e16000 Background: Pancreatic ductal adenocarcinoma (PDAC) remains a lethal malignancy with limited therapeutic options. Dysregulation of metal ion homeostasis is implicated in tumor progression and therapy resistance. This study aims to systematically identify metal ion transport-related prognostic genes, construct a reliable risk model, and discover novel therapeutic agents using artificial intelligence. Methods: Transcriptomic data from GEO databases (GSE183795 as training set, GSE28735 as validation set) and single-cell RNA-seq data (GSE155698) were analyzed. Differential expression analysis, functional enrichment, and protein-protein interaction networks were constructed. A prognostic risk signature was developed using LASSO-Cox regression. The tumor immune microenvironment was characterized using CIBERSORT. An innovative GraphBAN model integrated with CNN, ESM, GCN, and ChemBERTa was employed for drug prediction, followed by molecular docking. Single-cell analyses including trajectory inference and cell-cell communication were performed. Results: We identified and validated a five-gene prognostic signature (SLC20A1, SLC39A10, SLC5A3, SLC11A1, SLC4A4) significantly associated with overall survival in PDAC. The risk model demonstrated robust predictive power in both training (3-year AUC = 0.73) and external validation cohorts (5-year AUC = 0.97). High-risk patients exhibited an immunosuppressive microenvironment characterized by M2 macrophage infiltration. GraphBAN prediction and molecular docking identified Elephantin and Sinularin as high-affinity binders to SLC39A10 and SLC4A4, respectively. Single-cell analysis revealed the specific expression dynamics of these genes in macrophage and neutrophil subpopulations and delineated their evolving roles along pseudotemporal trajectories. Conclusions: We established a novel metal ion transport-related gene signature as an independent prognostic indicator for PDAC. Our integrative AI-driven framework successfully predicted candidate drugs targeting this pathway, providing a promising strategy for personalized therapy and highlighting the therapeutic potential of modulating metal ion homeostasis in PDAC.

KRAS G12D is the predominant oncogenic driver in pancreatic ductal adenocarcinoma (PDAC). While most investigational KRAS-G12D inhibitors are oral small molecules limited by gastrointestinal toxicities and suboptimal tumor exposure, HRS-4642 is a new, high-affinity, noncovalent KRAS-G12D inhibitor. Formulated as a liposomal nanoparticle for intravenous administration, it is designed to enhance tumor accumulation and prolong the duration of target inhibition. This phase 1b/2 study evaluated HRS-4642 in combination with nab-paclitaxel and gemcitabine (AG) in patients with advanced KRAS G12D-mutant PDAC. As of 5 December 2025, 68 patients were screened and 31 (1 previously treated patient and 30 treatment-naive patients) were enrolled and treated. In the phase 1b portion, no dose-limiting toxicities were observed, and the starting dose (500 mg on day 1 and 1,200 mg on day 8, every 3 weeks) was selected as the recommended phase 2 dose. In the phase 2 portion, with a median follow-up of 12.3 months (95% confidence interval (CI) = 12.2-13.0), the primary endpoint was met-the confirmed objective response rate in 30 treatment-naive patients was 63.3% (95% CI = 43.9-80.1). Grade >= 3 treatment-related adverse events (TRAEs) occurred in 90.3% patients, primarily hematologic toxicities consistent with AG chemotherapy. No TRAEs led to treatment discontinuation or death. In conclusion, HRS-4642 combined with AG demonstrates promising antitumor activity and a manageable safety profile in advanced KRAS G12D-mutant PDAC, supporting further investigation. Clinicaltrials.gov registration: .

KRASG12D is the predominant oncogenic driver in pancreatic ductal adenocarcinoma (PDAC). While most investigational KRAS-G12D inhibitors are oral small molecules limited by gastrointestinal toxicities and suboptimal tumor exposure, HRS-4642 is a new, high‑affinity, noncovalent KRAS-G12D inhibitor. Formulated as a liposomal nanoparticle for intravenous administration, it is designed to enhance tumor accumulation and prolong the duration of target inhibition. This phase 1b/2 study evaluated HRS-4642 in combination with nab-paclitaxel and gemcitabine (AG) in patients with advanced KRASG12D-mutant PDAC. As of 5 December 2025, 68 patients were screened and 31 (1 previously treated patient and 30 treatment-naive patients) were enrolled and treated. In the phase 1b portion, no dose-limiting toxicities were observed, and the starting dose (500 mg on day 1 and 1,200 mg on day 8, every 3 weeks) was selected as the recommended phase 2 dose. In the phase 2 portion, with a median follow-up of 12.3 months (95% confidence interval (CI) = 12.2-13.0), the primary endpoint was met-the confirmed objective response rate in 30 treatment-naive patients was 63.3% (95% CI = 43.9-80.1). Grade ≥3 treatment-related adverse events (TRAEs) occurred in 90.3% patients, primarily hematologic toxicities consistent with AG chemotherapy. No TRAEs led to treatment discontinuation or death. In conclusion, HRS-4642 combined with AG demonstrates promising antitumor activity and a manageable safety profile in advanced KRASG12D-mutant PDAC, supporting further investigation. Clinicaltrials.gov registration: NCT06520488 .

