4009 Background: The addition of immune checkpoint inhibitors (ICIs) to chemotherapy (chemo) in the neoadjuvant/adjuvant setting for gastric cancer (GC) has yielded mixed efficacy. Target population and treatment regimen remain to be optimized. This study compared the efficacy of serplulimab (anti-PD-1 antibody) plus chemo versus placebo plus chemo as neoadjuvant therapy and serplulimab versus chemo as adjuvant therapy for resectable GC. Methods: Patients with PD-L1 positive (PD-L1 CPS ≥ 5), histologically confirmed, untreated, resectable gastric or gastroesophageal junction (GEJ) adenocarcinoma were randomized 1:1 to receive 3 cycles of neoadjuvant intravenous (iv) serplulimab (4.5 mg/kg) or placebo, plus chemo (iv oxaliplatin, 130 mg/m 2 and oral S-1, 40-60 mg based on body surface area), followed by post-surgery adjuvant serplulimab monotherapy (up to 17 cycles) or adjuvant chemo (5 cycles), Q3W. The primary endpoint was investigator (INV)-assessed event-free survival (EFS). Efficacy superiority was first evaluated and established in patients with PD-L1 CPS ≥ 10 followed by that in the PD-L1 CPS ≥ 5 population. Results: Between November 26, 2019 and April 19, 2024, 588 patients were enrolled across 57 sites, with 292 randomized to the serplulimab group and 296 to the placebo group. As of the data cutoff date of August 19, 2025 with a median follow-up duration of 35.9 months, INV-assessed median EFS was significantly longer in the serplulimab group (n = 193) than in the placebo group (n = 217) in the PD-L1 CPS ≥ 10 population (not reached [NR], 95% CI 43.0–not estimable [NE] vs. 42.0 months, 95% CI 20.5–NE; HR 0.65, 95% CI 0.47–0.90; p = 0.0082), and in the PD-L1 CPS ≥ 5 population (NR, 95% CI 37.9–NE vs. 35.9 months, 95% CI 21.3–52.0; HR 0.73, 95% CI 0.56–0.94; p = 0.0152), meeting the protocol-specified superior criteria. Blinded independent central review-assessed median EFS was consistent with that of the investigator. Pathological complete response rate was higher in the serplulimab group than in the placebo group (21.6% vs 6.4%; odds ratio 3.95). Median OS was immature in both groups. Grade ≥ 3 treatment-related adverse events (TRAEs) were reported in 136 (46.6%) and 172 (58.5%) patients in the serplulimab and placebo groups, respectively. Discontinuation of any component of the study regimen due to TRAEs occurred in 19 (6.5%) and 31 (10.5%) patients in the respective groups. Conclusions: Neoadjuvant serplulimab plus chemo, followed by adjuvant serplulimab monotherapy, significantly prolonged EFS in patients with PD-L1-positive, resectable GC or GEJ adenocarcinoma. Improvements in other efficacy endpoints were also observed along with a favorable safety profile compared to neoadjuvant/adjuvant chemo. This world-first chemotherapy-free regimen (adjuvant) represents a promising treatment option for this indication. Clinical trial information: NCT04139135 .

Whether to change adjuvant regimen after ineffective neoadjuvant chemotherapy in locally advanced gastric cancer (LAGC) remains unclear. We conducted an exploratory study on whether graded histologic regression (GHR) < 50

The integration of intelligent consumer electronics into FemTech offers unprecedented opportunities for personalized oncology. However, deploying multimodal wearable systems to monitor treatment responses in specific molecular subtypes, such as RAS/RAF-wildtype colorectal cancer (CRC) in women, requires stringent privacy safeguards and clinical interpretability on edge devices. This paper presents ExplainCRC, an edge-deployable, privacy-preserving consumer wearable framework tailored for the efficacy stratification of female patients with RAS/RAF-wildtype CRC. ExplainCRC fuses consumer-grade sensor streams—photoplethysmography (PPG), electrodermal activity (EDA), skin temperature, and acceleration—into a unified representation using a multilayered attention encoder network. To establish trust with clinical experts and female patients, we employ layer-wise relevance propagation (LRP) to quantify the temporal contributions of each sensor stream to health outcome predictions. Addressing the critical privacy demands of women’s health data, the system leverages federated learning secured by a Gaussian differential privacy mechanism (ϵ = 2.8, δ = 10−5). Furthermore, we developed a mixed-precision model compression pipeline optimizing ExplainCRC for seamless execution on mobile platforms. Extensive evaluations across three public datasets—WESAD, PPG-DaLiA, and TCGA-COAD (utilizing genomic features as static surrogates for outcomes in a 3-category scheme)—demonstrate robust performance. Explain-CRC achieves a high explanation fidelity (0.867 and 0.843 on the two wearable benchmarks; 0.863 averaged across all three), and its throughput on a mid-range mobile platform reaches 21.4 frames per second for the compressed model (12.8 FPS for the full model), a 1.67× latency reduction relative to its own uncompressed counterpart. These technical results motivate, but do not yet establish, a path toward home-based monitoring of targeted-therapy responses, which will require dedicated clinical data collection and validation.

