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Pollution and progression: Air quality and stage of lung cancer diagnosis across the U.S.
8003 Background: Air pollution contributes to increased lung cancer incidence, but whether it accelerates tumor progression, resulting in more advanced stage at diagnosis, is not well understood. Understanding environmental and social factors influencing late-stage presentation can guide targeted prevention efforts. Methods: We identified primary lung cancer cases from the National Cancer Database (NCDB; 2010–2023) across 2,803 U.S. counties. Individual-level data were linked to county-level annual averages of PM₂.₅ (μg/m³) and NO₂ (ppb). Generalized estimating equation logistic models with county-level clustering assessed associations between chronic pollution exposure and odds of advanced-stage (III–IV vs. I–II) diagnosis, adjusting for median household income and educational attainment. Pollutants were z-score standardized (mean = 0, SD = 1) and summed to create a combined Pollution Burden metric. Effect modification by histology and socioeconomic status was tested. Results: Among 1,023,140 patients (mean age 68.5 ± 10.8 years; 51.3% female), 67.1% presented with advanced-stage disease. Each standard deviation increase in PM₂.₅ was associated with 4.8% higher odds of advanced-stage diagnosis (95% CI: 3.5–6.1%; p < 0.001; Table 1). In multi-pollutant models, PM₂.₅ remained significant (OR = 1.062, 95% CI: 1.047–1.076; p < 0.001), with combined pollution burden linked to a 3.1% increase in odds (95% CI: 1.5–4.7%; p < 0.001). Low-SES communities had higher advanced-stage rates regardless of pollution exposure (69.7% vs. 63.6%; p < 0.001), equating to approximately 6,100 excess annual diagnoses. Effects varied by histology, with small cell carcinoma showing the highest advanced-stage rate (91.2%), followed by adenocarcinoma (67.3%) and squamous cell carcinoma (58.6%). Conclusions: Higher PM₂.₅ exposure and lower socioeconomic status were independently associated with later-stage lung cancer diagnosis across over 1 million cases from 2,803 U.S. counties. Low-SES communities showed 6 percentage points higher advanced-stage rates irrespective of pollution levels. These findings highlight how environmental factors that may accelerate cancer progression and social barriers to accessing care can jointly delay early-stage diagnosis. Targeted pollution control and expanded lung cancer screening in underserved communities could reduce the burden of advanced-stage disease. Odds of advanced-stage lung cancer by air pollutant exposure. Pollutant Model Mean ± SD OR 95% CI Lower 95% CI Upper P-value PM₂.₅ (μg/m³) Single-pollutant 8.17 ± 1.58 1.048 1.035 1.061 <0.001 PM₂.₅ (μg/m³) Multi-pollutant 1.062 1.047 1.076 <0.001 NO₂ (ppb) Single-pollutant 6.93 ± 3.93 1.009 0.993 1.026 0.28 NO₂ (ppb) Multi-pollutant 0.978 0.963 0.994 0.007 Combined Burden Z_PM2.5 + Z_NO2 1.031 1.015 1.047 <0.001
Mortality trends from malnutrition and gastrointestinal cancer in US adults: A retrospective analysis.
