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A first-in-human phase I clinical trial evaluating the safety, tolerability, and preliminary efficacy of the novel fas ligand (FasL) inhibitor M3T01 in adults with advanced solid tumors.
TPS2670 Background: Tumor-specific T cells undergo apoptotic cell death following FasL binding to the fas (CD95) receptor. FasL is upregulated in many advanced cancers and is expressed by tumor endothelial cells, macrophages, and activated T and natural killer (NK) cells. Consequently, FasL contributes to tumor progression through deletion of tumor-specific T cells and impaired T cell tumor infiltration. Preclinical studies demonstrate that FasL blockade facilitates increased T cell tumor infiltration and enhances efficacy of immune checkpoint inhibitors and adoptive cell therapies. M3T01 is a fully human IgG4/kappa monoclonal antibody that potently inhibits FasL. This is an ongoing first-in-human phase I clinical trial (NCT06719362) evaluating the safety, tolerability and preliminary antitumor efficacy of M3T01 as monotherapy and in combination with pembrolizumab in adults with advanced solid tumors. Methods: The primary objectives are to evaluate the safety/tolerability, dose-limiting toxicity (DLT), and maximum tolerated dose (MTD) of M3T01. Secondary objectives are to characterize the pharmacokinetics, pharmacodynamics, immunogenicity, and preliminary antitumor efficacy of M3T01 as monotherapy and in combination with pembrolizumab. A sub-study will evaluate paired tumor biopsies (pre-treatment and cycle 2 day 8) to evaluate for changes in the tumor microenvironment induced by FasL inhibition. Eligible patients have unresectable or metastatic solid tumors that are refractory to standard systemic therapy. Patients must have adequate organ function, measureable disease per RECIST v1.1 or RANO 2.0, and an ECOG performance status of 0-1. Dose escalation through a 3 + 3 design will evaluate M3T01 as monotherapy and in combination with pembrolizumab (administered intravenously every 3 weeks). Monotherapy cohorts 1-4 (100 to 600 mg) have been completed without DLT. After completion of the dose escalation portion of the trial, dose expansion cohorts will open to evaluate M3T01 in combination with standard systemic therapies in the treatment of patients with glioblastoma, gastric/esophageal adenocarcinoma, and head and neck squamous cell carcinoma. Clinical trial information: NCT06719362 .
New paradigm for antibiotic selection in hard-to-treat drug-resistant infections following HSCT.
e18627 Background: HSCT patients are highly susceptible to severe infections. Conventional antimicrobial susceptibility testing (AST) (phenotypic and molecular), does not reflect in vivo infection conditions and evaluates antibiotic activity against a single “primary” pathogen at serum-based concentrations. These approaches fail to account for polymicrobial biofilms, bacterial-fungal interactions, and limited antibiotic penetration into infected tissues, resulting in ineffective antibiotic selection. AtbFinder is a novel, culture-independent, non–MIC-based phenotypic test that selects antibiotics under conditions mirroring each patient’s infection environment. It preserves polymicrobial biofilms from clinical samples and tests antibiotics at clinically achievable, site-specific concentrations, including tissue-penetration-adjusted levels for lungs. We compared clinical outcomes following AtbFinder-guided versus standard AST-guided antibiotic selection in HSCT patients with severe infections. Methods: This prospective, open-label, IIT pilot study included 12 HSCT febrile patients (6 sepsis, 6 respiratory infections). All patients had failed two antibiotic regimens selected by standard AST within the preceding 30 days. 64% had mixed bacterial–fungal infections, and 45% harbored ESKAPE pathogens. No antibiotics were administered for 5d prior to enrollment. AtbFinder evaluated up to 184 antibiotics per patient within 6–20 hours. Clinical outcomes were compared with matched retrospective controls treated with antibiotics selected with standard AST at the same hospitals. Controls were selected from patients managed during the same time period immediately prior to AtbFinder implementation and were matched by HSCT status, infection type, and clinical severity. Results were benchmarked against broth microdilution and PCR-based resistance gene detection. Results: At 30 days following completion of AtbFinder-guided therapy, all patients achieved clinical and laboratory-confirmed infection resolution, compared with 40% of matched controls (p<0.001). Use of broad-spectrum antibiotics decreased by 65% (p<0.01). ICU length of stay was reduced by 74%, and 90-day hospital readmission was 0% in the AtbFinder group versus 45% in controls. Among patients with ESKAPE pathogens, AtbFinder-guided antibiotic selection demonstrated comparable efficacy, whereas the control group showed a 3.5-fold lower response rate (p<0.01). Molecular analyses confirmed preservation of patient-specific polymicrobial biofilm communities within the AtbFinder assay. Conclusions: In this prospective pilot study, antibiotic selection guided by a polymicrobial biofilm–preserving phenotypic assay was associated with improved clinical outcomes, reduced broad-spectrum antibiotic use, and shorter ICU stays in HSCT patients with hard-to-treat and antibiotic-resistant infections.
Tumor-informed versus tumor-agnostic ctDNA assays for molecular residual disease detection in colorectal cancer: A systematic review and meta-analysis.
3595 Background: Circulating tumor DNA (ctDNA) is increasingly used for detection of molecular residual disease (MRD) following curative-intent treatment for colorectal cancer (CRC). Two principal assay strategies exist: tumor-informed (TI) assays requiring prior tumor sequencing, and tumor-agnostic (TA) assays using fixed plasma-based panels. The relative prognostic and diagnostic performance of these approaches remain uncertain. Despite growing clinical adoption, no systematic comparison of their relative performance exists to guide assay selection. Methods: We performed a systematic review and meta-analysis in accordance with PRISMA 2020 guidelines. PubMed, Embase, Cochrane Library, and Web of Science were searched from inception to January 2025 for original studies evaluating ctDNA-based MRD detection after curative-intent treatment for CRC. Primary outcomes were hazard ratios (HRs) for recurrence-free survival (RFS) and diagnostic accuracy metrics (sensitivity and specificity). Random-effects models (DerSimonian-Laird estimator) were used to pool effect estimates; heterogeneity was assessed using I² statistics. Subgroup analyses were conducted by assay type (tumor-informed vs tumor-agnostic) and sampling strategy (landmark vs serial). Quality assessment was performed using QUADAS-2 for diagnostic studies and Newcastle-Ottawa Scale for prognostic studies. Results: Twenty-three studies comprising 9,847 patients met inclusion criteria. Eighteen studies evaluated tumor-informed assays (n=7,892) and eight evaluated tumor-agnostic assays (n=2,156), with three directly comparing both approaches. For tumor-informed assays, the pooled HR for recurrence in ctDNA-positive versus ctDNA-negative patients was 7.58 (95% CI, 6.21–9.25; I²=24%). For tumor-agnostic assays, the pooled HR was 4.12 (95% CI, 3.18–5.34; I²=18%). Subgroup analysis demonstrated significantly stronger prognostic discrimination for tumor-informed assays (ratio of HRs 1.84; 95% CI, 1.38–2.45; p<0.001). In serial sampling settings, tumor-informed assays achieved higher sensitivity for MRD detection than tumor-agnostic assays (88% vs 62%; p=0.002). At landmark timepoints, specificity was similar between approaches (97% vs 94%; p=0.08). Between study heterogeneity was low to moderate across analyses. Conclusions: Tumor-informed ctDNA assays demonstrate superior prognostic performance and higher sensitivity with serial sampling compared with tumor-agnostic approaches for MRD detection in colorectal cancer. TI assays may be preferred when longitudinal monitoring is feasible, while TA assays remain useful when tumor tissue is unavailable, or rapid results are needed. These findings support selection of ctDNA assay strategies based on clinical context.