368 Background: Co-inhibition of lymphocyte activation gene-3 (LAG-3) and programmed cell death protein-1 (PD-1) may enhance antitumor responses for patients (pts) with advanced/metastatic esophageal squamous cell carcinoma (ESCC). We evaluated the efficacy and safety of LBL-007, a novel, fully human anti-LAG-3 IgG4 monoclonal antibody (mAb), with tislelizumab (TIS), a humanized IgG4 anti-PD-1 mAb, and chemotherapy (CT) in pts with unresectable, locally advanced/metastatic ESCC, regardless of baseline PD-L1 status. Methods: In this phase 2, randomized, active-controlled, open-label trial (NCT06010303), pts ≥18 years with ECOG PS ≤1 and no prior systemic therapy were randomized 2:1 to LBL-007 (600 mg IV Q3W) + TIS (200 mg IV Q3W) + CT (Arm A; A) or TIS (200 mg IV Q3W) + CT (Arm B; B); CT was 60-80 mg/m 2 cisplatin + 750-800 mg/m 2 5-FU or 175 mg/m 2 paclitaxel IV Q3W. Primary endpoint was overall response rate (ORR) per investigator-assessed RECIST v1.1. Secondary endpoints were progression-free survival (PFS), duration of response (DoR), disease control rate (DCR), and incidence and severity of treatment-emergent adverse events (TEAEs). Results: As of May 30, 2025, 118 pts were randomized (A: n=78; B: n=40). Median age (range) was 61.5 (44-80) years in A and 65.5 (46-80) in B; 85.9% of pts in A and 87.5% in B were male. Median follow-up (range) was 12.5 (0-18.5) months (mo) in A and 11.5 (0.4-18.8) in B. Confirmed ORR (95% CI) was 61.5% (49.8-72.3) in A and 60.0% (43.3-75.1) in B (Table). Median PFS (95% CI) was 8.2 (5.7-9.2) mo in A and 6.9 (5.6-8.2) in B (HR, 0.85 [95% CI, 0.54-1.34]; P =0.4753). The most common TEAEs were anemia (A: 63 [81.8%]; B: 27 [67.5%]), neutrophil count decreased (A: 53 [68.8%]; B: 24 [60.0%]) and WBC count decreased (A: 48 [62.3%]; B: 21 [52.5%]). Grade ≥3 treatment-related TEAEs occurred in 77.9% of pts in A and 65.0% in B. TEAEs led to discontinuation in 23 (29.9%) pts in A and 11 (27.5%) in B, and to death in 2 (2.6%) and 2 (5.0%) pts, respectively. Immune-mediated AEs occurred in 40 (51.9%) pts in A and 20 (50%) in B, and infusion-related reactions in 7 (9.1%) and 2 (5.0%) pts, respectively. Conclusions: In pts with advanced/metastatic ESCC, adding LBL-007 to TIS + CT did not improve ORR versus TIS + CT alone, which was consistent with historical data in this population. PFS was numerically longer with LBL-007 but not statistically significant. The safety profile of the triplet was manageable and consistent with the known profiles of the individual agents. Clinical trial information: NCT06010303 . Efficacy. Arm An=78 Arm Bn=40 ORR, n (%)95% CI 48 (61.5)49.8-72.3 24 (60.0)43.3-75.1 Complete response 2 (2.6) 1 (2.5) Partial response 46 (59.0) 23 (57.5) Stable disease 23 (29.5) 12 (30.0) Progressive disease 4 (5.1) 3 (7.5) Not evaluable (NE) 3 (3.8) 1 (2.5) DCR, n (%)95% CI 71 (91.0)82.4-96.3 36 (90.0)76.3-97.2 DoR, median, mo95% CI 7.25.7-12.3 7.34.1-NE

