BACKGROUND:Oxaliplatin-induced peripheral neuropathy (OIPN) affects up to 80% of patients receiving oxaliplatin-based chemotherapy, and effective preventive strategies remain limited. Huangqi Guizhi Wuwu Decoction (HQGZWWD), a traditional Chinese herbal formula included in China's National Classic Famous Formulas, is widely used for OIPN in clinical practice, but high-quality clinical evidence remains lacking. PURPOSE:This study evaluated the efficacy and safety of HQGZWWD for OIPN prevention and explored its neuroprotective mechanisms. METHODS:We conducted a multicenter, randomized, double-blind, placebo-controlled trial at 12 tertiary hospitals in China. Adults with colorectal cancer scheduled to receive XELOX chemotherapy were randomly assigned (1:1) to oral HQGZWWD granules or placebo (47.5 g per sachet, twice daily) throughout chemotherapy. Participants, outcome assessors, and statisticians were blinded. The primary outcome was the incidence of grade ≥2 chronic OIPN in the modified intention-to-treat population, analyzed using logistic regression with multiple imputation for missing data. RESULTS:A total of 360 participants were enrolled, and 354 were included in the modified intention-to-treat analysis. Grade ≥2 chronic OIPN occurred in 21.3% of patients receiving HQGZWWD group and 38.6% in the placebo group (OR, 0.43; 95% CI, 0.27-0.69; P<0.001). Adverse events were comparable between groups (OR, 1.27; 95% CI, 0.68-2.39; P=0.524). In animal models, HQGZWWD increased pain thresholds, preserved dorsal root ganglia, reduced IL-1β, MCP-1, and MDA levels, and enhanced SOD activity. Consistently, clinical serum enzyme-linked immunosorbent assay (ELISA) analyses further validated these mechanisms, demonstrating that HQGZWWD significantly attenuated chemotherapy-induced elevations of pro-inflammatory cytokines (IL-1β, MCP-1) and oxidative stress marker (MDA), while preserving antioxidant enzyme (SOD) activity in CRC patients receiving XELOX chemotherapy. CONCLUSION:HQGZWWD significantly reduced the incidence of OIPN without increasing toxicity. Preclinical findings suggest that these effects may involve reduced oxidative stress and improved mitophagy. These findings support HQGZWWD as a promising preventive strategy for OIPN. TRIAL REGISTRATION:The trial is registered with ClinicalTrials.gov (NCT04913376).

Background:Gastric cancer is the fifth most common malignancy worldwide and a major cause of cancer-related mortality, with over 750,000 deaths annually. Neoadjuvant chemotherapy remains the standard treatment for human epidermal growth factor receptor 2 (HER2)-positive gastric cancer, but recent evidence suggests that incorporating immunotherapy could offer synergistic effects. However, clinical benefits are limited in patients with low HER2 expression or programmed death-ligand 1 (PD-L1) levels due to primary or acquired resistance. To address this, we are conducting a prospective study to evaluate the efficacy and safety of a four-drug neoadjuvant regimen combining RC48 [a HER2-targeted antibody-drug conjugate (ADC)], adebrelimab (a PD-L1 inhibitor), apatinib (a VEGFR2 inhibitor), and S-1 (an oral fluoropyrimidine) in patients with locally advanced HER2-positive gastric cancer. Methods:The DAWN trial is a prospective, open-label, phase II clinical trial designed to enroll 32 treatment-naïve patients with resectable, locally advanced HER2-positive gastric adenocarcinoma. Eligible patients will receive 3-4 cycles of neoadjuvant therapy, with each cycle lasting 21 days. The treatment regimen includes: RC48: 2.5 mg/kg, intravenous (iv), day 1, every 3 weeks (q3w). Adebrelimab: 1,200 mg, iv, day 1, q3w. S-1: For patients with a body surface area (BSA) ≤1.5 m2, 50 mg orally, twice daily (bid), days 1-14, q3w; for BSA >1.5 m2, 60 mg orally, bid, days 1-14, q3w. Apatinib: 250 mg orally, once daily (qd), q3w. The primary endpoint is the pathological complete response (pCR) rate. Secondary endpoints include major pathological response (MPR) rate, R0 resection rate, disease-free survival (DFS), overall survival (OS), and safety. All patients must provide written informed consent before enrollment. The study protocol was approved by the independent ethics committee at each participating institution. Discussion:Previous preclinical and clinical studies have demonstrated the synergistic effects among chemotherapy, immunotherapy, anti-angiogenic therapy, and anti-HER2 antibody-drug conjugates (ADCs). We hypothesize that the combination of these four therapeutic strategies could significantly enhance treatment efficacy in HER2-positive gastric cancer, particularly in combined positive score (CPS) PD-L1-negative patients. Trial Registration:This study was registered at ClinicalTrials.gov (Identifier: NCT06385873).

