Adding anti-PD-1 or anti-VEGF therapy to chemotherapy improves survival in patients with advanced gastric cancer, yet outcomes remain poor. This Phase Ib/II trial aimed to evaluate the efficacy and safety of combining sintilimab, the bevacizumab biosimilar IBI305, and CapeOX chemotherapy as a first-line treatment for patients with HER2-negative advanced gastric or gastroesophageal junction adenocarcinoma (GA/GEJA). In phase Ib, no dose-limiting toxicities (DLTs) that served as the primary endpoint were observed (N = 9). In phase II, the primary endpoint of the objective response rate (ORR) in the efficacy-evaluable population (N = 54) was 87.0% (95% CI: 75.1–94.6%), achieving the pre-specified target was reached. Secondary endpoints included progression-free survival (PFS), overall survival (OS), disease control rate (DCR), duration of response (DoR), and safety. The DCR was 98.1% (95% CI: 90.1–100.0%). At a median follow-up of 20.3 months, median PFS and DoR were 12.2 months (95% CI: 9.2–18.1) and 12.5 months (95% CI: 9.4–NE), respectively, while the median OS was not reached. A clinical benefit was observed regardless of PD-L1 CPS, Claudin-18.2 expression status, or the presence of peritoneal metastases. Treatment-related adverse events of grade ≥3 occurred in 66% of patients; the most common were neutropenia (14%), fatigue (13%), and thrombocytopenia (11%). The limitations of the study include the single-arm, non-randomized design and the modest sample size, which necessitate confirmation in larger randomized controlled trials. Nonetheless, sintilimab plus IBI305 and chemotherapy demonstrated promising antitumor activity and favorable PFS with manageable toxicity in HER2-negative advanced GA/GEJA. Trial number: NCT05640609. Previous evaluations on anti-VEGF monoclonal antibody indicate its therapeutic potential in gastric cancer treatment. Here this group reports a phase Ib/II trial combining sintilimab/bevacizumab biosimilar IBI305/CapeOX chemotherapy as the first-line treatment on 54 patients with HER2-negative advanced gastric or gastroesophageal junction adenocarcinoma.

2519 Background: CLDN18.2 expression has been observed in various solid tumors especially in gastric cancer, indicating its potential as a novel target for anti-tumor therapy. IBI389 is an anti-CLDN18.2/CD3 bispecific antibody that induces immune synapse formations by linking CD3 molecules in T-cell receptor complexes and CLDN18.2 antigens on the membrane of tumor cells. Herein, we report preliminary results from a phase I study to evaluate safety and efficacy of IBI389 in patients (pts) with advanced solid tumors. Methods: Eligible pts with advanced solid tumors who failed or were intolerant to standard treatments were enrolled. The dose escalation of IBI389 monotherapy used intra-patient dose escalation with accelerated titration and the classic 3+3 design (0.003 µg/kg to 600 µg/kg). Selected dose levels were expanded in pts with advanced gastric/gastroesophageal junction cancer (G/GEJ C) and pancreatic ductal adenocarcinoma (PDAC). The primary objective was safety. Secondary objective was efficacy assessed by investigator per RECIST v1.1 including objective response rate (ORR) and disease control rate (DCR). Results: As of January 9, 2024, a total of 114 pts were enrolled (males: 67.5%, median age: 60.0 years, G/GEJ C: 32.5%, PDAC: 57.9%, stage IV: 81.6%). No dose-limiting toxicity (DLT) was observed during dose escalation. The MTD was not reached. In all pts, treatment-emergent adverse events (TEAEs) occurred in 112 (98.2%) pts including 76 (66.7%) pts with grade ≥3 TEAEs. Treatment-related adverse events (TRAEs) occurred in 111 (97.4%) pts including 63 (55.3%) pts with grade ≥3 TRAEs. The most common grade ≥3 TRAEs (≥ 4%) were gamma-glutamyl transferase increased (21.9%), lymphocyte count decreased (13.2%) and nausea (4.4%). Cytokine release syndrome (CRS) related adverse events occurred in 65 (57.0%) pts including 1 (0.9%) pts with grade 3 CRS and no grade 4 or 5 CRS. TEAEs leading to dose interruption and treatment discontinuation occurred in 44 (38.6%) and 8 (7.0%) pts. Preliminary efficacy of IBI389 was observed in pts with CLDN18.2 expression ≥10% (immunohistochemistry 2+/3+). In G/GEJ C pts with previous treatments ≥2 lines receiving IBI389 at various dose levels ranging from 10µg/kg to 600 µg/kg (n=26), 8 pts had partial response (PR) and 11 pts had stable disease (SD). The ORR was 30.8% (95%CI: 14.3-51.8) and DCR was 73.1% (95%CI: 52.2-88.4). Conclusions: IBI389 showed manageable safety profiles in pts with advanced solid tumors and preliminary efficacy in CLDN18.2-positive pts with G/GEJ C. Clinical trial information: NCT05164458 .

