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Aberrant somatic hypermutation in large B-cell lymphomas and its relationship to mutational signatures, including a novel haloalkane pattern.
7076 Background: Diffuse large B cell lymphoma (DLBCL) is a genetically complex disease, often characterized by the simultaneous occurrence of multiple mutations within single driver genes. Here, while activation-induced cytidine deaminase (AID)-driven aberrant somatic hypermutation (aSHM) is recognized as a major contributor to mutation, many genes could be heavily mutated due to other mechanisms. In this study, we evaluate clinical DLBCL samples identified as hypermutated, to assess the presence of AID driven mutation and the contribution of other defined mutational signatures which may contribute to clinicopathologic heterogeneity. Methods: Clinical samples of DLBCL tested by a hybrid-capture next-generation sequencing (NGS) panel targeting up to 468 genes, were identified. Hypermutated cases were selected based on the qualifying criteria of having three or more co-occurring mutations in at least 1 gene. Based on the mutational position from transcriptional start site and inter-mutational distance, cases were initially classified as having aSHM or Kataegis. Mutational signature analysis was performed using all high-confidence somatic single-base substitutions (SBS) identified and interpreted according to COSMIC SBS signatures v3.5. A predominant signature was defined when >40% of the mutations were attributed to the signature. Wherever possible, correlation between the morphological type, molecular subtype, and mutational signatures was performed. Results: Out of the 216 samples identified as hypermutated, most (n=172, 79.6%) were classified as having aSHM, 9.3% (n=20) as Kataegis and 11.1% (n=24) were unclassifiable. The 3 most common genes targeted by aSHM were PIM1(n=66), SOCS1(n=55) and BCL2(n=35). By contrast, SGK1(n=16), MYC(n=12), GNA13(n=6) and ITPKB(n=6) were the common targets of Kataegis. The most frequent dominant molecular signatures included AID (n=82) and Clock-like aging(n=48), followed by Haloalkane (n=24), MMR deficiency (n=17) and the SBS39 (n=14) signature of unknown etiology. Based on morphology and immunophenotype, cases were primarily stratified as either Germinal Center B-cell like (GCB; n=86) or Non-GCB (n=87), with lower representation of Primary mediastinal B cell lymphomas (n=21), High grade B cell lymphomas with MYC and BCL2 translocations (n=18), and DLBCL special subtypes (n=4). The same top 3 molecular signatures were identified across all subtypes, except in GCB, where MMR deficiency constituted the 3rd most frequent signature. Conclusions: In DLBCL, mutational signatures are primarily driven by endogenous processes, namely AID and Aging. The identification of a haloalkane signature in a small proportion of cases is a novel finding, raising suspicion for the role of exogenous influences, either environmental or therapeutic in origin. Further studies are needed to better define this cohort.
The early discharge clinic: A safe and efficient model for intensive outpatient management of hematologic malignancies.
e13558 Background: Hematologic malignancies often necessitate complex treatment regimens that can result in prolonged hospitalizations, increasing healthcare costs, and straining resources while diminishing patients' quality of life. To address these challenges, Northwell Health established New York State’s first Early Discharge Clinic (EDC), designed to facilitate a safe and efficient transition from inpatient to outpatient care. Methods: We describe nine pillars (Clinic Hours and Access, Scheduling, Laboratory Services, Infusion support, Urgent Radiology, Procedures, Pharmacy Services, Hospital Readmission Protocol, and Support Services) that actuated the operationalization of the program, report early outcomes, and compare length of stay to historic matched controls. Results: Analysis showed that between 2023 and 2025, a total of 181 unique patients accounted for 325 enrollments, with an average LOS reduction of 14.8 days. During the first two years of operation, patients had a median of five evaluations, nearly all received blood products; when required, time to first antimicrobial was < 48 minutes. Eleven non-scheduled re-admissions occurred during the first week post discharge. Conclusions: The program demonstrated a safe and effective model for outpatient management of patients undergoing intensive therapy for hematologic malignancies. These findings offer valuable insights into the potential of EDCs to enhance care delivery while optimizing resource utilization.
BMS-986504 in patients (pts) with advanced solid tumors with homozygous <i>MTAP</i> deletion ( <i>MTAP</i> -del): Exploratory pharmacodynamic (PD) and biomarker analyses from CA240-0007.
3146 Background: The MTA-cooperative PRMT5 inhibitor BMS-986504 selectively binds to the PRMT5-MTA complex, a synthetic lethal target in MTAP -del cancer cells, while sparing MTAP –wild-type normal cells. In the phase 1 CA240-0007 study, BMS-986504 was well tolerated and had antitumor activity in pts with MTAP -del advanced solid tumors (ORR, 23%; median DOR, 10.5 mo). BMS-986504 also demonstrated dose-dependent reductions in plasma symmetric dimethylarginine (SDMA) levels, a PD biomarker of PRMT5 inhibition. Here, we report expanded PD and genomic analyses and initial results of exploratory proteomic analyses from CA240-0007. Methods: Pts with advanced, unresectable, or metastatic solid tumors with homozygous MTAP -del received BMS-986504 (50–800 mg) in 3-wk cycles. Analyses of SDMA levels and proteomic profiles from paired plasma samples (baseline and C2D1) were performed using mass spectrometry and SomaScan 11K, respectively. Tumor genomic information was extracted from local pathology reports. ORR was assessed per RECIST v1.1. Results: Among 78 pts with paired samples at data cutoff (22 Sept 2025; median f/u, 15.9 mo), dose-dependent reductions were seen in plasma SDMA levels, with the greatest reductions at 400 mg QD (median, 60.3%; n = 31) and 600 mg QD (median, 60.3%; n = 23). Proteomic pathway enrichment analysis demonstrated downregulation of PI3K/Akt/mTOR, Myc target, cell cycle, and DNA damage repair (DDR) pathways with BMS-986504 on C2D1 (n = 87), consistent with the expected effect of PRMT5 inhibition; a trend toward deeper modulation of PRMT5-regulated pathways was observed at higher doses. No proteins at baseline (n = 94) were found to be significantly associated with ORR (false discovery rate > 0.05). Responses in clinically evaluable pts with NSCLC (n = 33) or PDAC (n = 35) were observed regardless of EGFR , KRAS , or TP53 status. In pts with NSCLC, STK11 and SMARCA4 alterations were numerically higher in nonresponders. No gene alterations were associated with response in PDAC, except GABRA6 alterations (n = 2, both responders). A trend toward higher ORRs was seen in pts with alterations in DDR genes ( CHEK2, FANCD2, XRCC4 , and/or MSH2 ), consistent with the role of PRMT5 in DDR via regulation of mRNA splicing. ctDNA analysis will be presented. Conclusions: BMS-986504 demonstrated robust dose-dependent PD effects in pts with advanced solid tumors in plasma SDMA and proteomic analyses. Downregulation of PRMT5-regulated pathways was observed with BMS-986504 treatment. Response was seen regardless of EGFR, KRAS , and TP53 alterations in NSCLC or PDAC, and DDR gene alterations were associated with improved response. These findings further support the MOA of BMS-986504 and its ongoing investigation in the phase 2/3 MountainTAP-9, -29, and -30 studies as a potential treatment option in pts with MTAP -del advanced solid tumors. Clinical trial information: NCT05245500 .