e15675 Background: Gastrointestinal cancer is the significant public health issue worldwide, contributing to a substantial cancer related death. Malnutrition, a complex multifactorial condition linked to higher morbidity and mortality. This study aimed to investigate the mortality trends and disparities among malnourished and gastrointestinal cancer patients in the United States. Methods: We conducted a retrospective analysis using the Centers for Disease Control and Prevention Wide-ranging Online Data for Epidemiologic Research (CDC WONDER) Multiple Cause-of-Death database. We analyzed average age adjusted mortality rates (AAMRs) from 1999 to 2023 per 1,000,000 population using ICD−10 codes for malnutrition (E40-E46) and gastrointestinal cancer (C15-C26). Data were extracted using demographic characteristics (sex, race/ethnicity, and age), U.S. census region, and metropolitan status. Join-point regression program was utilized to evaluate annual percentage changes (APC) and average annual percentage change (AAPC) with 95% confidence intervals. Results: Over 24 years, 60,016 deaths involved malnutrition and gastrointestinal cancer. The overall AAMR increased from 1999 to 2023 (AAMR: 10.2, 95% CI: 9.76 to 10.64; AAPC: 2.99, 95% CI: 2.39 to 3.62). Men had higher rates than women (13.06 vs. 7.86). Among races, the highest AAMR was observed in Non-Hispanic Black (16.02), followed by Hispanic (10.26), Asian/Pacific Islanders (9.72), and White (9.54). Regionally, the West had the highest rates (11.26), then Midwest (11.12), South (10.84), and Northeast (6.58). Stratified by urbanization, rural areas showed higher AAMRs (11.05) than urban areas (8.55). Conclusions: Mortality from concurrent malnourishment and gastrointestinal cancer has increased overall and remains highest among males, Black populations, Western region, and residents of rural areas which could be due to low resources, poverty and poor healthcare system as compared to urban. These disparities highlight the urgent need for targeted, equitable public health interventions to reduce mortality in these vulnerable groups. Deaths and age-adjusted mortality rates (AAMRs) per 1,000,000 for trends related to malnutrition and gastrointestinal cancer mortality in adults in the United States between 1999 and 2023. Variable Deaths (n) AAMR (95% CI) in 2023 Overall 60,016 19.08 (18.78-19.38) SEX Female 26,048 15.98 (15.33-16.62) Male 33,968 27.49 (26.57-28.42) RACE/ETHNICITY NH Asians 2,294 15.73 (13.72-17.74) NH Blacks 8,840 27.82 (25.84-29.81) NH White 43,015 21.04 (20.39-21.69) Hispanics 5,161 19.02 (17.43-20.62)
Intrathecal (IT) therapy–associated pseudoprogression (PsP) in leptomeningeal metastases (LM) from solid tumors.
2037 Background: Intracranial PsP following systemic immunotherapy has been recognized. IT therapy is a cornerstone of LM management, and prior studies support the safety and feasibility of IT immunotherapy. The occurrence of PsP specifically after IT immunotherapy for LM remains unreported. This study aims to characterize the clinical and proteomic profile of IT therapy–associated PsP (IT-PsP). Methods: This prospective case series consecutively enrolled LM patients receiving IT therapy between February 2024 and January 2026. Patients were treated with IT pemetrexed (PM) alone or combined with immunotherapy (PD-1 inhibitors, PD-1/CTLA-4, or PD-1/VEGF antibodies). Treatment response was assessed per RANO-LM criteria. Based on the iRANO criteria, IT-PsP was considered as radiographic progression without significant worsening of LM-related symptoms or neurological deficits. Furthermore, patients were defined as IT-PsP only if they also met at least one of the following criteria without salvage LM-directed therapy: sustained conversion of cerebrospinal fluid (CSF) cytology to negative, subsequent neuroimaging improvement, or absence of progressive neurological symptoms/signs with stable disease for ≥3 months. CSF proteomics was analyzed via Olink Target 96 Immuno-Oncology panel. Results: Of 144 enrolled patients, 75 received IT PM and 69 received IT immunotherapy plus PM. IT–PsP was identified in 12 patients (8.3%). Median age was 53.5 years (range 30–66) and 10 were female. Primary tumors were lung adenocarcinoma (n=11) and breast cancer (n=1). None received concurrent systemic immunotherapy. The median time to PsP occurrence was 5.2 months (range 1.5–12) after the first IT treatment. PsP incidence was significantly higher in the combination group (15.9%, 11/69) than with IT PM alone (1.3%, 1/75) (P=0.002). 6 (50%) achieved sustained conversion to negative CSF cytology. Radiographically, lesions improved in 7 patients (58.3%) and remained stable in 2 (16.7%). All PsP patients were followed up for a median of 7.1 months (range 1–13.6) with no neurological progression. Median overall survival from enrollment and from PsP onset were not reached. CSF proteomic profiling revealed that IT-PsP samples, compared to both progressive LM and pre-treatment samples, showed significant downregulation of tumor-associated proteins (CCL20, LAP TGF-beta-1, IL8, CCL4). Furthermore, compared to post-treatment response samples, IT-PsP was associated with significant upregulation of inflammatory markers, including Gal-9, IL15, and ADA. Conclusions: This study characterizes the clinical features and distinct CSF proteomic signature of IT-PsP in LM. The significantly higher PsP incidence with IT immunotherapy underscores that, in the immunotherapy era, relying exclusively on neuroimaging to define LM progression necessitates careful re-evaluation.
