Most membrane-bound organelles have been linked to the initiation and execution of ferroptosis. However, the role of the Golgi apparatus and its resident proteins in ferroptosis remain elusive. Here we show that ferroptosis inducer triggers rapid oxidation of Golgi membrane lipids in the early phase of ferroptosis, resulting in disruption of Golgi pH. The Golgi-localized transmembrane protein TMEM87A is identified to mediate ferroptosis resistance through buffering Golgi pH. Depletion of TMEM87A leads to Golgi overacidification, which impairs FSP1-mediated reduction of coenzyme Q. In vivo, TMEM87A ablation suppresses the progression of multiple murine tumors including melanoma, colorectal cancer and liver cancer. TMEM87A ablation also enhances antitumor T cell responses and potentiates PD1 blockade therapy. Clinically, tumoral TMEM87A expression negatively correlates with immunotherapy response and treatment outcome. Our study reveals that TMEM87A functions as a suppressor of tumoral ferroptosis by maintaining Golgi pH homeostasis and targeting TMEM87A is potent to augment cancer immunotherapy.

QuestionIs anti-programmed cell death 1 therapy effective and safe as first-line therapy in patients with advanced melanoma predominantly of acral subtype?FindingsIn this phase 3 randomized clinical trial of 256 patients with advanced melanoma (160 acral subtype [62.7%]), toripalimab as first-line therapy significantly improved blinded independent central review-assessed progression-free survival compared with dacarbazine with an acceptable safety profile.MeaningToripalimab could be used as a new first-line treatment option for advanced melanoma, particularly where acral cutaneous melanoma is the predominant subtype. ImportanceProgrammed cell death 1 (PD-1) inhibitors have been the standard first-line treatment for advanced melanoma; however, their clinical benefit in advanced melanoma predominantly of acral subtype remains unclear.ObjectiveTo evaluate the efficacy and safety of toripalimab (a PD-1 inhibitor) vs dacarbazine as the first-line treatment in advanced melanoma predominantly of acral subtype.Design, Setting, and ParticipantsThis multicenter, open-label, positive-control phase 3 randomized clinical trial enrolled patients with advanced melanoma from January 22, 2018, to July 12, 2023. Eligible patients had histologically confirmed stage III or IV melanoma and no prior systemic therapy for advanced melanoma. Data were analyzed from September 23 to November 27, 2023.InterventionPatients were randomized (1:1) to receive toripalimab, 240 mg, every 2 weeks for up to 2 years, or dacarbazine, 1000 mg/m2, every 3 weeks until disease progression or intolerable toxic effects. Patients in the dacarbazine group were allowed to receive toripalimab after radiographic disease progression.Main Outcomes and MeasuresProgression-free survival (PFS) assessed by blinded independent central review (BICR) per Response Evaluation Criteria in Solid Tumors, version 1.1.ResultsThe analysis included 256 patients (median [range] age, 58 [18-85] years; 113 females [44.3%] and 142 males [55.7%]), among whom 160 participants (62.7%) had acral melanoma; 127 were randomized to receive toripalimab and 128 to dacarbazine (1 patient was excluded for Good Clinical Practice violation). The median (range) follow-up period was 11.8 (0.1-62.5) months. Toripalimab significantly reduced the risk of disease progression or death by 29.2% (hazard ratio, 0.71; 95% CI, 0.53-0.95; P = .02) compared with dacarbazine as assessed by BICR . Consistent PFS benefit was observed in most predefined subgroups, including patients with acral subtype. The BICR-assessed objective response rate of 11.0% (95% CI, 6.2%-17.8%) vs 8.6% (95% CI, 4.4%-14.9%), and the median duration of response of 13.8 (95% CI, 5.9-not evaluable) months vs 6.9 (95% CI, 3.8-not evaluable) months, respectively, also favored toripalimab over dacarbazine. Grade 3 or worse treatment-related adverse events occurred in 36 patients (28.3%) receiving toripalimab, with the most common (>= 3%) being increased lipase (11 patients [8.7%]), anemia (5 patients [3.9%]), increased gamma-glutamyltransferase (4 patients [3.1%]), hyponatremia (4 patients [3.1%]), and increased blood triglycerides (4 patients [3.1%]).Conclusions and RelevanceThis phase 3 randomized clinical trial found that as a first-line treatment for advanced melanoma predominantly of acral subtype, toripalimab showed a significant PFS benefit over dacarbazine and an acceptable safety profile.Trial RegistrationClinicalTrials.gov Identifier: NCT03430297 This randomized clinical trial evaluates the efficacy and safety of toripalimab vs dacarbazine as the first-line treatment in advanced melanoma predominantly of acral subtype.