Impact of time-of-day (ToD) of single-agent immune-checkpoint inhibitor (ICI) on survival in advanced non–small cell lung cancer (aNSCLC) with PD-L1 ≥ 50%: Analysis of the NOTCH collaborative REAL-SAIF study.
8602 Background: There is growing evidence and interest in the role of chrono-immunotherapy. Previous studies showing benefit of earlier ToD were limited by small cohorts with heterogenous groups and ToD cut-offs. Using one of the largest UK cohort, we explored this further. Methods: 896 patients treated with 3-weekly ICI monotherapy between 2017-2023 from 16 UK centres were included in this retrospective study. Early 30-day deaths were excluded. Multiple imputations were used for data missing at random (except ToD) with pooled estimates. The primary endpoint was overall survival (OS). A sinusoidal Cox model was used for multivariate analysis to represent the cyclical nature of ToD. Results: Median OS and progression-free survival (PFS) were 19.1 (95%CI 17.2-20.9) and 10.1 (95%CI 9.2-11.7) months. Baseline demographics were median age 70-years, 50% male, 77.3% non-squamous histology, and 91% pembrolizumab as ICI of choice. Mean C1 and C2 ToD was 13:18 and 13:12 respectively. 44.1% and 66.5% of patients received C2 within 1 and 4 hours from prior ToD. ToD was not correlated with age or socioeconomic deprivation. Age (HR 1.01; p =0.008), male sex (HR 1.25; p =0.005), performance status (PS) ≥2 (HR 1.22; p =0.038), squamous histology (HR 1.30; p =0.004), liver metastasis (HR 1.51; p =0.001), albumin (HR 0.98; p <0.001), and neutrophil-lymphocyte ratio (NLR) (HR 1.60; p <0.031) were associated with OS. PS ≥2 (HR 1.23; p =0.026), squamous histology (HR 1.26; p =0.010), albumin (HR 0.98; p =0.001), and PDL1% (HR 0.99; p =0.012) were associated with PFS. There was no correlation between C1 or C2 ToD with OS/PFS. There was a significant interaction between NLR and C1 ToD for both OS (HR 1.48; p <0.001) and PFS (HR 1.30; p =0.014), with a change in HR <1.0 for high NLR after 14:00 and 12:30 respectively. Conclusions: ToD alone was not associated with survival in aNSCLC ICI monotherapy. NLR has a strong interaction with ToD. A low NLR with early ToD and a high NLR with later ToD were correlated with improved OS/PFS. The relationship of ToD with survival is complex and further research is required before adoption into routine practice. Multivariate Cox model for OS and PFS. PFS[HR (95%CI); p -value] OS[HR (95%CI); p -value] Age 1.00 (1.00-1.01) 0.286 1.01 (1.00-1.02) 0.008 Male sex 1.14 (0.98-1.32) 0.093 1.25 (1.07-1.46) 0.005 Performance status ≥2 1.23 (1.03-1.48) 0.026 1.22 (1.01-1.48) 0.038 Squamous histology 1.26 (1.06-1.50) 0.010 1.30 (1.09-1.56) 0.004 Brain metastasis 1.24 (0.99-1.57) 0.062 1.24 (0.97-1.59) 0.091 Liver metastasis 1.32 (1.03-1.69) 0.029 1.51 (1.17-1.94) 0.001 Albumin 0.98 (0.97-0.99) 0.002 0.98 (0.96-0.99) <0.001 NLR 1.16 (0.76-1.76) 0.498 1.60 (1.05-2.46) 0.031 PDL1% 0.99 (0.99-1.00) 0.012 1.00 (0.99-1.00) 0.091
Efficacy and safety of immune checkpoint inhibitor rechallenge in advanced hepatocellular carcinoma: A systematic review and meta-analysis.
e16192 Background: Immune checkpoint inhibitors (ICIs) are integral to the treatment of advanced hepatocellular carcinoma (HCC); however, most patients eventually experience disease progression. The clinical efficacy and safety of ICI rechallenge following prior ICI failure remain poorly defined. We conducted a systematic review and meta-analysis to evaluate outcomes of ICI rechallenge in advanced HCC. Methods: A systematic search of PubMed, Embase, and the Cochrane Library was performed through January 2026 to identify studies evaluating ICI rechallenge in adults with advanced or unresectable HCC previously treated with ICIs. Eligible studies included rechallenge with PD-1, PD-L1, CTLA-4 inhibitors, or their combinations. Primary outcomes were objective response rate (ORR) and disease control rate (DCR). Secondary outcomes included progression-free survival (PFS), overall survival (OS), treatment-related adverse events (TRAEs), grade ≥3 adverse events, immune-related adverse events (irAEs), and treatment discontinuation. Pooled proportions were calculated using a random-effects model to account for interstudy heterogeneity. Results: Four retrospective cohort studies comprising 201 patients were included in the quantitative synthesis, with one case report included qualitatively. The pooled ORR with ICI rechallenge was 20.1% (95% CI: 15.2–25.6; I² = 47%), and the pooled DCR was 57.4% (95% CI: 49.1–65.4; I² = 42%). Median PFS across studies ranged from 4.0 to 6.0 months, and median OS ranged from 9.2 to 12.1 months. Dual immune checkpoint blockade with CTLA-4 and PD-1 inhibitors yielded higher response rates compared with PD-1/PD-L1 monotherapy rechallenge. The pooled incidence of grade ≥3 adverse events was 21.8% (95% CI: 16.4–27.8). Immune-related adverse events were generally manageable, and treatment discontinuation due to toxicity occurred in less than 10% of patients. Conclusions: Immune checkpoint inhibitor rechallenge in advanced HCC following prior ICI failure is associated with meaningful antitumor activity and an acceptable safety profile, particularly with combination immunotherapy strategies. These findings support ICI rechallenge as a therapeutic option in carefully selected patients and highlight the need for prospective studies to optimize patient selection and rechallenge strategies.