Divergence between regulatory approvals and guideline recommendations in multiple myeloma: Helping solve physician’s dilemmas with a real-time updated evidence library.
e23047 Background: Despite the large number of trials and emergence of new therapies/combinations in multiple myeloma (MM), guidelines highlight uncertainties in ranking all treatment options and providing therapy sequencing recommendations. Physicians must exercise their best judgement and rely on package inserts and individual trial data for treatment decisions. For therapies for which regulatory assessment is delayed or not pursued, there is additional uncertainty around the availability and quality of the data informing off-label use. We aimed to understand the alignment between guideline recommendations and regulatory endorsement in multiple myeloma and assess whether creation of a living evidence library could help address these gaps. Methods: We conducted a REal-time AI-assisted Living systematic review (REAL-SLR) in MM, compliant with PRISMA and Cochrane guidelines. Clinical trials reporting on efficacy and/or safety of treatments for MM were identified in PubMed and international conference proceedings and included based on predefined criteria. Critical clinical data on efficacy (survival and response), safety and quality of life was extracted in the REAL-SLR. Results: The daily-updated REAL-SLR included 712 critical path studies in MM (301-newly diagnosed; 413-relapsed/refractory) as of January 19, 2026. Evidence was stratified according to disease stage, prior treatment exposure/refractoriness, risk/cytogenetic profile, transplant eligibility, treatment pathway, and intervention class, and mapped against regulatory documents and international guidelines. Among 266 studies reporting on treatments recommended in US guidelines, only 153 (58%) involved FDA-approved regimens/combinations. In contrast, among 144 studies supporting therapies recommended by the European Hematology Association, majority (85%) aligned with European Medicines Agency approvals. Similar REAL-SLRs conducted in non-small cell lung cancer, breast cancer, and prostate cancer, reveal a better overlap between US guidelines and FDA endorsement compared to MM (83%, 75%, and 90%, respectively). Trials stratification and daily maintenance of REAL-SLR allowed real-time identification of supporting evidence for therapies investigated, recommended, or discussed outside regulatory labeling, with almost half of the REAL SLR studies published just in the past 2 years and 5 new drug approvals in 2025 in MM. Conclusions: There is a pronounced guideline-regulatory divergence despite substantial growth and diversification of evidence in the past years across newly diagnosed and relapsed/refractory MM. Continuously maintained REAL-SLR that reflects disease and treatment pathways can complement guidelines and regulatory documentation, providing a living data support tool to make informed decisions for patient treatment.
Phase II trial of anti-PD-1 monoclonal antibody and FOLFOXIRI combined with long-course radiotherapy as the total neoadjuvant treatment for proficient, mismatch repair, locally advanced low rectal cancer (PANFORTE).
3621 Background: The current standard treatment for locally advanced low rectal cancer (LALRC) achieves a complete response (CR) rate of only 20–30%. Consequently, radical surgery frequently results in the loss of anal organs, severely affecting patients’ quality of life. Therefore, there is an urgent clinical need to identify novel strategies that can maximize tumor regression and preserve anal function. Recent trials have demonstrated radiotherapy showed a distinctive synergistic anti-tumor effect with immune checkpoint inhibitors. Therefore, this study aims to assess the efficacy and safety of an immunotherapy-based total neoadjuvant therapy (TNT) in patients with proficient mismatch repair (pMMR) LALRC. Methods: Eligible patients (pts) on this investigator-initiated phase II study had pMMR LALRC with ECOG performance status ≤ 1 and an inferior tumor margin distance from the anal verge (DAV) ≤ 5 cm. Eligible patients receive 4 cycles of FOLFOXIRI plus serplulimab (200 mg). Subsequently, they undergo long-course radiotherapy combination with capecitabine and 2 cycles of serplulimab (200 mg), followed by another 4 cycles of FOLFOXIRI and serplulimab (200 mg). The primary endpoint is CR rate with the sum of clinical complete response (cCR) and pathological complete response (pCR). Secondary endpoints include sphincter preservation rate and safety. Results: Between November 2023 and April 2025, 53 patients were enrolled with male percentage 62.3%, median age of 55 years (Range, 28–72) and median DAV of 3 cm (Range, 0.4–5.0). 92.5% (49/53) of patients completed the full TNT regimen. Among the 51 patients eligible for endpoint assessments, the overall CR rate was 68.6% (35/51), and the sphincter preservation rate was 94.1% (48/51). 31 (60.8%) patients achieving cCR opted for a watch-and-wait approach, whereas 20 patients underwent surgery. 20% (4/20) achieved pCR and 70% (17/20) had a tumor regression grade (TRG) of 2. The most common AEs was neutropenia (grade 3-4, 66.0% [35/53]). Other grade 3-4 AEs included leukopenia (32.1%, 17/53), lymphopenia (20.8%, 11/53), and thrombocytopenia (18.9%, 10/53). Immune-related 3-4 AEs comprised myocarditis (1.9%,1/53) and elevated transaminases (1.9%,1/53). Conclusions: Our study indicates that this TNT regimen significantly enhances CR rates and anal preservation in pMMR LALRC compared to historical benchmarks, with an acceptable safety profile. These findings suggest that this new approach may be an alternative treatment option for LALRC patients who strongly desire anal preservation. Clinical trial information: NCT06099951 .