Hypoxia, a hallmark of solid tumors, drives malignant progression and represents a major therapeutic challenge. Metabolic reprogramming induced by hypoxia creates unique metabolic vulnerabilities that can be exploited therapeutically. Here, we systematically compared the metabolic network differences between hypoxic and normoxic cells, and developed DepFormer, a transformer-based deep learning model, to nominate hypoxia-dependent metabolic genes in tumor cells. Oxidative phosphorylation was identified as the most significantly hypoxia-dependent metabolic pathway, and FLAD1 was predicted to be one of the key hypoxia-dependent metabolic genes. FLAD1 locus is amplified, and FLAD1 expression is upregulated across various tumor types, especially in hypoxic tumors. FLAD1 depletion disrupts activity of mitochondrial complex II, causing succinate/fumarate imbalance, which in turn prevents cancer cells from adapting to hypoxia. We further identified a drug-like inhibitor of FLAD1, which selectively inhibits growth of hypoxic tumor cells. Our study establishes DepFormer as an effective framework for predicting state-specific metabolic dependencies and reveals FLAD1 as a metabolic vulnerability and an innovative therapeutic target for hypoxic tumors.

Importance:Programmed cell death 1 (PD-1) inhibitors have been the standard first-line treatment for advanced melanoma; however, their clinical benefit in advanced melanoma predominantly of acral subtype remains unclear. Objective:To evaluate the efficacy and safety of toripalimab (a PD-1 inhibitor) vs dacarbazine as the first-line treatment in advanced melanoma predominantly of acral subtype. Design, Setting, and Participants:This multicenter, open-label, positive-control phase 3 randomized clinical trial enrolled patients with advanced melanoma from January 22, 2018, to July 12, 2023. Eligible patients had histologically confirmed stage III or IV melanoma and no prior systemic therapy for advanced melanoma. Data were analyzed from September 23 to November 27, 2023. Intervention:Patients were randomized (1:1) to receive toripalimab, 240 mg, every 2 weeks for up to 2 years, or dacarbazine, 1000 mg/m2, every 3 weeks until disease progression or intolerable toxic effects. Patients in the dacarbazine group were allowed to receive toripalimab after radiographic disease progression. Main Outcomes and Measures:Progression-free survival (PFS) assessed by blinded independent central review (BICR) per Response Evaluation Criteria in Solid Tumors, version 1.1. Results:The analysis included 256 patients (median [range] age, 58 [18-85] years; 113 females [44.3%] and 142 males [55.7%]), among whom 160 participants (62.7%) had acral melanoma; 127 were randomized to receive toripalimab and 128 to dacarbazine (1 patient was excluded for Good Clinical Practice violation). The median (range) follow-up period was 11.8 (0.1-62.5) months. Toripalimab significantly reduced the risk of disease progression or death by 29.2% (hazard ratio, 0.71; 95% CI, 0.53-0.95; P = .02) compared with dacarbazine as assessed by BICR . Consistent PFS benefit was observed in most predefined subgroups, including patients with acral subtype. The BICR-assessed objective response rate of 11.0% (95% CI, 6.2%-17.8%) vs 8.6% (95% CI, 4.4%-14.9%), and the median duration of response of 13.8 (95% CI, 5.9-not evaluable) months vs 6.9 (95% CI, 3.8-not evaluable) months, respectively, also favored toripalimab over dacarbazine. Grade 3 or worse treatment-related adverse events occurred in 36 patients (28.3%) receiving toripalimab, with the most common (≥3%) being increased lipase (11 patients [8.7%]), anemia (5 patients [3.9%]), increased γ-glutamyltransferase (4 patients [3.1%]), hyponatremia (4 patients [3.1%]), and increased blood triglycerides (4 patients [3.1%]). Conclusions and Relevance:This phase 3 randomized clinical trial found that as a first-line treatment for advanced melanoma predominantly of acral subtype, toripalimab showed a significant PFS benefit over dacarbazine and an acceptable safety profile. Trial Registration:ClinicalTrials.gov Identifier: NCT03430297.

