4014 Background: Checkpoint inhibitors combined with anti-angiogenic therapy represents one of the standard first-line therapies for advanced hepatocellular carcinoma (aHCC). Nilvanstomig (ZG005) is a recombinant humanized anti-PD-1/TIGIT bispecific antibody. By blocking both pathways, it can synergistically activate T cells and enhance the anti-tumor activity of NK cells. This study evaluated ZG005 plus bevacizumab vs. sintilimab plus IBI305 (a bevacizumab biosimilar) as first-line therapy for aHCC. Methods: In this randomized, open-label, multicenter, phase 2 trial conducted in China, patients with aHCC who had not previously received systemic treatment were randomly assigned (1:1:1) to receive ZG005 10 mg/kg plus bevacizumab 15 mg/kg (Arm A); ZG005 20 mg/kg plus bevacizumab 15 mg/kg (Arm B); or sintilimab 200 mg plus IBI305 15 mg/kg (Arm C). All treatments were administered intravenously every 3 weeks until disease progression or unacceptable toxicity. Randomization was stratified by baseline AFP level ( < 400 vs. ≥400 ng/mL), macrovascular invasion or extrahepatic metastasis (presence vs. absence). The primary endpoint was IRC-assessed PFS per RECIST v1.1, with key secondary endpoints including PFS per mRECIST, ORR and DCR by both criteria, and OS. Results: As of the data cutoff (Nov 25, 2025), 95 patients were enrolled and received at least one dose of treatment (Arm A, n = 31; Arm B, n = 32; Arm C, n = 32). Baseline characteristics were well-balanced across the treatment arms. For all patients enrolled, the median age was 61 years (range, 37-75), with 85.3% of patients being male. Disease characteristics included BCLC stage B (28.4%) or C (71.6%), Child-Pugh score A5 (83.2%) or A6 (16.8%), baseline AFP ≥400 ng/mL in 45.3% of patients, and HBV positivity in 73.7%. Macrovascular invasion and/or extrahepatic metastasis were present in 71.6% (68/95) of patients. With a median follow-up of about 5 months, the IRC-assessed ORR was 32.3% in Arm A, 37.5% in Arm B, and 25.0% in Arm C per RECIST v1.1; the corresponding ORRs per mRECIST were 54.8%, 50.0%, and 34.4%. The IRC-assessed median PFS per RECIST v1.1 was not reached in Arm A or B, compared with 5.8 months in Arm C (Arm A vs. C: HR 0.40, 95% CI 0.15-1.05; Arm B vs. C: HR 0.28, 95% CI 0.10-0.79). The safety profiles were comparable across the three arms. No grade ≥3 hemorrhagic adverse events were reported in either Arm A or B. Conclusions: The combination of ZG005 and bevacizumab as first-line treatment in patients with aHCC demonstrated an early encouraging efficacy with an acceptable safety profile. Higher response rates and prolonged PFS were observed with the ZG005-based regimens. Longer follow up of the current study and future phase 3 trials are warranted to validate the efficacy and safety of ZG005 in combination with bevacizumab in aHCC. Clinical trial information: NCT06558227 .

4003 Background: QLS31905, a Claudin18.2/CD3 bispecific antibody, showed manageable safety and encouraging efficacy in Claudin18.2-positive patients (pts) with gastrointestinal tumors in a phase 1 trial. Here we report the safety and efficacy of QLS31905 plus chemotherapy in the first-line treatment of Claudin18.2-positive pts with pancreatic cancer (PC) and gastric cancer (GC). Methods: This phase 1b/2 trial recruited Claudin 18.2-positive (defined as ≥1% of tumor cells with ≥1+ staining intensity) pts with locally advanced unresectable or metastatic PC and GC who had not received systematic anti-tumor therapy. Pts with PC were administered QLS31905 at 350 μg/kg, 500 μg/kg, or 800 μg/kg Q2W or Q3W combined with gemcitabine plus nab-paclitaxel (Cohort 1). Pts with GC were administered QLS31905 at 500 μg/kg or 800 μg/kg Q3W combined with oxaliplatin plus capecitabine (Cohort 2). The primary endpoints were maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) in phase 1b and was objective response rate (ORR) in phase 2. Results: As of Dec 11, 2025, 88 pts with PC and 43 pts with GC were enrolled. No dose-limiting toxicity occurred. MTD was not reached. RP2D was determined as 800 μg/kg Q3W for both pts with PC and GC. Grade ≥3 treatment-related adverse events (TRAEs) occurred in 63 (71.6%) pts and 26 (60.5%) pts in Cohort 1 and Cohort 2, respectively. Ten pts (11.4%) in Cohort 1 and four pts (9.3%) in Cohort 2 discontinued any of the study treatment due to TRAEs. No QLS31905-related death occurred in both cohorts. In 82 efficacy-evaluable pts with PC, ORR and disease control rate (DCR) was 59.8% (95% confidence interval [CI], 48.34%-70.44%) and 89.0% (95% CI, 80.18%-94.86%), respectively. Median progression-free survival (PFS), duration of response (DoR), and overall survival (OS) was 8.74 months (95% CI, 7.16-10.71), 8.94 months (95% CI, 5.32-not evaluable [NE]), and 15.87 months (95% CI, 13.14-NE), respectively. In 15 pts with low Claudin18.2 expression in Cohort 1, ORR, DCR, median PFS, and median OS was 60.0% (95% CI, 32.29%-83.66%), 93.3% (95% CI, 68.05%-99.83%), 11.04 months (95% CI, 7.33-NE), and 15.61 months (95% CI, 3.98-NE), respectively. In 43 efficacy-evaluable pts with GC, ORR and DCR was 74.4% (95% CI, 58.83%-86.48%) and 93.0% (95% CI, 80.94%-98.54%), respectively. Median PFS and DoR was 10.09 months (95% CI, 6.87-NE) and not reached, respectively. In nine pts with low Claudin18.2 expression in Cohort 2, the ORR, DCR, median PFS, and 9-month PFS rate and was 77.8%, 100%, not reached, and 83.33%, respectively. Conclusions: QLS31905 plus chemotherapy in first-line treatment for Claudin18.2-positive pts with PC and GC showed manageable safety and potential efficacy. A phase 3 trial is ongoing to further confirm the efficacy and safety of QLS31905 in pts with PC. Clinical trial information: NCT06041035 .

