In this phase 3 trial, penpulimab combined with chemotherapy was assessed against a regimen of placebo plus chemotherapy for the first-line treatment of recurrent or metastatic nasopharyngeal carcinoma (R/M NPC). 291 patients were randomised and allocated in a 1:1 ratio in order to receive penpulimab (n = 144; 200 mg) or placebo (n = 147; 200 mg), plus chemotherapy (cisplatin/carboplatin and gemcitabine) every 3 weeks. Patients followed by maintenance therapy with penpulimab or placebo after 6 cycles. The primary endpoint of this study was progression-free survival (PFS) according to RECIST v1.1, and a significantly longer median PFS in the penpulimab arm versus the placebo arm (9.63 versus 7.00 months; hazard ratio 0.45, 95% CI: 0.33-0.62, P < 0.0001) was demonstrated in this prespecified interim analysis. The key secondary endpoint was the overall survival (OS). However, the OS data were still immature, and the median OS was not achieved (hazard ratio, 0.94; 95% CI: 0.63-1.40). The occurrence of treatment-related adverse events (grade ≥ 3) was 89.0% and 85.9% in two arms, with the most common being reduced the quantity of neutrophil (56.2% vs. 62.0%), reduced the quantity of white blood cell (54.1% vs. 54.9%), and anemia (45.2% vs. 38.7%). In the penpulimab arm, 6 patients (4.1%) experienced immune-related adverse events (grade ≥ 3). Adding penpulimab to chemotherapy led to a notable enhancement in PFS for the first-line R/M NPC treatment, alongside a safety profile that was both manageable and tolerable. ClinicalTrials.gov identifier NCT04974398.

4004 Background: Alveltamig (ZG006) is an innovative trispecific T cell engager (Tri-TCE) targeting two distinct DLL3 epitopes on tumor cells and CD3 on T cells (DLL3/DLL3/CD3), designed to bridge tumor cells and T cells, thereby mediating T cell specific killing of tumor cells. Here we conducted a dose optimization study in refractory NEC. Methods: This is a randomized, multicenter, open-label phase 2 study evaluating ZG006 in NEC patients (pts) who failed at least one prior line of therapy. Pts were randomized 1:1 to receive ZG006 at either 10 mg or 30 mg every two weeks, following a priming dose of 1 mg. The primary endpoint is objective response rate (ORR) assessed by IRC per RECIST1.1. Results are reported for 64 pts who received at least one dose of ZG006. Biomarker based efficacy analyses were performed based on a threshold of ≥50% of tumor cells stained at any intensity for DLL3 with an investigational antibody against DLL3 (SP347, Roche Diagnostics). Results: As of Sep. 10, 2025, a total of 64 pts (32 at each dose group) were randomized and received at least one dose of ZG006. The median age was 56 years (range: 25-72), 35 (54.7%) were male. All pts had received ≥1 prior line of systemic therapy, with 65.6% had prior anti-PD-(L)1 treatment. The confirmed ORR in 10 mg and 30 mg groups were 21.9% (7/32) and 37.5% (12/32), respectively; Disease control rate (DCR) were 40.6% (13/32) and 62.5% (20/32), respectively. Among the 19 responders, primary tumor sites included cervix (8), gallbladder (4), stomach (3), rectum (3) and colon (1). Pts with ≥50% DLL3 staining in tumor cells had greater ORR, DCR, and progression-free survival (PFS). The confirmed ORR in 10 mg and 30 mg groups were 33.3% (6/18) and 56.3% (9/16), respectively; DCR were 50.0% (9/18) and 75.0% (12/16), respectively; With a median follow up of 6.4 months, median PFS were 3.02 and 8.41 months, respectively. Median DoR was not yet mature in both groups at data cut-off. Treatment-related adverse events (TRAEs) occurred in all pts. The most frequent events were pyrexia, cytokine release syndrome (CRS) and anaemia. Most CRS were Grade 1-2, with only four grade 3 CRS, resolved with supportive care. TRAEs led to treatment interruption in 15 pts (23.4%) and permanent discontinuation in 2 pts (3.1%, one in each dose group). No grade 5 TRAE. No significant difference was observed in the safety profile between these two dose groups. Conclusions: ZG006 demonstrated a robust and durable response and a manageable safety profile in previously treated NEC pts, with superior efficacy observed at the 30 mg dose. The confirmed ORR of 56.3% and median PFS of 8.41 months in pts with ≥50% DLL3 positive tumor cells are particularly encouraging, and support further development of ZG006 for this patient population at the 30 mg dose. Clinical trial information: NCT06440057 .