e15578 Background: Patients with RAS wild-type (RASwt) metastatic colorectal cancer (mCRC) progressing on first-line fluoropyrimidine-based chemotherapy plus anti-EGFR therapy have limited and often suboptimal second-line treatment options. Trifluridine/tipiracil (TAS-102) is an oral cytotoxic agent that inhibits tumor growth through incorporation into DNA and disruption of DNA function, potentially overcoming fluoropyrimidine resistance. We conducted a phase II study to evaluate the efficacy and safety of bevacizumab combined with TAS-102 and irinotecan in this setting. Methods: In this single-arm phase II trial (ChiCTR2100046678), patients with RASwt mCRC who progressed after first-line anti-EGFR therapy plus chemotherapy received TAS-102 (35 mg/m², days 1–5), bevacizumab (5 mg/kg), and irinotecan (180 mg/m²) every 2 weeks. The primary endpoint was progression free survival (PFS). Secondary endpoints included objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety. Results: From August 2021 to January 2026, 27 patients were enrolled. The median age was 59 years (range, 42-75), male accounted for 81.5%,Most patients (26/27) had an ECOG status of 1. As of data cutoff (January 2026), 24 patients had ≥1 postbaseline tumor assessment; 7 remained on treatment. Best overall responses included partial response in 5 patients (20.8%), stable disease in 18 (75.0%), and progressive disease in 1 (4.2%). The confirmed ORR was 20.8% (95% CI: 3.3–38.4%) and DCR was 95.8% (95% CI: 87.2–100.0%). With a median followup of [X] months, median PFS was 7.7 months (95% CI: 4.99–10.41) and median OS was 20.7 months (95% CI: 8.83–31.31). Grade ≥3 treatmentrelated adverse events (occurring in ≥5% of patients) were neutropenia (40%), leukopenia (24%), anemia (8%), and thrombocytopenia (8%). No treatmentrelated deaths were reported. Conclusions: The combination of bevacizumab, TAS-102, and irinotecan showed promising clinical activity and manageable toxicity as secondline therapy for RASwt mCRC patients who progressed on prior anti-EGFR-based treatment. These results support further evaluation of this regimen in randomized controlled trials. Clinical trial information: ChiCTR2100046678.

BACKGROUND:Fruquintinib, a highly selective vascular endothelial growth factor receptor 1, 2, 3 inhibitors, has demonstrated significant efficacy in phase III trials for metastatic colorectal cancer (mCRC). However, real-world evidence is essential to confirm its safety profile across diverse treatment settings. AIM:This subgroup analysis of a phase IV study aims to evaluate the safety of fruquintinib both as monotherapy and combination therapy in a real-world setting. METHODS:Phase IV-study data were categorized by treatment regimen into fruquintinib monotherapy and combination therapy groups. Safety profiles including TEAEs and TRAEs were recorded. RESULTS:Overall, 2798 patients were enrolled in the phase IV study (2019-2022) and received fruquintinib 5 mg/day or per physician's choice. Among them, 1888 patients received monotherapy, whereas 775 patients received combination therapy: fruquintinib + chemotherapy (n = 359), fruquintinib with immune checkpoint inhibitors (ICIs) (n = 493), and chemotherapy and ICI (n = 77), with overlap between combination groups. Drug exposure was the shortest with monotherapy (2.50 months) and longest with fruquintinib + ICI + chemotherapy (4.70 months). Monotherapy subgroup reported the lowest incidence of TEAEs (74.47%) and grade ≥3 TEAEs (23.94%), while the fruquintinib + chemotherapy subgroup reported the highest incidence (85.52%). CONCLUSION:Fruquintinib combination therapy demonstrated a satisfactory safety profile within the treatment groups.