Background:The relationship between collagen features (CFs) in the tumor microenvironment (TME) of esophageal cancer (EC) and the therapeutic response to neoadjuvant chemoimmunotherapy (nCIT) remains unclear. This study aimed to develop and validate a novel model based on CFs to predict the therapeutic response of patients with locally advanced EC to nCIT. Methods:In this retrospective study, 79 newly diagnosed patients with resectable locally advanced EC were enrolled and randomly divided into a training cohort (54 patients) and a validation cohort (25 patients) at a 7:3 ratio. Multiphoton imaging (MPI) was used to quantitatively analyze collagen in pretreatment biopsy tissues. Least absolute shrinkage and selection operator (LASSO) regression was applied to select significant CFs and calculate the collagen score. Univariate and multivariate analyses were performed to verify the predictive value of the collagen score for a good pathological response (GR). Results:LASSO regression identified collagen-related parameters in EC biopsy specimens: F1 (collagen percentage area), F2 (fiber density), F8 (mean of histograms), F9 (mean of histograms), F102 (Gabor_variance_90°_1 scale), F117 (Gabor_mean_150°_2 scale), and F138 (Gabor_variance_90°_4 scale), on the basis of which a formula was established to calculate the collagen score. Univariate analysis revealed a significant difference in the collagen score between the GR and non-GR groups (P<0.001), and multivariate analysis confirmed that the collagen score was an independent risk factor (P=0.001). These results were validated in the validation cohort (P=0.009 for univariate analysis, P=0.02 for multivariate analysis). For predicting the GR, the area under the curve (AUC) values of the collagen score in the experimental and validation cohorts were 0.819 [95% confidence interval (CI): 0.704-0.935] and 0.820 (95% CI: 0.645-0.995), respectively. Conclusions:MPI can be used to quantify the TME of EC on the basis of a collagen score, which has a certain ability to predict the efficacy of nCIT.

Current tissue-based biomarkers for gastric cancer (GC) immunotherapy face significant limitations due to tumor heterogeneity and sampling constraints. This study explores plasma proteome profiling as a non-invasive strategy to identify dynamic biomarkers predictive of treatment response. In a prospective cohort of 88 advanced GC patients receiving immunotherapy, we performed longitudinal plasma proteomic analysis at baseline and during cycles 2 and 4. Ridge regression was employed to develop composite protein scores, which were validated using Cox models and Kaplan–Meier analyses. Survival outcomes, including progression-free survival (PFS) and overall survival (OS), as well as biomarker dynamics, were assessed over a median follow-up period of 12.9 months. A baseline composite score integrating IFN-gamma, CSF-1, MIC-A/B, and ANGPT demonstrated superior discriminative power for immunotherapy response (area under the ROC curve [AUC]) = 0.77, 95

Background Advanced gastric cancer (aGC) exhibits substantial heterogeneity in response to combination immunotherapy. Circulating cell-free DNA (cfDNA) enables non-invasive profiling of tumor dynamics and may provide biomarkers for response prediction. Methods We enrolled 94 patients with aGC undergoing combination immunotherapy and assigned them to a discovery set (n=49) and an internal validation set (n=45). Plasma cfDNA was collected pre-treatment and post-treatment and profiled by low-pass whole-genome sequencing and whole-genome bisulfite sequencing in the discovery set, with targeted bisulfite sequencing used in the validation set. Results The discovery set included 34 responders and 15 non-responders, and the validation set included 30 responders and 15 non-responders. We found that responders showed longer cfDNA, lower cfDNA tumor fraction (median: 0.06 vs 0.01, p<0.001), reduced chromosomal instability (median genomic instability index: 0.026 vs 0.007, p<0.001), and higher global methylation (median: 0.715 vs 0.724, p=0.007). Additionally, the differentially methylated region (DMR) at chr20:25849353-25849490 consistently showed higher methylation in responders in both the discovery (adjusted p=0.006) and validation sets (adjusted p=0.049). A predictor based on this DMR outperformed programmed death-ligand 1 (PD-L1) combined positive score (CPS) with area under the curve (AUCs) of 0.79 (discovery: 95% CI 0.65 to 0.93) and 0.72 (validation: 95% CI 0.54 to 0.91). When integrating PD-L1 CPS with this DMR, the AUCs were 0.81 (discovery: 95% CI 0.67 to 0.95) and 0.75 (validation: 95% CI 0.56 to 0.94), respectively. For on-treatment monitoring, three DMRs increased specifically in responders; among them, increased methylation of chr8:110479193-110480324 and chr8:50891437-50892120 was associated with improved progression-free survival (median: 4.90 vs 11.57 months, p<0.001; median: 5.20 vs 10.20 months, p=0.007). Conclusion Integrated cfDNA profiling captures immunotherapy-associated molecular dynamics in aGC. A single pretreatment cfDNA methylation marker (chr20:25849353-25849490) improves response prediction beyond PD-L1 CPS and represents a potential predictive biomarker for combination immunotherapy.