This randomized clinical trial evaluates whether the addition of radiotherapy to adjuvant S-1 plus oxaliplatin chemotherapy increases disease-free survival among patients undergoing D2 gastrectomy for T4 or node-positive gastric cancer. QuestionIs adjuvant chemoradiotherapy more effective than chemotherapy alone in patients with gastric cancer and T4 or node-positive disease following D2 gastrectomy (ie, gastrectomy with D2 lymphadenectomy)?FindingsIn this randomized clinical trial involving 620 patients, adding radiotherapy to adjuvant S-1 plus oxaliplatin (SOX) chemotherapy after D2 gastrectomy did not significantly improve disease-free survival or overall survival compared with SOX alone.MeaningThese findings suggest that routine intensification with postoperative radiotherapy added to adjuvant SOX may not be warranted after D2 R0 resection for T4 or node-positive gastric cancer. ImportanceDespite advances in D2 gastrectomy (ie, gastrectomy with D2 lymphadenectomy) and adjuvant chemotherapy, the value of adding postoperative radiotherapy (RT) to adjuvant chemotherapy after D2 gastrectomy remains a topic of ongoing debate.ObjectiveTo assess whether the addition of RT to the S-1 plus oxaliplatin (SOX) chemotherapy regimen increases disease-free survival (DFS) in patients with T4 or node-positive gastric cancer after D2 gastrectomy.Design, Setting, and ParticipantsThis open-label, phase 3 randomized clinical trial was conducted between December 1, 2012, and August 30, 2022, at 5 large tertiary hospitals in China. Eligible patients were aged 18 to 70 years with gastric adenocarcinoma who underwent R0 resection with D2 lymphadenectomy, had pathologic stage T4 or node-positive disease, and had no evidence of metastasis (M0). Intention-to-treat statistical analyses were conducted from January 14 to March 31, 2025.InterventionsParticipants were assigned 1:1 to receive concurrent chemoradiotherapy (SOX RT) or chemotherapy alone (SOX). The SOX RT group received 1 cycle of induction SOX, followed by RT (50.4 Gy in 28 fractions) with concurrent S-1 (50 mg twice daily), and then 3 cycles of SOX. The SOX group received 6 cycles of SOX (S-1 30-40 mg/m2 twice daily on days 1-14; oxaliplatin 130 mg/m2 on day 1, every 3 weeks).Main Outcomes and MeasuresThe primary end point was 3-year DFS. Secondary end points included overall survival (OS) and adverse events.ResultsA total of 620 patients were randomly assigned to the SOX group (n = 311) or SOX RT group (n = 309). Patients had a median (IQR) age of 55 (47-62) years and included 401 males (64.7%). Overall, 274 patients (44.2%) had T4 disease, and 590 (95.2%) had node-positive disease. In the primary analysis for the prespecified 3-year DFS end point, there was no evidence of a between-group difference in DFS (SOX RT vs SOX: HR, 0.98; 95% CI, 0.73-1.33). Similarly, there was no evidence of a between-group difference in OS (HR, 0.86; 95% CI, 0.60-1.23). The Kaplan-Meier-estimated 3-year DFS rates were 70.5% in the SOX RT group and 69.3% in the SOX group (log-rank P = .93), and the corresponding 3-year OS rates were 80.8% and 78.4%, respectively (log-rank P = .41). At 5 years, the DFS rates were 60.0% and 57.3% (log-rank P = .76) and the corresponding OS rates were 73.7% and 71.4% (log-rank P = .55) in the SOX RT and SOX groups, respectively. Treatment-related adverse events were similar between groups.Conclusions and RelevanceIn this randomized clinical trial of patients with T4 or node-positive gastric cancer who underwent D2 gastrectomy, SOX RT did not significantly improve DFS or OS. Accordingly, among patients with D2-resected gastric cancer, the findings do not support routine addition of adjuvant chemoradiotherapy to chemotherapy.Trial RegistrationChinese Clinical Trial Registry Identifier: ChiCTR-TRC-12002919