Metastatic colorectal cancer (mCRC) patients who progress following the standard chemotherapy have maintained a favourable performance status. Nevertheless, there are limited effective treatment options, particularly for a considerable proportion of tumours with a microsatellite-stable (MSS) phenotype. Based on strong preclinical evidence demonstrating the synergistic effect between an anti-PD-1 antibody, tislelizumab, and an anti-VEGFR1-3 antibody, surufatinib, we evaluated their efficacy and safety in this population of patients with treatment-refractory disease. This single-arm phase II study that recruited patients with histologically confirmed mCRC who had received ≥ 3 previous lines of systemic therapy. Critical eligibility criteria included an Eastern Cooperative Oncology Group performance status of 0 to 1 and measurable disease according to RECIST version 1.1. Patients were administered 200 mg tislelizumab intravenously every 3 weeks combined with surufatinib 250 mg orally once daily until progressive disease, intolerable toxicity, or withdrawal of consent. The primary endpoint was progression-free survival (PFS). The secondary endpoints were the disease control rate (DCR), overall survival (OS), objective response rate (ORR), and safety. Sixteen patients (median age, 58 years) were enrolled between March 2022 and April 2025. The study was prematurely terminated for futility at a pre-planned ad hoc analysis. Only one patient achieved stable disease with a DCR of 6.3

e16346 Background: Cancer Treatment-Induced Thrombocytopenia (CTIT) is a common complication in patients with gastrointestinal (GI) cancers, often leading to treatment delays, dose reductions, and increased bleeding risk. Romiplostim N01 is recommended for CTIT but lacking specifically evidence in GI cancer. This study aims to explore the efficacy and safety of Romiplostim N01 in GI cancer patients with CTIT. Methods: This prospective, single-arm, multi-center study conducted from July 2025 to June 2027. 100 adult patients with GI cancers and developed CTIT (platelet count < 50×10⁹/L) following anticancer therapy will be enrolled. Patients received subcutaneous Romiplostim N01 (starting dose 3 µg/kg/week) for up to 8 weeks. The primary endpoint was the proportion achieving platelet count ≥50×10⁹/L at week 2 after treatment initiation. Secondary endpoints included the proportion of patients achieving a platelet response (increase ≥ 50×10⁹/L without transfusion) within 7 days, time to platelet recovery (≥50×10⁹/L, ≥100×10⁹/L), transfusion requirements, and safety. Results: As of January 20, 2026, a total of 21 subjects were enrolled (14 males, 7 females) with a median age of 67 years (range, 53-76). Primary tumor types included rectal cancer (23.8%, 5/21), colon cancer (19.0%, 4/21), cholangiocarcinoma (19.0%, 4/21), with the remaining being gastric cancer (3/21) and others. Most patients (20/21) had an ECOG status of 0-2. Thirteen patients had previously received immunotherapy, while the others underwent standard chemotherapy. Eighteen subjects received one dose of Romiplostim N01 (3 µg/kg/week), and three received two doses. The median baseline platelet count was 37×10⁹/L (range, 32-42×10⁹/L). Nineteen subjects (90.5%, 19/21) achieved the primary endpoint (platelet count ≥50×10⁹/L) within two weeks, and the median platelet count after response was 76×10⁹/L (range, 55-137×10⁹/L). The median time to platelet recovery ≥50×10⁹/L was 7 days (95% CI, 2.734-11.266), and the median time to platelet recovery ≥100×10⁹/L was 13.5 days (95% CI, 7.5-29.5). No patient required additional platelet transfusions. Adverse events were mild to moderate, primarily arthralgia and headache, and all resolved. No treatment-related serious adverse events (SAEs) were reported. Conclusions: Romiplostim N01 shows promising efficacy for CTIT in GI cancers, with most patients achieving rapid platelet recovery (median 7 days) and no need for transfusions. The manageable safety profile suggests it is a viable supportive care option. These findings will provide further support for its clinical use. Clinical trial information: ChiCTR2500106841.

e16399 Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with limited therapeutic options in advanced stages. Building upon the foundational evidence from the PAN-HEROIC-1 trial which demonstrated the clinical benefits of irinotecan liposome (II) and supported its approval for unresectable locally advanced or metastatic PDAC in China, this study aimed to evaluate the real-world safety and effectiveness of irinotecan liposome (II)-based combination regimens in patients with PDAC. Methods: This multicenter, prospective, real-world study included patients with pathologically or radiologically confirmed PDAC who were considered eligible by investigators for irinotecan liposome (II)-based combination regimens incorporating chemotherapy, chemoradiation, radiotherapy, immunotherapy, or targeted therapy. Patients were assigned to three cohorts according to treatment stage at enrollment: perioperative, first-line, and later-line treatment. Observational data were collected including adverse events, baseline characteristics, therapeutic regimens, and tumor response. The primary endpoint was treatment-emergent adverse events (TEAEs); secondary endpoints included overall survival (OS) and real-world progression-free survival (rwPFS), real-world time to progression (rwTTP), real-world objective response rate (rwORR), real-world disease control rate (rwDCR), real-world disease-free survival (rwDFS) and real-world duration of treatment (rwDOT). Results: As of August 30, 2025, a total of 236 patients were enrolled (perioperative, n = 23; first-line, n = 98; later-line, n = 115). The median age was 62.0 years (range, 33.0–83.0), with males and females accounting for 57.2% and 42.8%, respectively. Tumors were located in pancreatic head (25.4%), pancreatic body (11.4%), pancreatic tail (11.4%) and other pancreatic sites (51.7%). The most frequent metastasis site was the liver (39.0%). Baseline CA19-9 ≥37 U/mL was observed in 81.8% of patients. Any-grade TEAEs occurred in 36.9% of patients, with the most common being anemia (7.2%), nausea (6.8%), diarrhea (6.8%) and leukopenia (5.1%); grade ≥3 TEAEs occurred in 7.2% of patients. Median rwPFS was not reached in any cohort; the 6-month rwPFS rates were 83.3%, 66.4%, and 41.1% for the perioperative, first-line, and later-line cohorts, respectively. The median OS was not reached in any of the three cohorts. Conclusions: This real-world study revealed that the combination regimen based on irinotecan liposome (II) showed a manageable safety profile and encouraging effectiveness signals. Follow-up and patient enrollment are ongoing.