Multiomic profiling of early onset colorectal cancer in an irish tertiary cancer centre: Outcomes and correlative insights.
e15643 Background: Colorectal cancer (CRC) is a major global health concern as it is the second most fatal cancer worldwide. While incidence in average onset colorectal cancer (AOCRC, > 50 years) is declining, early onset colorectal cancer (EOCRC, < 50 years) is rising globally. The reasons for this phenomenon are poorly understood. Multiomic profiling holds promise for determining aetiology and guiding treatment strategies. Methods: Patients diagnosed with CRC were enrolled in this pilot translational study with acquisition of tumour, adjacent normal tissue, blood and faeces. Here we present the data from tumour samples. Seventy-nine patients were included, comprising 38 patients with EOCRC, and 41 with AOCRC. Tumour tissue was obtained from fresh frozen specimens. Targeted genomic, proteomic and transcriptomic analyses were performed, through targeted panel sequencing, LC/MS and RNAseq respectively. Data integration strategies included pathway enrichment analysis, immune cell deconvolution, metabolic reaction enrichment analysis (MaREA), and cross-omics correlation. Clinical, molecular and survival outcomes were compared between EOCRC and AOCRC groups. Results: Integrated multiomic profiling identified 6,726 transcripts and 5,957 proteins. Targeted genomic sequencing detected somatic mutations in 50% of tumours. Tumour sidedness was prognostically relevant, with right sided tumours enriched for KRAS (G12V) and PIK3CA (E545K) mutations and associated with inferior overall survival (p = 0.007). Proteomic and transcriptomic analyses demonstrated that EOCRC exhibits a molecular profile distinct from AOCRC, characterised by enrichment of immunosuppressive processes and activation of sirtuin (SIRT1) and RHO GTPase signalling. Metabolic reaction enrichment analysis identified EOCRC specific vulnerabilities, including reduced glutathione biosynthesis, impaired pyruvate dehydrogenase activity, and altered nucleotide synthesis, consistent with increased oxidative stress sensitivity and glycolytic reliance. NQO1 emerged as a candidate biomarker with concordant transcriptomic and proteomic upregulation. Clinically, EOCRC patients presented with more advanced disease yet demonstrated improved overall survival compared with AOCRC (p = 0.02). Targeted genomic profiling had potential clinical utility, with 20% of patients demonstrating actionable changes in management and 45% harbouring alterations relevant at relapse. Conclusions: EOCRC represents a biologically distinct subtype of MSS colorectal cancer, defined by immunosuppressive signalling and altered metabolic dependencies not observed in AOCRC. These findings support age informed molecular stratification and identify candidate biomarkers and metabolic vulnerabilities that may inform targeted therapeutic strategies for this rapidly rising patient population.
National disparities in outcomes among hospitalizations for myelodysplastic syndromes complicated by sepsis: The impact of insurance, hospital type, and geographic region.
e18583 Background: Prior studies show that sepsis outcomes vary by insurance, hospital type, and geographic location; however, whether these disparities apply to patients with myelodysplastic syndromes (MDS) remains unclear. Methods: We used the Nationwide Inpatient Sample (2015–2017) and identified hospitalizations with MDS and sepsis using ICD-9/10 codes. Survey-weighted univariate and multivariable logistic regression evaluated in-hospital mortality and complications (AKI, shock, ARDS, DIC, mechanical ventilation). Mean length of stay (LOS) and hospital charges were additionally calculated. Results: Among 10,357 hospitalizations (mean age 70.2 years; 43.7% female), females had lower odds of AKI (OR 0.78) but similar mortality (0.98). Hispanic ethnicity was associated with lower mortality (0.80) and ARDS (0.80), while Black race had higher odds of mechanical ventilation (2.47). Urban teaching hospitals had higher mortality (1.39) and complications, including shock (1.91), AKI (1.22), ARDS (1.22), and ventilation (2.46); urban non-teaching hospitals showed similar increases. Private insurance was associated with higher mortality (1.57), whereas Medicaid was associated with lower odds of complications. Mean LOS was 9.9 days and longer among privately insured and Medicaid patients (~14 days). Charges were higher at urban teaching versus rural hospitals ($75,677 vs $36,813) and highest in the West ($86,361). Conclusions: Hospital type and insurance were more strongly associated with mortality, complications, and costs than demographic factors, highlighting the influence of system-level disparities in MDS-related sepsis care. Baseline characteristics and multivariate analysis. Outcome / MetricN = 10357 Urban teaching Urban non-teaching Private Medicaid Female Black Hispanic South West Mortality OR 1.39 1.16 1.57 0.88 0.98 1.08 0.80 1.01 0.95 AKI OR 1.22 1.07 1.01 0.75 0.78 1.07 0.84 1.13 1.17 Septic Shock OR 1.91 1.69 1.03 0.73 0.92 0.93 1.04 1.04 0.92 Mechanical vent OR 2.46 2.35 0.89 0.74 0.90 2.47 1.06 0.99 0.92 ARDS OR 1.22 1.10 0.93 0.72 0.90 1.02 0.80 1.04 1.20 Mean LOS (days) 11.9 9.1 14.0 14.6 — 10.6 11.2 — — Mean charges ($) 75,677 65,599 73,468 60,932 66,490 — — 65,390 86,361 Reference group Rural Rural Medicare Medicare Male White White Northeast Northeast Adjusted odds ratios from survey-weighted multivariable logistic regression. Reference groups: male, White race, rural hospitals, Medicare, Northeast.
A phase 1b/2 study of AK130 (TIGIT/TGF-β bispecific fusion protein) combined with ivonescimab in advanced biliary tract cancer (BTC).
4142 Background: Chemotherapy (chemo) combined with or without PD-(L)1 inhibition is the standard first-line treatment for advanced BTC. After first-line treatment fails, patients (pts) lacking targetable genetic alterations (FGFR2, IDH1, or HER2 etc.) have limited options. For the majority, chemo (FOLFOX as the preferred regimen) is the default but suboptimal option. To date, the therapeutic potential of multi-target ICIs and anti-angiogenesis combination in the post-line regimen of BTC remains unexplored and constitutes a significant clinical demand. Additionally, early preclinical and clinical evidences support the combination blockade of TIGIT, TGF-β and PD-(L)1 plus anti-VEGF therapy in several solid tumors. AK130 is a TIGIT/TGF-β bispecific fusion protein. Ivonescimab, the first approved PD-1/VEGF bispecific antibody, has demonstrated promising efficacy in solid tumors, including BTC. Here, we aim to evaluate the efficacy and safety of AK130 plus ivonescimab in post-line BTC and the primary results from phase 1b is reported. Methods: This was an open-label, multi-center phase 1b/2 study. Pts who had progressed on prior chemo combined with or without a PD-(L)1 inhibitor were enrolled and treated with AK130 and ivonescimab. Phase 1b included dose escalation and expansion parts. In the escalation part, escalating doses of AK130 (10, 30, 45 mg/kg Q3W) were administered using a "3+3+3" design, with ivonescimab at 20 mg/kg Q3W (previously approved dose by NMPA). Dose-limiting toxicities (DLTs) were assessed. Based on safety profile, the expansion proceeded at selected doses, with up to 15 evaluable pts per dose. The primary endpoint of phase 1b was the incidence of AEs and DLTs. The secondary endpoint was ORR. Results: As of Jan 2026, a total of 23 pts was enrolled. 12 pts were enrolled in dose escalation across 3 dose levels (10, 30, 45 mg/kg AK130 Q3W; n = 3, 3, 6). No DLTs were observed, and no maximum tolerated dose (MTD) was established. All pts in the 10 mg/kg and 30 mg/kg groups experienced stable disease (SD). The 45mg/kg group was further expanded to 17 pts, including 15 pts that progressed on prior PD-(L)1 inhibition plus chemo.15 pts from 45mg/kg group were efficacy-evaluable with an ORR of 20.0% (3/15) and a DCR of 73.3% (11/15). 87.5% of the SD pts (7/8) reached shrinkage from baseline. 40.0% pts (6/15) had only one time evaluation and are continuing to be followed. Grade 3 or higher treatment-related adverse events (TRAEs) occurred in 39.1% (9/23) pts. The most common TRAEs were anemia and atopic dermatitis, each reported in 2 pts (8.7%). AK130 45 mg/kg Q3W is planned as the recommended phase 2 dose (RP2D), whose safety and efficacy will be further evaluated in phase 2. Conclusions: AK130 plus ivonescimab demonstrated potential anti-tumor activity with a manageable safety profile as a post-line option for advanced BTC, supporting its further development in this setting. Clinical trial information: NCT06938321 .