4114 Background: Hepatocellular carcinoma (HCC) with lung metastasis carries a dismal prognosis, and effective systemic treatments remain limited. Bispecific antibodies targeting multiple immune checkpoints have emerged as promising therapeutic strategies. This study assessed the efficacy and safety of QL1706, a PD-1/CTLA-4 bispecific antibody, in combination with bevacizumab in patients with HCC and lung metastases. Methods: This was a secondary analysis of a multicenter, phase Ib/II clinical trial. Eligible patients with unresectable, advanced HCC and confirmed lung metastases received QL1706 (5.0 or 7.5 mg/kg, cohort A) or QL1604 (PD-1 antibody, 200 mg, cohort B) plus bevacizumab every three weeks until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) per RECIST v1.1. Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. Results: In cohort A, 15 patients were included in this analysis. At a median follow-up of 19.2 months, the ORR was 53.3% (95% CI, 26.6–78.7) and the DCR was 73.3% (95% CI, 44.9–92.2). Median PFS was 9.9 months (IQR, 1.6–NE), with a 1-year PFS rate of 46.7%, and the 2-year OS was 66.7%. Among the 7 patients with measurable lung target lesions, the ORR was 71.4% (95% CI, 29.0–96.3), including 2 complete responses. In cohort B, 5 patients were included, with a median follow-up of 23.7 months. The ORR was 20.0% (95% CI, 0.5–71.6) and the DCR was 60.0% (95% CI, 14.7–94.7). Treatment-related adverse events occurred in 93.3% of patients in cohort A and 100.0% in cohort B, with grade ≥3 TRAEs observed in 53.3% and 40.0% of patients, respectively. Most adverse events were manageable, and no treatment-related deaths were reported. Conclusions: QL1706 plus bevacizumab demonstrated promising antitumor activity and a manageable safety profile in patients with HCC and lung metastases. The high response rate observed in lung lesions highlights the potential of intensified immunotherapy combined with anti-VEGF therapy for this subgroup, warranting further validation in phase III trials. Clinical trial information: NCT05603039 . Treatment-emergent adverse events of QL1706 / QL1604 and bevacizumab. All grades Grade ≥ 3 Cohort A (N = 15) Cohort B (N = 5) Cohort A (N = 15) Cohort B (N = 5) TEAEs 15 (100.0) 5 (100.0) 10 (66.7) 4 (80.0) irAEs 11 (73.3) 0 2 (13.3) 0 TRAEs 14 (93.3) 5 (100.0) 8 (53.3) 2 (40.0) Associated with QL1706 / QL1604 14 (93.3) 5 (100.0) 6 (40.0) 2 (40.0) Associated with bevacizumab 14 (93.3) 5 (100.0) 8 (53.3) 3 (60.0)

Background A combination of chemotherapy and immune checkpoint inhibitor therapy has been demonstrated to be effective as a first-line treatment of gastric or gastro-oesophageal junction (G/GEJ) cancer. The conventional treatment strategy for patients with advanced/metastatic human epidermal growth factor receptor 2-negative G/GEJ cancer is recommended. However, the response rate and enhancements in survival are still significantly insufficient. The present study will investigate the efficacy and safety of incorporating a bevacizumab biosimilar IBI305 into chemotherapy and immunotherapy as a first-line treatment for advanced or metastatic G/GEJ cancer.Methods and analysis This single-arm, open-label, prospective phase Ib/II clinical study will involve 57 participants. In phase Ib of the trial, patients with advanced or metastatic G/GEJ cancer will receive capecitabine and oxaliplatin (CapeOX) together with sintilimab (200 mg intravenously every 3 weeks) and IBI305 (7.5, 10 or 15 mg/kg intravenously every 3 weeks) in a 3+3 dose-escalation design to evaluate dose-limiting toxicities (DLTs) within 6 weeks of treatment initiation. In phase II, the patients will receive CapeOX combined with sintilimab and IBI305 at the recommended phase II dose. The primary objectives will be to assess DLTs (phase Ib) and the objective response rate (phase II). The secondary objectives will include progression-free survival, overall survival, disease control rate, duration of response, adverse effects, quality of life and safety.Ethics and dissemination The trial protocol was approved by the Ethics Committee of West China Hospital and ClinicalTrials. The final results will be published in a peer-reviewed journal upon completion of the study.Trial registration number NCT05640609.

Gastric cancer remains a major clinical challenge owing to its insidious onset and marked heterogeneity, which contribute to poor prognosis and limit the effectiveness of chemotherapy‑based systemic therapy. Antibody‑drug conjugates (ADCs) deliver potent cytotoxins to tumor cells with antigen specificity and have emerged as a therapeutic class that can enhance efficacy while reducing off‑target toxicity. Recent trials of ADCs targeting HER2, CLDN18.2, TROP2, CEACAM5/6, and HER3 demonstrate substantial therapeutic activity. Notably, the HER2‑directed agents trastuzumab deruxtecan and disitamab vedotin have improved survival and response in previously treated advanced disease. ADCs targeting CLDN18.2 and TROP2 have also yielded encouraging early results. Accumulating evidence from ongoing programs indicates movement into earlier lines of therapy in advanced gastric cancer, including evaluation in first‑line combination regimens. Broader clinical use has highlighted resistance mechanisms, including antigen loss or heterogeneity, impaired internalization and lysosomal processing, increased drug efflux, and an immunosuppressive tumor microenvironment that limits delivery. This review synthesizes clinical advances in ADC therapy for gastric cancer, delineates resistance biology, and evaluates strategies to overcome therapeutic resistance. Deeper mechanistic insight, biomarker‑guided patient selection, and continued innovation in targets, linkers, payloads, and rational combinations will be critical to overcome resistance and improve outcomes for patients with gastric cancer.