Association between T-cell LAG-3 expression and clinical benefit in patients with type 2 diabetes and metastatic melanoma treated with immune checkpoint inhibitors.
e14578 Background: Anti-PD-1/anti-LAG-3 combination checkpoint inhibitors, such as nivolumab/relatlimab (nivo/rela), show marked efficacy in treatment of metastatic melanoma. As with all immunotherapy, this success depends in part on the presence of the relevant target receptors on circulating immune cells. Type II diabetes mellitus (T2DM), a disease characterized by inflammation and immune dysregulation, has been observed in limited analyses to be associated with lower LAG-3 gene expression in peripheral blood. We hypothesized that patients with T2DM would also have lower baseline T-cell surface expression of LAG-3 and consequently worse clinical outcomes on nivo/rela. Methods: 90 patients with metastatic melanoma treated with ipilimumab/nivolumab (ipi/nivo) or nivo/rela were identified from the University of Pittsburgh Melanoma Center biospecimen repository. Baseline blood samples were available for 14 patients. Clinical outcomes were obtained via retrospective chart review. Statistical analysis utilized Kaplan-Meier and Cox Proportional Hazard models. Baseline T-cell surface expression of LAG-3 was quantified using flow cytometry. Results: 72% of the overall cohort (n = 65) received ipi/nivo and 28% (n = 25) received nivo/rela. 22% (n = 20) of patients had T2DM. Of those with baseline blood samples, 36% (n = 5) had T2DM. Kaplan-Meier analysis of patients treated with nivo/rela revealed no statistical difference in Overall Survival (p = 0.50) or Progression Free Survival (PFS) (p = 0.36) for patients with T2DM compared to those without. Flow cytometry results also demonstrated no statistically significant difference in baseline T-cell surface expression of LAG-3 in patients with T2DM. In sub-analysis of patients with T2DM, those treated with nivo/rela had significantly longer PFS compared to those treated with ipi/nivo (p = 0.02). Conclusions: Contrary to prior findings, this study demonstrates no difference in baseline T-cell surface expression of LAG-3 among patients with T2DM and indicates that nivo/rela remains an effective treatment option. Data regarding nivo/rela response in melanoma patients with T2DM remains limited. While sample size is limited, our findings support the use of this regimen for patients with T2DM and highlight the need for larger, multicenter studies to better inform treatment guidelines for diabetic patients with metastatic melanoma.
Real-world analysis of eribulin sequencing and outcomes in advanced breast cancer: An LMIC cohort study focusing on line of therapy and prior cyclin-dependent kinase 4/6 inhibitor exposure.
e13050 Background: In Low-and-Middle-Income Countries (LMICs), eribulin is often a late-line salvage. With increasing use of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i), optimal placement of eribulin requires investigation. We evaluated outcomes based on line of therapy and prior CDK4/6i exposure. Methods: Retrospective analysis of 99 patients with mBC treated with eribulin in India (2019– 2023). Primary endpoint was median progression-free survival (mPFS). Subgroups compared early-line (L2-3) vs. late-line (L4+) and prior CDK4/6i exposure using Mann-Whitney U tests. Median Overall Survival (mOS) was not calculated due to data immaturity, compounded by the inherent challenges of loss to follow-up and the lack of integrated survival registries in an LMIC setting. Results: Median age was 52 years; 79.8% had visceral metastases; 96% had ECOG PS 0-1. Overall mPFS was 4.04 months (mean 5.3 cycles). Line of Therapy: L2-3 use (72.7%) showed significantly longer mPFS vs. L4+ (4.88 vs. 2.14 months; p < 0.001). CDK4/6i Sequencing: Patients post-CDK4/6i (42.4%) achieved mPFS of 5.22 months vs. 4.07 months in CDK4/6i-naive patients (p = 0.02). TNBC Subset: Triple-negative subgroup (n = 23) mPFS was 3.12 months despite 91.3% visceral involvement. CBR and Safety: 6-month clinical benefit rate was 39.4%. Grade 3/4 neutropenia occurred in 31.3% of patients. Conclusions: Eribulin outcomes were significantly influenced by line of therapy, with superior mPFS in earlier-line settings (L2-3). Clinical activity was robust post-CDK4/6i, suggesting eribulin is an effective sequential option following targeted therapy failure in high-risk visceral disease.