Background:The optimal fractionation patterns and safety of hypofractionated radiotherapy remain poorly defined in locally advanced oesophageal squamous cell carcinoma (LA-ESCC). We aimed to determine the maximum tolerated fraction dose (MTFD) of split-course concurrent chemoradiotherapy (CCRT) following induction chemo-immunotherapy in patients with LA-ESCC. Methods:In this phase 1 study, patients (aged 18-80 years) with unresectable, histologically confirmed LA-ESCC (stage T1-4, N0-3, M0-1 disease; ECOG 0-1) were enrolled from one site in China (Sun yat-sen University Cancer Center, Guangzhou, Guangdong). Eligible participants had no prior treatment with chemotherapy, radiotherapy, surgery, or immunotherapy for ESCC and no evidence of deep ulceration on baseline esophagoscopy. Enrolled participants received two cycles of induction albumin-bound paclitaxel (260 mg/m2, d1), cisplatin (60 mg/m2, d1), and toripalimab (240 mg, d1) every three weeks, followed by definitive split-course radiotherapy with oral capecitabine (1000 mg/m2, twice daily on days 1-14 of each radiotherapy course). Radiotherapy was delivered in two courses separated by a 4-week break using volumetric modulated arc therapy. Three dose levels were evaluated sequentially in cohorts of six patients: level 1 (30 Gy in 10 fractions + 20 Gy in 10 fractions), level 2 (28 Gy in 7 fractions + 22 Gy in 10 fractions), and level 3 (25 Gy in 5 fractions + 25 Gy in 10 fractions). The primary endpoint was MTFD within 12 months after completion of CCRT. The primary endpoint and safety analysis were assessed in all patients who received any study treatment. The trial is registered with ClinicalTrials.gov, NCT06020885. Findings:Between Aug 31, 2023, and July 23, 2024, 18 patients were enrolled (n = 6 per dose), and all completed split-course CCRT per protocol. The MTFD was not reached, and dose level 3 was tolerable. The most common grade 3 toxicity was lymphopenia (72.2%), followed by esophagitis (11.1%). No grade 4 or 5 toxicities occurred. The objective response rate after induction therapy was 100%. After CCRT, the clinical complete response rate was 83.3%. With a median follow-up of 20.5 months, median progression-free and overall survival were not reached; 1-year rates were 88.9% and 94.4%, respectively. Interpretation:Fraction dose-escalated split-course CCRT following induction chemo-immunotherapy was feasible, well tolerated, and showed encouraging preliminary efficacy. Larger prospective studies are warranted. Funding:The National Key Research and Development Program of China and the Cancer Innovative Research Program of Sun Yat-sen University Cancer Center.

BACKGROUND:There is an unmet need for additional and more efficacious therapies for patients with unresectable metastatic oesophageal cancer. We aimed to evaluate the efficacy and safety of adding tiragolumab and atezolizumab to chemotherapy as first-line treatment for unresectable or metastatic oesophageal squamous cell carcinoma. METHODS:The SKYSCRAPER-08 randomised, double-blind, placebo-controlled, phase 3 trial was done at 67 centres in mainland China, South Korea, Thailand, Taiwan, and Hong Kong and enrolled adult patients (aged ≥18 years) with treatment-naive, unresectable locally advanced, unresectable recurrent, or metastatic oesophageal squamous cell carcinoma, with an Eastern Cooperative Oncology Group performance status of 0-1. Patients were randomly assigned (1:1) to receive tiragolumab (600 mg) plus atezolizumab (1200 mg) and chemotherapy (paclitaxel [175 mg/m2] and cisplatin [60-80 mg/m2]) or placebo and chemotherapy through intravenous infusion for six 21-day cycles. The primary outcomes were independent review facility-assessed progression-free survival and overall survival in the intention-to-treat population (defined as all randomly assigned patients, regardless of whether they received any study treatment). This study was registered with ClinicalTrials.gov, NCT04540211, and is ongoing. FINDINGS:Between Oct 30, 2020, and Nov 30, 2021, 461 patients were assigned to receive tiragolumab plus atezolizumab and chemotherapy (n=229) or placebo and chemotherapy (n=232); 406 (88%) were male and 55 (12%) female, and all patients were Asian. Median survival follow-up was 12·6 months (IQR 6·8-18·0). Median independent review facility-assessed progression-free survival (cutoff June 15, 2022) in the tiragolumab plus atezolizumab and chemotherapy group was 6·2 months (95% CI 5·7-7·2) versus 5·4 months (95% CI 4·4-5·5) in the placebo and chemotherapy group (HR 0·56, 95% CI 0·45-0·70; p<0·0001). Median overall survival (cutoff Feb 13, 2023) was 15·7 months (95% CI 13·3-20·4) and 11·1 months (95% CI 9·6-13·6; HR 0·70, 95% CI 0·55-0·88; p=0·0024). The most common grade 3-4 adverse events in the tiragolumab plus atezolizumab and chemotherapy group versus the placebo and chemotherapy group were white blood cell count decrease (46 [20%] of 228 vs 35 [15%] of 227), neutrophil count decrease (78 [34%] vs 78 [34%]), and anaemia (19 [8%] vs 24 [11%]). Serious adverse events occurred in 94 (41%) of 228 patients in the tiragolumab plus atezolizumab and chemotherapy group and 89 (39%) of 227 in the placebo and chemotherapy group; the most common serious adverse event was pneumonia (17 [7%] of 228 and 13 [6%] of 227). Treatment-related deaths occurred in six patients (3%) in the tiragolumab plus atezolizumab and chemotherapy group (immune-mediated lung disease, pneumonitis, cardiac arrest, gastrointestinal haemorrhage, hepatic failure, and bacterial pneumonia) and two (1%) in the placebo and chemotherapy group (gastrointestinal infection and death of unknown cause). No new safety signals were identified. INTERPRETATION:Independent review facility-assessed progression-free survival and overall survival were significantly better in the tiragolumab plus atezolizumab and chemotherapy group compared with chemotherapy alone for unresectable locally advanced, unresectable recurrent, or metastatic oesophageal squamous cell carcinoma. These data support the rationale for exploring dual checkpoint inhibition added to chemotherapy for this group of patients with a high unmet need. FUNDING:F Hoffmann-La Roche-Genentech.