Multi-study genomic survival modeling and gene panel recalibration across heterogeneous cohorts.
e13671 Background: Gene expression–based prognostic models and multigene panels are widely used for risk stratification in oncology. However, their performance often degrades when applied across heterogeneous cohorts, cancer types, or underrepresented populations, due to limited target sample sizes and variability in gene–outcome associations. Existing approaches relying on target-only modeling or naive pooling of external datasets may result in instability or bias. We sought to develop a transfer learning framework for genomic time-to-event analysis that enables population-aware prognostic modeling and gene panel recalibration while accounting for cross-cohort heterogeneity. Methods: We developed two complementary transfer learning approaches for high-dimensional survival data. TransSurv performs multi-study genomic survival modeling by selectively borrowing information from auxiliary cohorts using a penalized Cox proportional hazards framework with cohort-level screening to mitigate negative transfer. TransInf focuses on recalibration of existing multigene prognostic panels by integrating target cohort data with compatible external cohorts through gene-level transfer-aware inference. The methods were evaluated using transcriptomic and clinical data from The Cancer Genome Atlas (TCGA), METABRIC, and an independent triple-negative breast cancer (TNBC) cohort from Fudan University Shanghai Cancer Center. Model performance was assessed using concordance index (C-index) and time-dependent area under the curve (AUC) under repeated train–test splits. Results: Across multiple TCGA cancer types and stage-defined subcohorts, TransSurv demonstrated improved discrimination for overall survival compared with target-only penalized Cox models and a state-of-the-art multi-study survival learning approach, with consistent gains in C-index and time-dependent AUC. In the external FUSCC TNBC cohort, TransSurv achieved higher C-index for recurrence-free survival compared with target-only modeling. Using TransInf, recalibrated gene panels derived from established signatures showed improved prognostic discrimination in race-stratified TCGA cohorts and in the TNBC cohort relative to target-only or pooled analyses. The recalibrated panels retained biologically relevant genes while excluding features with inconsistent target-level associations. Conclusions: This transfer learning framework enables robust genomic survival modeling and gene panel recalibration across heterogeneous cohorts by selectively leveraging external data while preserving target-specific inference. The proposed methods support population-aware risk stratification and adaptation of existing prognostic tools, with potential relevance for precision oncology applications in settings with limited target cohort sizes.
Diagnostic and predictive utility of peritoneal tumor DNA in gastroesophageal cancer: A prospective multicenter study.
4101 Background: Gastric and gastroesophageal cancers (G/GEC) commonly spread to the peritoneum. Accurate peritoneal staging is critical for guiding intent and therapy, however staging PET, CT and peritoneal cytology have low sensitivity for peritoneal micro-metastases. Whilst circulating tumor DNA (ctDNA) poorly correlates with peritoneal disease, tumor DNA from the peritoneum (ptDNA) may identify early peritoneal metastases missed by conventional staging. We developed a tumor-informed whole-genome sequencing (WGS) platform to detect ptDNA and evaluated its accuracy in diagnosing peritoneal metastases and predicting survival in curative-intent G/GEC. Methods: This Australian multicenter prospective cohort study enrolled patients receiving curative-intent treatment for G/GEC (upfront surgery, perioperative FLOT or neoadjuvant CROSS/nivolumab). Tumor biopsies, blood, and peritoneal lavage fluid were collected at staging laparoscopy, and at surgery for those receiving neoadjuvant therapy. Tumor-informed WGS was used to identify ctDNA and ptDNA, which were correlated with disease free survival (DFS), peritoneal recurrence free survival (pRFS), non-peritoneal recurrence free survival (npRFS), and overall survival (OS) using multivariate Cox regression. The diagnostic utility of ptDNA for peritoneal metastases was evaluated by comparing true-negative patients ( > 2 years disease-free post-surgery alone) with an independently enrolled cohort of true-positive patients (macroscopic/cytology-positive peritoneal disease). Results: ptDNA was detected in 28 (30.4%) of 92 consecutive non-metastatic patients (59 with and 33 without neoadjuvant therapy). ptDNA-positivity significantly correlated with advanced cT and (y)pT stage. At a median follow-up of 17 months, there were 12 (13.0%) peritoneal and 10 (10.9%) non-peritoneal recurrences. ptDNA-positivity independently predicted poorer pRFS (HR 26.74, 95%CI 3.94-181.66), DFS (HR 4.51, 95%CI 1.77-11.47) and OS (HR 6.65, 95%CI 1.72-25.76), but not npRFS (HR 0.87, 95%CI 0.16-4.78). Importantly, 9 (60%) patients converted from ptDNA-positive to ptDNA-negative post-neoadjuvant treatment. Patients who remained ptDNA-positive had significantly worse pRFS (3/6 recurrences, HR 45.4, 95%CI 3.5-595.2) than those who were ptDNA-negative (0/25 recurrences). The diagnostic accuracy of ptDNA was validated in 10 true negative and 12 true positive patients. In this cohort, ptDNA achieved 100% sensitivity, specificity, positive and negative predictive values (95%CI 75.8-100%) for detecting peritoneal metastases. ctDNA data will be presented at the meeting. Conclusions: Tumor-informed WGS-based ptDNA accurately diagnoses peritoneal disease and predicts peritoneal recurrence post curative-intent treatment, informing its potential to personalize clinical management using intraperitoneal therapies.
Tumor microenvironment phenotypes and survival in fibrolamellar carcinoma: An exploratory study.