Mefatinib, a novel second-generation epidermal growth factor (EGFR) tyrosine kinase inhibitor that has shown promising antitumor activity in targeting non-small cell lung cancer (NSCLC) with common and uncommon EGFR-activating mutations. In this phase III, randomized, double-blind trial in China, 336 eligible patients with advanced nonsquamous NSCLC harboring EGFR L858R or exon 19 deletion (ex19del) were assigned (2:1) to receive either mefatinib (60 mg daily, n = 223) or gefitinib (250 mg daily, n = 113). The primary endpoint was progression-free survival (PFS), assessed by an independent review committee (IRC). The trial is registered with chinadrugtrials.org.cn (CTR20192297). After a median follow-up of 15.9 months for mefatinib and 18.5 months for gefitinib, mefatinib demonstrated a significantly longer median IRC-assessed PFS compared to gefitinib (13.7 vs. 9.7 months; hazard ratio [HR] = 0.68; 95% confidence intervals [CI]: 0.53-0.87; p = 0.002). The 30-month overall survival rate was 60.2% for mefatinib and 54.3% for gefitinib. Patients with EGFR ex19del had comparable PFS for both treatment arms (p > 0.100), whereas patients with EGFR L858R had significantly longer median PFS when treated with mefatinib than gefitinib (13.7 vs 8.3 months HR = 0.55 [95% CI: 0.38-0.78]; p = 0.001). Patients with EGFR L858R had a 30-month overall survival rate of 56.6% with mefatinib and 43.7% with gefitinib. Treatment-related adverse events ≥grade 3 were reported in 45.7% of the mefatinib group and 24.8% of the gefitinib group. No new safety signals were observed for mefatinib. Mefatinib demonstrated superior efficacy to gefitinib with a similar tolerability profile in the first-line treatment of EGFR-mutated advanced NSCLC.

BACKGROUND:Tumors are a major threat to human life and health. Neutrophil extracellular traps (NETs) have become a research focus in this context, especially regarding their role in tumor progression. Since the concept of NETs was introduced in 2004, its implications for tumor research have attracted significant scholarly attention. This study aims to explore research trends and cutting-edge hotspots in NETs and tumors through bibliometric analysis and provide new ideas for clinical applications. METHODS:We searched for literature on NETs and tumors published between 2004 and 2023 using the Web of Science database. Microsoft Excel 2019 was used for statistical analysis of influential articles, journals, authors, organizations, countries, and co-cited references. VOSviewer (version 1.6.16) and CiteSpace (V.5.8.R3) were employed for visualizing research data. RESULTS:The analysis covered 790 articles authored by 4768 individuals from 1134 organizations in 56 countries. China and the United States are the leading contributors. The mechanism of NETs in tumor occurrence and development is likely linked to coagulation, inflammation, and infection. Hot topics in research include dendritic cells and thrombosis, with a shift from laboratory studies to clinical applications, suggesting a growing focus on treatment over etiology. CONCLUSION:This study offers the most comprehensive bibliometric analysis of NETs and tumors to date. Future research may focus on developing targeted therapies that block the interaction between NETs and tumors, offering a new direction for cancer treatment.