BACKGROUND Esophageal cancer represents one of the most prevalent malignant tumors globally. Esophageal cancer lack of tumor markers in clinical diagnosis, unable to effectively monitor development, drug resistance and prognosis of tumor, lead to clinical treatment effect is poorer. Neoadjuvant chemoradiotherapy (neoCRT) can substantially enhance the prognosis for individuals diagnosed with locally advanced esophageal squamous cell carcinoma (ESCC). Nevertheless, treatment resistance still occurs, affecting the long-term survival of patients. AIM To investigate the genes and regulatory mechanisms associated with platinum-based resistance in ESCC. METHODS In this investigation, single-cell RNA sequencing results of ESCC were analyzed to obtain the dynamic remodeling of tumor microenvironment in ESCC patients following neoCRT. Six ESCC samples were analyzed for scRNA-seq analysis. Four patients achieved partial response after neoCRT and then underwent surgery, and 2 patients received surgery alone. Multiple immunofluorescence and western blot were used to verify the expression of characteristic genes and the distribution of tumor cells. Gene knockdown, cholecystokinin-8, flow cytometry, colony formation, and subcutaneous tumorigenesis were used to validate the role of signature genes in the development of platinum-resistant ESCC. RESULTS Analysis showed that individuals with ESCC after neoadjuvant chemoradiation, expressed in the tumor cell toxicity molecular effect of CD8+ T cell infiltration, inflammation macrophages subgroup abundance increase, LAMP3+ dendritic cell activation, increase antitumor immune response. However, some residual malignant epithelial cells still survived, indicating that these cells may have drug resistance and the possibility of relapse. We analyzed this part of the cell gene expression, and screening to LGALS1 gene may be associated with drug resistance. LGALS1 exhibits elevated expression levels in tumor cells and is linked to cisplatin resistance. Functional verification indicated that knockdown of LGALS1 expression could up-regulate the sensitivity of esophageal squamous cell cells and tumors to cisplatin therapy by inhibiting intracellular epithelial-mesenchymal transformation, DNA damage repair and anti-apoptosis mechanisms. CONCLUSION These findings confirm LGALS1 is the key of ESCC of platinum resistance protein, targeted LGALS1 may be an effective means to overcome the neoadjuvant chemoradiation resistance.

Lung squamous cell carcinoma (LUSC) has a scarcity of actionable therapeutic targets. Through integrative multi-omics analysis combining Mendelian randomization and colocalization of LUSC genome-wide association studies with functional quantitative trait loci, we identified the enzyme GGPPS as a causal driver with robust genetic support (PP·H4 = 74.1%) and showed that its elevated expression predicted reduced survival and accelerated tumor progression. Functional interrogation demonstrated that GGPS1 knockdown potently suppressed proliferation in vitro (CCK-8, EdU and colony formation) and in vivo (xenografts studies). Mechanistically, GGPPS drives oncogenesis through its catalytic activity in mediating protein geranylgeranylation: geranylgeranylated RHOA activated ROCK1-dependent phosphorylation of the p65 subunit of NF-κB to induce transcription of IL1B, whereas geranylgeranylated RAC1 promoted STAT1 nuclear translocation for direct IL1RAP transactivation. Critically, pharmacological inhibition abolished GGPPS-driven geranylgeranylation-dependent signaling: JSH-23 reversed both the proliferation mediated by RHOA and NF-κB p65 and the upregulation of IL1B potentiated by GGPS1 overexpression; and NSC23766 blocked the RAC1/STAT1-dependent IL1RAP activation amplified by GGPPS elevation, confirming that both axes are indispensable for GGPPS-dependent proliferation. Collectively, this GGPPS-mediated geranylgeranylation axis, converging on IL-1 pathway amplification, represents a central therapeutic vulnerability in LUSC, highlighting GGPPS as a promising macromolecular target for this recalcitrant malignancy.

