e15663 Background: Colorectal cancer is the third most common tumors and the second leading cause of cancer-related deaths worldwide. Most patients are diagnosed with locally advanced rectal cancer (LARC), which is associated with high recurrence risks and low survival rates. The standard treatment for LARC is preoperative neoadjuvant chemoradiotherapy combined with total mesorectal excision (TME). However, only a small proportion of patients achieve pathological complete response (pCR) after treatment, and approximately 30% develop distant metastases following neoadjuvant therapy. How to strengthen or optimize the preoperative neoadjuvant therapy of LARC to benefit more patients is a critical focus of current clinical research. High-dose-rate brachytherapy (HDR-BT) offers the potential to deliver higher radiation doses to tumors while sparing surrounding tissues and organs from radiation damage. Limited studies have investigated the combination of total neoadjuvant therapy (TNT) with HDR-BT. This retrospective study aims to compare the efficacy and safety of TNT combined with HDR-BT versus TNT alone, with the goal of providing new insights into comprehensive treatment strategies for LARC patients. Methods: Patients with LARC who received neoadjuvant therapy in our hospital from May 2016 to July 2024 were retrospectively screened according to inclusion and exclusion criteria. Clinical information, neoadjuvant treatment regimens, and serological indexes were collected. Pathological staging, tumor regression grade, R0 resection status, overall survival (OS), disease-free survival (DFS), Recurrence-free survival (RFS), and incidence of adverse reactions were recorded. The efficacy and safety of the two groups were compared. Results: This study included a total of 86 patients, with 50 in the TNT group and 36 in the TNT+HDR-BT group. There was no statistical significance in the distribution of clinical characteristics, concurrent and consolidation chemotherapy regimens between the two groups. In the TNT+HDR-BT group, 11 patients (31.4%) achieved pathological complete response (pCR), which was numerically higher than 10.0% in the TNT group (P = 0.013). The median follow-up time in the TNT+HDR-BT group and the TNT group was 68.7 months and 56.7 months, respectively. 5 year DFS was 72.2% in the TNT+HDR-BT group and 59.8% in the TNT group (HR = 0.66, 95% CI 0.31-1.43, P = 0.292). 5 year RFS was 82.5% in the TNT+HDR-BT group and 67.2% in the TNT group (HR = 0.45, 95% CI 0.17-1.16, P = 0.091). 5 year OS was 87.9% in the TNT+HDR-BT group and 70.3% in the TNT group (HR = 0.34, 95% CI 0.11-1.04, P = 0.046). Conclusions: Compared with TNT, TNT combined with HDR-BT in the treatment of LARC patients significantly increased the proportion of pCR and showed a trend of better survival outcomes.

This study aimed to evaluate the efficacy and safety of apatinib, an oral VEGFR2 tyrosine kinase inhibitor, combined with docetaxel and S-1 (DS) as first-line therapy for metastatic gastric cancer (mGC) patients whose median overall survival (mOS) with chemotherapy typically remains below 12 months. In this prospective, multi-center, single-arm phase II trial (NCT03154983), patients received docetaxel (75 mg/m2, day 1) and S-1 (body surface area-based dosing, days 1-14) every 3 weeks, plus daily apatinib (500 mg), for up to 6 planned cycles. 45 patients were enrolled, with a median follow-up time of 12.4 months. Median progression-free survival (PFS) and overall survival (OS) were 7.6 months (95% CI: 5.8%-9.4%) and 12.4 months (95% CI: 9.3%-15.5%), respectively in the full analysis set. Patients completing ≥4 cycles achieved a better mOS of 14.5 months (95% CI: 12.0%-17.1%). The objective response rate (ORR) and disease control rate (DCR) were 62.2% (95% CI, 46.5%-76.2%) and 82.2% (95% CI, 67.9%-92.0%), respectively, including one complete response (CR). Grade 3-4 treatment-related adverse events occurred in 48.9% of patients, most commonly oral mucositis and neutropenia. These findings support apatinib plus DS as a promising biomarker-independent first-line treatment strategy for mGC.