Efficacy and safety of TACE with or without MWA followed by sequential targeted and immunotherapy in HCC beyond the up-to-7 criteria.
e16288 Background: Although accumulating evidence suggests survival benefits of transarterial chemoembolization (TACE) combined with microwave ablation (MWA) in early-stage hepatocellular carcinoma (HCC), high-quality data are limited in patients with high tumor burden, particularly beyond the UP-to-7 criteria. This study evaluated the efficacy and safety of TACE with or without MWA followed by sequential targeted and immunotherapy in this population. Methods: We retrospectively analyzed patients with radiologically or histologically confirmed HCC beyond the UP-to-7 criteria who received TACE with or without MWA followed by sequential targeted and immunotherapy. Eligible patients had an ECOG performance status of 0–1, Child–Pugh ≤B7, and were suitable for locoregional therapy. Patients with tumor involvement > 70% of the liver, diffuse disease, or prior systemic or locoregional treatments were excluded. The primary endpoint was progression-free survival assessed by mRECIST; overall survival and safety were secondary endpoints. Baseline was defined as the first TACE. Results: Eighty patients treated between October 2018 and December 2023 were included. The median age was 66 years (range, 45–81); 30 and 40 patients had hepatitis B and C, respectively. Patients had BCLC stages A–C, a median tumor diameter of 7.1 cm, and a median follow-up of 68.4 months. Forty-one patients received TACE followed by targeted and immunotherapy (T+T+I), and 39 received TACE plus MWA followed by targeted and immunotherapy (T+M+T+I). Median progression-free survival was 5.7 vs 11.4 months, and median overall survival was 16.5 vs 40.2 months, respectively. Multivariable Cox regression analysis identified treatment modality as an independent predictor of both progression-free survival and overall survival. No increase in treatment-related adverse events was observed. Conclusions: Based on mRECIST, TACE combined with MWA followed by sequential targeted and immunotherapy appears to be an effective and safe treatment option for HCC beyond the UP-to-7 criteria. PFS and OS by group. T+T+I T+M+T+I P value PFS 0.001 Median, months 5.7（3.6-7.7） 11.4（8.7-14.1） 1-year, % 24.4% 46.2% 2-year, % 2.4% 27.3% 3-year, % 14.5% OS ＜0.001 Median, months 16.5（10.9-22.1） 40.2（34.3-46.2） 1-year, % 65.9% 92.3% 3-year, % 19.5% 63.3% 5-year, % 4.9% 30.6%
Efficacy and safety of PD-1 inhibitor plus chemotherapy vs chemotherapy alone in advanced gastric cancer patients with low or negative PD-L1 expression.
4041 Background: Advanced gastric and gastroesophageal junction (GEJ) adenocarcinoma remains a major global health challenge with limited treatment options and poor prognosis in metastatic or unresectable disease. Immune checkpoint inhibitors targeting the programmed death-1 (PD-1) pathway, when combined with standard chemotherapy, have improved outcomes in overall populations, as shown in pivotal trials such as CheckMate-649 and KEYNOTE-859. However, efficacy is strongly influenced by tumor PD-L1 expression, with patients exhibiting low or negative PD-L1 expression (combined positive score [CPS] <1 or <5, or tumor area positivity [TAP] <5%) derive less pronounced benefit. Subgroup analyses from ORIENT-16 and RATIONALE-305 show heterogeneous results, leaving uncertainty regarding the benefit of PD-1 inhibitors in this subgroup. We aimed to evaluate the efficacy and safety of first-line PD-1 inhibitor–chemotherapy combinations versus chemotherapy alone in this clinically important population. Methods: A systematic search of PubMed/MEDLINE, Embase, Cochrane Library, Scopus, ClinicalTrials.gov, and major oncology conferences was conducted through January 16, 2026. We included Phase III randomized controlled trials comparing PD-1 inhibitor plus chemotherapy with chemotherapy alone in adults with treatment-naïve advanced gastric or GEJ adenocarcinoma and low/negative PD-L1 expression (CPS <1, <5, or TAP <5%). Meta-analyses were conducted using RevMan 5.4 with the generic inverse variance method for time-to-event outcomes (HR) and Mantel–Haenszel method for dichotomous outcomes (RR). Heterogeneity was assessed using I². Primary outcomes were overall survival (OS) and progression-free survival (PFS); secondary outcomes included objective response rate and safety. Results: Four Phase III RCTs (CheckMate-649, KEYNOTE-859, ORIENT-16, RATIONALE-305) comprising 4,761 patients were included. Subgroup data from patients with low/negative PD-L1 expression were analyzed. PD-1 inhibitors did not improve OS (HR 0.92, 95% CI 0.81–1.03, P=0.16; I²=0%) or PFS (HR 0.84, 95% CI 0.70–1.02, P=0.08; I²=47%). Results were consistent across CPS and TAP methods. Toxicity was significantly increased, with higher grade ≥3 adverse events (RR 1.48, P<0.001) and immune-related adverse events (any grade RR 2.80; grade ≥3 RR 4.30). Conclusions: In advanced gastric/GEJ adenocarcinoma with low/negative PD-L1 expression, first-line PD-1 inhibitor plus chemotherapy provides no survival benefit and substantially increases toxicity. These findings support biomarker-guided treatment selection and highlight the need for alternative therapeutic strategies.