Importance:Despite advances in D2 gastrectomy (ie, gastrectomy with D2 lymphadenectomy) and adjuvant chemotherapy, the value of adding postoperative radiotherapy (RT) to adjuvant chemotherapy after D2 gastrectomy remains a topic of ongoing debate. Objective:To assess whether the addition of RT to the S-1 plus oxaliplatin (SOX) chemotherapy regimen increases disease-free survival (DFS) in patients with T4 or node-positive gastric cancer after D2 gastrectomy. Design, Setting, and Participants:This open-label, phase 3 randomized clinical trial was conducted between December 1, 2012, and August 30, 2022, at 5 large tertiary hospitals in China. Eligible patients were aged 18 to 70 years with gastric adenocarcinoma who underwent R0 resection with D2 lymphadenectomy, had pathologic stage T4 or node-positive disease, and had no evidence of metastasis (M0). Intention-to-treat statistical analyses were conducted from January 14 to March 31, 2025. Interventions:Participants were assigned 1:1 to receive concurrent chemoradiotherapy (SOX RT) or chemotherapy alone (SOX). The SOX RT group received 1 cycle of induction SOX, followed by RT (50.4 Gy in 28 fractions) with concurrent S-1 (50 mg twice daily), and then 3 cycles of SOX. The SOX group received 6 cycles of SOX (S-1 30-40 mg/m2 twice daily on days 1-14; oxaliplatin 130 mg/m2 on day 1, every 3 weeks). Main Outcomes and Measures:The primary end point was 3-year DFS. Secondary end points included overall survival (OS) and adverse events. Results:A total of 620 patients were randomly assigned to the SOX group (n = 311) or SOX RT group (n = 309). Patients had a median (IQR) age of 55 (47-62) years and included 401 males (64.7%). Overall, 274 patients (44.2%) had T4 disease, and 590 (95.2%) had node-positive disease. In the primary analysis for the prespecified 3-year DFS end point, there was no evidence of a between-group difference in DFS (SOX RT vs SOX: HR, 0.98; 95% CI, 0.73-1.33). Similarly, there was no evidence of a between-group difference in OS (HR, 0.86; 95% CI, 0.60-1.23). The Kaplan-Meier-estimated 3-year DFS rates were 70.5% in the SOX RT group and 69.3% in the SOX group (log-rank P = .93), and the corresponding 3-year OS rates were 80.8% and 78.4%, respectively (log-rank P = .41). At 5 years, the DFS rates were 60.0% and 57.3% (log-rank P = .76) and the corresponding OS rates were 73.7% and 71.4% (log-rank P = .55) in the SOX RT and SOX groups, respectively. Treatment-related adverse events were similar between groups. Conclusions and Relevance:In this randomized clinical trial of patients with T4 or node-positive gastric cancer who underwent D2 gastrectomy, SOX RT did not significantly improve DFS or OS. Accordingly, among patients with D2-resected gastric cancer, the findings do not support routine addition of adjuvant chemoradiotherapy to chemotherapy. Trial Registration:Chinese Clinical Trial Registry Identifier: ChiCTR-TRC-12002919.

Background:Gastric cancer is one of the most lethal malignancies in the world, but effective therapeutic options for patients with this disease remain limited. Claudin-18.2 (CLDN18.2) has emerged as a promising therapeutic target, yet the functional role of CLDN18.2 and the mechanisms of CLDN18.2-directed immunotherapy remain poorly understood. This study aims to explore the antitumor effects and related mechanisms of the CLDN18.2-CD3 bispecific antibody. Methods:The antitumor efficacy and immunological mechanisms of the CLDN18.2-CD3 bispecific antibody IBI389 were evaluated through two preclinical models: a human peripheral blood mononuclear cell (PBMC)-reconstituted AGS xenograft and a B-hCD3EDG murine KPC pancreatic cancer model. Stable CLDN18.2-overexpressing cell lines were established for in vitro functional assays. Tumor growth inhibition was assessed through volume and weight measurements. Immune modulation was analyzed via flow cytometry, multiplex immunofluorescence, cytokine profiling, and histopathology. Human gastric cancer tissue microarrays were further used to validate spatial findings. Results:CLDN18.2 overexpression enhanced the proliferation and migration of gastric and pancreatic cancer cells in vitro. In vivo, IBI389 significantly suppressed tumor growth, with the greatest efficacy achieved when combined with programmed death-1 (PD-1) blockade. Mechanistically, IBI389 increased the abundance of tumor-infiltrating CD8+ T cells; reshaped the cytokine milieu toward an antitumor profile characterized by elevated interleukin (IL)-2, tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ) levels with concomitant reductions in IL-4, IL-10, and IL-17A; and reduced the spatial distance between CLDN18.2+ tumor cells and CD3+ T cells. These spatial changes were consistent with observations of human gastric cancer tissues. Histopathological analysis of the liver, kidney, and spleen identified no overt drug-related toxicity. Conclusions:In this study, we demonstrated that IBI389 effectively redirects T cells to CLDN18.2-expressing tumors, suppresses tumor growth, and synergizes with PD-1 blockade and has a favorable safety profile. By virtue of its ability to enhance immune infiltration, remodel cytokine responses, and reduce tumor-immune spatial separation, IBI389 may have considerable potential as a novel therapeutic strategy for CLDN18.2-positive gastric cancer and related malignancies.

