tsRNA-mediated subtypes (Stromal_H, Stromal_L, Stromal_M) were identified, exhibiting significant differences in stromal activity, tumor microenvironment, and clinical outcomes. The Stromal_H subtype demonstrated the poorest prognosis, characterized by an immunosuppressive microenvironment and dysregulated DNA repair pathways. A random survival forest (RSF)-based prognostic signature (GCtsRNAscore) effectively stratified patients into high- and low-risk groups, with high-risk patients showing increased sensitivity to targeted therapies (axitinib, bexarotene, dasatinib) and low-risk patients benefiting more from immunotherapy. Furthermore, tsRNA-Asp-3-0024 was significantly upregulated in GC tissues and cell lines, where it promoted proliferation and inhibited apoptosis.DiscussionOur study establishes tsRNAs as powerful biomarkers for molecular subtyping and prognostic prediction in GC. The tsRNA-defined subtypes and GCtsRNAscore model provide a novel framework for personalized treatment strategies. The functional characterization of tsRNA-Asp-3-0024 highlights its potential as both a therapeutic target and a prognostic indicator, paving the way for tsRNA-based precision medicine in GC.

170 Background: This is a randomized, double-blind, multicenter phase 2/3 study comparing the efficacy and safety of serplulimab (a novel anti-PD-1 antibody) plus bevacizumab and XELOX chemotherapy vs. placebo plus bevacizumab and XELOX as first-line treatment for metastatic colorectal cancer (mCRC). Our previous presentation at the 2024 ASCO Meeting showed the progression-free survival results. Here we present the updated efficacy and safety findings together with subgroup analysis results after a median follow-up of 31.0 months. Methods: A total of 114 patients with mCRC and no prior systemic therapy were randomized 1:1 (serplulimab arm, n = 57; placebo arm, n = 57) to receive intravenous (IV) serplulimab (300 mg) plus bevacizumab (7.5 mg/kg) and XELOX (IV oxaliplatin [130 mg/m 2 ] and oral capecitabine [1000 mg/m 2 ]) (group A) or placebo plus bevacizumab and XELOX (group B) once every 3 weeks. Stratification factors were PD-L1 expression level, ECOG PS score, and primary tumor site. The primary endpoint was independent radiological review committee (IRRC)-assessed PFS per RECIST 1.1. Secondary endpoints included other efficacy endpoints, safety, pharmacokinetics, biomarker explorations, and quality-of-life assessments. Results: In the phase 2 part, by the data cutoff of June 30, 2024, sustained improvements in PFS (16.6 vs. 10.7 months, stratified HR 0.66, 95% CI 0.37–1.19) and DOR (17.7 vs. 11.3 months, stratified HR 0.45, 95% CI 0.20–0.98) were observed for patients in group A compared to group B in the modified intent-to-treat population (n = 112; two patients in group A did not receive any intended study treatment). 32/55 (58.2%) patients in group A and 35/57 (61.4%) in group B have died. Median overall survival (OS) was 25.6 months in group A and 21.2 months in group B (stratified HR 0.86, 95% CI 0.53–1.42). A trend of PFS and OS benefits was similarly observed for the patients with a microsatellite stable (MSS) status (PFS: 16.8 vs. 10.1 months, stratified HR 0.65, 95% CI 0.33–1.29; OS: 23.5 vs. 20.2 months, stratified HR 0.79, 95% CI 0.45–1.38). 39 (70.9%) patients in group A and 34 (59.6%) in group B had grade ≥3 treatment-related adverse events. Serplulimab/placebo-related serious TRAEs occurred in 13 (23.6%) patients in group A and 14 (24.6%) patients in group B. Conclusions: With a follow-up duration of 31.0 months, improved survival benefits demonstrated with the addition of serplulimab were maintained in the first-line treatment of mCRC patients including those with MSS status alongside a manageable safety profile. The phase 3 part of this study is currently ongoing to further evaluate serplulimab plus bevacizumab and XELOX as a first-line treatment option in mCRC. Clinical trial information: NCT04547166 .