Cancer cachexia (CCx) is a complex, multifactorial syndrome associated with poor outcomes, yet its clinical identification is often hindered by unreliable recall of historical body weight. We developed an interpretable machine learning (ML) framework to detect CCx by integrating routinely collected metabolic and inflammatory hematological features from the nationwide multicenter INSCOC cohort in China (N = 16,858). Using a systematic, data-driven strategies, we identified a stable and biologically coherent set of features that collectively characterize a cachexia-associated phenotype. The final model demonstrates consistent predictive discrimination for CCx in both test cohort (AUC: 0.758, 95% CI: 0.742-0.775) and validation cohort (AUC: 0.748, 95% CI: 0.730-0.766). Importantly, this phenotype-based model generalizes under strict temporal validation and enables objective identification of CCx in real-world clinical settings without reliance on recalled body weight. Together, our findings support a conceptual shift from a purely weight-based syndrome of CCx toward an integrative metabolic-inflammatory phenotype.

Supportive care in cancer (SCC), which encompasses the management of symptoms and treatment-related adverse effects, as well as the promotion of physical and psychological well-being throughout the whole course of treatment into follow-up of survivors, can significantly improve the quality of life and clinical outcomes of cancer patients. Over the past decade, substantial progress has been achieved in SCC-related clinical research globally. However, development and implementation of SCC in China still face considerable challenges, largely attributable to regional disparities in medical resources, limited financial support, and sociocultural factors. This comprehensive review delineates the current state of SCC in China based on a nationwide cross-sectional survey, highlighting the unmet needs of cancer patients, survivors, and healthcare providers. Key issues included insufficient social and financial support, suboptimal symptom management, inadequate patient education, and limited use of electronic patient-reported outcomes (ePROs). These findings underscore an urgent need to develop standardized protocols, enhance multidisciplinary collaboration, and promote digital health tools to improve the application and quality of SCC in China.

Recently, various basic research and clinical studies have revealed the further potential of poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitor Olaparib and histone deacetylase inhibitor Chidamide in lung cancer. However, no research available was found to report whether there is a synergistic effect of Olaparib in combination with Chidamide. This research was conducted to investigate whether there is a synergistic effect between the two drugs and the underlying mechanism in lung cancer cell lines. Here, we treat lung cancer cell lines with Olaparib with or without Chidamide in vivo and in vitro. Based on that, we found that there were synergistic effects between Olaparib and Chidamide. Combined use of them cooperatively downregulated the expression of MYBL2, which was responsible for the downregulation of BRCA1, a main member of DNA damage repair. Simultaneously, Olaparib-induced inhibition of PARP expression leads to the 'synthetic lethality' of cells. On the other hand, MYBL2 may regulate the expression of cycle protein dependent kinase 1, causing G2M cell cycle arrest. Consequently, the combination of Olaparib and Chidamide synergistically induces cell apoptosis through synthetic lethality and cell cycle arrest to exert an antitumor effect.

Gastric cancer (GC) remains a leading cause of cancer-related morbidity and mortality worldwide, with poor prognosis for advanced-stage patients. Therefore, in-depth exploration of the mechanisms underlying GC initiation and progression, as well as the development of novel therapeutic strategies, is of crucial importance. Cellular senescence is a stable cell cycle arrest program that plays a dual role in GC. It exerts tumor-suppressive effects via growth arrest but also promotes tumor progression and immune evasion by remodeling the tumor microenvironment (TME) through senescence-associated secretory phenotype (SASP). This review comprehensively elucidates the molecular mechanisms of cellular senescence in GC and the core regulatory networks involving gene regulation, epigenetic modifications, metabolic reprogramming, and cell cycle arrest. Additionally, the review highlights how senescent cells foster an immunosuppressive microenvironment via SASP, forming a self-reinforcing feed-forward loop. Regarding therapeutic strategies, we summarize potential approaches targeting cellular senescence, including senescence induction, senescent cell clearance, SASP modulation, and multi-target synergistic therapy by integrating epigenetic regulation, metabolic intervention, and immune microenvironment modulation. Despite progress, numerous challenges remain. Future studies should leverage multi-omics technologies, novel models' development, and large-scale clinical trials to advance the clinical translation of GC cellular senescence research, providing new insights for improving prognosis.