4045 Background: Tecotabart vedotin (TV; LM-302) is a novel and potent MMAE-based ADC targeting CLDN18.2. Previous data (ASCO 2025, abstract#4039) demonstrated promising efficacy and manageable safety profile of TV plus PD-1 inhibitor in patients (pts) with systemic therapy-naive advanced gastric or gastroesophageal junction (G/GEJ) cancer. Updated phase II results of TV plus toripalimab (T) with or without chemotherapy in this first-line setting are presented. Methods: Eligible pts had histologically confirmed, no prior systemic therapy, HER2-negative G/GEJ adenocarcinoma with CLDN18.2 positivity (IHC 2+/3+ in ≥1% of tumor cells). Pts received TV (1.8 mg/kg Q2W) plus T (3 mg/kg Q2W), with or without capecitabine or S-1. The primary endpoint was PFS per RECIST v1.1. Secondary endpoints were efficacy, safety, PK, and biomarker analysis. Data cutoff: November 25, 2025. Results: A total of 71 pts with G/GEJ adenocarcinoma were enrolled: 39 in the TV+T cohort and 32 in the TV+T+Chemo cohort. Baseline CLDN18.2 high expression (≥25%) was presented in 82.1% of pts in the TV+T cohort and 84.4% in the TV+T+Chemo cohort. PD-L1 CPS ≥1 was observed in 61.5% and 81.3% of pts, respectively. Median follow-up was 16.16 months in the TV+T cohort and 14.82 months in the TV+T+Chem cohort. The median PFS (95% CI) was 10.68 months (6.28, NE) and 12.55 months (6.80, NE), respectively. Among pts with CLDN18.2 ≥25%, the median PFS (95% CI) was 12.22 months (6.87, NE) and NE (8.44, NE), the median DOR (95% CI) was 13.86 months (9.36, NE) and NE (7.10, NE), ORR was 64.5% and 69.2%, and DCR was 96.8% and 96.2%, respectively. Median OS was not reached in either cohort. In pts with CLDN18.2 <25%, TV+T (N=7) and TV+T+Chemo (N=5) showed a median PFS (95% CI) of 5.72 (1.15, NE) and 6.80 (5.55, NE) months, ORR of 14.3% and 40.0%, DCR of 71.4% and 100%, and OS (95% CI) of 10.78 (2.56, NE) months and NE (8.25, NE), respectively. TRAEs occurred in all pts. Grade ≥3 TRAEs occurred in 66.7% of pts in the TV+T cohort and 81.3% of pts in the TV+T+Chemo cohort. The most common Grade ≥3 TRAEs (incidence ≥20%) were decreased neutrophil count in the TV+T cohort, and decreased neutrophil count and decreased white blood cell count in the TV+T+Chemo cohort. TEAEs leading to dose reduction occurred in 17.9% (Grade ≥3: 12.8%) and 43.8% (Grade ≥3: 18.8%) of pts, respectively. TEAEs led to treatment discontinuation occurred in 15.4% (Grade ≥3: 7.7%) and 31.3% (Grade ≥3: 28.1%), respectively. No treatment-related deaths were reported. Conclusions: TV+T, with or without chemotherapy, demonstrated encouraging anti-tumor activity and manageable safety as first-line treatment for CLDN18.2-positive advanced G/GEJ cancer. The doublet shows comparable efficacy to the triplet with enhanced tolerability, supporting further large-scale clinical investigation. Clinical trial information: NCT05934331 .