BackgroundAbdominal primary Ewing sarcoma (ES) is extremely rare and carries a dismal prognosis when metastatic. First-line therapy typically involves multi-agent regimens like VDC/IE, with irinotecan-based combinations reserved for relapsed/refractory disease. This case is unique due to the achievement of long-term survival using first-line irinotecan and cisplatin in a patient with aggressive abdominal ES.Case presentationA 25-year-old female presented initially with hematochezia, and a huge abdominal mass after postoperative pathology confirmed a diagnosis of high-grade ES/PNET with rapid postoperative progression with new splenic metastases and regional lymph node involvement (no pulmonary metastases). Owing to factors related to treatment tolerance, she received an individualized treatment approach consisting of irinotecan plus cisplatin combined chemotherapy. Serial tumor response assessments demonstrated continuous reduction, culminating in a complete response (CR) that has been maintained to the present. The progression-free survival (PFS) has reached 76 months, representing a significant achievement in terms of long-term, high-quality survival.ConclusionThis case suggests that for selected patients with advanced ES, a regimen of irinotecan plus cisplatin may be considered as a potential first-line option. Larger studies are needed to validate these findings.

Biliary tract cancers (BTCs) exhibit substantial genomic heterogeneity, which is further compounded by the presence of co-mutations, thereby increasing therapeutic complexity. Utilizing a large discovery cohort of 2,378 patients and an independent immunochemotherapy (ICT) cohort of 59 patients, this study investigates the patterns of co-mutation in BTCs and their clinical implications. We identified co-mutation features with potential relevance for guiding targeted therapeutic strategies. Furthermore, we delineated deleterious co-mutations (DCMs) and deleterious single mutations (DSMs) associated with adverse clinical outcomes. By integrating DCMs and DSMs, we classified BTCs into three genomic subtypes: wild-type (WT), single-hit (SH), and multi-hit (MH). The MH subtype is characterized by a high co-mutation burden and specific mutational signatures. Despite having a high prevalence of microsatellite instability and abundant actionable alterations, this subtype shows a significantly worse response to ICT. It is also associated with shorter overall survival. In contrast, the WT subtype exhibits the best outcomes. Our findings provide a molecular framework for stratifying BTC patients. MH tumors might be prioritized for genotype-matched targeted therapy, although direct comparative evidence is still lacking.

The present study aims to develop amorphous solid dispersions (ASDs) of LY-11h, a previously reported acylhydrazide-based histone deacetylase (HDAC) inhibitor with poor aqueous solubility, by integrating hot-melt extrusion (HME) with fused deposition modeling (FDM) 3D printing technology. Systematic pre-formulation studies and in vivo pharmacokinetic assays identified HPMC-AS as the optimal polymer, with 5% HPC-EF as a plasticizer to balance melt processability and filament mechanical performance. LY-11h ASDs were successfully prepared by HME. Subsequent comprehensive solid-state characterization efforts yielded definitive confirmation of the complete conversion of crystalline LY-11h to its amorphous form within the polymer. This transformation was accompanied by the observation of uniform drug distribution and molecular drug-polymer interactions. Equilibrium solubility measurements demonstrated a significant solubility enhancement of LY-11h in ASDs relative to the crystalline drug, and the formulation exhibited pH-dependent solubilization with suppressed release in acidic fluid and improved solubility in neutral intestinal fluid. The ASD formulation was fabricated into 3D-printed dosage forms with four distinct geometric shapes, which demonstrated adequate structural integrity and homogeneous component distribution, as verified by Raman mapping. Drug-release studies revealed that tablet geometry significantly influenced the release profiles through differences in surface-area-to-volume ratio. The optimized formulation exhibited pH-dependent, controlled, and sustained drug release. Furthermore, kinetic modeling elucidated that release was dominated by diffusion and mild polymer erosion. These investigations provide a rational framework for the advanced manufacturing of LY-11h ASDs, and the realized geometry-tunable release provides a basis for further development of individualized drug-delivery strategies.