Background:While immunotherapy plus chemotherapy is the current first-line standard for gastric or gastroesophageal junction adenocarcinoma (GC/GEJC), subgroup analyses in patients with peritoneal metastasis are limited and show inconsistent benefits across trials (e.g., ATTRACTION-4, CheckMate 649). This post-hoc analysis evaluated the efficacy of immunotherapy plus chemotherapy in patients with or without peritoneal metastases. Methods:This is an exploratory post-hoc analysis of the randomised, double-blind, phase 3 RATIONALE-305 trial. Treatment-naïve patients aged ≥18 years with advanced GC/GEJC were enrolled across 13 countries from December 13, 2018, to February 9, 2021. Patients were randomised (1:1) to tislelizumab (200 mg intravenous every 3 weeks) plus chemotherapy or placebo plus chemotherapy until disease progression or unacceptable toxicity. Patients with or without peritoneal metastasis at baseline were identified and reanalysed. Outcomes included overall survival (OS) and progression-free survival (PFS) in the intention-to-treat population, and safety in all patients who received at least one dose of study drug. RATIONALE-305 is registered with ClinicalTrials.gov, NCT03777657. Findings:Among the 997 randomised patients, 434 (43.5%) had peritoneal metastases at baseline. Tislelizumab plus chemotherapy significantly improved OS versus placebo plus chemotherapy irrespective of peritoneal metastasis status, with consistent benefits observed in patients with peritoneal metastases (hazard ratio [HR], 0.78; 95% confidence interval [CI], 0.64-0.96) and those without peritoneal metastases (HR, 0.79; 95% CI, 0.65-0.95). The OS benefits were greater in patients with a programmed death ligand-1 tumour area positivity score of ≥5%, regardless of peritoneal metastasis status. Significant PFS benefit was also observed with tislelizumab plus chemotherapy in both patients with peritoneal metastasis (HR, 0.80; 95% CI, 0.64-0.98) and without peritoneal metastasis (HR, 0.77; 95% CI, 0.64-0.94). The safety profile was similar between treatment arms and consistent across subgroups. Interpretation:Tislelizumab plus chemotherapy significantly improved OS versus placebo plus chemotherapy in patients with GC/GEJC, irrespective of the presence of peritoneal metastases, with a comparable safety profile between treatment arms. Further dedicated prospective studies are warranted to validate these findings in this population. Funding:This study was supported by the Noncommunicable Chronic Diseases-National Science and Technology Major Project, National Natural Science Foundation of China, the Guangdong Basic and Applied Basic Research Foundation, Cancer Innovative Research Program of Sun Yat-sen University Cancer Center, Young Talents Program of Sun Yat-sen University Cancer Center, and Sanming Project of Medicine in Shenzhen.

Background: Colorectal cancer (CRC) is a major cause of cancer morbidity and mortality worldwide, and its progression is closely associated with redox imbalance. The biological role and upstream regulation of the antioxidant enzyme glutathione peroxidase 3 (GPx3) remain poorly understood in CRC. Methods: This study integrated analyses from clinical CRC tissues, in vitro functional experiments, molecular biology assays, and public The Cancer Genome Atlas datasets. Techniques included gene expression profiling, N6-methyladenosine methylation analysis, mitochondrial reactive oxygen species detection, lipophagy assays, lipid droplet staining, transcriptomic and proteomic analyses, ferroptosis sensitivity testing, and in vivo xenograft and metastasis models to investigate the role and underlying mechanisms of GPx3 in CRC. In addition, lung metastatic burden was assessed using in vivo bioluminescence imaging and high-resolution micro-computed-tomography scanning. Results: GPx3 was substantially down-regulated in CRC tissues and cells, primarily due to N6-methyladenosine modification catalyzed by methyltransferase-like protein 3 (METTL3) and METTL14. Down-regulation of GPx3 expression elevated mitochondrial reactive oxygen species, impaired lipophagy flux, and caused excessive lipid droplet accumulation. Multiomics analyses identified Dickkopf-1 (DKK1) as a downstream target negatively regulated by GPx3 through reactive-oxygen-species-dependent β-catenin signaling. The GPx3–DKK1–solute carrier family 7 member 11 (SLC7A11) axis modulated lipid peroxidation and influenced ferroptosis sensitivity. In vivo xenograft and metastatic models showed that GPx3 suppressed tumor growth and metastasis, and these effects were partially reversed by DKK1. Conclusion: This study demonstrates that METTL3/14-mediated N6-methyladenosine modification is a key upstream mechanism leading to GPx3 down-regulation in CRC. Down-regulation of GPx3 expression promotes malignant progression by increasing mitochondrial oxidative stress, disrupting lipophagy, and cooperating with the DKK1–SLC7A11 pathway to reduce ferroptosis sensitivity. Targeting this regulatory axis may provide promising molecular strategies for CRC diagnosis and therapy.