Intracranial activity of trastuzumab deruxtecan in HER2-low breast cancer with brain metastases: A systematic review and meta-analysis.
e13082 Background: Human epidermal growth factor receptor 2 (HER2)–low breast cancer, defined as HER2 immunohistochemistry (IHC) 1+ or IHC 2+/in situ hybridization–negative, represents a newly targetable subtype comprising nearly half of all breast cancers. Brain metastases are a common and morbid complication of metastatic breast cancer, yet patients with active central nervous system (CNS) disease are frequently excluded from clinical trials. Trastuzumab deruxtecan (T-DXd), an antibody–drug conjugate with a cleavable linker and potent topoisomerase I inhibitor payload, has demonstrated substantial intracranial activity in HER2-positive disease. However, the intracranial efficacy of T-DXd in patients with HER2-low breast cancer remains incompletely characterized. Methods: A systematic literature search was conducted across PubMed/MEDLINE, Embase, CENTRAL, ClinicalTrials.gov, and Web of Science from database inception through January 1, 2025. A total of 2,275 records were identified and screened. Eligible studies included randomized controlled trials and prospective or retrospective clinical studies evaluating trastuzumab deruxtecan in patients with HER2-low metastatic breast cancer and measurable brain metastases. Studies were required to report intracranial objective response rate (IC-ORR), defined as complete or partial intracranial response among CNS-evaluable patients, assessed by study-defined criteria (RECIST 1.1 or RANO-BM). Results: Five studies comprising 62 patients with HER2-low metastatic breast cancer and brain metastases were included. Using a random-effects proportional meta-analysis with Freeman–Tukey double arcsine transformation, the pooled intracranial objective response rate (IC-ORR) was 46% (95% CI, 27–65%). Between-study heterogeneity was moderate (I² = 47.7%, p = 0.11), with consistent directionality of intracranial activity observed across included cohorts. Conclusions: Across five studies, T-DXd demonstrated clinically meaningful intracranial activity in HER2-low metastatic breast cancer with brain metastases, yielding a pooled IC-ORR of 46%. This provides one of the first quantitative benchmarks of CNS response in HER2-low disease, where evidence has been limited to small, heterogeneous cohorts. These findings support dedicated prospective trials in HER2-low patients with active CNS disease and standardized intracranial endpoints to refine patient selection and expected benefit. Summary of outcomes. Study Year CNS-Evaluable Patients (N) Intracranial Responders (CR+PR) IC-ORR (%) Zhou et al. 2025 15 7 46.7 (21.0–73.0) Batista et al. 2024 6 3 50.0 (12.0–88.0) Lazaratos et al. 2024 6 4 66.7 (22.0–96.0) Duan et al. 2025 9 6 66.7 (30.0–93.0) Burnside et al. 2024 26 6 23.1 (9.0–44.0) Pooled estimate (random effects) — 62 26 46.0 (27.0–65.0)*
ASC4FIRST wk 144 analysis: Efficacy and safety and tolerability with asciminib (ASC) vs investigator-selected tyrosine kinase inhibitors (IS TKIs) in newly diagnosed (ND) chronic myeloid leukemia in chronic phase (CML-CP).
6583 Background: In ASC4FIRST (NCT04971226) primary (wk 48) (Hochhaus A et al. N Engl J Med . 2024) and key secondary (wk 96) (Cortes JE et al. Blood . 2025) analyses, ASC had superior efficacy and improved safety/tolerability vs IS TKIs. ASC was approved for ND CML-CP in numerous countries. We report the ASC4FIRST wk 144 analysis (cutoff: Sep 29, 2025). Methods: In this multicenter, open-label, phase 3 study, patient (pts) with ND CML-CP were randomized 1:1 to ASC 80 mg once daily or an IS TKI at label doses, stratified by ELTS risk category and prerandomization-selected TKI (imatinib [IMA] or a second generation [2G] TKI). Primary endpoints were major molecular response (MMR) rates at wk 48 with ASC vs all IS TKIs, and ASC IMA vs IS TKI IMA . Results: Pts were randomized to ASC (n=201) or IS TKIs (n=204). Median follow-up was 38.1 mo with ASC vs 37.4 mo with all IS TKIs, 36.2 mo with ASC IMA vs 35.3 mo with IS TKI IMA , and 39.2 mo with ASC 2G vs 38.5 mo with IS TKI 2G . At cutoff, more pts were ongoing tx with ASC vs all IS TKIs (78.6% vs 55.9%), ASC IMA vs IS TKI IMA (81.2% vs 50.0%), and ASC 2G vs IS TKI 2G (76.0% vs 61.8%). MMR rate at wk 144 continued to be superior with ASC vs all IS TKIs (77.1% vs 53.4%; tx difference, 23.9%; P< .001 ) and ASC IMA vs IS TKI IMA (79.2% vs 47.1%; tx difference, 32.6%; P< .001 ), and higher with ASC 2G vs IS TKI 2G (75.0% vs 59.8%; tx difference, 15.2%; P= .01 ). MR 4 and MR 4.5 rates at wk 144 were higher with ASC vs all IS TKIs (56% vs 36%; 42% vs 25%), ASC IMA vs IS TKI IMA (58% vs 33%; 44% vs 20%), and ASC 2G vs IS TKI 2G (53% vs 39%; 41% vs 29%). Long-term outcomes with ASC vs all IS TKIs, ASC IMA vs IS TKI IMA , and ASC 2G vs IS TKI 2G included probability of event-free survival at wk 144 post randomization (85% vs 69%; 83% vs 63%; 87% vs 75%), and estimated progression-free survival (98% vs 95%; 97% vs 93%; 99% vs 97%) and overall survival (99% vs 97%; 99% vs 96%; 99% vs 99%), at 3 yrs post randomization. No new postbaseline mutations emerged with ASC after wk 96; 1 each emerged with IMA and nilotinib. Safety/tolerability remained favorable with ASC vs IMA vs 2G TKIs including grade ≥3 AEs (49% vs 52% vs 63%), AEs leading to discontinuation (6% vs 13% vs 14%), and AEs leading to dose adjustment/interruption (37% vs 44% vs 63%); exposure-adjusted arterial occlusive event rates were 1.3, 0.5, and 1.1 cases per 100 pt-tx yr, respectively. Median exposure duration was 37.4 mo, 33.8 mo, and 37.3 mo, respectively. No deaths occurred during tx or ≤30 d after last dose. Conclusions: At wk 144, ASC had consistently higher molecular response rates and favorable safety/tolerability vs all IS TKIs with no new tx-emergent mutations. Together with wk 48 and 96, this analysis reinforces ASC’s improved benefit-risk profile and supports ASC as a tx option for ND CML. Clinical trial information: NCT04971226 .