e15560 Background: A phase II study suggested that the combination of fruquintinib (Fru) and trifluridine/tipiracil (TAS-102) could prolong progression-free survival (PFS) and overall survival (OS). However, the benefits are limited due to tolerability associated with continuous administration. This study aimed to explore the efficacy and safety of intermittent administration of Fru and TAS-102 as a 3L treatment for mCRC patients(pts). Methods: This was a single-center, single-arm, phase II study (ChiCTR2300078241). The primary endpoint was objective response rate (ORR). Secondary endpoints included PFS, OS, disease control rate (DCR), and safety. The ORR was set to ≤1% in the null hypothesis using a two-sided αof 0.05. To reject the null hypothesis and achieve an expected ORR of 10% with an 80% power, a minimum of 29 pts was required. Considering a dropout rate of 15%, the study planned to enrol 35 mCRC pts who had failed two standard treatment regimens. Eligible pts received oral Fru (3 mg, once daily, on days 1-5 and 8-12) and TAS-102 (35 mg/m², twice daily, on days 1-5) every two weeks until disease progression or unacceptable toxicity occurred. Results: A total of 35 pts were enrolled between August 2023 and March 2025. The median age was 58 years (range: 19-77). RAS mutations were present in 54.3% of pts, 62.9% had left-sided colon or rectal cancer, 54.3%, 40.0% and 45.7% had liver metastases, peritoneal metastases and multiple metastases respectively. As of December 15, 2025, 33 pts had discontinued study treatment and 2 pts were ongoing treatment. The ORR and DCR were 11.4% (4/35) and 80.0% (28/35) respectively. The median PFS (mPFS) was 7.2 (95% CI: 5.0–9.4) months(m), and median OS was 18.2 (95% CI: 10.8–25.7) m. mPFS in RAS-mutant and RAS wild-type pts were 7.2 (95% CI: 4.3-10.1) m and 6.7 (95% CI: 2.9-10.6) m, respectively (p = 0.527), with ORRs of 15.8% and 7.7% respectively. mPFS in pts with and without liver metastases were 7.0 m (95% CI: 3.0-11.0) and 7.2 m (95% CI: 6.2-8.2), respectively (p = 0.315), with ORRs of 10.5% and 12.5% respectively. Patients without peritoneal metastases or multiple metastases obtained better mPFS (7.9 m vs. 4.4 m, p = 0.041 ; 7.9 m vs. 3.7 m, p = 0.017), with ORRs of 14.3% vs. 7.1% and 15.8% vs. 6.3%. Treatment-related adverse events (TRAEs) were generally manageable and tolerable. The most common hematological TRAEs (any grade, grades 3-4) included neutropenia (80.0%, 28.6%), leukopenia (68.6%, 22.9%), and anemia (51.4%, 5.7%). Non-hematological TRAEs were mostly grades 1-2, including anorexia (37.1%), fatigue (28.6%) and nausea (14.3%). One case of grade 3 hypertension was reported. No treatment-related deaths were observed. Conclusions: An intermittent Fru+TAS-102 schedule demonstrated encouraging activity with manageable toxicity in refractory mCRC. Clinical trial information: ChiCTR2300078241.