Cachexia as an inpatient vulnerability phenotype in lung cancer: A National Inpatient analysis.
e23225 Background: Cancer cachexia is a multisystem metabolic syndrome characterized by involuntary tissue catabolism and systemic inflammation. In pivotal randomized interventional trials, cachexia has been defined as a composite syndrome incorporating nutritional, inflammatory, and tissue-loss domains. This trial-anchored framework was applied to a national inpatient cohort to evaluate associations with acute outcomes among hospitalized lung cancer patients. Methods: A survey-weighted analysis of the National Inpatient Sample (2016–2022) was conducted among adult lung cancer hospitalizations identified using ICD-10-CM code C34*, excluding childbirth- and delivery-related admissions. Cachexia was defined using a trial-anchored, multi-domain syndromic framework requiring ≥1 ICD-10–mapped domain: nutritional depletion (E43, E44, E46, R62.7, R63.4), skeletal muscle loss (M62.84, M62.5*), systemic inflammatory or metabolic burden (E88.09, R77.0), or clinician-recognized cachexia (R64); burden was categorized as 0, 1, or ≥2 domains. The primary outcome was in-hospital mortality; secondary outcomes included sepsis (A40/A41, R65.20, R65.21), acute kidney injury (N17*), ICU-level care proxied by invasive mechanical ventilation (5A1935Z, 5A1945Z, 5A1955Z), length of stay, and CCR-adjusted cost. Results: The weighted cohort comprised 3,197,184 hospitalizations (unweighted n = 639,437). Cachexia prevalence was 25.3%, with domain prevalences of nutritional depletion 22.2%, skeletal muscle loss 0.16%, inflammatory/metabolic burden 1.69%, and clinician-recognized cachexia 5.45%. Unadjusted outcomes were worse among hospitalizations with cachexia versus without: mortality 13.35% vs 7.40%, sepsis 20.17% vs 12.14%, acute kidney injury 21.73% vs 16.03%, and invasive mechanical ventilation 7.15% vs 4.80%. Mean length of stay was 7.96 vs 5.50 days, mean cost $24,662 vs $20,336, and mean charges $91,313 vs $74,016. After adjustment, cachexia was independently associated with higher in-hospital mortality (aOR 1.79, 95% CI 1.75–1.83), with a graded dose–response by domain burden (1 domain aOR 1.68, 95% CI 1.64–1.72; ≥2 domains aOR 2.45, 95% CI 2.34–2.55). Cachexia was also associated with sepsis (aOR 1.57, 95% CI 1.54–1.60), acute kidney injury (aOR 1.26, 95% CI 1.24–1.28), invasive mechanical ventilation (aOR 1.40, 95% CI 1.36–1.44), longer length of stay (+2.26 days), and higher hospitalization cost (+$5,132). Conclusions: A trial-anchored, syndromic cachexia phenotype is common among hospitalized lung cancer patients and identifies a graded, dose-dependent inpatient vulnerability signature associated with increased mortality, complications, and resource utilization. This framework translates cachexia trial concepts into real-world inpatient oncology and offers a scalable phenotype for risk stratification and evaluation of emerging anti-cachexia therapies.
Five-year overall survival in lung adenocarcinoma: Real-world results from three French nationwide cohorts (2000–2010–2020).