Sotorasib has introduced new therapeutic opportunities for Kirsten rat sarcoma viral oncogene homolog (KRAS)G12C-mutant tumors, but resistance emerging within months poses a major clinical challenge. Mitogen-activated protein kinase (MAPK) pathway reactivation is a key driver of sotorasib resistance, yet its mechanisms remain incompletely elucidated. We observe that MAPK pathway reactivation following sotorasib treatment is largely independent of RAS activity and instead driven by accumulation of sotorasib-bound KRASG12C (soto-KRASG12C). Mechanistically, accumulated soto-KRASG12C promotes activation of the Rac family small GTPase 1 (RAC1)- p21-activated kinase 1 (PAK1) axis through interaction with DExD/H-box helicase 9 (DHX9), thereby reactivating the MAPK pathway. DHX9 shuttles between the nucleus and cytoplasm, and its interaction with soto-KRASG12C results in its cytoplasmic retention. Co-treatment with an Son of Sevenless 1 (SOS1) inhibitor also leads to sustained suppression of soto-KRASG12C levels. Furthermore, combining sotorasib with either a DHX9 inhibitor or an SOS1 inhibitor significantly enhances its anti-tumor efficacy in both KRASG12C-mutant and sotorasib-resistant models. These findings provide previously uncharacterized mechanistic insights to guide therapeutic strategies aimed at overcoming sotorasib resistance.

Hepatocellular carcinoma (HCC), which accounts for approximately 75–85% of primary liver cancers, ranks 4th in newly diagnosed cases among various types of cancer in China, and is the 2nd leading cause of cancer-related mortality, thereby posing a significant threat to the life and health of the Chinese population. Since the publication of the “Guidelines for Diagnosis and Treatment of Primary Liver Cancer in China” in June 2017, which were updated by the China’s National Health Commission in December 2019 and December 2021, additional high-quality evidence from researchers worldwide regarding the diagnosis, staging, and treatment of HCC has emerged, necessitating another update to the guidelines. The new edition (2024 Edition) was written by more than 120 multidisciplinary experts in the field of HCC in China, which not only reflects the real-world situation in China but also may reshape the nationwide diagnosis and treatment of HCC. The new guideline aims to encourage the implementation of evidence-based practice and improve the national average 5-year survival rate for patients with HCC, as proposed in the “Healthy China 2030: A Vision for Health Care.”

Objectives:Hepatocellular carcinoma (HCC) is among the most frequently occurring malignant tumors of the digestive tract and is associated with an increased mortality rate worldwide. This study aimed to develop and validate a prognostic model based on immunogenic cell death (ICD)-related genes to predict patient survival and guide individualized treatment strategies for HCC. Methods:ICD-related genes were identified from the GeneCards database using a relevance score threshold of >10. A combination of least absolute shrinkage and selection operator (LASSO) regression and multivariate Cox analysis was used to screen prognostic genes and construct a risk score model. Immune cell infiltration was evaluated through single-sample gene set enrichment analysis (ssGSEA) and cell-type identification by estimating relative subsets of RNA transcripts (CIBERSORT) algorithms. Associations between risk groups and the tumor microenvironment (TME), N6-methyladenosine (m6A) regulators, and immune checkpoint expression were analyzed. Drug sensitivity was predicted based on the risk stratification. The reliability of the model was validated in internal cohorts and further confirmed by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC). Results:A six-gene signature (CFHR3, G6PD, IGHM, KPNA2, PON1, and SERPINE1) was identified and used to calculate the risk scores. This study found that high-risk patients exhibited significantly poorer overall survival in both the training and validation datasets. The nomogram integrating the risk score and clinical factors showed strong predictive performance. High-risk patients demonstrated reduced immune cell infiltration, altered expression of immune checkpoints and immunosuppressive factors, and a distinct m6A modification pattern, suggesting a higher likelihood of immune escape. This study also revealed that the risk model effectively predicted sensitivity to multiple anticancer drugs. Conclusion:This study developed a robust ICD-related six-gene prognostic model for HCC that can accurately stratify patient risk, reflect the tumor immune landscape, and provide guidance for immunotherapy and personalized treatment strategies.