Abstract Background: Trastuzumab rezetecan (SHR-A1811) is a novel HER2-directed ADC approved for pretreated HER2-mutant NSCLC (Lancet Oncol, 2025). ADCs may enhance antitumor immunity and synergize with immunotherapy. We conducted an open-label, phase 1/2 (dose-escalation/efficacy-exploration) study (NCT05482568) to evaluate SHR-A1811 in combination therapy for HER2-altered NSCLC and here report data from phase 2 Cohort D of 1L SHR-A1811 ± adebrelimab (anti-PD-L1 mAb) for HER2-mutant NSCLC. Methods: Patients (pts) were randomized (1:1) to receive SHR-A1811 (4.8 mg/kg, iv, Q3W) + adebrelimab (1200 mg, iv, Q3W) or SHR-A1811 (4.8 mg/kg, iv, Q3W) alone, stratified by PD-L1 expression (TPS, <1% vs ≥1%). The primary endpoint was ORR per investigator. Results: 68 pts (PD-L1 TPS <1%/1-49%/≥50%, 50.0%/41.2%/8.8%; exon 20 insertions/A775_G776insYVMA, 89.7%/55.9%) were treated. At data cutoff (Oct 20, 2025), median follow-up was 16.7 mo. Confirmed ORR was 69.4% (95% CI 51.9-83.7) with SHR-A1811 + adebrelimab (combo) vs 81.3% (95% CI 63.6-92.8) with SHR-A1811; median DoR was not reached (NR) and 16.6 mo (95% CI 8.5-NR), respectively. PFS events occurred in 10 pts (27.8%) with combo vs 13 (40.6%) with SHR-A1811; median PFS was NR (95% CI 15.3-NR) vs 17.9 mo (95% CI 9.7-NR; HR 0.65, 95% CI 0.28-1.47). Efficacy by PD-L1 TPS is shown in Table 1. A trend toward improved PFS with addition of adebrelimab was seen across subgroups. All grade ≥3 TRAEs occurring in ≥10% were hematologic in both arms. ILD occurred in 2 (5.6%) pts with combo and 1 (1.3%) with SHR-A1811. TRAEs led to discontinuation of SHR-A1811 in 2 (5.6%) and adebrelimab in 4 (11.1%) in combo arm and SHR-A1811 in 2 (6.3%) in monotherapy arm. Conclusions: SHR-A1811 ± adebrelimab as 1L therapy showed robust activity with manageable safety in HER2-mutant NSCLC. Early data suggest clinical benefits with addition of adebrelimab, regardless of PD-L1 expression, driven by durablity of disease control. Citation Format: Shun Lu, Zhengbo Song, Ziming Li, Haiyong Wang, Yan Yu, Qitao Yu, Shaozhang Zhou, Zhiyong He, Yan Wang, Yiping Zhang, Songyan Han, Rui Meng, Guoqun Zhang, Longhua Sun, Xueqin Chen, Yong Mao, Yongsheng Li, Yongzhong Luo, Kangsheng Gu, Xuhong Min, Bo Jin, Runxiang Yang, Yanqiu Zhao, Liqiang Zhong, Jun Wang, Zhiguo Zhou, Chengzhi Zhou, Kaijun Zhang, Xiaotong Li, Xinjing Ma, Liju Zong, You Li. SHR-A1811 ± adebrelimab as first-line (1L) treatment for advanced HER2-mutant NSCLC: A randomized phase 2 cohort from a phase 1b/2 study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT301.

OBJECTIVE:To compare camrelizumab plus capecitabine and oxaliplatin followed by camrelizumab plus apatinib (camre+CAPOX followed by camre+apa), CAPOX alone, and camrelizumab plus CAPOX followed by camrelizumab (camre+CAPOX followed by camre) as initial treatment for gastric or gastro-oesophageal junction adenocarcinoma. DESIGN:Randomised, open label, phase 3 study. SETTING:75 hospitals in China, 13 March 2019 to 16 August 2021. PARTICIPANTS:885 adults (≥18 years) with previously untreated, human epidermal growth factor receptor 2 (HER2) negative, unresectable, locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma. INTERVENTIONS:Patients were randomised (2:2:1) to receive camre+CAPOX followed by camre+apa, CAPOX only, or camre+CAPOX followed by camre, stratified by Eastern Cooperative Oncology Group performance status, peritoneal metastasis, and programmed death ligand 1 (PD-L1) combined positive score. Assignment to camre+CAPOX followed by camre was introduced midway through enrolment. MAIN OUTCOME MEASURES:The primary endpoint was overall survival for camre+CAPOX followed by camre+apa versus CAPOX alone in the PD-L1 positive population (combined positive score >1) and the overall population who received at least one dose of study drug. Comparisons of camre+CAPOX followed by camre versus CAPOX alone and of camre+CAPOX followed by camre+apa versus camre+CAPOX-camre were descriptive. Safety was assessed in all patients who received at least one dose of study drug. RESULTS:352 patients received camre+CAPOX followed by camre+apa, 349 received CAPOX alone, and 177 received camre+CAPOX followed by camre. At the time of data cut off, 454 of 592 (76.7%) deaths had occurred in the PD-L1 positive population and 709 of 878 (80.8%) in the overall population. Overall survival was longer with camre+CAPOX followed by camre+apa than with CAPOX alone in the PD-L1 positive population (median 15.0 v 12.5 months; hazard ratio 0.80 (95% CI 0.65 to 0.98); one sided P=0.02) and in the overall population (median 13.5 v 12.1 months; hazard ratio 0.80 (0.68 to 0.94); one sided P=0.004). Use of camre+CAPOX followed by camre also showed longer overall survival versus CAPOX in the PD-L1 positive population (median 15.3 v 12.5 months; hazard ratio 0.76 (0.58 to 0.97); one sided nominal P=0.01) and overall population (median 14.2 v 12.1 months; hazard ratio 0.80 (0.65 to 0.98); one sided nominal P=0.02). No overall survival benefit was observed with camre+CAPOX followed by camre+apa versus camre+CAPOX followed by camre. Treatment related adverse events of grade ≥3 occurred in 239 of 352 (67.9%) patients in the camre+CAPOX followed by camre+apa group, 158 of 349 (45.3%) in the CAPOX alone group, and 83 of 177 (46.9%) in the camre+CAPOX followed by camre group. CONCLUSIONS:Initial treatment with camrelizumab plus CAPOX followed by camrelizumab based maintenance was associated with longer overall survival than CAPOX alone in human epidermal growth factor receptor 2 (HER2) negative, unresectable, locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma. Exploratory comparisons between the two camrelizumab based regimens showed no additional survival benefit, with higher rates of treatment related adverse events of grade ≥3 and treatment discontinuations when apatinib was added during maintenance. TRIAL REGISTRATION:ClinicalTrials.gov NCT03813784.