8600 Background: Long-term (5-year) real-world overall survival (OS) in non–small cell lung cancer (NSCLC) remains poorly documented especially in prospective condition. The French nationwide KBP program comprises prospective cohorts conducted every 10 years since 2000 to evaluate lung cancer prognosis. In 2020, 8,941 patients were included across 81 non-academic public hospitals, with lung adenocarcinoma (LA) representing the most frequent histologic subtype. Building on previously reported 3-year survival results[1], we assessed temporal changes in 5-year OS and described the characteristics of long-term survivors with LC using the 2000, 2010, and 2020 cohorts. Methods: Patients with lung cancer, all stages, diagnosed in non-academic public hospitals in 2000, 2010, and 2020 were included in the French nationwide KBP cohorts, all conducted using the same prospective methodology. For the 2020 cohort, patient inclusion occurred between 1 January and 31 December 2020. Vital status was collected during follow-up. Five-year OS was estimated using the Kaplan–Meier method and compared across the 2000, 2010, and 2020 cohorts, overall and stratified by stage at diagnosis. In the 2020 cohort, a descriptive comparative analysis was performed between long-term survivors (≥5 years) and patients who died before this term. In the 2020 cohort, multivariable Cox proportional hazards models are ongoing to identify prognostic factors associated with OS. Prespecified covariates include age, sex, ECOG PS, smoking status, stage at diagnosis. These analyses remain preliminary and will be updated for the conference, as the 5-year vital status follow-up has recently been completed. Results: Among the 1,640, 3,199, and 5,009 patients with LA included in the 2000, 2010, and 2020 KBP cohorts, respectively, 5-year vital status was available for 99.3%, 96.2%, and 83.4% of patients. 5-year OS was 29.4% (95% CI, 28.1–30.7) in 2020, compared with 14.4% (95% CI, 13.3–15.7) in 2010 and 4.7% (95% CI, 3.0–7.2) in 2000, corresponding to an absolute improvement of 15.0% over the last decade. In the 2020 cohort, long-term survivors (≥5 years; n = 772) were 47.8% female, only six patients had an ECOG performance status ≥3, 48.2% were current smokers, 19.8% never-smokers and 32.0% former smokers. The distribution of stage at diagnosis among long-term survivors was 37.6% stage I, 9.9% stage II, 20.9% stage III, and 31.6% stage IV. Conclusions: 5-year real-world OS in LA has markedly improved over the last two decades with an increasing proportion of long-term survivors. Ongoing stage-stratified and multivariable analyses will further characterize long-term survival patterns. [1] https://evidence.nejm.org/doi/full/10.1056/EVIDoa2400443.
Second-generation H1 antihistamine use with survival and immune-related outcomes in lung cancer and melanoma patients receiving immune checkpoint inhibitors.
11153 Background: Immune checkpoint inhibitors (ICIs) are standard of care for melanoma and lung cancer but are associated with immune-related adverse events and variable outcomes. Previous studies suggest that H1 antihistamine use may be associated with improved outcomes, potentially through histamine-mediated modulation of the tumor microenvironment. However, real-world evidence is limited. Methods: We conducted a multicenter retrospective study using the TriNetX Global Collaborative Network. Adult patients (≥18 years) with melanoma or lung cancer receiving ICIs (pembrolizumab, nivolumab, ipilimumab, atezolizumab, durvalumab, cemiplimab, or avelumab) were identified. Patients were categorized by exposure to second-generation H1 antihistamines (cetirizine, loratadine, fexofenadine, desloratadine, or levocetirizine) within 3 months before or during ICI initiation. One-to-one propensity score matching was performed based on demographics, baseline comorbidities, cancer characteristics, prior treatments, and conditions commonly associated with antihistamine use, including allergic and atopic disorders. The index date was defined as first ICI exposure, and outcomes were assessed from day 1 to day 180. The primary outcome was overall survival. Secondary outcomes included hospitalization and immune-related adverse events (irAEs), defined using a composite endpoint of organ-specific immune-mediated toxicities based on prior published methodology. Results: After matching, 2,141 melanoma and 11,812 lung cancer patients were included. In lung cancer patients, H1 antihistamine use was associated with reduced all-cause mortality (HR 0.769, 95% CI 0.727–0.815), lower hospitalization rates (HR 0.862, 95% CI 0.821–0.906), fewer intensive care unit admissions (HR 0.867, 95% CI 0.797–0.943) and reduced emergency department use (HR 0.940, 95% CI 0.899–0.984). 6-month overall survival was 80.93% in antihistamine users vs 75.98% in non-users. It was also associated with decreased endocrine (HR 0.843, 95% CI 0.776–0.916), and musculoskeletal irAEs (HR 0.840, 95% CI 0.752–0.938). In patients with melanoma, H1 antihistamine use was associated with reduced all-cause mortality (HR 0.685, 95% CI 0.581–0.808), lower hospitalization rates (HR 0.837, 95% CI 0.734–0.955), and reduced neutropenia (HR 0.441, 95% CI 0.266–0.729). 6-month overall survival was 88.15% vs 83.20%, respectively. No statistically significant differences were observed across other major immune-related organ systems. Conclusions: Second-generation H1 antihistamine use was associated with improved early survival and reduced healthcare utilization among melanoma and lung cancer patients treated with ICIs, without a significant increase in irAEs. Despite the retrospective design and potential confounding, prospective validation is warranted.