Objective: Camrelizumab-based regimens show promising efficacy in esophageal cancer patients, according to previous pivotal trials. Given the strict eligibility criteria in pivotal trials, real-world studies are essential to evaluate the efficacy and safety of camrelizumab-based regimens in a broader patient population under routine clinical practice. Therefore, this study aimed to explore the efficacy and safety of camrelizumab-based regimens for the treatment of advanced esophageal cancer patients in real world settings. Methods: A total of 192 advanced esophageal cancer patients receiving camrelizumab-based regimens were included in this study. The specific camrelizumab-based regimens were decided by the investigators according to the patients' physical condition. For efficacy assessment, treatment response and survival were assessed. For safety assessment, adverse events were collected. The median (range) follow-up duration was 7.2 (0.7-58.8) months. Results: Objective response rate and disease control rate were 18.8% and 84.4%, respectively. Camrelizumab-based regimens achieved the median [95% confidence interval progression-free survival (PFS) and overall survival (OS) of 6.8 (5.4-8.2) and 17.4 (12.8-21.9) months, respectively. Compared to patients receiving camrelizumab monotherapy, progression-free survival was prolonged in patients receiving camrelizumab combination therapy (P = 0.007), especially in patients receiving camrelizumab plus chemotherapy (P = 0.017), camrelizumab plus apatinib (P = 0.041), and camrelizumab plus chemotherapy and apatinib (P = 0.014). overall survival was not different between patients with camrelizumab combination therapy and camrelizumab monotherapy (all P > 0.05). Multivariable Cox regression analysis suggested that camrelizumab plus apatinib (vs. camrelizumab monotherapy) was independently associated with prolonged PFS (hazard ratio = 0.493, P = 0.049). The incidence of total adverse events was 71.4%. Most adverse events were grade 1-2 (64.0%). Common adverse events included fatigue (20.8%), anorexia (19.3%), and leukopenia (15.6%). Conclusion: Camrelizumab shows satisfactory efficacy and safety in advanced esophageal cancer patients, and the camrelizumab combination regimens seem to bring prolonged PFS than its monotherapy. The real-world design reflects routine clinical practice, supporting the generalizability of these findings. However, potential confounders may exist and the broad range of follow-up durations may contribute to variability in survival data. Therefore, our results should be interpreted cautiously.

Gastric cancer (GC) remains a formidable public health challenge in China, characterized by a high incidence and mortality rate. A significant proportion of patients are diagnosed with advanced or metastatic disease, where traditional chemotherapy has historically offered limited survival benefits. However, driven by a deeper molecular understanding of GC heterogeneity, the paradigm of GC treatment is undergoing a revolutionary shift from a "one size fits all" approach toward precision medicine. The identification of predictive biomarkers, such as human epidermal growth factor receptor 2 (HER2/ERBB2; MIM: 164870) expression, microsatellite instability-high (MSI-H) status, PD-L1 (CD274; MIM: 605402) expression, and Claudin 18.2 (CLDN18; MIM: 609210) overexpression, has established biomarker-guided strategies as the unequivocal future direction for managing advanced GC. In particular, the emergence of immune checkpoint inhibitors (ICIs) and agents targeting Claudin 18.2 has revolutionized the landscape of first-line (1L) treatment for GC. China has achieved accelerated breakthroughs in gastric cancer drug research and development, leading to more innovative therapies and improved diagnostic/treatment regimens, providing patients with more abundant and effective treatment options and significantly improving the landscape of diagnosis and treatment. Nevertheless, integrating complex biomarkers and novel agents into practice poses challenges, including inconsistencies in biomarker testing and the need for nuanced treatment regimen selection. Without standardized guidelines, inconsistent application may lead to suboptimal patient outcomes and inefficient use of healthcare resources. This expert consensus has been jointly formulated with the aim of further enhancing and standardizing the biomarker testing and precision medicine of 1L therapy for advanced GC.

77 B ackground: Currently, the standard first-line/second-line treatment for advanced colorectal cancer with RAS mutations is chemotherapy combined with bevacizumab. Patients with colorectal cancer confirmed maintenance therapy can effectively improve progression-free survival, improve patient quality of life. Therefore, this study aims to evaluate the efficacy and safety of bevacizumab combined with mFOLFOX6/FOLFIRI sequential bevacizumab combined with capecitabine as first-line/second-line conversion therapy for RAS-mutated advanced colorectal cancer. M ethods: This is an open-label, single-center study in previously untreated patients with RAS mutant mCRC. Eligible patients received first-line chemotherapy of bevacizumab (5mg/m 2 ) combined with mFOLFOX6/FOLFIRI for 12 cycles randomly, during which the efficacy was assessed every 4 cycles, then followed by bevacizumab(7.5mg/m 2 ) in combination with capecitabine maintenance therapy which assessed every 2 cycles until disease progression, and then switched to the second-line therapy FOLFIRI/mFOLFOX6 combined with bevacizumab which was assessed every 4 cycles until disease progression or intolerable toxicity. Imaging studies were performed to assess treatment efficacy according to RECIST1.1 criteria, and the primary endpoint was progression-free survival (PFS), including first-line PFS and second-line PFS after progression, and the secondary endpoints included disease response rate (ORR), disease control rate (DCR), overall survival (OS), and safety. R esults: This study recruited 78 subjects from January 2021 to May 2024. As of September 10, 2024, a total of 70 subjects were analyzable for the first-line treatment, of which 6 subjects met the surgical criteria after treatment and achieved NED status; 45 patients reached the first-line PFS endpoint, with a median PFS (mPFS) of 249 days (95% CI: 204.4-293.6), an ORR of 38.6%, and a DCR of 95.7% . Twenty patients entered the first-line maintenance therapy, with a mPFS of 358 days (95% CI: 53.8-662.2). For the second-line treatment, a total of 43 subjects were analyzable, of which 35 patients reached the second-line PFS endpoint, with a second-line mPFS of 171 days (95% CI: 89.8-252.1). 41 subjects underwent at least one efficacy evaluation, with ORR of 14.6% and DCR of 75.6%. The most common grade 3 treatment-related adverse events were neutropenia, leukopenia, anemia, hypertension, diarrhea, and thrombocytopenia. There were no treatment-related deaths. No new adverse events occurred during the entire combination treatment period. C onclusions: This real world study has demonstrated good tolerability and encouraging clinical efficacy, especially with potential implications for treatment planning and management strategies for advanced colorectal cancer with RAS mutations. Clinical trial information: ChiCTR2100042553 .