Situs inversus totalis (SIT) is a rare congenital laterality anomaly characterized by complete mirror-image transposition of the thoracic and abdominal viscera. Although SIT is not a proven cancer-predisposition syndrome, cancer in this setting challenges the spatial assumptions that guide diagnosis, staging, surgery, radiotherapy, and surveillance. We conducted a retrospective, single-center observational study of patients with radiologically confirmed SIT treated at our cancer center between July 2017 and December 2025. Patients with histologically confirmed malignancy were included. Clinical, pathological, imaging, treatment, and follow-up data were extracted from medical records. Overall survival (OS) was summarized descriptively; Kaplan-Meier analysis was used only to visualize survival and censoring patterns. Among 11 patients with SIT, 6 had histologically confirmed malignancies. Median age was 66.5 years (range, 47–76), and median follow-up was 47.5 months (range, 30–55). Tumors included hepatocellular carcinoma, lung squamous cell carcinoma, lung adenocarcinoma, cervical adenocarcinoma, poorly differentiated abdominal adenocarcinoma, and follicular lymphoma transformed to high-grade B-cell lymphoma. Treatment included surgery, radiotherapy, chemotherapy, immunotherapy, targeted therapy, transarterial chemoembolization, and autologous stem cell transplantation. 4 patients died, and 2 were alive at last contact. Pooled median OS was 50 months and was interpreted only descriptively. Across cases, outcomes reflected tumor type, stage, and molecular features, whereas SIT mainly affected lesion localization, laterality recognition, nodal or vascular mapping, operative orientation, and treatment planning. Malignancy in SIT is best understood as cancer within a reversed anatomical coordinate system. Standard oncologic care remains feasible but requires explicit anatomical verification and multidisciplinary planning.

PURPOSE:This study aims to evaluate the value of contrast-enhanced ultrasound (CEUS) for assessing the response of osteosarcoma (OS) to neoadjuvant chemotherapy (NAC). METHODS:A total of 84 patients with OS were recruited prospectively between July 2020 and April 2024. All patients received NAC and surgical treatment, and underwent CEUS before and after NAC, respectively. Time intensity curve was used to analyze tumor parameters, including time to peak intensity (TPI), peak intensity (PI), area under curve (AUC) and gradient of PI (Grad). RESULTS:After NAC, the PI, AUC and Grad have decreased, and the degrees of decline were more significant in good response patients. Univariable and multivariable logistic regression analyses identified PI% as a significant and independent indicator of good response to NAC (OR = 1.064, 95% CI: 1.033, 1.097, p < 0.001). A cutoff value of 24.44% of PI% revealed the AUC, sensitivity, specificity, positive and negative predictive values were 0.848, 93.1%, 72.7%, 64.3%, 95.2%, respectively (p < 0.005). The negative likelihood ratio and positive likelihood ratio are 0.09 and 3.41. The repeatability of CEUS parameters, inter-observer and intra-observer were good. The Bland-Altman analysis of TPI, PI, AUC and Grad showed smaller biases and narrower consistency limits. CONCLUSION:CEUS can effectively evaluate the pathological response of OS after NAC, and PI% is a sensitive indicator.

The urgent need for single-dose vaccines to combat infectious diseases in resource-limited regions has driven the development of a novel polysaccharide-enhanced delivery platform. In this study, a single-dose vaccine platform has been successfully built, which employed the Hepatitis B surface antigen as the model antigen, and the dimethyl-dioctadecyl-ammonium bromide/poly (lactic acid) (DDAB/PLA) nanoparticles (NPs) as delivery and adjuvant systems. Subsequently, alginate, a biocompatible polysaccharide, was utilized to fabricate composite microcapsules (MCs) via spray-drying, named Ag@NPs + Ag@NPs-MCs, enabling dual antigen delivery: sustained release from alginate-encapsulated Ag@NPs and immediate release of free HBsAg. The mice immunized with the single-dose vaccine induced a sustained increase in antibody levels, promoted cytokines secretion, and greatly improved immune memory T/B cells during the six-month evaluation of sustained immunity. The single-dose vaccine also induced effective short-term immune protection. These immune-boosting effects could be attributed to the vaccine formulations regulating antigen release behavior and the antigen-depot effect at the injection. Therefore, Ag@NPs + Ag@NPs-MCs is a promising platform for a single-dose vaccine against infection.