BACKGROUND:Perioperative chemo-immunotherapy shows variable outcomes in resectable gastric or gastro-oesophageal junction adenocarcinoma. We evaluated the efficacy and safety of neoadjuvant serplulimab with S-1 plus oxaliplatin (SOX) chemotherapy followed by adjuvant serplulimab versus neoadjuvant placebo plus SOX followed by adjuvant SOX in patients with PD-L1-positive, locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma. METHODS:In this randomised, double-blind, multicentre phase 3 ASTRUM-006 study, patients were screened at 75 hospitals in China and Thailand. Eligible patients aged 18-70 years with PD-L1 combined positive score (CPS) ≥5, resectable gastric or gastro-oesophageal junction adenocarcinoma were randomly assigned 1:1 to neoadjuvant serplulimab or placebo (intravenous; 4·5 mg/kg) plus SOX chemotherapy (intravenous oxaliplatin 130 mg/m2 on day 1, and oral S1 40-60 mg twice daily on days 1-14) for three cycles (cycle length 21 days), followed by adjuvant serplulimab (up to 17 cycles; serplulimab group) or SOX (five cycles; placebo group). The primary endpoint was investigator-assessed event-free survival (defined as the time from randomisation to the occurrence of progressive disease or local or distant recurrence, other new malignancies, or death), with efficacy first evaluated in PD-L1 CPS ≥10, then in the intention-to-treat (CPS ≥5) population. This study is registered with ClinicalTrials.gov, NCT04139135, and is ongoing. FINDINGS:Between Nov 26, 2019, and April 19, 2024, 1646 patients were screened, of whom 588 patients (median age 61·0 years [IQR 55-66]; 124 [21%] female and 464 [79%] male) at 57 hospitals in China were randomly assigned to the serplulimab group (n=292) or placebo group (n=296). With a median follow-up duration of 42·7 months (IQR 24·3-53·6), median event-free survival was significantly longer with serplulimab than with placebo in the PD-L1 CPS ≥10 population (not reached [NR] vs 42·0 months; hazard ratio 0·65 [95% CI 0·47-0·90]; p=0·0082). With a median follow-up of 35·9 months (IQR 23·5-49·4), median event-free survival was also significantly longer with serplulimab than with placebo in the intention-to-treat population (NR vs 35·9 months; 0·73 [95% CI 0·56-0·94]; p=0·015). Grade 3 or worse treatment-related adverse events occurred in 136 (47%) patients in the serplulimab group and 172 (59%) patients in the placebo group; 19 (7%) and 31 (11%) patients in the respective groups discontinued treatment due to treatment-related adverse events. INTERPRETATION:Neoadjuvant serplulimab plus SOX followed by adjuvant serplulimab significantly improved event-free survival and demonstrated a better safety profile compared with neoadjuvant and adjuvant SOX in PD-L1-positive, resectable gastric or gastro-oesophageal junction adenocarcinoma. Extended follow-up for the overall survival data is warranted to confirm a survival advantage of this perioperative strategy with a chemotherapy-sparing adjuvant component for this indication. FUNDING:Shanghai Henlius Biotech.

ABSTRACT Objective To investigate the prevalence, characteristics, and clinical implications of germline mutations in a consecutive cohort of Chinese colorectal cancer (CRC) patients, providing insights that may inform population‐specific genetic testing strategies. Methods A total of 1094 CRC patients from two centers were retrospectively analyzed using a 53‐gene hereditary cancer panel. Germline variants were classified according to ACMG/AMP guidelines. Clinical characteristics, molecular features, and survival outcomes were examined, and mutation frequencies were compared with published data. Results Germline pathogenic/likely pathogenic (P/LP) mutations were identified in 9.3% of patients, with mismatch repair (MMR) genes most frequently affected (4.2%). Higher mutation rates were associated with early‐onset CRC, nonmetastatic disease, and a family history of cancer. Compared to Western populations, Chinese patients showed significantly lower frequencies of MUTYH and APC mutations (both 0.4% vs. 2.0%, p < 0.01) but higher rates of MMR mutations. Among the 106 germline variants detected, 63.2% were in NCCN‐recommended genes, while 36.8% were found in non‐NCCN genes, primarily within homologous recombination repair and Fanconi anemia pathways. Patients harboring germline P/LP mutations had significantly better progression‐free survival (HR = 0.52, p < 0.001). Notably, 50.0% of mutation carriers had no family history, and 29.4% were diagnosed after age 65, highlighting the limitations of current criteria‐based testing strategies. Conclusions This study reveals distinct germline mutation patterns and clinical features in Chinese CRC patients, underscoring the need for population‐specific genetic testing and tailored screening to improve prevention, early detection, and personalized treatment in Asian populations.