Programmed cell death protein-1 (PD-1) inhibitors plus chemotherapy have been the standard of care in the first-line treatment of advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma; however, the survival benefits are modest in patients with low programmed death ligand 1 (PD-L1) expression. Here we investigated the efficacy and safety of cadonilimab (PD-1/cytotoxic T lymphocyte antigen-4 (CTLA-4) bispecific antibody) plus chemotherapy as first-line treatment in G/GEJ adenocarcinoma. The prespecified interim analysis is reported here. This was a randomized, double-blind, placebo-controlled phase 3 study. Eligible patients were adults with untreated, unresectable, locally advanced or metastatic G/GEJ adenocarcinoma. Patients were randomized 1:1 to receive cadonilimab (10 mg kg−1 every 3 weeks) or placebo plus chemotherapy (every 3 weeks). The primary endpoint was overall survival (OS) in the intention-to-treat population (one-sided significance level, P = 0.025). Secondary endpoints included OS in patients with a PD-L1 combined positive score ≥5, progression-free survival, objective response rate, duration of response and safety. As of 18 August 2023, 610 patients from 75 study centers were randomized to cadonilimab (n = 305) or placebo (n = 305). With a median follow-up of 18.7 months, the cadonilimab group had a significantly longer median OS (14.1 versus 11.1 months; hazard ratio (HR) 0.66; 95 NCT05008783 . In a prespecified interim analysis of the randomized, double-blind phase 3 COMPASSION-15 trial, patients with advanced HER2-negative gastric/GEJ cancer treated with the anti-PD-L1/CTLA-4 bispecific Ab cadonilimab plus chemotherapy showed significantly improved overall survival compared with patients treated with placebo plus chemotherapy as first-line treatment.

Objective: To investigate the value of a machine learning model that integrates radiomics features and peripheral blood inflammatory markers in predicting the prognosis of patients with unresectable esophageal squamous cell carcinoma (ESCC) receiving PD-1 inhibitor combined with concurrent chemoradiotherapy. Methods: A retrospective collection was conducted involving 105 patients with unresectable ESSC who received PD-1 inhibitors combined with concurrent chemoradiotherapy at the First Affiliated Hospital of the University of Science and Technology of China from January 2020 to August 2023. These patients were randomly divided into a training set (n=74) and a validation set (n=31). Radiomics features were extracted from arterial phase CT images obtained before initial treatment, with feature selection performed using Pearson Correlation and LASSO-COX methods. Baseline clinical characteristics were analyzed, and hematological parameters were collected before the start of immunotherapy and within 4-6 weeks post-treatment to calculate inflammatory markers. Subsequently, independent radiomics features influencing patient prognosis were identified using a multivariate Cox proportional hazards model, and these features were incorporated into a clinical feature-based multivariate Cox model to derive independent prognostic factors combining radiomics and clinical characteristics. Nomograms were constructed to predict the 2-year progression-free survival (PFS) of patients based on the results of COX analysis involving clinical characteristics, radiomic features, and combined indicators. The models were evaluated and assessed using ROC curves and calibration curves. Results: In the training cohort, the AUC was 0.705 for the clinical model, 0.573 for the radiomics model, and 0.834 for the combined model. In the validation cohort, the AUC was 0.784 for the clinical model, 0.775 for the radiomics model, and 0.872 for the combined model. Conclusion: The combined model integrating the radiomic feature NGTDM-busyness, the inflammatory marker ΔNLR, and the clinical characteristic M stage offers the optimal predictive value for the 2-year PFS in patients.

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.