4150 Background: Fibrolamellar carcinoma (FLC) is a very rare liver cancer affecting children, adolescents, and young adults. FLC is characterized by a robust immune tumor microenvironment (TME), but the clinical relevance of TME phenotypes is unknown. Methods: This de-identified study was approved by the Genetic Alliance Organization Institutional Review Board (IRB #IRB00003999). Subjects consented under XCELSIOR: A Patient-Centric Platform Study for Precision Oncology (NCT03793088). From this database, FLC TMEs were classified using the BostonGene framework into immune–stromal subtypes: fibrotic (F), immune desert (ID), immune-enriched fibrotic (IE-F), and immune-enriched non-fibrotic (IE-NF), and further dichotomized into immune-active (IE-F, IE-NF) and immune-cold (F, ID) groups. Associations were assessed using chi-square and non-parametric tests. Overall survival (OS) and time to first progression (TTP1) were evaluated using Kaplan–Meier methods and log-rank tests. Results: Forty-seven subjects (21 females, mean age 20.7 years) were included. TME subtype distribution was: F 46.8%, ID 17.0%, IE-F 21.3%, and IE-NF 14.9%. TME phenotypes were not associated with sex (p = 0.15) or age at diagnosis (p = 0.81). During a median follow-up of 3.7 years, 20 deaths (42.6%) occurred. Median overall survival (OS) for the entire cohort was 75.1 months. Median OS by TME subtype were: F 58.8 months, ID not-reached, IE-F 54.6 months, and IE-NF 75.1 months. Median OS was 86.0 months in the immune-cold group and 54.6 months in the immune-active group (log-rank p = 0.69). Conclusions: In this preliminary analysis with uncompleted dataset of FLC, immune–cold TME phenotypes were not significantly associated with overall survival, although trends toward improved outcomes were observed in immune-active subtypes. These findings should be interpreted as hypothesis-generating due to small numbers. Larger data are needed to clarify the prognostic role of the TME in FLC. Tumor microenvironment subtypes and clinical outcomes in fibrolamellar carcinoma. TME group N (%) Female (n, %) Median age (years, IQR) Deaths (n, %) Median OS (months, 95% CI) Fibrotic (F) 22 (46.8) 12 (57.1) 20.2(17.2–23.8) 12 (60.0) 58.8(43.1–74.5) Immune Desert (ID) 8 (17.0) 5 (23.8) 20.1(17.2–27.7) 1 (5.0) Not reached Immune-cold (F + ID) 30 (63.8) 17 (81.0) 20.2 (17.3–23.8) 13 (65.0) 86.0 (43.0–129.0) Immune-Enriched Fibrotic (IE-F) 10 (21.3) 3 (14.3) 16.1(12.1–28.1) 4 (20.0) 54.6(41.1–68.2) Immune-Enriched Non-Fibrotic (IE-NF) 7 (14.9) 1 (4.8) 18.9(17.7–23.6) 3 (15.0) 75.1(36.6–113.6) Immune-active (IE-F + IE-NF) 17 (36.2) 4 (19.0) 18.7 (13.8–25.0) 7 (35.0) 54.6 (26.2–83.1) Total 47 (100.0) 21 (100.0) 20.1(16.7–23.6) 20 (42.6) 75.1(43.4–106.8) Abbreviations: TME, tumor microenvironment; IQR, interquartile range; OS: overall survival, CI: confidence interval. Note: Percentages are calculated within columns.
Safety, immunogenicity, and efficacy of Ad5.F35-GUCY2C-PADRE vaccine in patients with GI cancers at high risk of relapse: Results from a phase 2A trial.
3617 Background: Guanylyl cyclase C (GUCY2C) is an intestinal tumor antigen ectopically expressed in some gastroesophageal and pancreatic cancers, highly expressed in nearly all colorectal cancers (CRC), and retained in metastases. Adenovirus serotype 5 (Ad5)-based cancer vaccines, including those targeting GUCY2C, are limited by pre-existing neutralizing antibodies (NAbs) targeting Ad5. Ad5.F35-GUCY2C-PADRE is a chimeric Ad5 vector (fiber of serotype 35) developed to overcome anti-Ad5 immunity and induce durable antitumor T-cell responses. We report initial immunogenicity, safety, and recurrence outcomes from a phase 2A dose-finding study in patients with resected GI malignancies. Methods: This open-label phase 2A study enrolled patients with resected, high-risk GI adenocarcinomas (CRC, pancreatic, gastric, and small bowel) with no evidence of disease 4-24 wks after standard adjuvant therapies. Oligometastatic stage IV CRC patients were also allowed (n=8). Patients were randomized to receive three i.m. administrations of Ad5.F35-GUCY2C-PADRE at 1×10 11 , 1×10 12 , or 5×10 12 viral particles (vp) at 4-wk intervals. Primary endpoints were safety and GUCY2C-specific T-cell responses (IFNγ ELISpot). Exploratory endpoints included the impact of NAbs on T-cell responses and RFS, and the impact of dose on immunological and clinical outcomes. Results: Forty-six patients (29 CRC) completed treatment and were evaluable. Vaccination was well tolerated with no DLTs or TRSAEs; AEs were predominantly grade 1-2 flu-like symptoms. GUCY2C-specific T-cell responses increased in frequency and magnitude in a dose-dependent manner. Nearly all patients receiving higher doses produced T-cell responses regardless of NAb status (Table), supporting Ad5.F35 overcoming pre-existing NAbs. At the 2-year follow-up, there was a dose-dependent improvement in RFS among stage II-III CRC patients (Table), and RFS was significantly improved among immune responders vs non-responders ( P < 0.05). Conclusions: Ad5.F35-GUCY2C-PADRE is safe, overcomes pre-existing Ad5 immunity, and induces robust, dose-dependent GUCY2C-specific T-cell responses. Vaccine-induced immunity is associated with improved RFS in CRC, supporting further development of the off-the-shelf Ad5.F35 platform for cancer vaccines and Ad5.F35-GUCY2C-PADRE for CRC recurrence prevention. Clinical trial information: NCT04111172 . Dose (vp) Magnitude of GUCY2C-Specific T-cell Response 1 % of Patients with a GUCY2C-Specific T-cell Response (N/N) 2 CRC 3 Recurrences (%; N/N);Median RFS 1x10 11 9 33% (5/15) 50% (4/8); 512 days 1x10 12 92 94% (15/16) 17% (1/6); not reached 5x10 12 218 100% (15/15) 0% (0/7); not reached P < 0.0001 P < 0.0001 P = 0.051 1 Median SFCs/5×10 5 PBMCs ; 2 at 4 weeks after 1 st vaccination ; 3 excluding stage IV patients .
Rural-urban disparities in demographics, clinical characteristics, and hospitalization burden among young non-smoking adults with lung cancer in the United States.
e20645 Background: Recent reports indicate a rise in lung cancer incidence among young non-smokers, yet rural-urban differences in patient characteristics and potential gaps in availability of resources remain poorly understood. We sought to investigate rural-urban differences in early-onset lung cancer patients via a national database. Methods: We analyzed hospitalization data from the National Inpatient Sample (2016-2022) for young adults (ages 18-50) hospitalized with lung cancer. We first determined the prevalence of smoking among all young lung cancer patients. Subsequently, we restricted our analysis to non-smokers and compared baseline demographics and hospitalization burden between those admitted to rural versus urban centers. Hospital charges were adjusted for inflation using appropriate survey weighting methodology. Results: Among 97,855 young adults hospitalized with lung cancer, 60.62% were smokers. Smokers were slightly older than non-smokers (mean age 45.41 vs 43.30 years). Among the 38,535 non-smokers, only 4.07% (n=1,570) were treated at rural centers, with the remainder at urban hospitals (n=36,965). Rural patients were older (44.75 vs 43.24 years, p<0.001), more likely to be White (79.28% vs 50.42%, p<0.001), and had higher rates of diabetes (19.43% vs 12.50%, p=0.0007) and prior myocardial infarction (2.23% vs 0.95%, p=0.0243). Notably, rural patients demonstrated nearly four-fold higher suicidality (1.91% vs 0.51%, p=0.0013) despite comparable rates of depression (10.83% vs 9.74%, p=0.5316) and opioid use (3.19% vs 2.31%, p=0.3176). Rural centers had fewer cases with metastatic disease (57.32% vs 67.69%, p=0.0002) and lower utilization of palliative care (11.15% vs 17.98%, p=0.0035). Rural hospitalizations were significantly shorter (4.76 vs 6.96 days, p<0.001) with markedly lower charges ($45,300 vs $112,080, p<0.001). Conclusions: Young non-smoking lung cancer patients at rural centers demonstrate distinct demographic profiles and concerning mental health disparities, particularly elevated suicidality. The significantly shorter hospital stays and lower charges at rural facilities, coupled with reduced palliative care utilization, suggest potential gaps in access to comprehensive oncologic and supportive care services. These findings underscore the urgent need for improved mental health screening and enhanced oncology resources in rural healthcare settings.