Metabolic reprogramming is a prominent feature of cancer cells,and metabolic disorders seriously impair the prognosis of patients with cancer.This study investigated the metabolic disorders and metabolic load in patients with common cancers.A total of 15762 INSCOC patients were included in the study,and 21 blood indexes were used to quantitatively evaluate the metabolic disorders and metabolic load of patients.It was defined as a metabolic disorder if outside the normal range,and was counted as 1 point.Then the metabolic disorder load of the patient was calculated.One-way analysis of variance was used to compare the metabolic load of patients with common cancers.The rate of metabolic disorders was 96.0％,and only 4％(640 cases)of the patients were within the normal range.The top three indexes with the highest metabolic disorder rate were low-density lipoprotein cholesterol(45.7％),total cholesterol(34.2％)and prealbumin(30.0％).The top three indicators with the lowest metabolic disorders were high-density lipoprotein cholesterol(0.5％),albumin(4.0％),and total protein(5.1％).The incidence of metabolic disorders was different among cancer types,gender,age,TNM stage and treatment mode(P＜0.05).Patients with different types of cancer had different metabolic disorder loads,among which patients with biliary tract cancer had the highest metabolic disorder load(5.87±3.34),and patients with nasopharyngeal cancer had the lowest(3.83±2.06).The metabolic disorder load of patients with gastric,esophageal and colorectal cancer showed statistically significant differences among the four age groups(＜45,45-59,60-69 and ≥70 years old),among which the metabolic disorder load of prostate cancer patients in the＜45 age group was the lowest(2.00±2.83).The highest metabolic disorder load was found in patients with biliary cancer ≥70 years old(7.00±4.25).The metabolic disorder load of women was higher than that of men(4.26±2.51 vs.4.09±2.58,P=0.050).The metabolic disorder load of patients with different TNM stages was stage Ⅰ:3.39±2.17,stage Ⅱ:3.72±2.23,stage Ⅲ:3.84±2.33,and stage Ⅳ:4.57±2.71,respectively.In patients with cervical and pancreatic cancer,immunotherapy increases the metabolic burden.Among the malignant tumors with diabetes mellitus and hypertension,the metabolic disorder load was the highest in patients with biliary malignancy(6.95±2.94,6.22±3.30).Among smoking and drinking patients,liver cancer patients had the highest metabolic disorder load(5.66±3.04,5.80±3.17).This study shows that the incidence of metabolic disorders is high and the burden of metabolic disorders is heavy in patients with cancer.This study emphasizes the importance and necessity of maintaining the stability of the internal environment of patients with cancer and implementing metabolic regulation therapy.Moreover,for the first time in a large sample study,it was unexpectedly found that the metabolic disorder rate of albumin and total protein in patients with cancer was significantly lower than that reported in the traditional literature,suggesting that the diagnosis of malnutrition in patients with cancer should not rely on albumin or total protein,and malnutrition and hypoproteinemia should be distinguished.