Tenosynovial giant cell tumors (TGCTs), a rare benign mesenchymal neoplasm of synovial tissue, often incurs chronic pain, joint destruction and repeated surgery, markedly impairing quality of life. Historically, surgery was the only effective option. The colony-stimulating factor 1 receptor (CSF1R) inhibitor pexidartinib broke this therapeutic deadlock, pioneering systemic therapy and shaping subsequent drug development. Further exploration of pexidartinib and associated clinical studies in the field of TGCT have continued following its approval, with updated data and outcomes continuing to play a crucial role in guiding the clinical application of pexidartinib for treatment of TGCT. This review provides a comprehensive summary of the preclinical and clinical development of pexidartinib for treatment of TGCT, and highlights the recent updates in clinical studies and findings since its approval. These include long-term efficacy, optimization of therapeutic strategies, management of risks associated with long-term use, and real-world patient-reported outcomes, all of importance and value for patients and physicians in clinical practice. Here we aim to provide guidance for the improved clinical application of this drug class to enhance patient benefits in TGCT treatment.

Pleurotus citrinopileatus polysaccharide (PCFP) demonstrates anti-glioma potential. We found that PCFP significantly inhibited the survival rate of glioma cells as determined by MTT assay. Additionally, 100 mg/kg PCFP significantly inhibited the growth of U251 tumors in nude mice xenograft models, with a tumor inhibition rate of 61.41%; no significant toxicity was observed in organs such as the liver, spleen, or heart. Mechanistically, PCFP upregulated E-cadherin and Cleaved Caspase 3 while downregulating N-cadherin and Bcl-2, and inducing apoptosis. PCFP also suppressed the protein expression of CHI3L1 and regulated the JAK1/STAT1 and NF-kappa B signaling pathways. Additionally, PCFP administration improved intestinal microbiota imbalance, increasing the relative abundance of beneficial bacteria while concomitantly reducing that of harmful ones in tumor-bearing mice. In summary, our results indicated that PCFP has the potential for development as a novel anti-glioma drug that acts by targeting the CHI3L1/JAK1/STAT1/NF-kappa B pathway and ameliorating glioma-induced intestinal dysbiosis.

11529 Background: First-line treatment for osteosarcoma includes various combinations of four agents: high-dose methotrexate (HD-MTX), doxorubicin (DOX), cisplatin (DDP), and ifosfamide (IFO), achieving overall efficacy rate of 41-77% and remaining the most effective systemic therapy to date. However, patients (pts) with progression after first-line therapy lack a defined second-line standard, available treatments yield objective response rate (ORR) <20% with 5-year survival <10%. Though anti-angiogenic tyrosine kinase inhibitors have limited monotherapy efficacy, preclinical studies show they enhance intratumoral drug delivery and reverse multidrug resistance, thereby synergizing with chemotherapy. Thus, apatinib, a highly selective VEGFR-2 inhibitor, was added to the previously failed first-line chemotherapy-the most effective systemic therapy-to investigate whether it could reverse chemoresistance and restore response to the original regimen. Methods: This ambispective cohort study enrolled pts with advanced osteosarcoma who had tumor progression after first-line chemotherapy with HD-MTX, DOX, DDP and IFO at our center. Subsequently, low-dose apatinib (250 mg/d) was administered in combination with the same four-drug chemotherapy regimen. The primary endpoint was the ORR. Secondary endpoints included disease control rate (DCR), median progression-free survival (PFS), median overall survival (OS) and adverse events (AEs). Results: From Jan 2018 to Jul 2025, 37 pts were enrolled, with 9 in the retrospective cohort and 28 in the prospective cohort. Of these, 27 (73%) were male and 10 (27%) were female, with a median age of 21 years (range: 10–67). 36 pts were diagnosed as conventional osteosarcoma (96.9%). Primary tumors were located in the femur (21, 56.8%), tibia and humerus (8, 21.6%), pelvis (6, 16.2%), clavicle and rib (2, 5.4%). Metastatic disease was present in 29 pts (78.4%). The most common sites of metastasis were the lung (28, 78.1%) and bone (6, 18.8%). Partial remission was seen in 8 pts, and stable disease in 23 (ORR: 21.6%, DCR: 83.8%). After a median follow-up of 17 months (mos), PFS was 5.8 mos (2.5–9.1), OS was 14.5 mos (10.3–18.7). Pts with lactate dehydrogenase <245 U/L had superior PFS (7.2 vs 3.3 mos; HR=0.28, 0.1–0.8, P=0.01), with a trend of OS benefit (14.5 vs 11.6 mos, P=0.74). Pts with alkaline phosphatase <150 U/L had a trend of PFS benefit (6.3 vs 5.8 mos, P=0.7) and significant better OS (20.3 vs 11.7 mos; HR=0.41, 0.17–1.01, P=0.046). Prognosis was not associated with gender, age, primary site, stage or first-line therapy response. AEs were consistent with known safety profiles and manageable. Conclusions: Low-dose apatinib combined with previously resistant first-line chemotherapy showed promising efficacy, providing a feasible therapeutic strategy for osteosarcoma pts lacking effective second-line choices.