Camrelizumab (CAM) combined with apatinib plus chemotherapy as a first-line treatment shows good efficacy in advanced or metastatic esophageal squamous cell carcinoma (ESCC) patients. This study aimed to explore the potential of CAM combined with apatinib plus irinotecan (IRT) as a second-line treatment in advanced or metastatic ESCC patients. A total of 59 advanced or metastatic ESCC patients receiving CAM combined with apatinib plus IRT as second-line treatment were enrolled in this study between January 2020 and March 2024. The primary endpoint was progression-free survival (PFS), with secondary endpoints including overall survival (OS), the objective response rate (ORR), the disease control rate (DCR), and the assessment of toxicity. Concurrently, a model was constructed utilizing patients’ clinical characteristics and radiomic features to predict the patients’ prognoses. At the time of analysis, 58 patients were withdrawn due to disease progression (n = 9), death (n = 43), or lost to follow-up (n = 6), and 1 patient was ongoing. The ORR and DCR were 37.7

e15515 Background: Although Fruquintinib (Fru) monotherapy is one of the standard treatments for third line mCRC patients(pts), combination of Fru and other anti-cancer treatments, such as chemotherapy, immunotherapy is widely used in Chinese real world clinical practice due to its synergistic or additive anticancer effect and also by potentially reducing drug resistance. A phase IV study evaluating the safety of fruquintinib in Chinese patients with mCRC demonstrated a favorable safety profile. With the increasing number of CRC patients receiving Fru therapy, it is crucial to understand its safety profile as combination therapy. This subgroup analysis of the phase IV study aims to evaluate the safety of Fru monotherapy and combination therapy in real-world setting. Methods: The data of mCRC patients were obtained from the Phase IV study (NCT04005066). Based on the treatment received, the study population was grouped into Fru monotherapy and combination therapy groups. At each follow up visit, the safety profile of the patients, including Treatment Emergent Adverse Events (TEAE) and Treatment Related Adverse Events (TRAE) was assessed and recorded. Results: A total of 2798 mCRC patients enrolled in the phase IV study between April 2019 to September 2022, received Fru administration at a dose of 5mg/day once daily for 21 days in the 28 days cycle or as determined by physicians. Fru monotherapy was administered to 1888 pts while 910 pts received combination therapy with 775 pts combined with Immune Checkpoint Inhibitor (ICI) and or chemo therapy and 135 pts combined with other anti-cancer treatment including Chinese Traditional Medicine or target therapy. For those 775pts who combined with ICI or chemo could be further divided into Fru +chemo (359 pts), Fru +ICI (493 pts), with 77 pts (Fru+ chemo + ICI) overlapped. The median treatment duration for the Fru monotherapy subgroup was 2.50 months while it was 4.70 months for the Fru + chemo+ ICI subgroup. 74.47% patients reported any grade TEAE and 23.94% reported grade ≥3 TEAE in the Fru monotherapy subgroup while 83.87% reported any grade TEAE and 26.06% reported grade ≥3 TEAE in the combination therapy group. The most common TRAEs in monotherapy and combination treatment subgroups were palmar-plantar erythrodysesthesia (PPES) (19.70% vs 22.84%) followed by hypertension (17.00% vs 16.52%). Among the Grade ≥3 TRAE, hypertension (6.73% vs 7.74%) and PPES (2.54% vs 1.81%) were the top two TRAEs in mono and combination treatment groups respectively. Conclusions: Fruquintinib demonstrated a satisfactory safety profile in monotherapy and combination therapy groups. The combination therapy groups demonstrated a longer treatment duration time, it might indicate an improved patient outcome. Clinical trial information: NCT04005066 .

174 Background: Fruquintinib and TAS-102 are two globally recognized standard therapies for mCRC patients who have previously undergone standard chemotherapy. A phase II exploratory study suggested that the combination of TAS-102 and fruquintinib could prolong progression-free survival (PFS) and overall survival (OS) in these patients. However, the benefits are sometimes limited due to tolerability issues associated with continuous dosing. This study aimed to investigate the efficacy and safety of intermittent administration of TAS-102 combined with fruquintinib as a third-line treatment for mCRC patients. Methods: This open-label, single-arm, single-center, exploratory clinical trial enrolled mCRC patients who had failed at least two standard treatment regimens. Eligible patients received oral fruquintinib (3 mg, once daily, on days 1-5 and 8-12) and TAS-102 (35 mg/m², twice daily, on days 1-5) every two weeks until disease progression or unacceptable toxicity occurred. The primary endpoint was objective response rate (ORR). Secondary endpoints included OS, PFS , DCR, and safety. Results: From August 2023 to September 2024, 26 eligible patients were enrolled. The median age of the patients was 58 years (range: 19-77), with 61.5% being female. RAS mutations were present in 57.7% of patients, 57.7% had left-sided colon or rectal cancer, 57.7% had liver metastases, and 76.9% had multiple metastases. As of September 10, 2024, 22 patients had undergone at least one tumor assessment, and 12 patients were still on treatment. Among them, 18.2% (4/22) achieved partial response , and 50% (11/22) had stable disease as the best response. Median PFS (mPFS) was 135 days (95% CI: 60.52-209.48). mPFS in RAS-mutant and RAS wild-type patients was 161 days (95% CI: 63.37-258.63) and 135 days (95% CI: 60.20-209.80), respectively, with ORRs of 25% and 12.5%. mPFS in patients with liver metastases (LM) and non-LM was 135 days (95% CI: 45.42-224.58) and 161 days (95% CI: 87.84-234.16), respectively, with ORRs of 14.3% and 25%. mPFS in patients with multiple metastases was 135 days (95% CI: 71.86-198.14), with an ORR of 17.6%. Median OS was not yet mature. Treatment-related adverse events (TRAEs) were generally manageable and tolerable. The most common hematological TRAEs (any grade, grades 3-4) included leukopenia (76.9%, 11.5%), neutropenia (73.1%, 11.5%), and anemia (53.8%, 7.7%). Non-hematological TRAEs were mostly grades 1-2, including anorexia (46.2%) and fatigue (19.2%). One case of grade 3 hypertension was reported. No treatment-related deaths were observed. Conclusion s: These preliminary results suggest that intermittent administration of TAS-102 in combination with fruquinitinib as a third-line treatment for patients with mCRC reduces hematological toxicity and is well tolerated, with encouraging clinical results. Clinical studies are ongoing. Clinical trial information: ChiCTR2300078241 .