Evaluating trust in health information sources among persons with a cancer diagnosis: An analysis of the HINTS database.
e23342 Background: Trust in health information sources plays a critical role in how patients understand and adhere to their care plan. A cancer diagnosis often prompts patients to seek information within and beyond the clinical setting. The perceived trustworthiness of these sources can vary considerably and influences care decisions. To better understand how cancer patients trust information sources, national survey data such as the Health Information National Trends Survey (HINTS) provide a valuable insight. This study aims to analyse the HINTS database to evaluate trust patterns and explore how they correlate with demographic factors. Methods: The 2025 HINTS dataset was used to identify participants with a cancer diagnosis. Weighted unadjusted proportions and means were used to produce descriptive and analytic statistics. Responses of “A lot” to questions on level of trust were categorized as “trusted” and other responses categorized as “not trusted”. Weighted multivariate logistic regression with jack-knife analysis was used to examine the association between sociodemographic factors and trust in information sources. Results: Information on cancer from doctors was the most trusted source of information, and information from religious organizations was least trusted. Hispanic race was associated with lower odds of trust in information from doctors and from scientists. Male sex was associated with lower odds of trust in information from scientists and government health agencies. Having a college degree was associated with higher odds of trust in information from scientists. Conclusions: This study shows that cancer patients of Hispanic origin had a lower level of trust for health information from doctors and scientists. It will be important for future research to explore possible factors contributing to this finding. Also, it is recommended for future research to include “birthplace” to see if this factor influences trust levels within people of same race. This study shows that male cancer patients had a relative lack of trust in health information from scientists and government health agencies. Patients without a college degree also had lower odds of trusting information from scientists. These findings need to be investigated further to identify possible factors behind them. Association between sociodemographic factors and trust in information sources. Variables Odds Ratio (95% CI) SE p-value Trust in Doctors Race White, non-Hispanic Black, non-Hispanic Hispanic Other Races (including multiracial) Ref0.61 (0.24, 1.61)0.40 (0.18, 0.91)0.62 (0.29, 1.32) 0.290.160.15 0.320.030.22 Trust in Scientists Race White, non-Hispanic Black, non-Hispanic Hispanic Other Races (including multiracial) Ref0.99 (0.37, 2.63)0.37 (0.18, 0.74)0.71 (0.35, 1.48) 0.480.130.26 0.98<0.010.36 Sex at birth Female Male Ref0.48 (0.32, 0.72) 0.09 <0.01 Educational Level No college degreeCollege degree and above Ref1.84 (1.17, 2.88) 0.42 <0.01 Trust in Government Health Agencies Sex at birth Female Male Ref0.57 (0.35, 0.94) 0.14 0.03
Emiltatug ledadotin (Emi-Le), a B7-H4–directed antibody-drug conjugate (ADC), in patients with aggressive adenoid cystic carcinoma (ACC): Phase 1 interim analysis.
6010 Background: ACC is a rare cancer that typically arises in the salivary glands but can affect various organs. About 40% of patients (pts) have an aggressive form of ACC (referred to as ACC-I; Ferrarotto et al., Clin Cancer Res 2021) characterized by solid/basaloid or high-grade transformation histology and poor prognosis with median progression-free survival (PFS) of 2–3 months and median overall survival (OS) of approximately 3 years. There are no approved systemic therapies for recurrent or metastatic ACC. B7-H4 is an immune checkpoint protein with elevated expression in ACC and other cancers. Emi-Le (XMT-1660) is a B7-H4-directed ADC with an auristatin F-HPA microtubule inhibitor payload. Here we report antitumor activity results from the Phase 1 ACC-specific dose escalation/backfill cohort, along with safety data for all enrolled pts (NCT05377996). Methods: Adult pts with select advanced or metastatic solid tumors, including aggressive ACC, were enrolled. Eligibility criteria for ACC pts required features consistent with aggressive disease that included 1 of the following: 1) clinically aggressive phenotype, defined as < 3 years to recurrence/progression or de novo metastatic disease with atypical metastatic sites and solid tumor morphology, and/or 2) molecular features consistent with poor prognosis (activating NOTCH1–4 mutations or c-Myc positive or p63 negative/low per IHC). Across dose escalation and backfill, eligible pts received Emi-Le at doses of 7.2–115 mg/m 2 IV per Q3W or Q4W cycle. Pts with ACC received Emi-Le at doses of 57.4–89 mg/m 2 IV per Q3W or Q4W cycle. Primary objectives included safety and preliminary antitumor activity. Results: As of October 1, 2025, 221 pts were dosed. Of these, 35 pts had ACC, with a median of 1 prior line of therapy (range 0–3), median age 58 years, and 57% were female. For the safety set of 221 pts, Emi-Le was well tolerated with no new safety signals identified. The most common treatment-related adverse events (TRAEs) were proteinuria (49.8%), transient AST increase (49.3%), and fatigue (41.2%). The only Grade 3 TRAEs in ≥10% of pts were transient AST increase (17.6%) and proteinuria (17.6%). TRAEs leading to treatment discontinuation occurred in 3.6% of pts. No treatment-related deaths were reported. Among 25 evaluable (≥1 post-baseline scan) pts with ACC, objective response rate was 40% (9/25 confirmed, 1/25 unconfirmed ongoing and on treatment) and disease control rate was 76% (19/25). At data cut-off, median PFS (95% CI: 13.0 weeks, not reached [NR]) and OS (95% CI: 26.6 weeks, NR) have not been reached. Conclusions: Based on these data, Emi-Le appears to demonstrate favorable tolerability and promising antitumor activity in pts with aggressive ACC who have no available treatments and a poor prognosis. Further clinical development is ongoing. Clinical trial information: NCT05377996 .