Ferroptosis is a type of intracellular, iron-dependent cell death that differs from apoptosis, necrosis, and autophagy. Ferroptosis is characterized by excessive lipid peroxidation. Iron-dependent, non-apoptotic cell death is linked to several liver diseases. Although numerous ferroptosis-associated genes and pathways have been linked to liver disorders, the exact mechanisms by which ferroptosis contributes to disease initiation and progression remain incompletely understood. In this review, we discuss the initiation and role of ferroptosis in the pathophysiology of liver diseases, including acute liver injury, liver fibrosis, hepatocellular carcinoma, viral hepatitis, autoimmune hepatitis, alcohol-associated liver disease, and NAFLD/MASLD. We first describe the regulatory function of ferroptosis before highlighting its relevance and underlying processes in several distinct liver disorders. In addition, we briefly discuss the potential clinical relevance of ferroptosis-related molecules and pathways as candidate biomarkers and therapeutic targets in liver diseases, with emphasis on their possible value in biomarker discovery, patient stratification, disease evaluation, and clinical translation. We also emphasize the context-dependent role of ferroptosis, in which its induction may be therapeutically beneficial in hepatocellular carcinoma or activated hepatic stellate cells, whereas excessive hepatocyte ferroptosis may aggravate non-malignant liver injury.

Hepato-pancreato-biliary (HPB) cancers affect human health and impose a significant burden on older adults. However, a comprehensive assessment of the global HPB disease burden in older adults is lacking. This research analyzed the trends in the burden of these cancers in older adults (aged 60–89 years) from 1992 to 2021 using data from the Global Burden of Disease Study (GBD) 2021. We examined the incidence, mortality, and disability-adjusted life years (DALYs) of liver cancer (LC), gallbladder and biliary tract cancer (GBTC), and pancreatic cancer (PC) in 204 countries and territories. Temporal trends were assessed using joinpoint regression and decomposition analysis with a focus on key global, regional, and national patterns. The incidence and mortality rates of LC and PC showed a consistent increase, particularly in regions with a high Socio-Demographic Index (SDI), whereas GBTC rates declined globally. Metabolic risk factors such as high Body Mass Index (BMI) were associated with increased DALYs for LC and PC. Projections indicate that the burden of these cancers will continue to increase. Our findings highlight the significant global disparities in the burden of HPB cancers among older adults, underscoring the need for targeted prevention and treatment strategies, particularly in regions with high SDIs. Fully assessed the global disease burden of hepato-pancreato-biliary cancers in older adults. Covered all factor variables and data that can be obtained. Based on the GBD database containing a large deposition of high-quality data. Provided insights for the medical and health management of hepato-pancreato-biliary cancers.