Background:Concurrent chemoradiotherapy (CCRT) for abdominal cancer frequently induces muscle loss, weight loss, and malnutrition. Objective:This exploratory randomized phase II trial evaluated whether a multidisciplinary, mobile health (mHealth)-based multimodal rehabilitation program could preserve handgrip strength and muscle mass in patients with abdominal cancer undergoing CCRT. Methods:In this prospective, multicenter, randomized, open-label phase II trial (NCT05325554), 111 eligible patients with abdominal malignancies scheduled for CCRT were randomly assigned (1:1) to receive either multidisciplinary mHealth rehabilitation care (MRC; n=57) or standard care (SC; n=54). The MRC program was delivered by a dedicated multidisciplinary team using the AiNST mHealth platform and wearable heart rate monitors. The primary end point was handgrip strength at the end of CCRT (analyzed with analysis of covariance adjusting for baseline). Secondary end points were exploratory and analyzed without multiplicity adjustment; sensitivity analysis using false discovery rate (FDR) correction was performed. Results:Between February 2022 and April 2023, 111 patients were enrolled. Adherence was high (n=93, 83.9% achieved exercise targets). After adjusting for baseline handgrip strength, the MRC group had significantly higher handgrip strength at the end of CCRT than the SC group (adjusted mean difference 4.87 kg, 95% CI 3.36-6.38; P<.001). Exploratory analyses of secondary end points (without multiplicity adjustment) showed that the MRC group also had better preservation of body weight (P=.005), skeletal muscle mass (P<.001), serum albumin (P=.009), prealbumin (P=.02), and lower rates of hematological toxicity (P<.05), as well as improved psychological status (distress thermometer [DT] and Hospital Anxiety and Depression Scale [HADS]) and nutritional scores (Nutritional Risk Screening 2002 [NRS-2002] and Patient-Generated Subjective Global Assessment [PG-SGA]) at the end of CCRT (all P<.05). All nominally significant secondary end points remained significant after FDR correction (q<.05). These findings are preliminary and should be interpreted with caution due to the open-label design, population heterogeneity, and exploratory secondary analyses. Conclusions:In this exploratory phase II trial, a multidisciplinary, mHealth-based multimodal rehabilitation program was associated with better preservation of handgrip strength, muscle mass, and nutritional status, as well as lower rates of certain treatment toxicities, compared with SC. However, definitive conclusions are limited by the open-label design, heterogeneity of tumor types, and short follow-up. Larger, blinded phase III trials are needed to confirm these findings.

Concurrent chemoradiotherapy (CCRT) for abdominal cancer frequently induces chemoradiotherapy‑induced muscle loss, weight loss, and malnutrition. This randomized phase II trial evaluated whether a multidisciplinary, mHealth‑based multimodal rehabilitation program could preserve handgrip strength and muscle mass in abdominal cancer patients undergoing CCRT. In this prospective, multicenter, randomized, open‑label phase II trial (NCT05325554), 111 eligible patients with abdominal malignancies scheduled for CCRT were randomly assigned (1:1) to receive either multidisciplinary mHealth rehabilitation care (MRC, n=57) or standard care (SC, n=54). The MRC program was delivered by a dedicated multidisciplinary team comprising oncologists, rehabilitation physicians, nurses, clinical nutritionists, and psychologists. Using the AINST mHealth platform and wearable heart rate monitors, the team provided coordinated, individualized exercise, nutritional, and psychological interventions based on weekly assessments and real‑time data. The SC group received routine oncology care. The primary endpoint was change in handgrip strength from baseline to CCRT completion. Secondary endpoints included body weight, skeletal muscle mass, nutritional biomarkers, quality of life, psychological status, and adverse events. Between February 2022 and April 2023, 111 patients were enrolled. Adherence was high, with 83.9% (47/56) of MRC patients achieving preset exercise targets. Compared with SC, the MRC group demonstrated significantly less decline in handgrip strength at all time points (all p < 0.001). The MRC group also showed better preservation of body weight (mean difference 1.3 kg, p=0.005) and a significantly lower proportion of patients with >5% weight loss (10.7% vs. 32.7%, p=0.005). Skeletal muscle mass was also better preserved (mean difference 1.3 kg, p<0.001). The MRC group had less decline in serum albumin (p=0.009) and prealbumin (p=0.019), and lower incidences of ≥G3 leukopenia (5.4% vs. 19.2%, p=0.037) and ≥G1 thrombocytopenia (16.1% vs. 34.6%, p=0.026). Nutritional and psychological benefits persisted at 4‑week post‑CCRT follow‑up. A multidisciplinary, mHealth‑based multimodal rehabilitation program effectively preserves handgrip strength, muscle mass, and nutritional status while reducing treatment toxicity in abdominal cancer patients undergoing CCRT. The multicenter implementation using standardized digital tools supports its scalability and translation into real‑world clinical pathways. Clinical Trial Registration: ClinicalTrials.gov NCT05325554.Registration Date 03/08/2022.