TP53 loss in relation to mTORC1 activation and autophagy suppression shaping an immune-cold phenotype in microsatellite-stable colorectal cancer.
e15521 Background: Loss of TP53 is one of the most common alterations in microsatellite-stable colorectal cancer (MSS CRC). It is known to affect both cellular metabolism and immune regulation, yet how these processes interact remains unclear. This study explored how TP53 loss shapes tumor metabolism, autophagy, and immune balance using multi-omics integration. Methods: We analyzed four public datasets: GSE146009 (paired tumor-normal RNA-seq), TCGA-COAD/READ (n=647, mutation-annotated), GSE108989 (11,138 single-cell T cells), and CPTAC colon proteome/phosphoproteome cohorts. Pathway activity was quantified by single-sample gene-set enrichment (ssGSEA) and Seurat module scoring. Group comparisons used Kruskal-Wallis and Wilcoxon tests with false-discovery-rate correction. Results: In the TCGA cohort, TP53-mutant tumors showed higher mTORC1 signaling and lower autophagy activity compared with wild-type tumors (FDR<0.01). FOXP3 expression increased across wild-type, missense, and null classes, while CD8A levels remained stable, producing a progressive drop in the CD8A/FOXP3 ratio (p<0.001). In GSE146009, tumors displayed higher FOXP3, CTLA4, and CD274 and a lower CD8A/FOXP3 ratio than adjacent normal tissue (FDR<0.05). Single-cell analysis confirmed that regulatory and exhausted CD8⁺ T cells had stronger mTORC1 and autophagy signaling but weaker IFNG activity compared with effector subsets. Proteomic data from CPTAC cohorts supported these findings: p53-low tumors showed increased phosphorylation of EIF4EBP2 (S65) and RPS6KB1 (T421/S424) and reduced inhibitory phosphorylation of RPTOR (S705/T725/S726), consistent with sustained mTORC1 activation and suppressed autophagy. Conclusions: Across transcriptomic, single-cell, and proteomic layers, TP53 loss is linked to metabolic activation and immune suppression through the mTORC1-autophagy pathway. This mechanism creates a FOXP3-dominant, immune-cold microenvironment and suggests that targeting mTORC1 and autophagy may help overcome immunotherapy resistance in TP53-mutant MSS CRC. Summary of key metabolic and immune pathway differences by TP53 status in colorectal cancer. Metric Comparison Effect p/FDR mTORC1 score TP53 mutant vs WT +0.13 <0.001 Autophagy score TP53 mutant vs WT -0.12 0.004 FOXP3 expression WT→missense→null ↑trend 0.005 CD8A/FOXP3 ratio WT→missense→null 1.28→0.96 <0.001 EIF4EBP2 S65 phospho p53-low vs high +1.1 trend RPTOR S705/T725/S726 p53-low vs high -0.6→-1.6 trend Values represent median group differences. P-values adjusted using false discovery rate (FDR) correction.