Real-world comparison of remission status in newly diagnosed multiple myeloma treated with daratumumab-based versus bortezomib-based first-line therapy.
e19572 Background: The introduction of CD38 monoclonal antibodies has transformed the frontline management of newly diagnosed multiple myeloma (NDMM). However, real-world differences in remission status between daratumumab-based and proteasome inhibitor–based first-line regimens remain incompletely characterized outside of clinical trials. Methods: We conducted a retrospective cohort study using the TriNetX Global Collaborative Network. Adult patients (≥18 years) with NDMM were identified using ICD-10-CM codes and stratified by first-line treatment exposure to either daratumumab-based or bortezomib-based regimens. Patients receiving both agents were excluded to maintain mutually exclusive cohorts. Baseline demographics and disease remission status were assessed using diagnosis-level data available within the basic TriNetX platform. Results are reported descriptively Results: A total of 21,820 patients receiving first-line bortezomib-based therapy and 19,600 patients receiving first-line daratumumab-based therapy were identified across 123 and 109 healthcare organizations, respectively. Patients treated with daratumumab were slightly younger (mean age 71 vs 73 years), with similar sex distribution between cohorts. Remission status differed between treatment groups. Among patients receiving daratumumab, 46% were documented as being in remission compared with 33% in the bortezomib cohort. Conversely, a higher proportion of patients in the bortezomib group were classified as not having achieved remission (81% vs 87%) and fewer patients were documented as having relapsed disease in the bortezomib cohort (18% vs 33%). Conclusions: In this large real-world analysis of patients with NDMM, first-line daratumumab-based therapy was associated with a higher prevalence of documented remission compared with bortezomib-based therapy. These findings highlight meaningful differences in disease status between frontline treatment strategies in routine clinical practice. Further studies incorporating longitudinal outcomes and time-to-event analyses are warranted to better contextualize these observations. Documented remission in newly diagnosed multiple myeloma by first-line therapy. First-line therapy Patients with documented remission (%) Bortezomib-based 33 Daratumumab-based 46
Direct oral anticoagulants versus low-molecular-weight heparin for venous thromboembolism in primary brain tumors: A TriNetX real-world analysis.
2054 Background: Venous thromboembolism (VTE) is a common complication in patients with primary brain tumors and is associated with poor outcomes. Although therapeutic anticoagulation is required for VTE treatment, its use in this population is challenging because of the increased risk of intracranial hemorrhage (ICH). Optimal anticoagulant selection remains uncertain, as concerns regarding ICH have limited randomized trial data in patients with primary brain tumors. Therefore, comparing ICH risk between direct oral anticoagulants (DOACs) and low-molecular-weight heparin (LMWH) is critical to optimizing anticoagulation in this high-risk group. Methods: This retrospective cohort study used the TriNetX Global Collaborative Network to identify adults (≥18 years) with primary malignant brain tumors who developed VTE within one year of tumor diagnosis. Patients with secondary malignant neoplasms were excluded. Cohorts included patients treated with DOACs (apixaban, rivaroxaban, edoxaban, or dabigatran) or LMWH (enoxaparin, dalteparin, or tinzaparin) after VTE diagnosis. The index date was defined by cohort entry criteria, and outcomes were assessed over 180 days. 1:1 propensity score matching was performed across demographic and clinical characteristics, including age, sex, race, cardiovascular disease, diabetes, kidney disease, coagulation disorders, obesity, and substance use. Intracranial hemorrhage and all-cause mortality were evaluated using risk estimates and Kaplan-Meier survival analyses. Results: After propensity score matching, 6,114 patients were included in each cohort. DOAC therapy was associated with a significantly lower risk of intracranial hemorrhage compared with LMWH over 180 days (3.9% vs 7.3%; risk ratio, 0.54; 95% CI, 0.46–0.64; p<0.001). In addition, all-cause mortality at 180 days was significantly lower in the DOAC cohort than in the LMWH cohort (24.8% vs 31.3%; risk ratio, 0.79; 95% CI, 0.75–0.84; p<0.001). These findings were consistent across the matched population, demonstrating improved safety and survival outcomes associated with DOAC use in patients with primary malignant brain tumors and VTE. Conclusions: In this large real-world cohort of adults with primary brain malignancy and VTE, DOAC treatment was associated with a lower intracranial hemorrhage risk and reduced mortality at 180 days compared with LMWH after propensity score matching. These findings support the safety of DOACs in patients with primary brain tumors and warrant further prospective evaluation of anticoagulant selection in this high-risk population.
Thrombotic events in patients receiving immune checkpoint inhibitors: Incidence, risk factors, and prognostic outcomes from a retrospective cohort study.
e24155 Background: Immune checkpoint inhibitors (ICIs) have transformed cancer outcomes across multiple malignancies. However, emerging evidence suggests that thrombotic events, including venous thromboembolism (VTE) and arterial thromboembolism (ATE) are serious complications that may affect survival. The true incidence, timing, risk factors, and impact of these events in ICI patients remain unknown. This study aims to determine their incidence, identify independent risk factors, and evaluate effects on outcomes and survival. Methods: We conducted a retrospective cohort study of adult patients treated with ICIs at a tertiary academic center. Thrombotic events were classified as VTE or ATE occurring from ICI initiation through follow-up. Clinical, laboratory, and treatment-related variables were collected, including use of anticoagulants or antiplatelet agents, prior thrombotic history, age, sex, tumor type, stage, ICI regimen, and performance status. Outcomes assessed included overall survival (OS) . Kaplan–Meier methods and multivariable Cox proportional hazards models were used to evaluate survival impact and identify independent predictors. Results: Among 746 patients treated with immune checkpoint inhibitors (median age at initiation 65.1 years; 64.7% male; 94.1% ECOG 0–1), 125 thrombotic events (TE) occurred over a median follow-up of 23 months, corresponding to a cumulative incidence of 16.3%. Of these events, 105 (84.0%) were venous thromboembolism (VTE) and 20 (16.0%) were arterial thromboembolism (ATE). Of all TE, 20.8% occurred within 0–6 months, 8.0% at 6–12 months, 5.6% at 13–18 months, and 4.0% at 18–24 months (38.4% within 24 months). VTE accounted for 21.9% of all events in the first 0–6 months and declined in proportion among subsequent events, while ATE increased progressively (11.5%, 50.0%, 85.7%, and 100% across successive intervals). TE was associated with worse overall survival (log-rank p<0.001) and remained significant on multivariable analysis (HR 2.63, 95% CI 1.90–3.58, p<0.001). Independent predictors of TE included prior VTE (HR 1.92, p=0.035), lower baseline hemoglobin (HR 0.87, p=0.01), and older age at immunotherapy initiation (HR 1.02 per year, p<0.001). Conclusions: Thrombotic events are common in patients receiving immune checkpoint inhibitors, with a higher incidence than reported in clinical trials and consistent with real-world data and are independently associated with worse survival. A temporal shift from early venous to late arterial events highlights the need for time-dependent risk stratification.