2604 Background: Immunotherapy in combination with antiangiogenic agents has shown promising antitumor activity compared with either agent alone. We report efficacy and safety data from the final analysis of the phase 2 BGB-A317-Fruquintinib-201 trial evaluating the programmed cell death-1 antibody TIS combined with the selective vascular endothelial growth factor receptor (VEGFR)-1, -2, and -3 inhibitor F in pts with advanced solid tumors. Methods: This was an open-label, multicenter, two-part study with a safety run-in followed by dose-expansion. Eligible pts were adults with advanced or metastatic unresectable gastric cancer (GC), microsatellite stable colorectal cancer (MSS CRC), or locally advanced surgery-/radiotherapy-ineligible and programmed death ligand-1–positive (PD-L1+; defined as PD-L1 ≥1%) stage IIIB/IV non-small cell lung cancer (NSCLC). F 5 mg daily (3 weeks on, 1 week off) plus TIS (300 mg IV Q4W) was administered as second-line therapy for pts with GC, third-line therapy for pts with MSS CRC, and first-line therapy for pts with PD-L1+ NSCLC. The primary outcome measure was overall response rate (ORR) per RECIST v1.1. Secondary endpoints included other efficacy measures and safety. Results: The median study follow-up was 11.6 months (mo; range, 0.4-32.8). A total of 84 pts were enrolled (GC, n=31; MSS CRC, n=31; PD-L1+ NSCLC, n=22). One study treatment component-related death was reported in the GC cohort and 1 in the PD-L1+ NSCLC cohort. The recommended phase 2 dose was established at F 5 mg daily (3 weeks on, 1 week off) in combination with TIS with no observed dose-limiting toxicities. Efficacy and safety are reported in the Table. Any-grade treatment-emergent adverse events (TEAEs) occurred in 83 (98.8%) pts; proteinuria (32.1%), hypoalbuminemia (27.4%), and hypothyroidism (25.0%) were most common. 9/32 (10.7%) pts had grade ≥3 immune-mediated AEs. Conclusions: Despite the limited sample size, TIS+F demonstrated moderate antitumor activity in pts with advanced solid tumors, with manageable safety observed in pts with GC and MSS CRC. Further investigation of TIS+F is warranted in the GC and MSS CRC settings. Clinical trial information: NCT04716634 . GC (N=31) MSS CRC (N=31) PD-L1+ NSCLC (N=22) ORR, n (%) 4 (12.9) 3 (9.7) 9 (40.1) Disease control rate, n (%) 23 (74.2) 23 (74.2) 15 (68.2) Clinical benefit rate, n (%) 10 (32.3) 12 (38.7) 13 (59.1) Median progression-free survival, mo (95% CI) 4.6 (3.4, 7.4) 4.6 (3.6, 7.2) 15.6 (1.8, NE) Median overall survival, mo (95% CI) 10.5 (5.2, 14.6) 10.0 (4.7, 15.2) NR (6.0, NE) Median duration of response, mo (95% CI) NR (5.6, NE) 11.9 (3.7, NE) NR (7.7, NE) Grade ≥3 TRAE, n (%) 10 (32.3) 12 (38.7) 14 (63.6) Serious TRAE, n (%) 3 (9.7) 3 (9.7) 9 (40.9) TEAE leading to discontinuation of any study treatment, n (%) 5 (16.1) 3 (9.7) 7 (31.8) CI, confidence interval; NE, not evaluable; NR, not reached.

Objective: To illustrate the potential role of SMARCAL1 on malignancy, immune regulation and related pathway in liver cancer. Methods: In our study, we examined the expression patterns, clinical features and survival analysis from TCGA and GEO datasets. Immunedeconv package was employed for evaluating the association between the immune infiltration components and SMARCAL1 expression. Knockdown experiment was performed to examine the impacts of SMARCAL1 on cell viability, apoptosis, and classical Hippo-YAP pathway. Meanwhile, the association between SMARCAL1 expression and drug sensitivity was constructed through CTRP, PRISM and GDSC databases. Finally, we also discovered novel inhibitors of SMARCAL1 activity against liver cancer and YAP activity through virtual screening and western blot assay. Results: SMARCAL1 exhibited increased expression in LIHC and was linked to unfavorable outcomes for patients. SMARCAL1 expression was associated with specific clinical features, drug sensitivity, and immune microenvironment characteristics. Additionally, SMARCAL1 was closely related to the activity of Hippo-YAP pathway. Finally, deferoxamine mesylate and its parent compound deferoxamine were identified as candidate inhibitors of SMARCAL1 activity, showing significant ability to inhibit proliferation and the downstream protein YAP1. Conclusion: Targeting SMARCAL1 could be a promising strategy for liver cancer treatment.

Kirsten rat sarcoma (KRAS) is frequently mutated in colorectal cancer (CRC). In recent years, mutant KRAS has shed its “undruggable” label, with two clinically approved inhibitors now available. Besides aberrantly activating intrinsic tumor cell growth signaling, oncogenic KRAS contributes to the development of an immunosuppressive tumor microenvironment (TME), especially in CRC. This suggests KRAS inhibition may enhance responsiveness to immunotherapy, supporting the rationale for combining mutant KRAS inhibitors with immune checkpoint blockade (ICB). Mutant KRAS is considered as an ideal immunological target. Emerging therapeutics, including vaccines, TCR-T cell therapies and antibodies, are being developed to treat KRAS-mutant CRC patients that leverage peptides or peptide/major histocompatibility complex class I (MHC-I) complexes generated by mutant KRAS. Here, we provide an overview of targeting mutant KRAS in CRC immunotherapy, discussing challenges and future directions.