Purpose:Genome-wide association studies (GWASs) have identified single-nucleotide polymorphisms (SNPs) at the 6p21.1 locus associated with gastric cancer (GC) risk. However, the underlying biological mechanisms remain poorly understood. Materials and Methods:We conducted fine-mapping analysis of the 6p21.1 region using large-scale GC GWAS data (10,254 cases and 10,914 controls). Functional annotation, luciferase reporter assays, Electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) experiments were performed to identify functional variants. The eQTL and colocalization analyses were used to determine the susceptibility gene. Mechanistic investigations included phenotypic assays under normoxic and hypoxic conditions, along with seahorse, immunofluorescence and ATP assays to assess mitochondrial function. Results:We identified rs9381024 as the independent association signal at 6p21.1, with rs2235679, in strong linkage disequilibrium with rs9381024, emerging as a potential causative SNP. The T risk allele of rs2235679 reduced APOBEC2 expression by enhancing the binding of transcriptional repressor MZF1, thereby suppressing promoter activity. Expression analysis revealed a progressive decrease in APOBEC2 levels with gastric lesions severity, becoming nearly undetectable in GC tissues. Functionally, reduced APOBEC2 expression significantly promoted the proliferation of GC cells under hypoxic conditions but not under normoxia. Mechanistically, downregulation of APOBEC2 activated mitophagy to maintain mitochondria homeostasis via HIF-1α/BNIP3 pathway under hypoxia, ultimately driving tumor growth. Conclusion:Our findings provide novel mechanistic insights into how genetic variants at 6p21.1 contribute to GC risk and progression, highlighting the tumor-suppressive role of APOBEC2.

Non-small cell lung cancer (NSCLC) is the most common pathological type of lung cancer, characterized by high morbidity and mortality. Traditional treatments, including surgery, chemotherapy, and radiotherapy, have long been the mainstay of management. However, the advent of targeted therapy and immunotherapy, particularly immune checkpoint inhibitors (ICIs) such as anti-PD-1/PD-L1 antibodies, has significantly improved patient survival outcomes. These advancements have transformed the therapeutic landscape for early-stage, locally advanced, and advanced NSCLC without actionable gene mutations. Despite multiple ICIs being approved for clinical use, critical questions regarding the optimal beneficiary population and predictive biomarkers remain under investigation. To address these challenges, the Yangtze River Delta Lung Cancer Cooperation Group (ECLUNG; Youth Committee) has formulated an expert consensus on the diagnosis and treatment of NSCLC with ICIs. This consensus aims to provide standardized and evidence-based recommendations to optimize diagnostic precision and therapeutic decision-making in NSCLC.

e16033 Background: The combination of immune checkpoint inhibitors (ICIs) and chemotherapy has become the standard first-line (1L) treatment for advanced gastric/gastroesophageal junction adenocarcinoma (GC/GEJC), but the efficacy still needs to be improved. Fruquintinib, an oral and highly selective VEGFR 1/2/3 inhibitor, has shown a synergistic antitumour effect when paired with ICIs/chemotherapy. This study was aimed to evaluate the efficacy and safety of fruquintinib combined with CAPEOX and sintilimab as a 1L therapy in GC/GEJC. Methods: In this phase Ib/II trial, patients (pts) aged 18-75 years without prior exposure to anti-cancer treatment were enrolled. The Ib phase employed a 3+3 dose escalation design, pts were treated with fruquintinib 3mg/d, po, d1-14 (dose level; DL1), 4mg/d (DL2), or 5mg/d (DL3) in combination with fixed dose of sintilimab (200mg, iv, d1), oxaliplatin (130 mg/m 2 , iv, d1) and capecitabine (800 mg/m 2 , bid, po, d1-14) every 3 weeks. After up to 6–8 cycles, fruquintinib in combination with sintilimab would be administered as maintenance therapy. The primary objective of phase Ib was to determine the DLT in first treatment cycle defining the MTD and PR2D. Additional 61 pts were enrolled in the phase II dose expansion stage using RP2D. Primary endpoint of phase II was ORR per RECIST 1.1. Secondary endpoints included DCR, PFS, OS, DOR, surgical conversion rate, safety and identification of molecular biomarkers for efficacy. Results: At data cut-off (December 25, 2025), 24 pts (8 in phase Ib; 16 in phase II) had been enrolled. The pts were characterized with a median age of 59 years (range, 51-67), 45.8% GEJC, 75% lymph node metastasis, and 41.7% liver metastases. 20 pts had PD-L1 CPS available and 70% (14/20) were CPS ≥1, 30% (6/20) were CPS≥5. Two consecutive DLTs were observed at DL3, so DL2 was identified as MTD. Fruquintinib 4mg/d was defined as the RP2D. Of the 22 pts evaluable for tumor response, 18 pts achieved PR, 4 pts achieved SD. The confirmed ORR was 81.8%, the DCR was 100%. After a median follow-up of 17.74 months, the median PFS was 9.0 months (95% CI: 4.40–NA) and OS was not mature yet. Conversion surgery had been conducted in 4 pts after multidisciplinary team evaluation, with one case of pathological CR. The R0 resection rate was 100% (4/4) and R0 surgical conversion rate was 18.2% (4/22). Most TRAEs were grade 1-2 and grade 3/4 TRAEs occurred in 41.7% of pts, with platelet count decreased (12.5%) ranking the most frequent. There were no treatment related deaths in the trial. Conclusions: Fruquintinib plus sintilimab and CAPEOX showed encouraging clinical outcomes and manageable safety for untreated advanced GC/GEJC. The trial is still recruiting, more data including the subgroup analysis and potential predictive response biomarkers would be further analyzed and reported. Clinical trial information: NCT06329973 .