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

BACKGROUND Human epidermal growth factor receptor 2 (HER2)-negative advanced gastric cancer lacks convenient prognostic biomarkers. Peripheral blood neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR) and systemic immune-inflammation index (SII) reflect tumour inflammatory status. This study hypothesizes the four indicators independently predict overall survival (OS) of such patients. AIM To determine the predictive value of NLR, PLR, LMR, and SII for survival in HER2-negative advanced gastric cancer. METHODS We retrospectively enrolled 262 HER2-negative advanced gastric cancer patients (2021-2024) split into disease control (n = 203) and progression (n = 59) groups. Baseline and inflammatory markers were collected. Kaplan-Meier, Cox regressions, nomogram and receiver operating characteristic curve analyses were performed to assess survival predictors. RESULTS In the disease progress group, the NLR, PLR and SII were significantly higher than in the disease control group, whilst the LMR was significantly lower; the median OS in the disease control group (19.1 months) was significantly longer than in the disease progress group (9.2 months). Multivariate Cox regression analysis revealed that elevated NLR, elevated PLR and elevated SII were independent risk factors for OS, whilst a reduced LMR was an independent protective factor. The nomogram constructed using these four indicators demonstrated good predictive performance, with a combined area under the curve of 0.764 (95% confidence interval: 0.676-0.853). CONCLUSION Pretreatment NLR, PLR, LMR, and SII predict survival in HER2-negative advanced gastric cancer; combined use with a nomogram aids prognosis, screening, and treatment.

Objective: This study aimed to identify neutrophil extracellular trap-related genes (NET-RGs), explore their prognostic significance, and predict drug interactions in peripheral T-cell lymphoma (PTCL).Methods: Differentially expressed NET-RGs (DE-NRGs) between PTCL and normal tissues were screened. Functional enrichment analysis was conducted. Bioinformatics and machine learning were used to identify hub genes and assess their diagnostic value. Univariate and multivariate analyses were used to evaluate prognostic roles. Correlation and immune infiltration analyses were performed to explore relationships with the tumor microenvironment (TME). Clinical data were collected from PTCL patients who received potential agents (lenalidomide) as first-line treatment.Results: A total of 31 DE-NRGs were identified (18 upregulated and 13 downregulated), enriched in inflammatory response, extracellular matrix organization, and infection involvement. Four hub genes (AKT2, MAPK14, IRF1, and TNF) were identified as effective PTCL diagnostic markers. Higher AKT2/MAPK14 expression correlated with poorer overall survival (OS), while elevated TNF expression associated with better OS; AKT2 and TNF independently predicted OS. These genes were implicated in modulating TME remodeling. Potential therapeutic agents (e.g. capivasertib, lenalidomide) were predicted, and lenalidomide may represent a feasible initial treatment option for PTCL, with an objective response rate (ORR) of 40.0% and a maximum survival duration exceeding 50 months.Conclusion: NET-RGs play crucial roles in diagnosis, prognosis, and TME regulation, and lenalidomide, a putative TNF-targeting agent, may represent a feasible initial treatment option in PTCL.