Pyridine is a prevalent structural motif in drug molecules, and modifying the pyridine core is a widely utilized strategy for lead optimization in drug discovery. Nitrogen scanning systematically evaluates the effects of varying the nitrogen position within pyridyl isomers, including the extension of the nitrogen atom one or two bonds outside the ring, often resulting in anilines or benzonitriles. This strategy aims to bring the hydrogen‐bonding site closer to the target protein, which can lead to substantial improvements in binding activity. In this study, a synthetic strategy is presented that transforms pyridines into anilines, with the original pyridine nitrogen atom externalized at either the ipso or ortho position. The approach employs a carbene insertion step prior to nitrogen isomerization, preserving the ring size and structural integrity throughout the transformation. This method demonstrates broad applicability, enabling the late‐stage functionalization of a variety of natural products and pharmaceutical agents, and underscores its versatility and potential in drug discovery applications.

AMPK activation enhances the efficacy of anti-PD-L1 therapy by increasing phosphorylation of ChREBP.

ChREBP promotes chemokine production and recruits TAMs to induce tumor immune evasion.

AMPK-mediated ChREBP phosphorylation inhibits the expression of chemokine and choline metabolism genes or proteins.

The absence of ChREBP inhibits tumorigenesis in immunocompetent mice.

Choline induced macrophages to acquire an immunostimulatory phenotype.

3022 Background: JSKN003 is a biparatopic HER2-targeting ADC conjugated with a topoisomerase I inhibitor (TOP1i) payload via a dibenzocylooctyne tetrapeptide linker. The efficacy and safety of JSKN003 in several solid tumors have been highlighted in previous reports. Methods: JSKN003-101 and JSKN003-102 are dose escalation and expansion studies involving Australian and Chinese patients (pts) with metastatic solid tumors. This pooled analysis of two studies was performed to assess the efficacy and safety in advanced HER2-overexpressing (IHC 3+) gastric or gastroesophageal cancer (GC/GEJC) and colorectal cancer (CRC) pts. Results: As of data cutoff (18 Dec 2024), 40 patients with HER2-overexpressing (IHC 3+ by local lab) gastrointestinal tumor (23 in GC/GEJC and 17 in CRC) were enrolled across 7 dose levels: 2.1 mg/kg (n = 1), 4.2 mg/kg (n = 1), 5.2 mg/kg (n = 1), 6.3 mg/kg (n = 33), 7.3 mg/kg (n = 1), 8.4 mg/kg (n = 2), 10.5 mg/kg (n = 1). The median follow-up time of two studies was 7.16 months. Most pts were heavily pretreated (37.5% had ≥3 lines of prior treatment; 45.0% received irinotecan; 67.5% received anti-HER2 therapy; 42.5% received IO therapy). Four of the 17 CRC pts were RAF/RAS mutations (n = 2 RAS-mut, n = 2 RAF-mut). Thirty-nine patients had at least one tumor assessment after baseline. The overall response rate (ORR) per RECIST v1.1 in HER2-overexpressing gastrointestinal tumor was 66.7% and the disease control rate (DCR) was 94.7%. Among 22 GC/GEJC pts, the ORR was 68.2% and DCR was 95.5%. The median progression-free survival (PFS) was 9.59 months (95% CI: 2.96, NE) with 66.3% (95% CI: 29.4, 87.1) PFS rate at 6 months. Among 17 CRC pts, the ORR was 64.7% (66.7% in RAF-wild pts, n = 15) and DCR was 94.1%. The mPFS was 13.77m (95% CI: 7.1, NE) with 94.1% (95% CI: 65, 99.2) PFS rate at 6 months. The median overall survival (OS) was not yet mature. Notably, one BRAF-mut patient achieved PR at first tumor assessment after baseline, two RAS-mut pts achieved PR and duration was over 48 weeks. The most common treatment-related adverse events (TRAEs) included nausea, diarrhea, neutropenia, decreased appetite, vomiting, rash, anemia and fatigue. Grade 3/4 neutropenia was observed in 2 (5.0%) pts, Grade 3/4 anemia was observed in 1 (3.0%) pts. No TEAEs led to death or treatment discontinuation. Interstitial lung disease (ILD) occurred in 3 (7.5%; n = 2 G1; n = 1 G2) pts. Conclusions: JSKN003 demonstrated promising efficacy in heavily pretreated pts with advanced HER2-overexpressing gastrointestinal tumors, with a manageable and predictable safety profile. Clinical trial information: NCT05494918 , NCT05744427 .