BACKGROUND:Clinically N3 (cN3) stage non-small cell lung cancer (NSCLC) has historically been considered unresectable. While neoadjuvant immunochemotherapy demonstrates unprecedented pathological responses in earlier-stage disease, its role in enabling surgical resection versus definitive immuno-chemoradiotherapy for cN3 NSCLC remains undefined. METHODS:This multicenter retrospective study (2017-2024) analyzed 196 patients with stage IIIB-IIIC (cT1-4 N3) NSCLC from two academic centers. Eighty-two patients received neoadjuvant immunochemotherapy followed by surgery (surgery group), while 114 underwent definitive immuno-chemoradiotherapy (radiotherapy group). Propensity score matching (PSM) balanced baseline characteristics. Primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS) and pathological complete response (pCR). RESULTS:After PSM (74 per group), no overall PFS difference was observed (surgery: 32.2 months vs. radiotherapy: 21.3 months, P = 0.094). But surgery was associated with a significant OS benefit (median not reached vs 71.3 months, P = 0.012). Furthermore, only surgical patients achieving pCR (PFS: not reached vs. 21.3 months, P = 0.001; OS: not reached vs. 71.3 months, P = 0.019) or nodal clearance (ypN0) (PFS: not reached vs. 21.3 months, P = 0.010, OS: not reached vs. 71.3 months, P = 0.009) showed superior PFS and OS versus radiotherapy. Recurrence pattern differed between the two groups: Among locoregional failure patterns, all events in the surgery group were regional lymph node recurrences, whereas radiotherapy failures primarily involved primary site progression (59.3%), followed by regional nodal recurrence (39.7%). CONCLUSION:Surgery after neoadjuvant immunochemotherapy demonstrated survival advantage over immuno-chemoradiotherapy in cN3 NSCLC. Significant survival benefits were confined to surgical patients attaining pCR or ypN0, highlighting the need for biomarker-driven patient selection.

The exon 19 deletion (19 Del) and the exon 21 L858R point mutation (21 L858R) are two main subtypes of EGFR-mutant lung adenocarcinoma (LUAD) with distinct response to targeted treatment and immunotherapy. Understanding the intratumor heterogeneity (ITH) of EGFR-mutant LUAD may explain the reason. 157 multi-region tumor samples and matched distant normal lung tissues from 29 treatment-naïve operable EGFR-mutant LUAD patients were collected to perform whole genome sequencing, panel sequencing and whole transcriptome sequencing. We aimed to comprehensively assess genomic and transcriptomic ITH between 19 Del and 21 L858R. The 21 L858R LUAD exhibited significantly higher copy number variation (CNV) ITH index (ITHi) compared to the 19 Del LUAD, but there was no significant difference in somatic single-nucleotide variant (SNV) ITHi between them. Meanwhile, 19 Del LUAD owned more clonal genetic alterations, while 21 L858R LUAD had more subclonal events. Both linear and branch evolution models existed in 19 Del and 21 L858R LUAD. Besides, 19 Del seemed to be more dominant for driving tumor development, while other driver mutations participated jointly with 21 L858R in tumor evolution. Moreover, 19 Del LUAD exhibited significantly higher immune score and checkpoint inhibition signature than 21 L858R. Additionally, it indicated that high-level TMB might be a favorable prognostic factor for EGFR-mutant LUAD. Our study demonstrated diverse genomic heterogeneity and tumor immune microenvironment in EGFR-mutant LUAD, which might elaborate on potential explanations for different efficacy between 19 Del and 21 L858R and provide valuable hints to treatment strategy.

MET proto-oncogene amplification (METamp) is associated with poor prognosis in gastric or gastroesophageal junction (G/GEJ) cancer. Currently, effective targeted therapies for G/GEJ cancer harboring METamp remain unavailable, and clinical evidence supporting the use of MET inhibitors in this disease population is limited. Here we report the results of a phase 2 study of savolitinib, an oral MET inhibitor, in patients with METamp G/GEJ cancer. This open-label, multicenter, phase 2 trial in China comprised an exploratory phase and a pivotal phase. Patients with METamp (gene copy number ≥10 for pivotal phase), locally advanced or metastatic G/GEJ cancer that had progressed following ≥1 (≥2 for pivotal phase) prior lines of systemic therapy received savolitinib orally. The primary endpoint was objective response rate (ORR) by independent review committee in the pivotal phase. In total, 110 patients were enrolled and received savolitinib, including 45 in the exploratory phase and 65 in the pivotal phase. Independent review committee-assessed ORR was 32.3% (95% confidence interval 21.2-45.1%) in the pivotal phase, which met the predefined efficacy threshold (lower limit of 95% confidence interval of ORR ≥15%). Among all patients enrolled (n = 110), grade ≥3 treatment-related adverse events were reported in 38 patients (34.5%); one (0.9%) treatment-related death occurred. Savolitinib monotherapy showed encouraging antitumor activities and a tolerable safety profile in heavily treated, later-line METamp G/GEJ cancers, supporting further investigation in randomized controlled trials. ClinicalTrials.gov identifier: NCT04923932 .