Comparative evaluation of the diagnostic value of microRNAs for early colorectal cancer detection in adults: Results of a systematic review and network meta-analysis.
e15530 Background: Circulating microRNAs (miRNAs) are promising non-invasive biomarkers for colorectal cancer (CRC), but their diagnostic performance has not been systematically compared across a broad spectrum of miRNAs. This network meta-analysis evaluated the diagnostic potential of circulating miRNAs and their panels for early CRC detection. Methods: A systematic review and network meta-analysis were conducted (PROSPERO CRD420251062003). PubMed and Embase were searched, including studies published from 2000–2025. Histologically confirmed CRC patients and healthy controls were eligible. The primary outcome was AUC. Risk of bias was assessed using QUADAS-2. Statistical analyses were performed in R. Results: Forty-eight studies (69 miRNAs/panels) were included. MiR-155 and MiR-182 served as reference markers. Funnel plots indicated substantial publication bias. Heterogeneity was significant (I²=74.8% [53.0–86.5]; Q=35.7, p<0.001). No miRNA showed statistically significant benefit over references. SUCRA ranking identified three miRNA-21-based panels and two standalone candidates among the top five tools. Conclusions: This network meta-analysis provides the most comprehensive comparative evaluation of circulating miRNAs for early CRC detection. The combination miRNA-21 + miRNA-25 + miRNA-18a + miRNA-22 demonstrated the highest diagnostic potential and represents a promising candidate for non-invasive clinical implementation. Further clinical applicability will be clarified by pooled sensitivity and specificity analyses. Top five circulating miRNAs/miRNA panels by SUCRA ranking. miRNA Pooled AUC SUCRA score 21 + 25 + 18a + 22 0.93 [0.88; 0.96] 0.889 21 + 92a + 221 0.89 [0.78; 0.95] 0.799 21 + 221 + 150 0.82 [0.74; 0.88] 0.797 760 0.92 [0.83; 0.97] 0.774 221 0.81 [0.67; 0.90] 0.754
Prediction of pathologic response using a taxane-based gene expression signature in RNA-sequencing data from breast cancer patients receiving neoadjuvant therapy.
549 Background: Taxanes are frequently used in both early and advanced breast cancer, but their use has not yet been guided by predictive biomarkers. We have previously validated a microarray-based 113-gene predictive signature for neoadjuvant taxane-based treatment across 6 independent cohorts, including I-SPY2. Here, we present our first validation of this signature in RNA-sequencing data. Methods: The study by Park et al. (2020; PMID: 33268821) enrolled 210 women with stage II–III invasive breast cancer, who received four cycles of neoadjuvant doxorubicin plus cyclophosphamide (AC) followed by four cycles of docetaxel (T) with trastuzumab (H) added for HER2-positive disease. We obtained pre-treatment TPM-normalized RNA-sequencing data from GEO (accession ID: GSE123845) for patients with available response data—pathologic complete response (pCR; n = 34) vs. residual disease (RD; n = 62)—following treatment completion (n = 96). To ensure compatibility between the RNA-sequencing data and microarray-based model, we performed frozen quantile normalization using the original training dataset for the model (GSE140494) as reference. We applied the signature on the normalized data to generate a response score for each patient in the range of 0-100 and evaluated the association between treatment response and patient score using logistic regression. Results: Increase in patient score was significantly associated with higher odds of pCR after adjusting for ER and HER2 status (one-sided P = 0.003), with a 50-point increase corresponding to an odds ratio of 3.44 (95% CI, 1.46-8.71), and an AUC of 0.74 for predicting pCR. Stratifying patients by median score revealed notable differences in pCR rates between low- and high-scoring patients. For ER+/HER2- patients (n = 28; median score = 26.6), the difference in pCR rates was 29% (0% vs. 29%) for patients below vs. above the median. Corresponding differences for triple-negative (n = 35; median score = 65.6) and HER2-positive patients (n = 33; median score = 51) were 13.8% (33.3% vs. 47.1%) and 39.4% (29.4% vs. 68.8%), respectively. Conclusions: We present the validation of a 113-gene predictive signature in RNA-sequencing data for achieving a pCR after taxane-based therapy. This is our first attempt at validating the signature in RNA-sequencing data, and the 7th successful validation overall across independent breast cancer cohorts. This result further highlights the signature’s potential as a tool to support taxane-based treatment guidance.
Survival and socioeconomic disparities in the elderly population with mycosis fungoides and Sézary syndrome: A comparative analysis of 2,690 patients by facility type.
7069 Background: Mycosis fungoides (MF) and Sézary syndrome (SS) are rare T-cell malignancies (0.26 and 0.36/100,000 person-years, respectively), that predominantly affect elderly patients, a population frequently underrepresented in clinical trials and with limited access to specialized care. While population-level outcomes are known, the impact of facility type on management and survival remains poorly studied. We utilized the National Cancer Database (NCDB) to conduct the largest retrospective cohort analysis comparing patient demographics, treatment patterns, and survival (OS) between Academic Cancer Programs (ACPs) and Community Cancer Programs (CCPs). Methods: Patients ≥75 years old diagnosed with MF/SS in the US from 2000 to 2020 were identified. Facilities were categorized as ACPs (Academic/research programs) and CCPs (Comprehensive community/integrated network programs). Demographic and clinical variables were compared. Overall survival (OS) was estimated using Kaplan–Meier methods, with Cox proportional hazards models performed to assess associations between facility type and survival. Results: A total of 2690 patients were identified (ACPs: 2176;CCPs: 514). Both cohorts showed male predominance (ACPs: 58%;CCPs: 64%) and were primarily White (ACPs: 84%;CCPs: 92%). Socioeconomic analysis revealed that ACP patients were more likely to belong to the highest income quartiles compare to CCP patients across all periods (2000: 43% vs 32%; 2008–2012: 36% vs 26%; 2012–2016: 39% vs 29%; and 2016–2020: 40% vs 30%; all p < 0.01). Notably, ACP patients were more likely to receive systemic treatment (71% vs 65%; p<0.05) and experienced shorter median times to treatment initiation (37 vs 48 days; p<0.05). Conversely, radiotherapy was utilized more frequently at CCPs (29% vs 15.2%; p<0.01). With a longer median follow-up at ACPs (37 vs 31 months; p< 0.05), a higher proportion of patients remained alive at the end of the study (42% vs 30%). OS was superior among patients treated at ACPs, with higher 2-, 5-, and 10-year survival rates and a longer median OS (4.9 vs 3.0 years; log-rank p=0.001). Conclusions: In elderly patients with mycosis fungoides and Sézary syndrome, management at an Academic Cancer Program was associated with a statistically significant and clinically meaningful overall survival advantage compared with Community Cancer Programs. This survival difference occurred alongside more frequent use of systemic therapies, expedited treatment initiation, and distinct socioeconomic differences between care settings. These findings highlight important system-level disparities and underscore the critical need to strengthen referral pathways and academic–community partnerships to improve access to specialized care and optimize outcomes for this vulnerable population.