First-in-class (FIC) oncology drugs-defined by their novel mechanisms of action or targeting of previously unaddressed molecular targets-have emerged as a leading force in cancer therapeutic innovation. In this Review, we delineate the global landscape of FIC oncology drug approvals between 2009 and 2024 and analyze the evolving characteristics of both approved FIC therapies and potential FIC (PFIC) candidates in clinical development. To clarify the underlying dynamics of this evolution, we construct an analytic framework encompassing four distinct archetypes of FIC development: new targets, new mutation subtypes, new modalities, and new multi-target strategies. This typology enables a systematic dissection of divergent translational trajectories and bottlenecks across the evolving FIC landscape. While most approved FIC drugs are driven by target novelty, PFIC candidates increasingly capitalize on technological breakthroughs, particularly in modalities such as cell and gene therapies, antibody-drug conjugates, proteolysis-targeting chimeras, cancer vaccines and bispecific antibodies. These advances not only expand the boundaries of druggability but also redefine how therapeutic interventions are conceived, delivered and translated into patient outcomes. Despite this momentum, critical bottlenecks-including the identification and validation of tractable targets, high clinical attrition rates, and persistent disparities in global access-continue to limit the real-world impact of oncology innovation. Looking forward, the convergence of artificial intelligence, next-generation modalities, and translational collaboration may serve as powerful engines for translating scientific breakthroughs into widely accessible therapies and for driving sustainable, mechanism-based innovations in oncology.

Background: The tumor microenvironment (TME) drives esophageal cancer (EC) progression and immune evasion, yet immune cell-type-specific genetic regulatory candidates associated with EC susceptibility remain incompletely characterized. This study aimed to prioritize immune cell-specific genetic regulatory candidates associated with EC susceptibility. Methods: We integrated single-cell expression quantitative trait loci (sc-eQTL) data with East Asian EC genome-wide association studies (GWAS; n = 160,589) to perform Mendelian randomization (MR). MR-prioritized candidates were further evaluated using tumor single-cell expression profiling, in silico perturbation analysis, The Cancer Genome Atlas Program (TCGA) transcriptomic correlations, phenome-wide association studies (PheWAS), and drug-repositioning analysis. Results: MR prioritized 18 gene-cell type pairs representing 16 immune cell-associated candidate genes (F-statistics >10), all of which remained significant within the prioritized candidate set after Benjamini-Hochberg correction. These findings supported a novel putative dual-axis immune evasion model. The TNFSF13B-associated inflammatory component showed monocyte-enriched tumor expression and transcriptomic associations with myeloid-derived suppressor cell (MDSC) markers CD33 (R = 0.63) and ITGAM (R = 0.47). Simultaneously, SLC25A29 showed CD8 effector memory T/NK-context MR signals but adipocyte-enriched tumor expression, suggesting a stromal metabolic-immune crosstalk hypothesis. In silico perturbation further linked SLC25A29 to CD8+ T cell effector-related programs, including GZMK. PheWAS did not identify evident severe pleiotropic safety signals for these hubs. Drug repositioning nominated TNFSF13B-directed agents, including belimumab, as testable repurposing candidates requiring further validation. Conclusions: This sc-eQTL-guided framework prioritizes immune cell-associated candidate genes and generates testable hypotheses linking germline genetic regulation, tumor single-cell expression localization, and TME remodeling in EC.

Purpose:East Asia has the highest gastric cancer incidence globally [1]. Real-world (rw) treatment patterns and outcomes for HER2-positive (HER2+) advanced gastric or gastroesophageal junction cancer (aGC/GEJC) remain poorly understood. Materials and Methods:This study enrolled adults with HER2+ aGC/GEJC diagnosed since January 2016 who received ≥2 lines of therapies (LOTs) with ≥6 months of follow-up across 31 centers in South Korea (KR), China (CN), Taiwan (TW), and Hong Kong (HK). Data were collected through November 2023. Treatment patterns, rw-efficacy outcomes, and adverse events of interest were analyzed descriptively. Results:Of 356 eligible patients (KR: 119, CN: 137, TW: 75, HK: 25), chemotherapy plus HER2-targeted monoclonal antibody was the most common 1st LOT regimen (61.0%), although utilization varied across countries/regions. Cross-country/region heterogeneity in treatment patterns emerged from the 2nd LOT onward. Median rw-overall survival varied across countries/regions (KR: 37.1; TW: 13.7; HK: 18.1 months); reliable survival estimation was precluded in CN due to ~50% loss to follow-up. Exploratory analyses suggested no survival benefit with trastuzumab use across multiple versus single LOT(s) (nominal p=0.96); however, sequential use of ≥2 HER2-targeted therapy types with distinct mechanisms of action (MoAs) may be associated with longer survival compared to a single type (nominal p=0.009). Conclusion:Cross-country/region heterogeneity in HER2+ aGC/GEJC treatment exists, likely driven by differential drug accessibility. Exploratory analyses suggested possible associations between HER2-targeted therapy and improved outcomes; however, inherent biases preclude causal inference. The sequential use of HER2-targeted therapies with distinct MoAs may be associated with clinical benefit, requiring prospective validation (NCT05606094).