Objectives:For advanced ovarian cancer (OC), particularly OC with HR-deficient, surgery combined with adjuvant chemotherapy and maintenance therapy with PARPi/bevacizumab is the standard effective first-line treatment regimen. However, the clinical benefit of therapy for HR-proficient advanced OC is limited, with no significant increase in the 5-year survival rate. Methods:In this case study, a patient with Stage IVB OC, who tested HR-proficient, but PD-L1 positive, experienced significant tumor shrinkage (>90 %) after undergoing 3 cycles of neoadjuvant chemotherapy using TC (Paclitaxel with Carboplatin) with Cadonilimab (a PD-1/CTLA-4 bispecific antibody) therapy. Results:This resulted in an R0 resection during intermittent debulking surgery. After surgery, while the patient received standard first-line chemotherapy with TC + bevacizumab, the CA125 level failed to normalize. Nonetheless, upon readministration of Cadonilimab, CA125 levels normalized and have been maintained to date. The patient has remained free of recurrence and metastasis for more than 23 months after neoadjuvant therapy, before the data cutoff date, March 10, 2025. Conclusions:This case illustrates that individuals suffering from advanced OC, particularly those with HR-proficient and PD-L1 positive status, may benefit from first-line treatment with Cadonilimab. Identifying the population that may benefit from immune therapy is crucial. The novel PD-1/CTLA-4 bispecific antibody merits further attention for managing advanced epithelial ovarian cancer.Trial registration: NCT05430906, registration date: June 20,2022.

Donafenib, a deuterium-modified sorafenib derivative, has improved survival outcomes in patients with advanced hepatocellular carcinoma (HCC). This study aimed to investigate the treatment-related adverse events and their associations with overall survival (OS) and time to progression (TTP) in patients with advanced HCC treated with donafenib. In this retrospective analysis, data from 334 patients with unresectable or metastatic HCC who had a Child–Pugh liver function score ≤ 7 and had not received prior systemic treatment were collected from the ZGDH3 study. Donafenib (0.2 g) was administered orally twice daily until either intolerable toxicity or disease progression occurred. The associations between adverse events (AEs) and OS/TTP were analyzed using the Kaplan–Meier method, and statistical significance was tested using the log-rank test. A stratified Cox proportional hazards model was used to estimate hazard ratios (HR) and 95

Sorafenib (Sora) is a first-line treatment for patients with advanced hepatocellular carcinoma (HCC). It can significantly improve the survival rate of patients with advanced HCC, but it is prone to drug resistance during treatment, so the therapeutic effect is extremely limited. Here, we demonstrate that an elevated expression of protein kinase p38γ in hepatocellular carcinoma cells diminishes the tumor cells’ sensitivity to Sora. Pirfenidone (PFD) can augment Sora’s inhibitory effect on hepatocellular carcinoma by specifically targeting p38γ. Our study further uncovers that pirfenidone can synergistically boost the anti-hepatocellular carcinoma impact of Sora by impeding the autophagy heightened by p38γ. Taken together, our findings suggest that pirfenidone can work in concert with Sora to intensify its anti-tumor effect on hepatocellular carcinoma, thereby offering a novel therapeutic approach for Sora-mediated tumor treatment. PFD is an inhibitor of p38γ, which may affect the Beclin pathway by inhibiting the function of p38γ, thereby inhibiting the level of autophagy, and ultimately achieving the effect of sensitizing Sora. Created with BioRender.com Graphical Headlights

Approximately 50% of B-ALL patients exhibit Blinatumomab (CD3/CD19 bispecific T-cell engager, BiTE) resistance, often with high tumor PD-L1 expression, limiting therapeutic efficacy. Combining Blinatumomab with PD-L1 blockade is promising but hindered by continuous infusion, short half-life, and high costs. We developed an economical, non-viral, single-dose intramuscular plasmid gene delivery for sustained (≥4 weeks) in vivo co-expression of CD3/CD19 BiTE and PD-L1 antibodies. This platform integrates T-cell-mediated cytotoxicity, immune checkpoint blockade, and antibody-dependent cytotoxicity. This strategy induced substantial leukemia cell regression, achieving an 80% complete remission (CR) rate in CD19⁺/PD-L1⁺ Nalm-6 xenografts and a 40% CR rate in the CD19 antigen-loss immune escape model. Anti-leukemic efficacy correlated with enhanced CD3⁺, CD8⁺ T-cell, CD3⁺CD56⁺ NKT-like cell expansion, and increased granzyme B/IFN-γ levels. Furthermore, in vivo-produced antibodies promoted B-ALL patient-derived CD3⁺ T-cell proliferation and CD19⁺ tumor cell clearance. This study presents a cost-effective, durable, and potent in vivo immunotherapy integrating T-cell engagement and PD-L1 blockade, offering a promising translational approach for B-ALL.