Revumenib as maintenance for AML following allogeneic stem cell transplantation.
6505 Background: Relapse after allogeneic stem cell transplantation (SCT) remains common in acute myeloid leukemia (AML). Revumenib is approved for relapsed/refractory (R/R) NPM1 mt or KMT2A r acute leukemia however its safety and efficacy as post-SCT maintenance has not been characterized. We report outcomes of revumenib maintenance post-SCT in adult and pediatric patients (pts) at our institution. Methods: Pts with NPM1 mt, KMT2A r or NUP98 r AML could continue post-SCT revumenib maintenance following response pre-SCT to revumenib monotherapy or combination on clinical trial. Revumenib was resumed at pre-SCT dose with adjustment for azoles. Results: Twenty-one pts were included (11 adult, 10 pediatric); median age 20 years (range, 1 – 69), 62% female. Most (n = 16, 76%) had KMT2A r, 4 (19%) had NPM1 mt, and 1 peds pt had NUP98 r. Pre-SCT, revumenib was given as monotherapy per AUGMENT-101 (NCT04065399, n = 8) or Expanded Access (NCT05918913, n = 2) or with oral decitabine and venetoclax per SAVE (NCT05360160, n = 11). Pts received a median of 3 (1 – 11) prior therapies, 12 pts (57%) had prior SCT, and 4 pts received SAVE frontline. Maintenance post-SCT on SAVE was planned for 1 yr. At current SCT, 19% were in first complete remission (CR1 following SAVE), 81% were in CR2+ (SAVE or monotherapy). Median time to initiate post-SCT revumenib was 2.8 months (1.4 – 5.7) with median duration of therapy of 6.7 months (0.5 – 36). With a median follow-up of 18.2 months (95% CI 17.2 – 44.3), median overall survival (OS) and event-free survival (EFS) from SCT have not been reached; 1- and 2-year OS were 89%; 1- and 2-year EFS were 84% and 73%, respectively. The 1-year cumulative incidence of relapse (CIR) was 11% and death was 5%. In CR2+, 2-year OS was 93% and 1-year CIR was 13%. At last follow up, 29% remain on revumenib, and 71% have discontinued (relapse 14%, toxicity 14%, completion 14%, pt choice 14%, other illness 9%). The most common any grade adverse event (AE) was thrombocytopenia (86%; grade >3 43%), leading to dose modification in 48% and discontinuation in 10%. Graft-versus-host-disease occurred in 14% (grade >3 5%), however no other AE led to dose modification. Infections occurred in 14% (grade ≥3 10%); one pt discontinued due to grade 4 septic shock. No QTc prolongation was seen. In contrast, in a historical SCT cohort with the same genotypes treated prior to the advent of menin inhibitors (Table 1), pts transplanted at CR2+ had 2-year OS of 33% and 1-year CIR of 46%. Conclusions: Revumenib maintenance post-SCT was feasible in this heavily pretreated cohort. Thrombocytopenia was common often requiring dose modification, but no other significant toxicities were observed. Outcomes appear favorable compared to historical cohorts, supporting prospective evaluation of menin inhibition as maintenance. Clinical trial information: NCT04065399 , NCT05918913 . Rev vs. historical cohort. N 1-yr OS(%) 2-yr OS(%) 1-year CIR(%) Median F/U (mos) Rev 21 89 89 11 18.2 Rev CR2+ 17 93 93 13 33.3 Hist. 320 60 51 39 76 Hist. CR2+ 124 45 33 46 92
Systemic antibiotic exposure and outcomes of immune checkpoint inhibitors in non–small cell lung cancer.
e20602 Background: Immune checkpoint inhibitors (ICIs) have transformed the management of solid tumors, particularly non–small cell lung cancer (NSCLC), yet durable benefit is achieved only in a subset of patients. The gut microbiota is a key modulator of antitumor immunity, and systemic antibiotic therapy (ABT), frequently prescribed in oncology, can disrupt microbial homeostasis. Observational studies suggest that ABT may impair ICI efficacy, but results remain heterogeneous, warranting an updated synthesis with tumor-specific analyses. Methods: We conducted a systematic review and meta-analysis according to PRISMA 2020 guidelines. PubMed, Scopus, and EMBASE were searched for studies published between 2018 and 2025 evaluating the association between ABT exposure and time-to-event outcomes in patients with solid tumors treated with ICIs. Eligible studies reported a clearly defined ABT exposure window. Random-effects models were considered primary. A pre-specified sensitivity analysis focused on NSCLC, the largest and most methodologically homogeneous subgroup. Results: Fifteen studies encompassing 52,489 patients were included. Overall, ABT exposure was associated with worse overall survival (OS; random-effects HR 1.16, 95% CI 1.03–1.29) and numerically inferior progression-free survival (PFS; random-effects HR 1.11, 95% CI 0.95–1.27).In the NSCLC sensitivity analysis, 45,896 patients were analyzed. For OS, moderate heterogeneity was observed (I² = 51%), with a pooled fixed-effect HR of 1.05 (95% CI 0.996–1.11), indicating a consistent trend toward worse survival with ABT exposure. For PFS, no heterogeneity was detected (I² = 0%), and ABT exposure was associated with a significantly increased risk of disease progression (HR 1.16, 95% CI 1.02–1.30), with concordant fixed- and random-effects estimates. Conclusions: ABT administered in temporal proximity to ICIs is associated with inferior survival outcomes, with particularly robust and consistent evidence for worsened PFS in NSCLC. These findings support a microbiome-mediated impairment of immunotherapy efficacy and underscore the importance of cautious ABT stewardship in patients with NSCLC receiving ICIs. Prospective studies integrating microbiome profiling and standardized ABT exposure definitions are warranted.