Self-reported ethnicity and outcomes of newly diagnosed multiple myeloma (NDMM) in the anti-CD38 monoclonal antibody era: A retrospective cohort study.
e19554 Background: Multiple myeloma has a well known disparity in incidence between non-Hispanic Black (NHB) and non-Hispanic White (NHW) persons, but less is known about differences in clinical course by ethnicity for patients treated with upfront anti-CD38 monoclonal antibody (mAb)-containing regimens. We thus performed a retrospective study of clinical outcomes in a diverse NDMM cohort. Methods: We describe 306 adult patients with self-reported ethnicity seen at Columbia University Medical Center, 5/2016-11/2024. Differences in disease characteristics were assessed with Kruskal-Wallis and Fisher’s Exact tests. Outcomes included measurable residual disease (MRD) negativity by flow cytometry (sensitivity: 10 -5 ) and overall survival (OS), analyzed with cumulative incidence methods and restricted mean survival time (RMST). Univariate and multivariate analyses were conducted. Results: Our cohort was comprised of 114 Hispanic, 9 non-Hispanic White (NHW), 65 non-Hispanic Black (NHB), and 118 “Other” patients. Most were ECOG 0-2 (91.8%). Hispanic patients were more likely to be male (66.7% vs 43.2%, p = 0.001/adjusted p = 0.005) and median hemoglobin was higher than in NHB (10.5g/dL vs 8.7, p < 0.001/0.001). Consensus Genomic Score (CGS) high risk disease incidence did not differ among ethnicities. Hispanic patients had lower-risk disease by ISS (p = 0.021/0.067), RISS (p = 0.016/0.063), and R2ISS (p = 0.038/0.102). Most CGS cytogenetic abnormalities were not enriched in Hispanic patients; t(14;20) was seen in 6.8% and 1.9% of NHB and Hispanic patients, respectively (p = 0.048/0.529). Patients of all ethnicities underwent autologous stem cell transplant at similar rates (overall 37.6%, 111/295). There were no differences in 6-month response or response depth. Median follow-up was 33.9 months; median OS was not reached. Cumulative incidence of MRD negativity was similar by ethnicity. Exploratory MRD negativity estimates (τ = 12 months) for Hispanic patients were numerically similar to those of NHB and of combined NHW + Other patients. Formal equivalence with 25% margin was not established (Hispanic vs NHB p = 0.061/0.063; vs NHW+Other 0.063/0.063). Pairwise 12 and 24 month RMST OS analysis demonstrated survival equivalence across all ethnicities and at 36 months showed equivalence among NHB, Hispanic, and Other patients. Ethnicity was not a prognostic factor in multivariate OS analysis. Conclusions: Despite differences in disease characteristics and limitations due to NHW sample size, MRD negativity outcomes did not differ among NHW, NHB, Hispanic, and Other patients. OS estimates were statistically equivalent in all ethnicities at 12 and 24 months. First line regimens containing anti-CD38 mAb appear effective across ethnicities; their administration may mitigate ethnicity-associated survival disparities. Further study is warranted.
Impact of venetoclax dosing on outcomes in AML: A single-center real-world study.
e18511 Background: VIALE-A established Aza and Venetoclax (Ven) as first-line therapy (1L) for acute myeloid leukemia for patients (pts) ineligible for intensive chemotherapy. Real-world (RW) use of Ven often differs in dose, schedule, timing of bone marrow biopsy (Bmbx) to assess response, and use of concomitant medications. We examined RW outcomes with 1L Ven at our center. Methods: Our cohort was diagnosed from 2018-2023. Chart abstraction was completed for 160 pts (data cutoff (DCO) 1 Dec 2025) to capture Ven dosing and duration, mutations, concomitant medications, Bmbx, and hematologic adverse events (HAE). Duration of remission (DoR) was defined as time from 1st composite complete response (CRc, per IWG criteria) to relapse, death, or start of 2L, with censoring at transplant or DCO. Ven dose intensity was calculated from dose, duration, and CYP3A inhibitor use. Differences were assessed using the log-rank test, with p<0.05 considered significant. Results: 863 cycles were recorded for 160 pts, with median follow-up of 191 days (d) (range 3-1758) and a median of 2 Ven cycles (1-33). There were 317 Bmbx for 134 pts. Of this number, 88 pts achieved CRc at a median of 41.5d (20-565) and 11 remained in remission at DCO. Overall CRc rate was 55% (66% for pts with Bmbx), with a median DoR of 155.5d (5-1341). Of pts achieving CRc, time to CRc differed significantly across Ven exposure groups (p<0.01). Patients receiving 21 +/- 3 d of Ven in cycle 1 (C1) had the highest CRc rate (68%); cumulative incidence of remission (CIR) was 27% at 28d (p=0.02), with median time to CRc of 34d (20–132) and median DoR of 176.5d (5–975). DoR did not differ across Ven exposure groups (p=0.21). Differing Ven dose intensities in C1 did not predict differing times to CRc (p=0.61) or DoR (p=0.45). 45% of pts with TP53 mutations (mut) achieved CRc vs 67% with RAS mut. Pts with neither mut had significantly longer DoRs (median 176.5d; 9-1341; p<0.001). 92% of CRc occurred by end of C3, 99% by end of C5. Pts experiencing HAE achieved CRc more frequently (71%) than those without and had a higher 28d CIR (21% vs 7%, p=0.02) and trend towards longer DoRs (p=0.07). The proportion experiencing HAE per cycle plateaued by C2 (56%). The median effective Ven dose decreased with increasing Ven cycles (50% reduction by C3), while median cycle length remained stable at 42d (14-1168). Conclusions: In our RW study, Ven cycles averaged 42d with frequent delays due to HAE. Over half of pts achieved remission lasting ~5 months (155.5d), with >10% still in remission at DCO. Mutation status significantly influenced DoR, whereas Ven duration >21 d or C1 dose intensity did not influence time to CRc or occurrence. Despite RW treatment variability, outcomes were comparable to VIALE-A. These results support the use of 21d Ven duration during induction to optimize the balance between achievement of CRc and DoR. The observed association between HAE and CRc is interesting and warrants further study as a potential prognostic marker.
Dietary supplement use among adult cancer survivors: Results from a large cross-sectional study in Poland.
e13782 Background: Dietary supplement use is common among adults with a history of cancer and may reflect unmet needs and safety risks, including non-disclosure and potential interactions with anticancer and supportive therapies. We used a nationwide health survey in Poland to quantify the prevalence and patterns of supplement use among adults with self-reported cancer. Methods: We conducted a cross-sectional analysis of pooled data from six annual editions (2020–2025, n = 1,271,102 respondents) of a nationwide web-based survey (Medonet). The analysis was restricted to respondents with a self-reported history of cancer (N = 79,588; 6.3% of all respondents). Supplement use in the prior 12 months was captured by frequency and by declared type or purpose (multiple-choice). Data were presented as mean (standard deviations, [SD]), median (interquartile ranges [IQR]) or number (n, %), as appropriate; survey-wave differences were assessed with chi-squared tests. Predictors of any supplement use were analysed with multivariable logistic regression with p < 0.05 considered statistically significant. Results: Among 79,588 adult respondents with a self-reported history of cancer, 62.4% (n = 49,649) were women and the mean age was 62.05 years (SD 12.68). Any dietary supplement use in the prior 12 months was reported by 61.8% (n = 49,165), including daily use in 26.9% (n = 21,446) and use several times per week in 12.7% (n = 10,128); 38.2% (n = 30,423) reported no supplementation. The most frequently selected types or purposes (multiple answers; % of the total cohort, N = 79,588) were multivitamin preparations (32.5%, n = 25,827), digestive preparations (16.8%, n = 13,379), hair/skin preparations (13.2%, n = 10,467) and preparations facilitating sleep (9.8%, n = 7,765). Supplementation patterns differed across survey waves (p < 0.001), with no supplementation ranging from 33.1% (2021) to 42.3% (2025) and daily use from 30.2% (2021) to 26.2% (2025). In multivariable logistic regression, men had lower odds of any supplementation than women (adjusted odds ratio [aOR] 0.675; 95% confidence interval [CI] 0.654-0.698), odds decreased slightly with age (aOR 0.994 per year; 95% CI 0.992-0.996), higher education was strongly associated with use (vs primary: vocational aOR 1.128; 95% CI 1.018-1.250; secondary 1.637; 1.489-1.800; bachelor 2.117; 1.902-2.356; MSc 2.444; 2.218-2.693) and supplement use was more likely among respondents reporting non-cancer comorbidities (aOR 1.103; 95% CI 1.055-1.153). Conclusions: In this nationwide sample, dietary supplement use was common, including frequent daily intake and declined from 2021 to 2025. Use clustered by patient characteristics, being less likely in men and older respondents and more likely with higher education and non-cancer comorbidities. Routine assessment and counselling on supplement safety should be integrated into cancer care and follow-up.