ABSTRACT Background Colorectal cancer (CRC) is a major health burden globally and in China, where 3%–5% of cases involve the BRAFV600E mutation, which is associated with aggressive disease and therefore a poor prognosis. Although the combination of encorafenib and cetuximab has demonstrated improved survival in BRAFV600E mutant metastatic CRC (mCRC), such treatments remain unavailable as chemotherapy‐free options in China. Methods The NAUTICAL CRC, a Phase II study in Chinese patients with BRAFV600E mutant metastatic CRC, includes a Safety Lead‐In (SLI) phase for tolerability assessment and a randomized phase comparing encorafenib/cetuximab vs. irinotecan‐based regimens, potentially bridging the treatment gap and evaluating safety, efficacy, and Quality of Life (QoL) outcomes in this Chinese population. Results No dose‐limiting toxicity was identified in the SLI phase (N = 10). In the Randomized phase (N = 97), the Doublet arm demonstrated superior progression‐free survival (PFS) of 4.2 months vs. 2.5 months in the Control arm (hazard ratio [HR]: 0.37, p = 0.0004) and longer overall survival (OS) of 11.6 months vs. 8.2 months (HR: 0.55). Treatment‐related adverse events were common but more severe in the Control arm. QoL measures consistently favored the Doublet arm, showing improved health status and reduced deterioration risk. Conclusions This NAUTICAL CRC Phase II study showed that the combination of encorafenib and cetuximab offers significant clinical benefits, improving PFS and OS, while providing manageable safety and important QoL advantages, making it a valuable treatment option for Chinese patients with previously treated BRAFV600E mutant mCRC. Trial Registration Clinical study registration number: NCT05004350

e16261 Background: Gemcitabine plus cisplatin remains the standard first-line therapy for advanced biliary tract cancers (BTCs). However, disease progression within 8 months in most patients underscores the critical unmet need for effective second-line therapies. Compared to traditional irinotecan, the liposomal irinotecan offers a superior therapeutic profile characterized by higher efficacy and lower toxicity. The combination of liposomes irinotecan with capecitabine(a standard treatment) is currently being explored as a novel therapeutic option in ongoing clinical studies. Methods: This multicenter, single-arm, phase II trial enrolled patients with advanced BTCs (intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, or gallbladder cancer) who had progressed on first-line gemcitabine-based therapy. Patients received the combination of liposomal irinotecan and capecitabine. Treatment continued until disease progression. The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), overall survival (OS) and safety. Results: Between April 2024 and November 2025, 20 patients were enrolled and treated. The median age was 62.5 years (51-74), and 65% were male (13/20). Tumor types included extrahepatic cholangiocarcinoma (20%), intrahepatic cholangiocarcinoma (40%), and gallbladder cancer (40%). The combination therapy demonstrated promising efficacy, with a median PFS (mPFS) of 5.5 months（95%CI [4.50-NA]）. And the longest duration of continuous treatment observed was 14.1 months. which compares favorably to historical benchmarks in this setting. Of the 14 evaluable patients, 3 (21.4%) achieved a partial response, 8 (57.2%) maintained stable disease, and 3 (21.4%) experienced progressive disease. The ORR was 21.4%. Treatment was well-tolerated, with a 30% incidence of grade≥3 treatment-related adverse events (TRAEs). Including decreased white blood cell count(5.0%), neutropenia(10.0%) and diarrhea(5.0%). No fatal TRAEs were observed. Conclusions: The regimen of liposomal irinotecan plus capecitabine showed encouraging anti-tumor activity with a manageable safety profile in patients with gemcitabine-pretreated advanced BTCs, suggesting a potential new therapeutic option for the second-line setting. The follow-up work on patient survival is underway, and more data will be disclosed in the future. Clinical trial information: NCT06430827 .

Abstract Malignant tumors are major diseases that seriously threaten human health, and the unmet clinical demand for treatments in the field of oncology has been persistently large. The research and development of new antineoplastic drugs has become a powerful means to address this demand. The purpose of this guideline is to provide a systematic overview and summary of clinical research on antineoplastic drugs in terms of study format, trial staging, mechanism of action, ethical review, trial process, patient needs, and the evaluation of efficacy and adverse events. It provides practical suggestions and references to aid the fundamental role of clinical research on antineoplastic drugs, i.e., to address clinical needs and maximize patient benefits.