4118 Background: China bears a high biliary tract cancer (BTC) burden, with cholangiocarcinoma rising incidence ( > 6/100,000 vs 0.3–6/100,000 globally) and high mortality ( > 4/100,000). Over 60% of BTC patients are diagnosed at advanced stage (stage III/IV), and nearly two-thirds are unresectable. GEMOX regimen is a widely recognized standard of care in China, favored for its reduced renal toxicity and better tolerability compared with GemCis. Envafolimab is the world's first subcutaneously (SC) injectable anti-PD-L1 monoclonal antibody approved by China's NMPA. We report the final analysis of this pivotal trial, the first global phase III study initiated to evaluate immunotherapy plus chemotherapy in this setting. Methods: In this multicenter, open-label, phase III study in China, eligible patients (pts) with previously untreated, unresectable locally advanced/metastatic BTC were randomized 1:1 to envafolimab (2.5 mg/kg SC weekly) + GEMOX (gemcitabine 1000 mg/m² d1, 8; oxaliplatin 85 mg/m² d1, Q3W) or GEMOX chemotherapy alone. Chemotherapy was limited to 6 cycles in both arms. Stratification factors: primary site, disease stage, prior therapy, and ECOG PS. Primary endpoint: OS. Secondary endpoints: PFS, ORR (RECIST v1.1 by BICR), and safety. Results: 472 pts were randomized; 462 treated (envafolimab+GEMOX n = 232; GEMOX n = 230). At the final analysis, the primary endpoint was met well. Envafolimab+GEMOX significantly improved OS vs GEMOX (HR 0.723; 95% CI 0.585–0.880; P = 0.0016). Median OS was 10.9 months vs 8.6 months; 36-mo OS rates were 12.5% vs 7.7%. OS benefit was observed across subgroups, notably in intrahepatic cholangiocarcinoma (HR 0.705) and metastatic disease (HR 0.704). Median PFS (BICR) was 4.8 vs 4.6 months (HR 0.899; 95% CI 0.713–1.132); notably, the gallbladder cancer subgroup showed more favorable PFS benefit (HR 0.628). ORR was 27.6% vs 20.9%. Grade 3–4 TEAEs occurred in 69.4% (combination) vs 56.1% (chemo). irAEs occurred in 20.7%. Conclusions: This study demonstrates that adding subcutaneously administered envafolimab to GEMOX significantly improves OS with a manageable safety profile in advanced BTC. Compared with other regimens, the combination showed robust efficacy with a low rate of irAEs. Those findings establish envafolimab, the world's first SC PD-L1 inhibitor, combined with GEMOX as a new, effective, and convenient standard of care for this population. Clinical trial information: NCT03478488 .

Chronic psychological stress is increasingly recognized as an important host-related determinant of cancer progression, yet how stress-associated neuroendocrine signaling reshapes the metastatic immune microenvironment remains incompletely understood. Here, using male mouse models of chronic restraint stress and chronic unpredictable mild stress, together with transcriptomic profiling, flow cytometry, functional assays, and a prospective clinical cohort, we investigated whether chronic stress promotes gastric cancer liver metastasis through glucocorticoid-associated neutrophil reprogramming, neutrophil extracellular trap (NET) formation, and hepatic immune remodeling. Chronic stress induced robust behavioral stress phenotypes, elevated corticosterone levels, and increased hepatic metastatic burden. Immune profiling revealed a myeloid-skewed and immunosuppressive hepatic niche characterized by neutrophil accumulation, impaired CD8+ T-cell effector function, and enhanced T-cell exhaustion. Mechanistically, glucocorticoids activated neutrophils through glucocorticoid receptor signaling, increased reactive oxygen species, and promoted NET formation, whereas pharmacological inhibition of glucocorticoid receptor signaling, degradation of NETs, or antibody-mediated neutrophil depletion attenuated stress-associated metastatic progression in vivo. In parallel, glucocorticoid stimulation increased hepatic lipocalin 2 (LCN2) expression and secretion, and conditioned medium from glucocorticoid-treated hepatocytes enhanced neutrophil migration, an effect attenuated by pharmacological LCN2 inhibition. In vivo, LCN2 blockade reduced circulating LCN2 levels and alleviated hepatic metastatic burden. In patients with gastric cancer liver metastasis, higher stress burden was associated with elevated cortisol and circulating myeloperoxidase-DNA levels and with shorter progression-free survival. Multivariable Cox regression further supported an association between Perceived Stress Scale-defined stress burden and shorter progression-free survival. Together, these findings support a stress-associated glucocorticoid-neutrophil-hepatic niche axis linking chronic stress to metastatic progression.

BACKGROUND:Resistance to anti-programmed cell death protein-1 (PD-1) treatment in gastric cancer (GC) is closely associated with an immunosuppressive tumor microenvironment. However, the role of neutrophils in resistance to anti-PD-1 therapy remains unclear. METHODS:Single-cell RNA sequencing was performed on tumor samples from patients with advanced GC receiving anti-PD-1 therapy to identify neutrophil subsets associated with neutrophil extracellular traps (NETs). Multilevel experimental validation was conducted using multiomics analysis, flow cytometry, multiplex immunofluorescence, and in vitro co-culture. Therapeutic strategies targeting NETs and CD8+ T-cell exhaustion were evaluated in a mouse model of YTN16 tumors. RESULTS:We identified a NETs-associated neutrophil subset enriched in patients with GC resistant to anti-PD-1 treatment. This subset was marked by CD177, and it exhibited a high potential for NETs release. Peripheral blood NETs levels and CD177+ neutrophil ratios in patients with GC act as markers for evaluating the efficacy of PD-1 inhibitors. Furthermore, transforming growth factor-β1 (TGF-β1), which was highly expressed in GC and spatially colocalized with CD177+ neutrophils, might induce neutrophils to release NETs via the Smad3-NFE2 axis. NETs promoted CD8+ T cell exhaustion by activating the MEK/ERK-c-Fos/JunB axis, as evidenced by increased PD-1/TIM3 expression and reduced interferon-gamma/tumor necrosis factor-alpha secretion. In vivo experiments confirmed that targeted inhibition of NETs formation using DNase I or TGF-β1 inhibitors significantly suppressed tumor growth and CD8+ T cell exhaustion. Notably, the MEK inhibitor trametinib reversed the immunosuppressive microenvironment associated with CD8+ T cell exhaustion and synergistically enhanced the antitumor efficacy with anti-PD-1 therapy. CONCLUSIONS:TGF-β1 drives CD177+ neutrophils to release NETs, which induce CD8+ T cell exhaustion via the ERK-c-Fos-JunB pathway, thereby mediating resistance to anti-PD-1 treatment in GC. Furthermore, targeting NETs formation and combining trametinib with PD-1 inhibitors can significantly reverse CD8+ T cell exhaustion, exert synergistic antitumor effects, and offer a potential therapeutic strategy for overcoming resistance to anti-PD-1 therapy in GC.