3030 Background: BL-M05D1 is a novel Claudin18.2-directed ADC with a potent topoisomerase I inhibitor Ed-04. Results for safety and efficacy data from a phase I study on BL-M05D1 in patients (pts) with locally advanced or metastatic (LA/M) Claudin18.2-expressing solid tumors are presented. Methods: Pts who had LA/M solid tumors enrolled in dose escalation and dose expansion phase, and treated with BL-M05D1 at 0.66, 2.0, 3.0, 4.0 or 5.0mg/kg on Day 1 every 3 weeks (D1 Q3W). Gastric cancer/gastroesophageal junction cancer (GC/GEJ), biliary tract cancer (BTC), and pancreatic cancer (PanC) patients with Claudin18.2-expressing enrolled in dose expansion phase were treated at 2.0, 3.0 or 4.0mg/kg D1 Q3W. Results: As of Nov 30, 2025, a total of 245 pts were enrolled (87 GC/GEJ, 53 BTC, 104 PanC) and 1 other). The most frequent grade≥3 TRAEs were all hematological, including thrombocytopenia (33.9%), neutropenia (32.7%), leukopenia (31.8%) and anemia (14.3%); non-hematologic TRAEs were relatively low. One pt at 5.0mg/kg group experienced grade 3 febrile neutropenia as a DLT. No treatment-related deaths or ILD were reported. In PanC, BL-M05D1 has demonstrated a promising efficacy with an ORR of 35.7% and mPFS of 5.6 mo at 4.0mg/kg in CLDN18.2-positive pts; in the second line pts, ORR was 50.0% with a mPFS of 5.7 mo. Furthermore, BL-M05D1 has shown promising efficacies in CLDN18.2-positive GC and BTC with an ORR of 39.2% and 37.9%, and mPFS of 5.4 mo and 5.9 mo, respectively, at 4.0mg/kg. Efficacy results are summarized below. Conclusions: BL-M05D1 has demonstrated a promising antitumor activity with a tolerable safety profile in pts with pretreated Claudin18.2-positive PanC, GC, and BTC. 4.0mg/kg D1 Q3W was chosen as RP2D. The data support further development of BL-M05D1 in Claudin18.2-positive PanC, GC, and BTC. Phase III studies are in preparation. Clinical trial information: NCT06349811 . PanC-Total * PanC CLDN 18.2 + # 4.0 mg/kg PanC CLDN 18.2 + # 1 Prior Chemo in 4.0mg/kg GC-Total * GC CLDN 18.2 + # 4.0 mg/kg GC CLDN 18.2 + # 1 Prior Chemo in 4.0 mg/kg BTC-Total * BTC CLDN 18.2 + # 4.0 mg/kg BTC CLDN 18.2 + # 1 Prior Chemo in 4.0 mg/kg N = 81 N = 28 N = 16 N = 79 N = 51 N = 29 N = 40 N = 29 N = 20 Median prior LoT (range) 2 (1-4) 2 (1- 3) / 2 (1-4) 1 (1-3) / 1 (1-3) 1 (1-3) / ORR, % (95% CI) 17.3 (9.8-27.3) 35.7 (18.6-55.9) 50.0 (24.7-75.3) 35.4 (25.0-47.0) 39.2 (25.8-53.9) 44.8 (26.4-64.3) 37.5 (22.7-54.2) 37.9 (20.7-57.7) 45.0 (23.1-68.5) DCR, % (95% CI) 74.1 (63.1-83.2) 89.3 (71.8-97.7) 100 (79.4-100) 88.6 (79.5-94.7) 88.2 (76.1-95.6) 86.2 (68.3-96.1) 92.5 (79.6-98.4) 93.1 (77.2-99.2) 90.0 (68.3-98.8) mFU for PFS (mo) 2.8 5.5 4.2 4.4 4.4 4.3 2.8 2.7 2.7 mPFS (mo) 4.0 5.6 5.7 4.4 5.4 7.7 6.9 5.9 5.9 * Efficacy analysis included all pts who received at least one dose of BL-M05D1 and with at least one post baseline scan. # PanC CLDN 18.2 +: IHC 2+/3+ ≥ 50%; GC CLDN 18.2 +: IHC 2+/3+ ≥ 40%; BTC CLDN 18.2 +: IHC1+/2+/3+≥30%.