T cell receptors (TCRs) are essential for adaptive immune recognition. Recently, computational tools have been developed to predict the interactions between TCR and epitope, and artificial intelligence models have been proposed to generate the complementarity determining region 3 (CDR3) region of β chain TCR. However, de novo design of experimentally validated, functional, full-length epitope-specific TCRs remains a significant challenge. Here, we developed TcrDesign, a deep learning framework based on large-scale, unlabeled TCR and epitope datasets to generate epitope-specific, full-length TCRs. TcrDesign comprises two modules: TcrDesign-B for TCR-pMHC binding prediction with state-of-the-art accuracy, and TcrDesign-G for functional full-length TCR sequence generation. Pre-trained on large-scale unlabeled datasets using transformer-based architectures, TcrDesign achieves state-of-the-art performance in both TCR-epitope binding prediction and de novo TCR sequence generation. Furthermore, epitope-major histocompatibility complex (MHC) binding and functional activation of TcrDesign-generated TCRs were experimentally validated. TcrDesign provides an efficient and modular approach for designing epitopespecific full-length TCRs, with experimental validation confirming its utility.

BACKGROUND:Combination therapy with vibostolimab plus pembrolizumab has previously shown promising antitumor activity in melanoma. We aimed to evaluate the efficacy and safety of vibostolimab coformulated with pembrolizumab as adjuvant therapy for high-risk resected melanoma. METHODS:This randomised, double-blind, phase 3 study was done at 205 global sites (hospitals and cancer centres). Participants aged 12 years or older with surgically resected, stage IIB-IV cutaneous melanoma per the American Joint Committee on Cancer Cancer Staging Manual 2017 (8th edition), with no evidence of metastatic disease after resection, were randomly assigned (1:1) to receive vibostolimab 200 mg coformulated with pembrolizumab 200 mg or pembrolizumab 200 mg alone intravenously every 3 weeks. Randomisation was done using an interactive response technology system and was stratified by risk-based staging and geographical region. Participants, investigators, and site staff were masked to group assignment. The primary endpoint was recurrence-free survival assessed in the intention-to-treat population. Safety was assessed in all participants who received at least one dose of the study treatment. The protocol-prespecified first interim analysis was an event-driven nonbinding futility analysis of recurrence-free survival that was planned for when 111 events had occurred (futility bar of observed HR 0·95). This study is registered with ClinicalTrials.gov (NCT05665595), and is closed to recruitment. FINDINGS:Between Jan 19, 2023, and March 6, 2024, 1402 participants were randomly assigned to receive coformulated vibostolimab-pembrolizumab (n=701) or pembrolizumab (n=701). At the first interim analysis, median study follow-up, defined as time from randomisation to data cutoff, was 4·2 months (IQR 1·9-6·7). The median age was 61·0 years (IQR 51·0-70·0), 829 (59%) of 1402 participants were male and 573 (41%) were female. 1107 (79%) of participants were White, 273 (19%) were Asian, and 22 (2%) were of other race or race was missing. At the time of the first interim analysis, a total of 119 (8%) of 1402 participants had had a recurrence-free survival event, including 67 (10%) of 701 in the vibostolimab-pembrolizumab group and 52 (7%) of 701 in the pembrolizumab alone group. The median recurrence-free survival was not reached in either group; the hazard ratio for recurrence-free survival in the vibostolimab-pembrolizumab group versus pembrolizumab alone group was 1·25 (95% CI 0·9-1·8). The most common (occurred in more than five participants) grade 3 or higher treatment-related adverse events were adrenal insufficiency in 13 (2%) participants, hepatitis in 11 (2%) participants, rash in 9 (1%) participants, maculopapular rash in 7 (1%) participants, and pruritus in 6 (1%) participants in the vibostolimab-pembrolizumab group and increased alanine aminotransferase in 7 (1%) participants in the pembrolizumab alone group. Treatment-related serious adverse events occurred in 74 (11%) participants and 30 (4%) participants, respectively. Treatment-related adverse events led to death in two (<1%) participants in the vibostolimab-pembrolizumab group (myasthenia gravis and myocarditis) and one participant (<1%) in the pembrolizumab group (myositis). The external data monitoring committee decided to discontinue the study according to prespecified futility criteria. INTERPRETATION:Vibostolimab coformulated with pembrolizumab did not provide additional clinical benefit versus pembrolizumab as adjuvant therapy in participants with resected stage IIB-IV melanoma. Pembrolizumab monotherapy remains a standard of care for resected high-risk melanoma. FUNDING:Merck Sharp & Dohme, a subsidiary of Merck & Co.