Hyperexpression of ChREBP is associated with a poor prognosis and “immune deserts” phenotype in CRC.

4010 Background: Targeting tumor-infiltrating Tregs presents a promising strategy to overcome resistance to immunotherapy in cancer treatment. LM-108 is a novel Fc-optimized anti-CCR8 monoclonal antibody designed to selectively deplete tumor-infiltrating Tregs while sparing peripheral Tregs. This pooled analysis of two phase 1/2 trials assesses the efficacy and safety of LM-108 in combination with anti-PD-1 therapy in patients with pancreatic cancer. Methods: Eligible patients (pts) with pancreatic cancer who had progressed on or after at least one prior line of systemic therapy were included. Treatment regimens included LM-108 at doses of 3 mg/kg Q3W, 3 mg/kg Q2W, 10 mg/kg Q3W, or 10 mg/kg Q2W, in combination with pembrolizumab (400 mg Q6W) or toripalimab (240 mg Q3W). The primary endpoint was ORR. Secondary endpoints were DCR, PFS, OS, DoR, safety, and biomarkers analysis. Data cutoff: December 2, 2024. Results: A total of 80 pts (median age: 63 years; 58.8% male) from China and Australia were treated. Of these, 48 pts had progressed on or after 1 prior line of therapy, and 32 pts had ≥2 lines. Eighteen pts (22.5%) had prior anti-PD-1 therapy, and 52 pts (65.0%) had liver metastases at baseline. TRAEs were reported in 76 pts (95.0%). Common TRAEs (≥25%) included increased AST, increased ALT, anemia, rash, pyrexia, decreased platelet count and increased conjugated bilirubin. Grade ≥3 TRAEs occurred in 42 pts (52.5%), the most common events (≥5%) were lipase elevation (7.5%), increased ALT (6.3%), increased AST (5.0%), immune-mediated enterocolitis (5.0%), hypokalemia (5.0%), and rash (5.0%). Median follow-up was 10.48 months (95% CI 7.20-12.65). Among 74 efficacy-evaluable pts, ORR was 20.3% (95% CI 11.8-31.2%) and DCR was 62.2% (95% CI 50.1-73.2%). Median DoR was 5.49 months (95% CI 3.02-8.87), PFS was 3.12 months (95% CI 1.61-4.86), and OS was 10.02 months (95% CI 6.41-13.11). Among 45 pts who had progressed on or after one prior line of therapy, ORR was 24.4% (95% CI 12.9-39.5%) and DCR was 71.1% (95% CI 55.7-83.6%), with a median DoR of 6.93 months (95% CI 3.02-NA), PFS of 4.86 months (95% CI 2.79-6.90), and OS not reached. The 12-month OS rate was 51.6% (95% CI 31.4-68.5%). Among these, 9 pts with high CCR8 expression (7 with baseline liver metastases) showed ORR of 33.3% (95% CI 7.5-70.1%) and DCR of 77.8% (95% CI 40.0-97.2%). Median PFS was 6.90 months (95% CI 1.22-NA), and OS was 9.15 months (95% CI 3.61-NA). Conclusions: LM-108 in combination with anti-PD-1 therapy demonstrated encouraging antitumor activity and a manageable safety profile in patients with pancreatic cancer who had progressed on or after prior systemic therapies. These findings support further investigation of LM-108 in combination with anti-PD-1 therapy as a potential treatment option for pancreatic cancer. Clinical trial information: NCT05199753 ; NCT05518045 .