As an emerging biomarker, tumor mutational burden (TMB) has attracted increasing attention from clinicians in predicting the efficacy of tumor immunotherapy. Currently, TMB is detected primarily by whole-exome sequencing or targeted panel sequencing on high-throughput sequencing platforms. However, the lack of uniformity in detection methods, threshold settings, and reporting formats, as well as the significant differences in TMB values among different cancer types, have hindered the standardized application of this biomarker in clinical practice. This consensus focuses on the definition, standardization of detection, clinical significance, and limitations of TMB, and provides consensus recommendations for the clinical application of TMB in real-world practice in China. This consensus is aimed at helping clinicians and laboratory personnel understand the clinical significance and testing standards of TMB, promoting more accurate interpretation of test results, and improving patient care.

Malignant peritoneal mesothelioma (MPeM) is a malignant tumor originating from the peritoneum. In recent years, the incidence of MPeM has been increasing. Because MPeM is insidious in onset and of strong local invasiveness, and most patients are found in advanced stage, early screening and treatment of the population at the high risk of malignant mesothelioma are of vital importance. The main treatment methods for MPeM include cytoreductive surgery, hyperthermic intraperitoneal chemotherapy, systemic chemotherapy and immunotherapy. To promote the homogenization and normalization of the diagnosis and treatment of malignant peritoneal mesothelioma, based on existing clinical research evidence, the Chinese Alliance of Research for Mesothelioma (ChARM) formulated the National Expert Consensus on the Clinical Diagnosis and Treatment of Malignant Peritoneal Mesothelioma in combination with expert opinions nationwide. The contents of expert consensus cover epidemiology, diagnosis, treatment and prognosis follow-up.

e15583 Background: Despite established first- and second-line standards with chemotherapy plus anti-VEGF or anti-EGFR agents, third-line options remain limited in colorectal cancer (CRC). Subtype-selective histone deacetylase (HDAC) inhibition may enhance tumor immunogenicity, supporting synergy with PD-1 inhibition plus VEGF-pathway blockade. We therefore conducted a proof-of-concept, single-arm, phase II trial evaluating chidamide plus serplulimab with regorafenib or fruquintinib as third-line therapy for advanced CRC; preliminary findings are presented. Methods: This single-arm, phase Ⅱ study (ChiCTR2300077213) enrolled adults (≥18 years) with pathologically confirmed CRC, ECOG performance status 0-1, measurable disease per iRECIST, and progression after ≥2 lines of systemic therapy. Patients(pts) received chidamide 20 mg orally twice weekly and serplulimab 3 mg/kg intravenously every two weeks, combined with either regorafenib 120 mg or fruquintinib 5 mg orally once daily for three weeks followed by one week off. Treatment continued until disease progression, intolerable toxicity, withdrawal of consent, or up to 2 years. The primary endpoints were safety and objective response rate (ORR) determined by investigators. Secondary endpoints included progression-free survival (PFS), overall survival (OS), disease control rate (DCR), PFS and OS rates at 6- and 12-month, quality of life (QoL), and nutritional score PG-SGA. Results: As of Jan 6, 2026, thirty pts had been enrolled, with a median age of 62.0 years. Most pts had a left-sided primary tumor (86.7%), and all were pMMR/MSS. Liver metastases were present in 22 pts (73.3%) and lung metastases in 13 pts (43.3%). Previous treatment lines ranged from 2 to 4, with 33.3% pts having received more than third-line treatment before. The incidence of ≥3 grade adverse events was 53.3% (n = 16). A total of 26 patients were evaluable for efficacy analysis at a median follow-up of 11.9 months. The ORR was 11.5% (95% CI: 2.4-30.2%) and DCR was 42.3% (95% CI: 23.4-63.1%), including 3 pts achieved partial response and 8 achieved stable disease. The median PFS was 3.0 months (95% CI: 2.3-5.9), and the 6-month PFS rate was 20.5% (95% CI: 9.1-46.3%). The median OS was 7.7 months (95% CI: 5.5-NA), with a 6-month OS rate of 65.9% (95% CI: 49.2-88.4%). Conclusions: Preliminary results indicated that chidamide plus serplulimab with regorafenib or fruquintinib is a feasible and promising third-line treatment option for advanced CRC, alongside manageable toxicity. Clinical trial information: ChiCTR2300077213.