Integrated tissue transcriptome deconvolution of grade-associated tumor microenvironment patterns in CNS tumors.
e14039 Background: Central nervous system (CNS) tumors exhibit marked tumor microenvironment (TME) heterogeneity, including immune exclusion and immunosuppression that may limit benefit from immunotherapy. We applied an integrated tissue transcriptome-based framework to define clinically relevant TME patterns associated with tumor grade. Methods: Tissue RNA sequencing from 39 CNS tumor tissue transcriptome samples comprising Low-Grade (LG, n=12) and High-Grade (HG, n=27) tumors was analyzed using complementary deconvolution approaches (quanTIseq, MCP-counter, EPIC, and xCell). Outputs were harmonized into a consensus TME profile summarizing overall immune infiltration, myeloid compartment activity, stromal/fibrotic programs, and immunosuppressive balance, and cross-method concordance was assessed to support robustness. Gene-set scoring (GSVA) and enrichment analysis (GSEA) quantified pathway-level programs including endothelial/angiogenesis, cancer-associated fibroblast (CAF), interferon-gamma (IFNγ) T-cell–inflamed, and antigen presentation (MHC class I/II). LG vs HG comparisons used nonparametric testing. Results: Consensus profiling demonstrated a sharp grade-associated separation in overall immune infiltration, which was higher in LG than HG (median 0.151 vs −0.108; p=0.010) with directionally concordant differences across deconvolution methods. HG tumors exhibited immunoregulatory skewing, including higher inferred regulatory T-cell abundance (Treg fraction median 0.035 vs 0.007; p=0.018) and higher Treg:CD8 ratio (median 0.147 vs 0.031; p=0.013). HG tumors also showed increased vascular/endothelial program activity (endothelial signature median −0.120 vs −0.260; p=0.032) with a trend toward increased CAF program activity (p=0.097). IFNγ T-cell–inflamed and MHC class I/II programs did not differ significantly by grade (all p≥0.37). Conclusions: Multi-algorithm consensus transcriptomic profiling identifies immune-enriched LG tumors and immune-excluded HG tumors characterized by Treg-associated immunosuppression and vascular/endothelial enrichment. These findings support TME-guided stratification of CNS tumors and motivate evaluation of combination strategies pairing immune modulation with anti-angiogenic and/or stromal-targeting approaches in HG disease.
Intrathecal (IT) PD-1/CTLA-4 antibody combined with pemetrexed (PM) for leptomeningeal metastases (LM) from solid tumors: Preliminary results of two single-center phase I studies.
2624 Background: IT PD-1 inhibitors, alone or combined with IT PM, have shown safety and feasibility in LM from solid tumors. Cadonilimab (AK104) and iparomlimab/tuvonralimab (QL1706) are novel bispecific PD-1/CTLA-4 antibody. Our preclinical animal studies demonstrated the safety of IT administration of these agents. This study evaluated the feasibility and potential clinical benefit of combing IT PD-1/CTLA-4 antibody with PM in patients with LM from solid tumors. Methods: Eligible patients had histologically confirmed solid tumors and positive CSF cytology. A rapid dose-escalation design was employed across three dose levels: AK104 at 15.625 mg, 31.25 mg and 62.5 mg; QL1706 at 25 mg, 37.5 mg and 50 mg. One patient was enrolled in each of the first two dose cohorts, while six were enrolled at the third dose cohort. The protocol would revert to a standard 3+3 design if any dose-limiting toxicities (DLT) occurred. IT PM was given at a fixed dose of 15 mg twice weekly for two weeks (induction), then weekly for four weeks (consolidation), followed by monthly maintenance until progression or death. IT PD-1/CTLA-4 antibody began at the fourth IT PM dose, administered every two weeks for six weeks, then monthly until progression or death. Continuation of previously administered systemic therapies was permitted during the study. Results: A total of 17 patients were enrolled (AK104: n=8; QL1706: n=9). Median age was 54 years (range 37–73); 13 were female. Primary tumors included lung adenocarcinoma (n=13) and breast cancer (n=4). 16 patients (94.1%) completed induction and consolidation therapy. No DLT occurred. Grade ≥3 adverse events (AEs) occurred in 64.7% (11/17) of patients. Specifically, grade ≥3 AEs attributed to IT PM were observed in 58.8% (10/17), primarily hematological toxicity (n=10), elevated hepatic aminotransferase (n=1) and fatigue (n=1). For IT PD-1/CTLA-4 antibody-related AEs, grade ≥3 occurred in 11.8% (2/17; rash n=1, diarrhea n=1), and grade 1-2 in 17.6% (3/17; rash n=3, fever n=1, diarrhea n=1). Clinical response rate was 41.2% (7/17) by RANO-LM criteria. Disease control rate was 82.4% (14/17). As of January 15, 2026, 8 patients had died, with 1 due to LM, 3 due to systemic progressive disease, and 4 due to non-cancer-related causes. Median follow-up time was 8.53 months (95%CI: 8.07-NA), and median overall survival was 8.53 months (95%CI: 6.3-NA). Conclusions: The study demonstrates the manageable safety and feasibility of IT PD-1/CTLA-4 antibody combined with PM, with no unexpected systemic or neurological toxicities observed. Preliminary results suggest potential clinical benefits, with a high clinical response rate and notable treatment responses even among those with severe conditions. ClinicalTrials.gov registration: NCT06762080/NCT06809530. Clinical trial information: NCT06809517 / NCT06809530 .