2607 Background: ASKG915 is a bifunctional fusion protein of PD-1 antibody fused with an IL-15 prodrug. Preclinical studies demonstrated the efficacy of ASKG915 in neoplastic models. Here, we present updated safety and efficacy results from a first-in-human, dose escalation and dose expansion of ASKG915 monotherapy in patients (pts) with advanced solid tumors. Methods: This open-label, multicenter, Phase 1/2 study in adult pts with advanced unresectable or metastatic solid tumors (NCT05867420) comprised two parts: dose escalation (Part 1) and dose expansion (Part 2). Pts with advanced solid tumors that were resistant/refractory to current standard treatment, and with at least 1 measurable lesion per RECIST 1.1, were eligible. The primary objective was safety. Secondary objectives included efficacy, pharmacokinetics, pharmacodynamics, and immunogenicity. Results: As of December 30, 2025, we have treated 104 pts at dose-escalation phase (n=19) and dose expansion phase (n=85). Primary tumor types included NSCLC (n=48, 46.2%), CRC (n=35, 33.6%), ovarian cancer (n=11, 10.6%), cervical cancer (n=4, 3.8%) and others (n=6, 5.8%). Most pts (83/104, 79.8%) had received two and more lines of prior treatment, and 71 pts (68.3%) had undergone previous immunotherapy. No dose-limiting toxicities was observed in dose escalation phase, and the maximum tolerated dose has not been reached up to 3 mg/kg. In SS set, any-grade treatment-related adverse events (TRAEs) were reported in 98/104 (94.2%) pts, with the most common being rash (39/104, 37.5%), anemia (37/104, 35.6%), and elevated aspartate aminotransferase (19/104, 18.3%). ASKG915 monotherapy exhibited dose-dependent efficacy across dose levels. In the EFR cohort, encouraging antitumor activity was observed at the mid-dose level or above in both late-line NSCLC that had progressed on prior immunotherapy and MSS CRC: a 30% confirmed partial response (PR) rate (3/10) in non-liver metastatic MSS CRC at the mid-dose level or above, and a 30% PR rate (3/10) in NSCLC patients at the high-dose level. Further efficacy data will be presented at the time of the conference. CD8+ T and NK cells demonstrated proliferative expansion at mid-to-high doses. Drug plasma exposure increased dose-dependently with low activated ASKG915 levels and no ADA impact after repeat dosing. Conclusions: ASKG915 demonstrated a promising clinical efficacy in pts with MSS CRC and NSCLC, with a well-tolerated safety profile. These results support further evaluation of ASKG915 as a monotherapy and in combination therapies. Clinical trial information: NCT05867420 .