ChREBP interacts with SP1 to promote the expression of chemokine and choline metabolism genes.

Introduction:Gastrointestinal (GI) cancers present significant clinical challenges characterized by dismal survival outcomes and suboptimal prognoses. Currently, only partial indicators are available to predict the response of immunotherapy. A critical gap remains in the development of models capable of accurately predicting response rates to immunotherapy regimens. In this study, we developed a machine-learning (ML) model based on factorial, molecular, demographic, and clinical data to predict the response rate. Methods:This multicentre retrospective study analyzed the clinical data of 506 patients, comprising 352 cases collected from Zhongnan Hospital of Wuhan University and Hubei Cancer Hospital, along with 154 cases obtained from the publicly available dataset of Memorial Sloan-Kettering Hospital. We used 14 features as input features, such as the patient's basic status, biochemical test results, and genetic test results. Eight ML methods were employed to build predictive models. Through rigorous validation using seven discriminative performance metrics (accuracy, precision, recall, F1-score, ROC-AUC, PR-AUC, and Brier score), the eXtreme Gradient Boosting (XGBoost) algorithm demonstrated superior predictive capability. Model interpretability was subsequently enhanced through Shapley Additive explanations (SHAP) analysis to elucidate feature contributions. Results:We selected XGBoost with the best predictive performance to predict response (AUC: 0.829 [95% CI: 0.72-0.91], accuracy: 78.43%, sensitivity: 86.67%, specificity: 72.31%). The Delong test and calibration curve indicated that XGBoost significantly outperformed the other models in prediction. The SHAP values indicate that chemotherapy contributes the most to the model's predictive accuracy (contribution score = 0.28), while Ki-67 exhibits the lowest contribution rate (0.01). In addition, the study showed that chemotherapy, higher hemoglobin (HGB), body mass index (BMI), age, lower neutrophil-to-lymphocyte ratio (NLR), and tumor stage positively influenced the output of the model. Conclusion:Interpretable XGBoost models have shown accuracy, efficiency, and robustness in determining the association between input features and response rates. Among the input features, chemotherapy and tumor stage played the most important role in the prediction model. Due to the varying efficacy of ICIs in gastrointestinal cancers, personalized predictive models can greatly assist clinical decision-making. This model fills this gap in clinical practice and can provide more precise support for personalized treatment and risk avoidance.

The differential metabolites identified by LC-MS from shChrebp or shNC MC38 tumors.

Tumor metabolic reprogramming has been recognized as a critical determinant in tumor development and cancer immunotherapy response. Aberrant choline metabolism is emerging as a defining hallmark of cancer. In this study, we found that carbohydrate-responsive element-binding protein (ChREBP)-mediated choline deprivation induced tumor-associated macrophage (TAM) reprogramming and maintained an immunosuppressive tumor microenvironment. Mechanistically, ChREBP interacted with SP1 to increase the expression of immunosuppressive chemokines CCL2 and CCL7 and choline transporter SLC44A1. As such, high CCL2 and CCL7 expression promoted recruitment of TAMs. Tumor cells with high SLC44A1 levels competed with M1-like TAMs for choline, inhibiting cGAS/STING signaling and promoting the repolarization of M1-like to M2-like macrophages. Clinically, ChREBP-SP1-choline metabolism axis expression was associated with poor clinical outcome in colorectal cancer. Thus, the study identified the interplay between tumors and TAMs via choline competition as a previously unknown immune evasion mechanism in the tumor microenvironment and proposes ChREBP as a potential immunotherapeutic target in cancer.Significance: ChREBP induces a choline-deprived tumor microenvironment and promotes chemokine secretion to facilitate immune evasion, suggesting targeting ChREBP as a therapeutic approach to improve the efficacy of immunotherapy.

Tumor cell ChREBP-mediated choline deprivation orchestrates TAMs reprogramming and immune evasion.