740 Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers with poor prognosis worldwide. Chidamide, a subtype-selective histone deacetylase (HDAC) inhibitor, has significant anti-tumor effects and extensive synergistic effects with immunotherapy. Envafolimab is a light-chain deficient PD-L1 antibody. Here we conducted a single-arm, multicenter, prospective phase Ⅱ clinical study (ChiCTR2200058431) to evaluate the efficacy and safety of Chidamide plus Envafolimab combined with S-1 as second-line treatment in advanced and metastatic pancreatic cancer. Methods: Patients with metastatic PDAC receive Envafolimab (400 mg, on day 1), Chidamide (20 mg orally twice weekly, on days 0, 3, 7, and 10), and S-1 (40-60 mg according to body surface area, orally twice daily from day 1 to 14) every 3 weeks until disease progression, unacceptable toxicity, or patient refusal. The primary end points are safety and ORR. The secondary endpoints were PFS, OS, DCR, QoL and nutrition score. Results: Recruitment completed with 16 patients as of September 2023 and the data cut-off for analysis was August 2024, 13 were evaluable. Median age was 66 (range 59 - 80), with 5 males and 11 females. After a median follow-up of 8.5 months, the ORR and DCR by RECIST v1.1 were 30.77% and 76.92%, respectively. Median PFS was 5.83 months (95%CI 2.592-9.068) and median OS was not reached. No new safety signals were observed. Grade ≥3 treatment-related adverse events (TRAEs) occurred in 31.25% of patients. The most common TRAEs were anemia (12.5%), decreased platelet count (6.25%) and neutropenia (12.5%). No treatment-related deaths occurred. Conclusions: Preliminary data suggest that Chidamide and Envafolimab in combination with S-1 may be an effective second-line treatment with a manageable safety profile for patients with PDAC. Clinical trial information: ChiCTR2200058431 . Efficacy evaluation. Efficacy Evaluation AII (N = 13) n(%) Best efficacy evaluation Partial Response (PR) 4（30.77%） Stable Disease (SD) 6（46.15%） Progressive Disease (PD) 3（23.08%） Objective response rate (ORR) 30.77% 95%CI 9.09-61.43 Disease control rate (DCR) 76.92% 95%CI 46.19-94.96 mPFS（95%CI） 5.83（2.592-9.068） mOS（95%CI） -（NR）