Acquired and intrinsic resistance to sunitinib is a major obstacle to improving the therapeutic efficacy of treatment for clear cell renal cell carcinoma (ccRCC). This study aimed to identify novel therapeutic targets and the potential molecular mechanisms to overcome sunitinib resistance in ccRCC. Utilizing genome-wide CRISPR/Cas9 screening and resistant transcriptomics, we identified that prostaglandin reductase 2 (PTGR2) is a novel therapeutic target to overcome sunitinib resistance in ccRCC. The silencing of PTGR2 enhanced the cytotoxic effects of sunitinib in ccRCC cells, as measured by cell viability assays, and suppressed tumor growth in xenograft models. Mechanistically, PTGR2 physically interacts with lysine specific demethylase 6A (KDM6A) via endogenous/exogenous co-immunoprecipitation. PTGR2 knockdown reduced KDM6A protein expression, while KDM6A overexpression partially reversed the sensitization effect of PTGR2 silencing, suggesting KDM6A is a major downstream effector. Our findings establish the PTGR2-KDM6A axis as a potential target for overcoming sunitinib resistance in ccRCC. Pharmacological inhibition of PTGR2 or targeted modulation of KDM6A activity represents a promising combination strategy to overcome sunitinib resistance and improve patient outcomes.

145 Background: Fruquintinib and TAS-102 are two standard therapies for patients (pts) with previous-treated mCRC worldwide. The study aimed to evaluate the efficacy and safety of fruquintinib plus TAS-102 as third-line treatment for mCRC. We previously reported that fruquintinib plus TAS-102 was well tolerated with encouraging clinical activity in pretreated mCRC. Here, we reported the updated results at the data cutoff of Sep 3, 2024. Methods: In this open-label, single-arm, multi-center, phase 2 trial (NCT05004831), pts with mCRC who had failed at least two prior standard treatment regimens were enrolled. Eligible pts received fruquintinib (4mg, qd, d1-21) and TAS-102 (35mg/m 2 , bid, d1-5, 8-12) orally every 4 weeks until disease progression or unacceptable toxicity. Primary endpoint was PFS (per RECIST v1.1). Secondary endpoints were OS, ORR, DCR and safety (per NCI-CTCAE v5.0). Results: From Mar 2022 to Aug 2023, 50 eligible pts were enrolled. Median age was 60 years (range 39-76) and 58.0% were male. 82% pts were of left-sided colon and rectal cancer, 42.0% pts were RAS mutant, 58.0% had liver metastasis and 18.0% had peritoneal metastasis. Prior treatments and proportion were standard chemotherapy 100%, anti-VEGF 88.0% and anti-EGFR 26.0%. As of Sep 3, 2024, ORR was 10.9% (95%Cl: 3.6-23.6) and DCR was 73.9% (95%Cl: 58.9-85.7). The median PFS was 6.33 months (m) (95% CI: 4.20-8.62). The 6-m, 9-m and 12-m PFS rates were 53.0% (95% CI: 40.2-70.0), 28.3% (95% CI: 17.4-45.9) and 23.1% (95% CI: 13.2-40.5), respectively. At a median follow-up of 17.6m, median OS was 18.4m (95% CI: 12.0-NA). The 6-m, 9-m and 12-m OS rates were 87.0% (95% CI: 77.8-97.3), 66.9% (95% CI: 54.0-82.9) and 64.3% (95% CI: 51.1-80.8), respectively. Median PFS was comparable in liver metastasis (LM) and non-LM pts (6.33m [95%CI: 4.13-8.62] vs. 6.46m [95%CI: 3.74-NA], P =0.54). Similar results were observed in peritoneal metastasis (PM) and non-PM pts (6.07m [95%CI: 3.74-NA] vs. 6.33m [95%CI: 4.20-8.27], P =0.95). None of RAS gene mutation, prior treatment lines ≥ 3, age ≥ 65 years, metastatic sites ≥ 2, peritoneal metastasis and right-sidedness were identified as factors significantly associated with PFS or OS (by univariable Cox proportional-hazards model). The most common treatment-related adverse events (TRAEs) of any grade and grade ≥ 3 were mainly hematological toxicities. TRAEs (any grade, grade ≥ 3) in ≥ 50% of pts including neutrophil count decreased (80.0%, 54.0%), white blood cell count decreased (70.0%, 26.0%), anemia (58.0%, 20.0%) and proteinuria (50.0%, 4%). No treatment-related deaths were observed. Conclusions: The updated analysis demonstrated encouraging survival benefits of fruquintinib plus TAS-102 as third-line treatment in patients with mCRC with acceptable toxicities. This regimen could be an alternative therapeutic approach for these patients. Clinical trial information: NCT05004831 .