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 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.

BACKGROUND:Patients with stage III gastric cancer (GC) face a high risk of recurrence after radical resection, and the significance of circulating tumor cells (CTCs) and Programmed death-ligand 1 (PD-L1) combined positive score (CPS) in adjuvant therapy remains unclear. METHODS:In this prospective observational cohort study, we analyzed 76 stage III GC patients post-D2 resection who received either chemotherapy alone (n = 46) or immunochemotherapy (n = 30) based on clinical decision-making. CTCs levels at baseline and after 6 treatment cycles were assessed using a folate receptor-based qPCR assay, while PD-L1 CPS was evaluated via immunohistochemistry. We also analyzed the time difference between CTCs elevation and radiological relapse. RESULTS:Although a single baseline CTCs lacked independent prognostic value, dynamic increases in CTCs during treatment served as an independent predictor of disease-free survival (DFS) and overall survival (OS) in GC patients (P = 0.019, P = 0.013). Notably, elevated CTCs significantly preceded radiographic recurrence confirmation by a median of 284.5 days (P < 0.001). In the immunochemotherapy cohort, PD-L1 CPS ≥ 5, but not CPS ≥ 1, might help identify patients with greater DFS and OS benefits (P = 0.038, P = 0.023). CONCLUSION:Dynamic monitoring of CTCs serves as a sensitive early-warning tool for recurrence and an independent prognostic indicator for DFS in stage III GC. Furthermore, a PD-L1 CPS threshold of ≥5 may help stratify candidates for adjuvant immunotherapy, though OS findings are exploratory pending validation in larger cohorts. This study confirms the clinical value of dynamic CTCs monitoring in prognostic assessment and early recurrence warning, as well as the potential significance of PD-L1 CPS in guiding patient selection for adjuvant immunotherapy in stage III GC.

1046 Background: BAT8010 is an ADC targeting HER2, while BAT1006 is a humanized monoclonal antibody targeting another epitope of HER2, with ADCC enhancement activity via completely devoid of fucose. Expansion cohort of 1st-line HER2-positive breast cancer (BC) patients enrolled, treated with BAT8010 + BAT1006. Methods: Patients in this open-label, multicenter clinical trial received BAT8010 + BAT1006 on day 1 of a 21-day cycle until intolerable or disease progression occurred. The study objectives included assessing tolerability, safety, pharmacokinetic characteristics, immunogenicity, and preliminary efficacy. Results: As of January 9, 2026, 46 HER2-positive BC patients were enrolled, and received BAT8010 2.4 mg/kg in combination with BAT1006 15 mg/kg. Favorable efficacy was observed with a manageable and predictable safety profile; dose optimization is ongoing in the BAT8010 2.1 mg/kg in combination with BAT1006 15 mg/kg dose cohort. Safety: Among the 46 patients who received at least one dose of BAT8010 in combination with BAT1006, at least one treatment-emergent adverse event (TEAE) was reported in 41/46 (89.1%) patients. The most common TEAEs (≥30%) were neutropenia, leukopenia, anemia, infusion-related reaction (IRR), thrombocytopenia, elevated alanine aminotransferase and diarrhea. Most TEAEs were Grade 1/2; however, Grade 3 or higher AEs were reported in 67.4% of patients, including neutropenia (27/46, 58.3%), leukopenia (16/46, 34.8%), and anemia (7/46, 15.2%). No cases of interstitial lung disease (ILD)/pneumonitis were reported. Efficacy: Among 46 patients with at least one tumor assessment, 1 patient achieved CR, 34 PR, and 11 SD, yielding an ORR of 76% (35/46) and a DCR of 100% (46/46); mPFS: not yet mature. Conclusions: BAT8010 in combination with BAT1006 is well-tolerated with manageable toxicity, and demonstrates promising preliminary antitumor activity in HER2-positive BC. Dose expansion studies in this patient population are ongoing, and further confirmatory clinical trials are planned to initiate for the additional validation of its safety and efficacy. Clinical trial information: NCT06376136 .