Bevacizumab plus chemotherapy is the standard first-line therapy for metastatic colorectal cancer (mCRC). To date, no phase 3 trial has compared first-line oral multitargeted TKI versus bevacizumab plus chemotherapy in RAS/BRAF wild-type mCRC. The open-label, noninferiority, randomized, phase 3 trial (ANCHOR; NCT04854668; CTR20210940) evaluated first-line anlotinib versus bevacizumab plus oxaliplatin and capecitabine (CapeOX) in this setting. Patients were centrally randomized (1:1) to receive 4-8 cycles of CapeOX in combination with either anlotinib (12 mg once daily on days 1-14) or bevacizumab (7.5 mg/kg on day 1) every 3 weeks, followed by maintenance therapy with anlotinib or bevacizumab plus capecitabine until unacceptable toxicity or disease progression. The primary endpoint was progression-free survival (PFS) assessed by an independent review committee in the intention-to-treat population. The hazard ratio (HR) for the noninferiority margin was 1.09. Between May 25, 2021, and August 30, 2023, 373 patients were assigned to the anlotinib group and 375 to the bevacizumab group. As of February 2, 2025, the median follow-up was 25.1 months (95% confidence interval [CI] 23.8-26.3). The median PFS was 11.0 months (95% CI 9.8-11.2) in the anlotinib group versus 11.0 months (9.7-11.2) in the bevacizumab group (stratified HR, 1.00; 95% CI 0.84-1.18; p = 0.87). The incidences of grade ≥3 treatment-related adverse events were 64.9% and 44.8%, respectively. Compared with bevacizumab plus CapeOX, anlotinib plus CapeOX showed similar antitumor activity but failed to reach the prespecified noninferiority margin for PFS and was associated with increased manageable toxicity.

BA1106 is a first-in-human anti-CD25 monoclonal antibody developed by Boan biotech, which demonstrated significant anti-tumor activity by depleting Treg cells and expanding CD8+ and CD4+T cells in tumor microenvironment in preclinical studies, without IL-2 signaling pathway suppression. A phase 1 study was conducted to evaluate the safety, pharmacokinetics and preliminary efficacy of BA1106 in solid tumors. Eligible patients with refractory, advanced or metastatic solid tumors were included in the dose escalation part of this study, which followed an accelerated-titration and a Bayesian optimal interval design. The primary endpoints included the safety, maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs). The secondary endpoints included pharmacokinetics, immunogenicity and preliminary efficacy. As of December 23rd, 2024, 31 patients (3 and 12μg/kg, n=1 each; 36, 108μg/kg, n=3 each; 216, 432, 720μg/kg, n=6; 1200ug/kg, n=5) have been treated with BA1106. One DLT (grade 3 hyponatremia) was observed at the dose level of 432μg/kg, and MTD was not reached. Treatment-related adverse events (TRAEs) of any grade were reported in 21 patients (67.7%). 9 (29.0%) patients suffered immune-related adverse events (irAEs) (grade 1 to 2), with rash (n=4, 12.9%), myoglobin blood increased (n=2, 6.5%), and lipase increased (n=2, 6.5%) being the most commonly observed. 3(9.7%) patients suffered grade 3 TRAEs. No patient was dead or premature withdrawal for TRAEs. Out of 26 patients with at least one efficacy assessment, 9 achieved stable disease (SD), with a disease control rate (DCR) of 34.6%. Tumor shrinkage and durable disease control were noted in 4 patients, including a small-cell neuroendocrine carcinoma (treatment duration 76 weeks, still ongoing), a pleural mesothelioma (treatment duration 33.9 weeks), a small bowel adenocarcinoma (treatment duration 22.9 weeks), and a hepatocellular carcinoma (treatment duration 22.1 weeks, still ongoing). The exposure of BA1106 increased with the dose escalation. No positive ADA was detected. A rapid and durable decrease in peripheral blood Treg cells and an increase in the Teff/Treg ratio were observed after first dose. BA1106 was well-tolerated and showed preliminary anti-tumor activity in solid tumors. Simultaneously, a clear decrease of Treg cells and increased Teff/Treg ratio were observed, what show the potential to combined with PD-1 inhibitors. This trial was registered in clinicaltrial.gov, NCT05650242. Dan Liu, Qingyuan Zhang, Zhijie Wang, Junye Wang, Ming Zhou, Deyong Song, Changlin Dou, Lin Shen. Preliminary safety and efficacy results of an anti-CD25 monoclonal antibody (BA1106) in patients with advanced solid tumors: The first-in-human study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT067.

Background:Currently, reliable and convenient markers for identifying patients with non-small cell lung cancer (NSCLC) who benefit from neoadjuvant immunochemotherapy remains elusive. Established static biomarkers, such as programmed cell death ligand 1 (PD-L1) expression and tumor mutational burden (TMB), exhibit limitations in capturing dynamic changes in the immune microenvironment and predicting treatment efficacy compared to dynamic biomarkers. This study aims to evaluate the value of dynamic peripheral blood markers in predicting pathological complete response (pCR) and survival outcomes in patients with NSCLC undergoing neoadjuvant immunochemotherapy. Methods:In this retrospective analysis, clinicopathological data, along with baseline and post-treatment laboratory results, were examined from 113 patients with NSCLC who received neoadjuvant immunochemotherapy between October 2019 and April 2023. The least absolute shrinkage and selection operator (LASSO) algorithm was employed to identify candidate dynamic peripheral blood markers, which were then further refined using logistic regression. An integrated nomogram model incorporating the optimal biomarkers was developed to predict individual pCR. Event-free survival (EFS) was analyzed using the Kaplan-Meier method, with comparisons performed via the Log rank test. Results:Dynamic alkaline phosphatase (dALP) and dynamic neutrophil-to-lymphocyte ratio (dNLR) emerged as independent predictors of pCR following neoadjuvant immunochemotherapy, as confirmed by LASSO and multivariate logistic regression. A predictive model, incorporating dNLR, dALP, degree of differentiation, and smoking history, demonstrated strong predictive capability (AUC = 0.745). Internal validation through bootstrapped resampling yielded a mean AUC of 0.728 (95% CI 0.686-0.749). Survival analysis revealed that patients who achieved pCR had significantly better EFS, and those with low dNLR and dALP values exhibited superior EFS compared to the high-value group. Conclusion:The findings indicate that dNLR and dALP can serve as independent predictors of pCR and EFS in patients with NSCLC treated with neoadjuvant immunochemotherapy. The pCR prediction model incorporating these two markers showed excellent predictive performance, providing valuable clinical guidance for selecting patients who are most likely to benefit from neoadjuvant immunochemotherapy.

Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality, with therapeutic outcomes often constrained by the complexity of the tumor microenvironment (TME). Comprising diverse cell types and signaling molecules, the TME is increasingly recognized as a critical determinant of tumor behavior and patient prognosis. Cancer-associated fibroblasts (CAFs), a dominant TME component, drive progression through intercellular communication. Although CAF-targeted therapies hold promise, the precise mechanisms underlying CAF-cancer cell interactions remain elusive. Leveraging single-cell sequencing, we identified ACTN1 as a gene highly expressed in CAFs and strongly correlated with NSCLC prognosis. We engineered an integrated hybrid nanovesicle composed of CAF membranes (cM) and a liposome core to encapsulate siRNA against ACTN1 (siACTN1). This represents the first CAF-membrane-coated siRNA system targeting ACTN1 for NSCLC therapy. The nanovesicles modulate cytokine secretion (IL-6 and CCL2) to inhibit NSCLC cell growth, migration, and invasion in vitro. In vivo studies corroborated these findings, demonstrating reduced cytokine secretion and attenuated tumor growth. By harnessing the intrinsic properties of CAFs for targeted siRNA delivery, these nanovesicles offer a novel strategy for TME modulation in NSCLC.

2527 Background: QLS31905 is a Claudin18.2/CD3 bispecific antibody. Here we report the updated data of a phase 1 study of QLS31905. Methods: This multicenter phase 1 trial (NCT05278832) recruited patients (pts) with advanced solid tumors who had progressive disease or were intolerable to or inapplicable of standard therapy. In dose-escalation stage adopting accelerated titration and interval 3+3 design, pts regardless of Claudin18.2 status were administered QLS31905 via intravenous infusion in 11 sequential single doses (0.5, 1.5, 5, 15, 45, 100, 200, 350, 500, 800, 1200 μg/kg qw or q2w) with priming dose from 350 μg/kg. In dose-expansion stage, Claudin18.2-positive (≥1% tumor cells) pts were recruited. The primary endpoint was dose limiting toxicities (DLT) and maximum tolerated dose (MTD) in dose-escalation stage, and was objective response rate (ORR) in dose-expansion stage. Results: As of Jul 26, 2024, 31 pts were included from 0.5 μg/kg qw to 1200 μg/kg q2w in dose-escalation stage, and 48 pts were included in five cohorts (100~200 μg/kg qw and 350~800 μg/kg q2w) in dose-expansion stage. The 1200 μg/kg q2w cohort is ongoing. There were 43 (54.4%) pts with gastric or gastroesophageal junction (G/GEJ) cancer and 26 (32.9%) with pancreatic adenocarcinoma (PAC). Over half of (61.8%) pts had received ≥2 lines of prior treatment. No DLT occurred. MTD was not reached. Treatment-related adverse events (TRAEs) occurred in 79 (100%) pts, of whom 34 (43.04%) were ≥grade 3. The most common ≥grade 3 TRAEs (≥3%) were lymphocyte count decreased (21.5%), γ-glutamyl transferase increased (3.8%), neutrophil count decreased (3.8%), cytokine release syndrome (CRS [3.8%]), and anemia (3.8%). CRS occurred in 17 (21.52%) pts including two pts with grade 3 and one with grade 4, and all recovered. Two pts (2.53%) discontinued treatment due to TRAEs of abdominal pain and CRS, respectively. No TRAE leading to death occurred. In 33 Claudin18.2-positive pts in 350~1200 μg/kg q2w cohorts, six pts (three with G/GEJ cancer and three with PAC) had partial response. ORR was 18.18% (95% confidence interval [CI]: 6.98%, 35.46%), disease control rate (DCR) was 87.88% (95% CI: 71.80%, 96.60%), median progression-free survival (PFS) was 4.21 months (95% CI: 2.99, 5.55), and median overall survival (OS) was 9.53 months (95% CI: 7.69, not evaluable). Among the Claudin18.2-positive pts in 350~1200 μg/kg q2w cohorts, ORR, DCR, median PFS, median OS was 15.79%, 89.47%, 4.40 months, 9.20 months in 19 pts with G/GEJ cancer, and was 25.00%, 91.67%, 3.94 months, not reached in 12 pts with PAC, respectively. QLS31905 exposure was generally linear with the administered dosage. There was no tendency of accumulation after multiple administrations. Conclusions: QLS31905 was safe and tolerable, and showed encouraging efficacy in Claudin18.2-positive pts with gastrointestinal tumors. QLS31905 is worthy of further exploration in combined therapy in phase 2 trials. Clinical trial information: NCT05278832 .