e16285 Background: Biliary tract cancers (BTCs) are mainly divided into cholangiocarcinoma (CHOL) and gallbladder cancer (GBC). Genomic characteristics of advanced BTCs are still needed to be investigated in large cohorts. The association of genomic alterations with clinical outcome remains elusive in advanced BTCs. Methods: Next Generation Sequencing with targeted panels were conducted for 4350 cases with advanced BTCs. Homologous recombination deficiency (HRD), tumor mutation burden (TMB), microsatellite instability (MSI) and HLA-Ⅰ subtypes were determined. The association of genomic alterations with clinical outcome was investigated in a multi-institutional subset. Results: Compared with historical cohorts which included mainly early stage diseases, the frequencies of KRAS and TP53 mutation in advanced BTCs significantly increased. Compared with GBC, CHOL had significantly more mutations in RTK-RAS pathway but significantly less mutations in other oncogenic pathways such as PI3K, HIPPO, NOTCH, and WNT. The proportion of HRD and TMB in GBC were significantly higher than that in CHOL, but no significant difference was observed for the proportions of MSI and HLA-Ⅰ homozygote subtype. Mutually exclusive or co-occurring mutations (CM) were analyzed. Some CM of TP53 mutations were significantly associated with overall survival (OS). Tumors with such a mutation were defined as the CM subtype of TP53, which had poor prognosis in all patients and in patients treated by immune checkpoint inhibitors (ICIs). Frame_Shift mutations (FM) and Multi_Hit mutations (MM) of TP53 were common in advanced BTCs, which indicated better prognosis in both first-line and second-line immunotherapy. Patients with the FM/MM of TP53 also showed better objective response rate (ORR) than those with the CM of TP53 (80% vs. 0%) in immunotherapy. Therapeutically relevant alterations (TRAs) were further analyzed. The most common TRAs in GBC and CHOL were PI3KCA and KRAS mutations, respectively. GBC had more ERBB2 alterations including amplification and mutations than CHOL (13% vs. 5%; p < 0.001), but FGFR2 fusions were detected almost only in CHOL (34 cases vs. 1 case; p < 0.001). Generally, KRAS mutations and other TRAs in CHOL were mutually exclusive, while the co-occurence of PI3KCA and other TRAs were common in GBC. Compared to the wild-type, IDH1 mutations indicated better immunotherapy prognosis in BTCs. In contrast, ATM, MET, NF1, and NRAS mutations were associated with poor prognosis of immunotherapy. Importantly, patients with PI3KCA mutations cannot benefit from the treatment with ICIs. IDH1/ERBB2 mutations had significantly better ORR than their wild-types (100% vs. 46.4%, p = 0.027). Conclusions: We reported novel findings about genomic heterogeneity between advanced CHOL and GBC in a large cohort. TP53 mutation and several TRAs were biomarkers of prognosis and immunotherapy outcomes.

Lung cancer is the leading cause of death and the most diagnosed cancer worldwide. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer; 85% of lung cancer patients are diagnosed with NSCLC. Though numerous treatments for lung cancer have been developed, the 5-year survival rate of patients with NSCLC remains low. Therefore, it is urgent to explore novel targets for NSCLC treatment. Growing evidence has revealed that circular RNAs (circRNAs) contribute to NSCLC progression. Besides, the data of circRNA microarray (GSE158695) has found that hsa_circ_0011536 is downregulated in NSCLC tissues. Nevertheless, the role of hsa_circ_0011536 in NSCLC remains unknown. In this study, RNA 6-methyladenosine (m6A) modification was detected by methylated RNA immunoprecipitation, the interaction of RNAs was determined using miRNA pulldown and luciferase reporter assay, while ferroptosis was identified by Cell Counting Kit-8 assay, intracellular iron content, and malondialdehyde level. Our findings demonstrated that hsa_circ_0011536 was downregulated in NSCLC cell lines. Mechanism investigation revealed that m6A modification enhanced the back-splicing of pre-ZMYM4 to increase hsa_circ_0011536 expression in A549 and NCI-H1299 cells. Moreover, hsa-miR-576-5p was the target of hsa_circ_0011536, while transferrin receptor (TFRC) was the downstream target of hsa-miR-576-5p in A549 and NCI-H1299 cells. Furthermore, hsa_circ_0011536 elevated TFRC expression by sponging hsa-miR-576-5p in A549 and NCI-H1299 cells, identified by luciferase reporter assay. In addition, hsa_circ_0011536 induced ferroptosis through hsa-miR-576-5p in A549 and NCI-H1299 cells. Therefore, this study revealed that m6A-induced hsa_circ_0011536 elevated TFRC expression to induce ferroptosis by sponging hsa-miR-576-5p in NSCLC. These results might provide novel therapeutic targets for NSCLC treatment.

Malignant mesothelioma of the tunica vaginalis testis (MMTVT) is a rare malignancy originating from mesothelial cells of the testicular tunica vaginalis. Due to its insidious onset and local aggressiveness, most patients are diagnosed at an advanced stage. The treatment modalities for MMTVT primarily include surgery, chemotherapy, and radiotherapy. With the advent of immunotherapy, patient survival has further improved. To standardize and homogenize the diagnosis and treatment of MMTVT in China, the Chinese Alliance of Research for Mesothelioma, combining existing research evidence and nationwide expert opinions, has formulated a national expert consensus on the clinical diagnosis and treatment of MMTVT. This consensus encompasses epidemiology, diagnosis, treatment, prognosis, and follow-up.