e16034 Background: BAT8010 is an ADC argeting HER2, while BAT1006 is a humanized monoclonal antibody targeting another epitope of HER2, with ADCC enhancement activity via completely devoid of fucose. Expansion cohort of ≥1st-line HER2-positive gastric/gastroesophageal junction cancer patients enrolled, treated with BAT8010 + BAT1006. Methods: Patients in this open-label, multicenter clinical trial received BAT8010 +BAT1006 on day 1 of a 21-day cycle until intolerable or disease progression occurred. The study objectives included assessing tolerability, safety, pharmacokinetic characteristics, immunogenicity, and preliminary efficacy. Results: As of January 5, 2026, 34 HER2-positive GC/GEJC patients were enrolled, with a median of 2 prior lines of therapy, and received BAT8010 2.4 mg/kg in combination with BAT1006 15 mg/kg.Favorable efficacy was observed with a manageable and predictable safety profile; dose optimization is ongoing in the BAT8010 2.1 mg/kg in combination with BAT1006 15 mg/kg dose cohort. Safety: Among the 34 patients who received at least one dose of BAT8010 in combination with BAT1006, at least one treatment-emergent adverse event (TEAE) was reported in 32/34 (94.1%) patients. The most common TEAEs (≥25%) were neutropenia, leukopenia, anemia, thrombocytopenia, elevated alanine aminotransferase, hypoalbuminemia, diarrhea, and infusion-related reaction (IRR). Most TEAEs were Grade 1/2; however, Grade 3 or higher AEs were reported in 68.8% of patients, including neutropenia (22/34, 64.7%), leukopenia (10/34, 29.4%), thrombocytopenia and anemia (each 5/34, 14.7%). No cases of interstitial lung disease (ILD)/pneumonitis were reported. Efficacy: Among 34 patients with at least one tumor assessment, 15 achieved PR and 18 SD, yielding an ORR of 44.1% (15/34) and a DCR of 97.1% (33/34); the mPFS was 7.52 months (95% CI: 4.53–NR).The overall survival (OS) data remain immature due to insufficient follow-up duration. Conclusions: BAT8010 in combination with BAT1006 is well-tolerated with manageable toxicity, and demonstrates promising preliminary antitumor activity in HER2-positive GC/GEJC. Dose expansion studies in this patient population are ongoing, and further confirmatory clinical trials are planned to initiate for the additional validation of its safety and efficacy. Clinical trial information: NCT06376136 .

ObjectiveCamrelizumab, a programmed death-1 inhibitor, is effective and safe for treating patients with advanced lung cancer according to previous phase 3 trials. However, relevant real-world clinical evidence is required. This study intended to explore the efficacy and safety of camrelizumab-based therapies in patients with advanced lung cancer.MethodsPatients with advanced lung cancer who received camrelizumab-based therapies as first-line or above treatment were consecutively enrolled in this study. The median follow-up duration was 5 months.ResultsA total of 298 subjects were enrolled. Objective response rate (ORR) and disease control rate (DCR) were 27.2% and 82.2%. Multivariable logistic regression analysis showed that previous pulmonary surgery [odds ratio (OR)=0.440, P=0.024], previous radiotherapy (OR=0.410, P=0.010), and Eastern Cooperative Oncology Group Performance Status (ECOG PS) score (>1 vs. 0~1) (OR=0.414, P=0.046) were independently and negatively associated with ORR. The median progression-free survival (PFS) [95% confidence interval] was 10.0 (7.8-12.2) months. Median overall survival (OS) was not reached. Multivariable Cox regression analysis suggested that brain metastasis [hazard ratio (HR)=1.548, P=0.036] and liver metastasis (HR=1.733, P=0.035) were independently associated with shorter PFS. Previous chemotherapy (HR=2.376, P=0.022), brain metastasis (HR=2.688, P=0.006), and liver metastasis (HR=2.583, P=0.039) were independently associated with shorter OS. Most adverse events were grade I or II. Grade III and IV adverse events rarely occurred. The occurrence of adverse events was associated with a higher DCR (P=0.003).ConclusionsCamrelizumab-based therapies may serve as potential treatments for patients with advanced lung cancer. However, further studies with an extended follow-up duration are warranted.