Immune checkpoint inhibitors (ICIs) have shifted the treatment paradigm of non-small cell lung cancer (NSCLC) over the last decade. Despite notable therapeutic advancements in responders, the response rate remains limited owing to the immunosuppressive tumor microenvironment (TME). Therefore, to improve the efficacy of ICIs, it is essential to explore alternative targets or signals that mediate immunosuppression. Immunoglobulin-like transcript (ILT) 5 is a negative regulator of immune activation in myeloid cells. However, the expression and function of ILT5 in NSCLC remain unknown. Here, we found that ILT5 was highly expressed in tumor-associated macrophages (TAMs) of NSCLC tissues and predicted poor patient survival. Functionally, ILT5 induces the M2-like polarization of TAMs, which subsequently decreases the density of T cells, and increases FOXP3+T cell accumulation, leading to an immunosuppressive TME. The combination of ILT5 expression with M2-like TAM density is a more reliable biomarker of patient survival than ILT5 expression alone. ILT5 knockout mitigates the reprogramming of TAM and T cell subsets toward immunosuppressive phenotypes and inhibits tumor growth in vivo. These findings highlight that ILT5 is a potential immunotherapeutic target and a promising prognostic biomarker for NSCLC.

INTRODUCTION:Following resection for gastroesophageal cancer, patients may experience symptoms like reflux, anorexia, and weight loss that can significantly impact their quality of life (QoL). Patient-reported outcomes (PROs) are becoming more important for symptom monitoring. Nevertheless, there is limited knowledge on symptom management post-gastroesophageal cancer resection. METHODS:A single-center, randomized controlled trial was conducted on postoperative patients with gastroesophageal cancer. Participants were randomly assigned to the PRO group and usual care (the control group), with a 1:1 ratio. The PRO-based symptom management included symptom assessment, monitoring, and personalized interventions such as lifestyle guidance, nutritional support, and drug therapy. An electronic system was developed on the Research Electronic Data Capture (REDCap) platform to monitor and assess patients' symptoms, QoL, and provide diagnosis and treatment. The study focused on five key symptom events: anorexia, reflux, depression, nutritional risk, and underweight. In the PRO group, assessments were conducted every 3-4 weeks for a minimum of 16 weeks. Interventions for this group primarily involved counseling, patient education, and medication prescriptions based on individual symptoms. The control group's symptoms and QoL were assessed only at baseline and week 16. The primary outcome measure was the total number of symptoms at 16 weeks, with secondary outcomes including the incidence of symptoms at the same time point. QoL was also evaluated as part of the study. RESULTS:Between April 2021 and May 2022, a total of 124 patients were divided into two groups: 60 in the PRO group and 64 in the control group. The PRO group exhibited notably fewer overall symptoms at the 16-week mark compared to the control group (1.20 ± 1.16 vs. 2.50 ± 1.47), along with a lower prevalence of nutritional risk (63.3% vs. 81.3%), anorexia (18.3% vs. 60.9%), reflux (13.3% vs. 57.8%), and depression (5.0% vs. 20.3%). The QoL scores were markedly higher in the PRO group. Furthermore, the PRO group displayed lower nutritional status, reflux, and depression scale trends, as well as higher anorexia trends when compared to the control group. CONCLUSIONS:PRO-based symptom management led to superior symptom control and enhanced QoL in postoperative gastroesophageal cancer patients when compared to standard care.