BackgroundGastric cancer (GC) is one of the most prevalent malignant tumors worldwide, often diagnosed at an advanced stage with a poor prognosis. Paclitaxel, nab-paclitaxel, and irinotecan, either as monotherapies or in combination with ramucirumab, are currently standard second-line treatments for GC. However, the efficacy of these therapies is limited, necessitating the development of new combination strategies to improve response rates. Immune checkpoint inhibitors (ICIs) have shown success in first-line treatment for advanced GC, leading to interest in immune rechallenge strategies for second-line treatment. Re-challenging patients with ICIs after progression on first-line treatment may restore immune responses and provide additional clinical benefit. Recently, cadonilimab (AK104), a bispecific antibody targeting PD-1 and CTLA-4, has demonstrated promising antitumor activity when combined with chemotherapy in advanced gastric and gastroesophageal junction (GEJ) adenocarcinoma. However, the efficacy and safety of nab-paclitaxel combined with AK104 for the treatment of advanced GC remain unclear. Furthermore, identifying predictive biomarkers of efficacy is essential to developing personalized treatment strategies. This study aims to explore the safety and efficacy of nab-paclitaxel combined with AK104 as a second-line treatment for patients who have progressed after first-line chemoimmunotherapy, focusing on evaluating the therapeutic effect of ICIs rechallenge in gastric cancer.MethodsThis is a prospective, multicenter, open-label, single-arm Phase II clinical study. Eligible patients were histologically or cytologically diagnosed with unresectable recurrent or metastatic GC, failed first-line chemotherapy in combination with immune checkpoint inhibitor, aged between 18-75 years old, expected survival ≥3 months, and with a physical status of 0 or 1 in the Eastern Cooperative Cancer Group (ECOG). Enrolled patients will receive intravenous cadonilimab (AK104) 6 mg/kg on days 1, and 15, and intravenous nab-paclitaxel 100 mg/m2 every four weeks on days 1, 8, and 15. The primary endpoints were objective response rate (ORR), and secondary endpoints were disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). The exploratory objective was to identify biomarkers associated with efficacy, mechanism of action, and safety. A total of 59 participants were planned to be recruited using Simon’s two-stage design. The trial was initiated in June 2024 in China.DiscussionThis study is the first prospective trial to evaluate the combination of nab-paclitaxel and cadonilimab as second-line treatment after first-line chemoimmunotherapy failure. By investigating immune rechallenge, it aims to reactivate anti-tumor immune responses and improve clinical outcomes in GC patients. The exploration of predictive biomarkers, such as ctDNA, TMB, MSI, PD-L1 expression, TIL profiles, and gut microbiota, will help personalize treatment and identify patients most likely to benefit from immune rechallenge. This trial could provide valuable insights into overcoming immune resistance and contribute to developing a promising second-line therapeutic strategy for advanced GC.Clinical trial registrationClinicalTrials.Gov, identifier NCT06349967

BACKGROUND:Immunotherapy combined with chemotherapy has become the standard treatment for HER2-negative gastric cancer (GC), but its clinical benefits remain limited, with a median progression-free survival (mPFS) of 6-8 months and median overall survival (mOS) of 15-18 months. These outcomes are particularly poor in patients with CPS < 1. The marked heterogeneity of GC, along with primary and secondary resistance, presents significant clinical challenges and underscores the urgent need for novel therapeutic strategies. RECENT ADVANCES:To address these limitations, several combination therapies are being explored. Anti-VEGF therapy combined with immune checkpoint inhibitors (ICIs) has shown synergistic effects by enhancing immune cell infiltration and reducing tumor-mediated immunosuppression, thereby improving response rates and survival. Radiotherapy combined with ICIs also holds promise, with low-dose radiation remodeling the tumor microenvironment and high-dose radiation inducing immunogenic cell death. Other potential combinations include PD-1/PD-L1 inhibitors paired with targeted therapies against HER2, FGFR2, DKK1, PARP, LSD1, HDAC, and other emerging targets. Novel approaches such as hyperbaric oxygen therapy, oncolytic viruses, metabolic modulators, and fecal microbiota transplantation are also under investigation to further enhance immune responses. CONCLUSION:These multimodal strategies represent a promising shift toward personalized, mechanism-driven immunotherapy sensitization. By targeting diverse pathways to overcome immune resistance, they aim to reshape the tumor microenvironment, restore immune responsiveness, and improve outcomes in GC. While many remain in early-stage development, accumulating evidence supports their potential. Future research should prioritize optimizing combination regimens, clarifying resistance mechanisms, and identifying predictive biomarkers through multi-omics and artificial intelligence to enable more precise, individualized immunotherapy.