Clinicopathologic features, actionable biomarkers, and treatment patterns in early-onset gastric cancer: A real-world Latin American cohort.
e23385 Background: Early-onset gastric cancer (EOGC), defined as diagnosis before age 50, is biologically aggressive and often diagnosed at advanced stages. However, real-world data from Latin America remain limited. We aimed to characterize clinicopathologic features, actionable biomarkers, treatment patterns, and survival in an EOGC cohort. Methods: We conducted a retrospective cohort study of EOGC at a high-complexity Latin American center over a 10-year period (2014–2023). Histology followed WHO and Lauren criteria. Biomarkers included HER2, PD-L1 CPS and MSI when available. Stage-specific treatment patterns were described, and overall survival (OS) was estimated using the Kaplan–Meier. Results: A total of 54 patients were included (median age at diagnosis: 41 years (IQR 35–46), and 68.5% were female). At diagnosis, 31.5% had stage I-II disease, 11.1% stage III, and 57.4% stage IV. Staging laparoscopy was performed in 57.4%, revealing neoplastic involvement in 42.6%. Aggressive pathology predominated, with poorly cohesive carcinoma/signet ring features in 68.5% and diffuse-type histology in 70.0%. Actionable molecular alterations were identified PD-L1 CPS ≥1 in 20.4%, HER2 positivity in 9.4% and MSI-high status in 5.7% of patients. Biomarker overlap was rare, with only one HER2/PD-L1–positive tumor and one PD-L1/MSI-high tumor. Among early-stage patients (stage II), 88.2% received perioperative and/or adjuvant systemic therapy, predominantly platinum-based regimens (86.7%), most commonly FLOT (40.0%). Curative-intent gastrectomy was performed in 76.5%, mainly total gastrectomy, and most operated patients received adjuvant therapy. Among stage III patients (n = 6), 83.3% received perioperative systemic therapy, all with platinum-based chemotherapy, most frequently FLOT (33.3%). Curative-intent gastrectomy was performed in 83.3%. Among stage IV patinetes n = 31, systemic therapy predominated. First-line treatment consisted mainly of platinum-based chemotherapy (87.1%), most commonly FOLFOX (54.8%), with trastuzumab added in HER2-positive tumors. Palliative surgery such as HIPEC was performed in 29.0%. Maintenance therapy was administered in 35.5%, primarily fluoropyrimidine-based, with immunotherapy or trastuzumab in selected patients. After progression, 48.4% received second-line therapy, mainly fluoropyrimidine- or taxane-based regimens. At 24 months, overall survival differed by clinical stage (log-rank p = 0.011), with OS rates of 100% stage I, 70% stage II, 50% stage III, and 40% stage IV. Conclusions: In this real-world Latin American cohort, early-onset gastric cancer showed aggressive features and molecular heterogeneity, underscoring the need for comprehensive biomarker profiling to enable targeted and immunotherapy-based strategies with potential survival benefit in young patients.
The prevalence of osteopenia in adult non-metastatic gastrointestinal cancer patients: A systematic review and meta-analysis.
e23187 Background: Improvements in survival among patients with gastrointestinal (GI) cancer have led to a shift in focus towards management of cancer-related sequelae, including osteopenia. We aimed to estimate the global prevalence of osteopenia in adults with non-metastatic GI cancer. Methods: We conducted a comprehensive search of MEDLINE, Embase, CINAHL, PubMed, Web of Science, Cochrane, and ClinicalTrials.gov from January 1, 1994 to October 2, 2025. Eligible studies measured bone mineral density (BMD) and reported the prevalence of osteopenia among patients diagnosed with non-metastatic GI cancer. Studies involving children (< 18 years) were excluded. Paired reviewers independently screened citations, selected studies, abstracted data, and assessed risk of bias using the Joanna Briggs Institute Critical Appraisal Checklist for Studies Reporting Prevalence Data. Pooled prevalence was estimated using a random effects generalized linear mixed model. Certainty of evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation framework. Results: 18 eligible studies (1635 patients), mostly prospective cohorts (10/18) measuring BMD following completion of cancer treatment (14/18), were included. The pooled prevalence of osteopenia was 40% (95% CI 33-48%; 95% PI 16-70%, I2= 88%; τ2= 0.39); certainty of evidence was moderate after downgrading for risk of bias. In a pre-specified subgroup analysis, osteopenia prevalence was higher in studies of gastric cancer (45%, 95% CI 39–50; 11 studies, 1,096 patients) than other GI cancers (30.6%, 95% CI 17.2–48.2; 7 studies, 539 patients; P = 0.08; low-credibility subgroup effect); however, comparisons are limited by small sample size. Prevalence was 40% in a sensitivity analysis limited to low risk of bias studies (95% CI 27-54; 9 studies, 957 patients). Conclusions: Moderate-certainty evidence suggests that the prevalence of osteopenia in adults with GI cancer is 40%. Our findings underscore the importance of bone health as a survivorship priority. Addressing this burden will require coordinated efforts in clinical practice, guideline development, and future research to improve screening, prevention, and management strategies for this vulnerable population.
Safety and efficacy of neoadjuvant chemotherapy (NAC) in older patients with locally advanced colon cancer (LACC): Results from FOxTROT 1 and the FOxTROT 2 safety cohort population.
3653 Background: The FOxTROT1 (FT1; NCT00647530) trial demonstrated feasibility and efficacy of six weeks of NAC for LACC compared with upfront surgery. The currently recruiting FOxTROT2 trial (ISRCTN83842641) is testing this approach in older or frail patients. Outcomes in older patients with LACC are inferior; therefore, new treatment strategies are required. Here in these trials we analyse the safety and efficacy of NAC in this group and report the DFS in the older subgroup of FT1 PMMR patients. Methods: Data from FT1 and the planned FT2 safety pilot (n=150) were combined and analysed by treatment arm and by age category (</> 70). Pre-specified endpoints included NAC delivery and perioperative complication rates for FT1 and FT2; DFS and pathological response are reported for FT1 patients by MMR status. We will update safety data for this presentation. Results: In FT1 292/1052 (27.8%) of patients were aged over 70; the median age of FT2 safety cohort was 76 (range 70-85). There were no significant differences by age in NAC delivery or in rates of peri-operative complications. For patients over 70, combining FT1&2 data, exploring those who received NAC, 88.5% completed the course as planned and 37.7% received an upfront or subsequent dose modification. Rates of peri-operative complications combining FT1&2 were similar between patients receiving NAC or upfront surgery: anastomotic leak (3.4% vs 3.3%), complication requiring hospital stay (FT1 9.3% vs 14.6%) or further surgery (2.6% vs 5.0%), and post-operative death (0.9 % vs 1.7%). For patients over 70 in FT1 16.4% were dMMR and 83.6% were pMMR. In pMMR patients overall NAC improved 3-year DFS (81.2% vs 75.4% without a DFS event; HR 0.70[0.52–0.94],p=0.02) compared with upfront surgery; results were consistent in older patients (81.2% vs 71.4%; HR 0.59[0.35-1.02],p=0.06). Conclusions: NAC is safe and well-tolerated in older adults, with no increase in perioperative morbidity and preserved treatment delivery compared to rates in younger patients and when compared with upfront surgery. Promising efficacy in terms of 3-year DFS and pathological response were observed in older patients with pMMR tumors, consistent to those seen in younger patients. These data support the use of NAC in older patients with LACC and continued recruitment to FT2 to evaluate the long term impact. Clinical trial information: NCT00647530 .