8045 Background: Stage IIIB-IIIC (N3) non-small cell lung cancer (NSCLC) is generally seen as unresectable, and Durvalumab following concurrent chemoradiotherapy (CCRT) is the standard of care for these patients. The use of immune checkpoint inhibitor (ICI) in neoadjuvant therapy has resulted in unprecedented rates of pathological response and lymph node downstaging, which has made resecting previous unresectable disease possible. However, it remains uncertain whether certain N3 patients may derive survival benefit from surgery after neoadjuvant immunotherapy. Methods: This multicenter retrospective study included patients with cN3 NSCLC who received inducing immunochemotherapy and completed surgery. As a comparison, patients with cN3 NSCLC who received ICI following CCRT, ICI plus CCRT, and CCRT following inducing immunochemotherapy were also included. 1:1 Propensity score matching (PSM) was implemented to balance important baseline characteristics included gender, age, smoking history, histologic type, differentiated degree, cT stage between patients with surgery and radiotherapy. Log-rank test was used to compared progression-free survival (PFS). Results: The median follow-up time of 82 patients with surgery and 114 patients with radiotherapy was 28.1 months and 21.8 months, respectively. In patients with surgery, 29 patients reach complete pathological response (pCR) and 53 patients reached node clearance. After PSM, 74 patients with surgery and 74 patients with radiotherapy showed balanced baseline characteristics. Before PSM, patients with surgery displayed a significant advantage in median PFS (24.6 months vs 21.3 months, p=0.040) but this advantage disappeared after PSM (31.3 months vs 30.8 months, p=0.132). In post-treatment subgroup analyses, patients reached pCR had better PFS than patients with radiotherapy (median PFS not reach vs 30.8 months, p=0.001). In addition, patients reached node clearance also had better PFS than patients with radiotherapy (median PFS not reach vs 30.8 months, p=0.010). In pre-treatment subgroup analyses, surgery did not outperform radiotherapy in male or female patients, smokers or nonsmokers, squamous or non-squamous carcinoma and poorly differentiated carcinoma. In patients with high or moderately differentiated tumors, patients with surgery had better PFS than patients with radiotherapy (median PFS not reach vs 13.2 months, p=0.001). Conclusions: In patients with cN3 NSCLC, surgery after neoadjuvant immunochemotherapy do not transcend ICI with CCRT in PFS. Only patients with high or moderately differentiated tumors, or reached pCR, node clearance after surgery have better PFS than patients with radiotherapy. Prospective clinical is needed to evaluate the benefit of surgery after neoadjuvant immunotherapy for cN3 NSCLC.

Cetuximab plus irinotecan, fluorouracil, and leucovorin (FOLFIRI) represents a first-line therapeutic standard for RAS/BRAF wild-type metastatic colorectal cancer (mCRC) patients. Despite this established approach, cetuximab β (CMAB009), as a modified antibody of cetuximab, prospectively selected for dual RAS/BRAF wild-type patients, has not yet been validated in the Chinese mCRC patients through phase 3 trial. In this study (ClinicalTrials.gov identifier: NCT03206151), patients with RAS/BRAF wild-type mCRC who were not suitable for radical resection were randomly assigned in a 1:1 ratio to receive cetuximab β plus FOLFIRI or FOLFIRI alone. The primary endpoint was blinded independent review committee-assessed progression-free survival (PFS). The secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), surgery rate for metastasis and R0 resection rate, and safety. From January 4, 2018 to September 2, 2021, a total of 505 eligible patients were enrolled and received study treatment; the median follow-up duration was 8.7 months (95% confidence interval [CI], 7.77 to 9.29) and 5.9 months (95% CI, 5.63 to 6.65) in cetuximab β plus FOLFIRI group and FOLFIRI group, respectively. Compared to FOLFIRI alone, cetuximab β plus FOLFIRI demonstrated statistically significant improvements in median PFS (13.1 vs. 9.6 months, hazard ratio [HR], 0.639; 95% CI, 0.468 to 0.872; P = 0.004), median OS (28.3 vs. 23.1 months, HR, 0.729; 95% CI, 0.551 to 0.965; P = 0.024), and ORR (69.1% vs. 42.3%, odds ratio, 3.090; 95% CI, 2.280 to 4.189; P < 0.001). Cetuximab β plus FOLFIRI exhibited manageable toxicity without novel safety signals. This study demonstrated that cetuximab β plus FOLFIRI provided significant clinical benefits as a first-line treatment for patients with RAS/BRAF wild-type mCRC. Compared to FOLFIRI alone, cetuximab β plus FOLFIRI therapy led to prolonged median PFS and OS while maintaining a manageable safety profile, offering a new treatment option for this patient population.

Cholesterol metabolism reprogramming serves a pivotal role in tumor onset and progression. The present study investigated lung adenocarcinoma (LUAD), focusing on the regulatory impact of cholesterol metabolism‑related genes (CMRGs). Consensus clustering identified distinct cholesterol metabolism‑related clusters in LUAD, followed by survival analysis and immune infiltration profiling for each cluster. A predictive model, constructed using cluster‑specific differentially expressed genes and the LASSO algorithm, was validated with an independent dataset. Furthermore, the model was utilized to predict potential responses to immunotherapy and chemotherapy for patients with LUAD. The functional role of the key gene GJB3 in LUAD progression was confirmed through in vitro experiments. Two distinct cholesterol metabolism‑related clusters were identified, exhibiting significant differences in prognosis, biological function and immune cell infiltration. A survival model, based on four genes, demonstrated strong predictive performance across multiple datasets. The low‑risk group showed improved responses to immunotherapy, while the high‑risk group exhibited heightened sensitivity to chemotherapy. In vitro assays revealed that GJB3 knockdown suppressed LUAD cell proliferation and invasion, significantly reducing the expression of epithelial‑mesenchymal transition‑related genes. These findings highlight CMRGs as potential prognostic biomarkers and suggest a foundation for personalized treatment strategies in LUAD.