LBA9509 Background: Tumor-infiltrating lymphocyte (TIL) therapy is effective in advanced melanoma but hampered by toxicity from high-dose IL-2 and lymphodepletion (cyclophosphamide/fludarabine). We explored a modified TIL therapy (GC101) featuring an IL-2-free protocol and a low-intensity preconditioning regimen. This phase II study evaluates the modified GC101 TIL therapy in anti-PD-1-resistant melanoma. Methods: MIZAR-003 (NCT06703398) is a multicenter, phase II, randomized, open-label trial across 25 sites in China enrolling advanced melanoma patients resistant to PD-1 antibodies. Key eligibility: ECOG 0–1, adequate organ function. Exclusion: uveal melanoma, prior cellular therapy within 6 months. A total of 98 patients will be randomized 1:1 to Arm A (GC101 TIL) or Arm B (investigator-choice chemotherapy). GC101 therapy consists of tumor resection, low-intensity preconditioning (cyclophosphamide 20 mg/kg/d, pre-infusion d -5 to- 3; hydroxychloroquine 600 mg, pre-infusion d -5), followed by infusion of IL-2-free TIL and sintilimab (100 mg at infusion, then 100 mg Q6W × 4). Patients in Arm B with IRC-confirmed disease progression may cross over to receive GC101 TIL. The primary endpoint is IRC-assessed PFS per RECIST v1.1. Secondary endpoints include IRC-assessed ORR, CR rate, DOR, and OS; investigator-assessed ORR, PFS, CR rate, DOR, and PFS2; and safety. Results: In this exploratory interim analysis (70% of expected events), 84 patients were randomized (Arm A: 44; Arm B: 40) between 02/2025 and 01/2026, with a median follow-up of 5.2M (range 1.1-12.0). Baseline characteristics were balanced. As assessed by IRC, Arm A significantly improved mPFS (4.1M [95% CI 2.8–5.6] vs 1.6M [95% CI 1.3-4.0]; HR 0.53 [95% CI 0.30-0.94], p=0.0310), ORR (45.2% vs 5.4%; p=0.0018), and DCR (80.6% vs 43.2%; p=0.0017). OS data are immature. In mucosal melanoma (n=6 per arm), mPFS was not reached vs 1.3M, with DCR of 100.0% vs 33.3%. Grade ≥3 treatment-related AEs (TRAEs) occurred in 36.8% (Arm A) vs 27.5% (Arm B); treatment-related SAEs in 13.2% vs 7.5%. No new safety signals were observed, and no TRAEs led to treatment discontinuation or death. Conclusions: GC101 TIL significantly improved PFS and ORR versus investigator-choice chemotherapy in anti-PD-1-resistant melanoma, with manageable safety, supporting its potential as a new later-line therapy. Clinical trial information: NCT06703398 .

TPS9594 Background: Although several immune checkpoint inhibitors have been approved for advanced melanoma, there remain significant unmet clinical needs, particularly for immune-cold subtypes such as mucosal and acral melanoma, which are frequently observed in Chinese patients (pts). IBI363 targets and activates tumor-specific T cells that express both PD-1 and IL-2Rα, leading to enhanced antitumor activity and reduced toxicity. Previous phase 1 studies of IBI363 reported manageable safety profiles with encouraging efficacy in advanced melanoma (2024 ASCO Annual Meeting [9562], ESMO Virtual Plenary [VP4-2024], SITC [1502]). Here, we present the trial in progress of a phase 2 study evaluating efficacy and safety of IBI363 monotherapy versus pembrolizumab in mucosal and acral melanoma. Methods: This multicenter, randomized, controlled, open-label, phase 2 study planned to enroll 180 pts. Main inclusion criteria are: 1) locally advanced unresectable or metastatic mucosal or acral melanoma; 2) no previous systemic treatment for melanoma; 3) at least one measurable tumor lesion (target lesions) per RECIST v1.1. Pts with active or symptomatic central nervous system metastasis are excluded. Pts are randomized in a 1:1 ratio to receive IBI363 1 mg/kg Q2W (with a priming dose of 100 μg/kg administered 7 days before the full dose) in the experimental arm or to receive pembrolizumab 200 mg Q3W in the control arm. Stratification factors include subtype (mucosal vs acral) and M staging (M0 vs M1a(0)/M1b(0) vs M1a(1)/M1b(1) or M1c/M1d, (0) indicating baseline lactate dehydrogenase [LDH] ≤ upper limit normal [ULN] and (1) indicating baseline LDH > ULN). The primary endpoint is progression-free survival (PFS) assessed by independent radiological review committee (IRRC) per RECIST v1.1. The secondary endpoints include investigator-assessed PFS, IRRC-assessed and investigator-assessed objective response rate (ORR), disease control rate (DCR), duration of response (DoR), time to response (TTR) per RECIST v1.1, overall survival (OS), safety, pharmacokinetics (PK) and immunogenicity. No interim analysis is planned. A total of 118 PFS events among 180 pts is estimated to demonstrate the superior efficacy of IBI363 compared to the control, with a power of 90% (α=0.025, one-sided). Clinical trial information: CTR20250280 .