Importance:Patients with extensive-stage small cell lung cancer (ES-SCLC) have poor prognoses and unmet medical needs. Objective:To evaluate the efficacy and safety of toripalimab plus etoposide and platinum-based chemotherapy (EP) vs placebo plus EP as a first-line treatment for patients with ES-SCLC. Design, Setting, and Participants:This multicenter, double-blind, placebo-controlled phase 3 randomized clinical trial (EXTENTORCH study) enrolled patients from September 26, 2019, to May 20, 2021, and was conducted at 49 sites in China. Eligible patients had histologically or cytologically confirmed ES-SCLC without previous systemic antitumor therapy for ES-SCLC. Data were analyzed between May 6, 2023, and June 1, 2024. Interventions:Patients were randomized (1:1) to receive toripalimab, 240 mg, or placebo plus EP every 3 weeks for up to 4 to 6 cycles, followed by maintenance with toripalimab or placebo until disease progression, intolerable toxic effects, or up to 2 years of treatment. Main Outcomes and Measures:The primary end points were investigator-assessed progression-free survival (PFS) and overall survival (OS). Whole-exome sequencing results identified correlative biomarkers for clinical efficacy. Results:Among 595 screened patients, 442 eligible patients were randomized (median [range] age, 63 [30-77] years; 366 [82.8%] male); 223 patients were randomized to toripalimab plus EP, and 219 to placebo plus EP. By April 20, 2023, the median (range) survival follow-up was 13.7 (0.0-42.7) months. Compared with placebo, toripalimab improved investigator-assessed PFS (hazard ratio [HR], 0.67 [95% CI, 0.54-0.82]; P < .001), and significantly reduced the risk of death (HR, 0.80 [95% CI, 0.65-0.98]; P = .03). The median OS was 14.6 (95% CI, 12.9-16.6) months in the toripalimab group vs 13.3 (95% CI, 11.8-14.4) months in the placebo group. Whole-exome sequencing results from 300 patients identified low intratumor heterogeneity, HLA-A11+ HLA-B62- haplotype, wild-type KMT2D and COL4A4, or sequence variations in CTNNA2 or SCN4A correlated with favorable PFS and OS in the toripalimab group. No new safety signals were observed. Grade 3 or higher treatment-emergent adverse event incidence was similar between the toripalimab and placebo safety set groups (199 of 222 patients [89.6%] vs 193 of 216 patients [89.4%], respectively). Conclusions and Relevance:In this phase 3 randomized clinical trial, adding toripalimab to first-line chemotherapy demonstrated significant improvements in PFS and OS for patients with ES-SCLC. The treatment exhibited an acceptable safety profile, supporting this combination regimen as a new treatment option for patients with ES-SCLC. Trial Registration:ClinicalTrials.gov Identifier: NCT04012606.

Purpose:Sensitivity to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) varies among individuals harboring exon 19 deletions (19del) at different amino acid positions and EGFR 19del or deletion-insertions (19delins), and the role of chemotherapy in this context remains unknown. Therefore, we investigated how chemotherapy and the EGFR 19del subtype affect the clinical outcomes of patients with advanced non-small cell lung cancer (NSCLC) treated with first-generation TKIs. Patients and Methods:Eighty patients at one hospital who harbored an EGFR 19del mutation were retrospectively included. Survival analyses were performed by comparing first-line treatments, EGFR 19del variants, and the coding positions at which the deletions began. Results:Among the 80 patients, 37 and 43 received first-generation TKIs and TKIs and chemotherapy, respectively. Progression-free survival (PFS) and overall survival (OS) were comparable between the two groups. The results were the same for patients with the EGFR p.E746 mutation (n = 56) and those with the p.L747 mutation (n = 23). However, in the subgroup of patients treated with TKIs, the results favored patients with EGFR p.E746 mutations over those with p.L747 mutations, as the median PFS differed by 4 months. In the EGFR p.L747 subgroup, PFS and OS were significantly longer in patients treated with chemotherapy and TKIs than in those treated with TKIs alone. Both EGFR p.L747 and treatment with TKIs were significant risk factors for poor PFS. Eastern Cooperative Oncology Group performance status was the only significant independent risk factor for poor OS. Compared with TKIs alone, combination therapy was associated with more grade III or IV toxicity effects. Conclusion:Additional chemotherapy did not benefit patients with p.E746 mutations but did significantly improve the PFS and OS of those with p.L747 mutations. Thus, chemotherapy + first-generation TKI combination therapy for patients with advanced NSCLC should be carefully selected.