3536 Background: Fruquintinib and TAS-102 are two standard therapies for patients (pts) with previous-treated metastatic colorectal adenocarcinoma (mCRC) worldwide. SUNLIGHT trial demonstrated improvement in progression-free survival (PFS) and overall survival (OS) of TAS-102 plus bevacizumab compared with TAS-102 alone. In this study, we aim to evaluate the efficacy and safety of fruquintinib plus TAS-102 as third-line treatment for mCRC pts. Methods: In this open-label, single-arm, multicenter, phase 2 trial (NCT05004831), pts with mCRC who had failed at least two prior standard treatment regimens were enrolled. Eligible pts received fruquintinib (4mg, qd, d1-21) and TAS-102 (35mg/m 2 , bid, d1-5, 8-12) orally every 4 weeks until disease progression or unacceptable toxicity. Primary endpoint was PFS (per RECIST v1.1). Secondary endpoints were OS, objective response rate (ORR), disease control rate (DCR) and safety (per NCI-CTCAE v5.0). Results: From Mar 2022 to Aug 2023, 50 eligible pts were enrolled. The median age was 60 years (range 39-76), male accounted for 58.0%. 82% pts were of left-sided colon and rectal cancer. 42.0% pts had RAS mutant and 58.0% had liver metastasis. Prior treatments and proportion were 5-FU 100%, anti-VEGF 88.0% and anti-EGFR 26.0%. As of Jan 10, 2024, 46 pts had at least one tumor assessment and 7 pts were still on treatment. 10.9% (5/46) pts achieved partial response (PR) and 63.0% (29/46) pts had stable disease (SD) as best response. The median PFS was 6.46 (95%Cl: 4.20-8.62) months (mo). The 6-mo, 9-mo and 12-mo PFS rates were 50.9%, 25.4% and 21.8%, respectively. The median PFS was 5.51 (95%Cl: 2.43-NA) mo, 5.84 (95%CI: 3.97-NA) mo and 6.59 (95%Cl: 4.79-NA) in RAS mutant pts (n=21), RAS wild-type pts (n=16), and RAS status unknown pts (n=13), respectively. The median PFS was comparable in liver metastasis (LM) and non-LM pts (6.59 [95%CI: 4.07-8.62] mo vs. 6.46 [95%CI: 3.74-NA] mo, p=0.77). Median OS was not mature with 15.5 mo of median follow-up time. Treatment-related adverse events (TRAEs) were generally manageable and tolerable. The most common hematological TRAEs (any grade, grade 3-4) included neutrophil count decreased (80.0%, 52.0%), white blood cell count decreased (70.0%, 24.0%), and anemia (54.0%, 20.0%). Non-hematological TRAEs were mainly grade 1-2 including loss of appetite (22.0%), malaise (14.0%), abdominal pain (12.0%), diarrhea (12.0%) and vomiting (10.0%). A grade 3 hypertension was reported. No treatment-related deaths were observed. Conclusions: These preliminary results indicate that fruquintinib plus TAS-102 as third-line treatment in patients with mCRC was well tolerated with encouraging clinical activity. The enrollment is closed and more OS data will be presented in the future. Clinical trial information: NCT05004831 .