Adding a PD-1/PD-L1 inhibitor to gemcitabine plus cisplatin (GemCis) has shown survival benefits in advanced biliary tract cancer (BTC). Dual inhibition of PD-1/PD-L1 and TIGIT may act synergistically, and further enhance antitumor effects. ZSAB-TOP was a single-arm, multicenter, phase 2 study (NCT05023109) evaluating efficacy and safety of first-line tislelizumab (a PD-1 inhibitor) plus ociperlimab (a TIGIT inhibitor) and GemCis in advanced BTC. Eligible patients received tislelizumab (200 mg) and ociperlimab (900 mg) on day 1 until unacceptable toxicity or disease progression, in combination with cisplatin (25 mg/m²) and gemcitabine (1000 mg/m²) on days 1 and 8 of a 21-day cycle for a maximum eight cycles. The primary endpoint was confirmed objective response rate (ORR) evaluated by the investigator, which was compared with a historical ORR of 25% with GemCis, with a statistical superiority setting at p ≤ 0.05. From March 8, 2022, to January 18, 2023, 45 patients were enrolled. Among the 41 patients in the efficacy analysis set, the confirmed ORR was 51.2% (95% CI 35.1–67.1), achieving the statistical superiority criteria (p = 0.0003). Patients who had TIGIT+/PD-L1+ (n = 16) tended to have a numerically greater confirmed ORR (75.0% [95% CI 47.6–92.7]). After a median follow-up of 14.6 months, median progression-free survival was 7.7 months (95% CI 6.0–9.4), with a median overall survival of 17.4 months (95% CI 11.7-not reached). Treatment-related adverse events of grade ≥3 occurred in 60.0% of patients; immune-mediated adverse events of any grade was observed in 42.2%, with the majority being grade 1 or 2. In conclusion, first-line tislelizumab and ociperlimab plus GemCis yielded clinically promising tumor response and survival outcomes in advanced BTC and were generally well tolerated without new safety signals.

Background CMG901 is a novel first-in-class antibody-drug conjugate with a humanised anticlaudin 18.2 antibody linked to microtubule-disrupting agent monomethyl auristatin E. We aimed to assess the antitumour activity and safety of CMG901 in patients with advanced gastric or gastro-oesophageal junction cancer and other solid tumours. Methods KYM901 is a multicentre, open-label, single-arm, phase 1 trial consisting of dose-escalation and dose- expansion stages. Patients with advanced solid tumours, including gastric or gastro-oesophageal junction and pancreatic cancers, were recruited from 31 hospital sites in China. Eligible patients were aged 18 years or older, were refractory to standard therapy or had no available standard-of-care regimen, and had an Eastern Cooperative Oncology Group performance status score of 0-1, a life expectancy of at least 3 months, and at least one measurable lesion. Patients received intravenous CMG901 every 3 weeks (03-34 mg/kg in dose escalation and 22-30 mg/kg in dose expansion) until disease progression, unacceptable toxic effects, initiation of new antitumour therapy, study withdrawal, or death. Primary endpoints were adverse events and dose-limiting toxic effects in the dose-escalation phase, and objective response rate and recommended phase 2 dose in the dose-expansion phase. Confirmed objective response was defined as a partial or complete response that was verified by follow-up imaging at least 4 weeks after the initial assessment. Safety was assessed in all patients who received at least one dose of CMG901 with at least one post-dose safety evaluation. Antitumour activity was assessed in all patients who received at least one dose of CMG901 (full analysis set) and in all CMG901-treated patients with at least one post-dose imaging evaluation and no major protocol deviations (efficacy analysis set). Dose-expansion data for patients with pancreatic cancer will be published separately. Due to small sample sizes, results in patients with other solid tumours (n=2) are not planned for publication. This ongoing trial is registered with ClinicalTrials.gov, NCT04805307. Findings Between Dec 24, 2020, and Feb 23, 2023, 27 patients were enrolled in the dose-escalation phase (median age 570 years [IQR 480-630]; 14 [52%] male, 13 [48%] female) and 107 patients with gastric or gastro-oesophageal junction cancer in the dose-expansion phase (median age 560 years [440-640]; 57 [53%] male, 50 [47%] female). As of Feb 24, 2024, one dose-limiting toxic effect (grade 3 pancreatitis) occurred at 22 mg/kg, and the maximum tolerated dose was not reached in the dose-escalation phase. All 27 patients reported at least one treatment-emergent adverse event, most frequently vomiting (19 [70%]), decreased appetite (16 [59%]), proteinuria (16 [59%]), and anaemia (15 [56%]), and five (19%) had drug-related grade 3 or worse treatment-emergent adverse events. In 107 patients, grade 3 or worse treatment-emergent adverse events occurred in 73 (68%) patients and serious adverse events occurred in 54 (50%) patients in dose expansion. The most common grade 3-4 adverse events were neutrophil count decreased (22 [21%]), anaemia (15 [14%]), and vomiting (11 [10%]). One treatment-related death was reported. At median follow-up of 90 months (IQR 44-129), among 113 patients with gastric or gastro-oesophageal junction cancer in the 22-30 mg/kg cohort full analysis set across both the dose-escalation and dose-expansion phases, the confirmed objective response rate was 28% (95% CI 20-38; 32 of 113 patients). In the 109 patients included in the efficacy analysis set, the confirmed objective response rate was 29% (95% CI 21-39; 32 of 109 patients). Based on overall safety, activity, and pharmacokinetics of CMG901, 22 mg/kg was the proposed recommended phase 2 dose. Interpretation CMG901 showed a manageable safety profile and had promising antitumour activity in patients with advanced gastric or gastro-oesophageal junction cancer. Copyright (c) 2025 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.