BACKGROUND:Studies on various thrombopoietic agents for cancer treatment-induced thrombocytopenia (CTIT) in China are lacking. This study aimed to provide detailed clinical profiles to understand the outcomes and safety of different CTIT treatment regimens. METHODS:In this retrospective, cross-sectional study, 1664 questionnaires were collected from 33 hospitals between March 1 and July 1, 2021. Patients aged >18 years were enrolled who were diagnosed with CTIT and treated with recombinant interleukin 11 (rhIL-11), recombinant thrombopoietin (rhTPO), or a thrombopoietin receptor agonist (TPO-RA). The outcomes, compliance, and safety of different treatments were analyzed. RESULTS:Among the 1437 analyzable cases, most patients were treated with either rhTPO alone (49.3%) or rhIL-11 alone (27.0%). The most common combination regimen used was rhTPO and rhIL-11 (10.9%). Platelet transfusions were received by 117 cases (8.1%). In multivariate analysis, rhTPO was associated with a significantly lower proportion of platelet recovery, platelet transfusion, and hospitalization due to chemotherapy-induced thrombocytopenia (CIT) than rhIL-11 alone. No significant difference was observed in the time taken to achieve a platelet count of >100 × 109/L and chemotherapy dose reduction due to CIT among the different thrombopoietic agents. The outcomes of thrombocytopenia in 170 patients who received targeted therapy and/or immunotherapy are also summarized. The results show that the proportion of platelet recovery was similar among the different thrombopoietic agents. No new safety signals related to thrombopoietic agents were observed in this study. A higher proportion of physicians preferred to continue treatment with TPO-RA alone than with rhTPO and rhIL-11. CONCLUSIONS:This survey provides an overview of CTIT and the application of various thrombopoietic agents throughout China. Comparison of monotherapy with rhIL-11, rhTPO, and TPO-RA requires further randomized clinical trials. The appropriate application for thrombopoietic agents should depend on the pretreatment of platelets, treatment variables, and risk of bleeding. PLAIN LANGUAGE SUMMARY:To provide an overview of the outcome of cancer treatment-induced thrombocytopenia in China, our cross-sectional study analyzed 1437 cases treated with different thrombopoietic agents. Most of the patients were treated with recombinant interleukin 11 (rhIL-11) and recombinant thrombopoietin (rhTPO). rhTPO was associated with a significantly lower proportion of platelet recovery and platelet transfusion compared with rhIL-11.

BACKGROUND:Whether or not the addition of immunotherapy to current standard-of-care treatments can improve efficacy in proficient mismatch repair (pMMR)/microsatellite-stable (MSS) metastatic colorectal cancer (mCRC), the predominant type of mCRC, is unclear. METHODS:This randomized, double-blind, phase 2 part of a phase 2/3 trial was conducted at 23 hospitals across China (ClinicalTrials.gov: NCT04547166). Patients with unresectable metastatic/recurrent colorectal adenocarcinoma and no prior systemic therapy were randomly assigned 1:1 to receive every-3-weeks intravenous serplulimab (300 mg) plus HLX04 (7.5 mg/kg) and XELOX (serplulimab group) or placebo (300 mg) plus bevacizumab (7.5 mg/kg) and XELOX (placebo group). The primary endpoint was independent radiology review committee (IRRC)-assessed progression-free survival (PFS). Secondary endpoints included other efficacy endpoints and safety. FINDINGS:Between July 16, 2021, and January 20, 2022, 114 patients were enrolled and randomly assigned to the serplulimab (n = 57) or placebo (n = 57) group. All patients had stage IV CRC, and 95.7% of the patients with available microsatellite instability (MSI) status were MSS. With a median follow-up duration of 17.7 months, median PFS was prolonged in the serplulimab group (17.2 vs. 10.7 months; hazard ratio [HR], 0.60; 95% confidence interval [CI], 0.31-1.14). Although the median overall survival (OS) was not reached for either group, a trend of an OS benefit was observed for the serplulimab group (HR, 0.77; 95% CI, 0.41-1.45). 36 (65.5%) and 32 (56.1%) patients in the serplulimab and placebo groups had grade ≥3 treatment-related adverse events, respectively. CONCLUSIONS:Serplulimab plus HLX04 and XELOX exhibits promising efficacy and is safe and tolerable in patients with treatment-naive mCRC. FUNDING:This work was funded by Shanghai Henlius Biotech, Inc.