SARS-CoV-2 infection, vaccination, and MGUS progression with COVID-19 outcomes in multiple myeloma: A systematic review.
e19550 Background: SARS-CoV-2 infection and vaccination have been associated with immune perturbations that may affect plasma cell biology. Whether these exposures influence progression from monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma (MM) through immune dysregulation or clonal selection remains uncertain, and patients with MM continue to demonstrate vulnerability to adverse COVID-19 outcomes. Methods: A systematic review with selective quantitative synthesis of observational studies in accordance with PRISMA guidelines. A PubMed search was conducted through December 2024. Eligible studies included adult populations with MGUS or MM reporting outcomes following SARS-CoV-2 infection or vaccination; case reports, narrative reviews, and studies without extractable data were excluded. Data sources included population-based longitudinal cohorts, multicenter registries, and real-world datasets. Outcomes included longitudinal biomarkers of MGUS progression, COVID-19–associated mortality in MM, and vaccine-era breakthrough infection and hospitalization. Risk of bias was assessed using ROBINS-I. MGUS outcomes were synthesized narratively; random-effects meta-analysis was performed for comparable mortality outcomes. Vaccine-era outcomes were summarized using hazard ratios (HRs) with 95% confidence intervals (CIs). Results: Eleven studies met inclusion criteria, with five eligible for quantitative synthesis. In population-based iStopMM cohorts, longitudinal mixed-effects models showed no association between SARS-CoV-2 infection (Exp[β]=1.01, 95% CI 0.91–1.12) or vaccination (Exp[β]=0.99, 95% CI 0.96–1.03) and change in M-protein trajectory, indicating stable MGUS clonal kinetics. In contrast, among MM cohorts during the early pandemic, COVID-19–associated mortality ranged from 24% in a New York City cohort to 34% in an international registry. Despite vaccination, MM remained associated with increased risk of breakthrough SARS-CoV-2 infection versus matched controls (HR 1.34, 95% CI 1.06–1.69) and markedly increased risk of hospitalization after breakthrough infection (HR 15.9, 95% CI 6.2–40.3), consistent with persistent immune dysfunction. Conclusions: Across population-based longitudinal cohorts, SARS-CoV-2 infection and vaccination were not associated with altered MGUS clonal dynamics or accelerated progression, providing reassurance regarding stability of premalignant plasma cell disorders. Intensified surveillance solely due to prior SARS-CoV-2 infection or vaccination is unlikely to be warranted in MGUS. In contrast, patients with MM continue to experience substantial COVID-19–related morbidity in the vaccine era, supporting ongoing prioritization of preventive and early therapeutic strategies.
Profiling <i> <i>NRG1</i> </i> fusions in NSCLC: A comparative analysis of DNA+RNA-NGS and DNA-NGS assays.
e20742 Background: The neuroregulin 1 ( NRG1 ) gene fusion is a rare but clinically significant target in non-small cell lung cancer (NSCLC). Recently, targeted therapies for NRG1 have been approved and incorporated into clinical guidelines. However, the underdetection of NRG1 fusions at the DNA level remains a considerable challenge. In recent years, DNA+RNA-NGS has been successively recommended in expert consensus documents and clinical guidelines, and has been reported to offer superior performance in detecting fusion genes in NSCLC. This study evaluates the detection rate of NRG1 fusions using DNA+RNA-NGS compared to DNA-NGS in NSCLC patients in a real-world setting, providing reliable evidence for clinical practice. Methods: This study enrolled Chinese NSCLC patients from March 2022 and November 2025. Among them, 5032 patients underwent DNA-NGS, while 11432 patients received DNA+RNA-NGS. The DNA+RNA-NGS approach involved extracting both DNA and RNA from the same tissue sample, with RNA reverse-transcribed into complementary DNA (cDNA) and then combined with DNA. Within a single reaction system, DNA-NGS was employed to identify SNVs/Indels while RNA-NGS targeted fusion genes. NRG1 fusion-positive cases were identified and analyzed separately within each cohort. Results: The results demonstrated a higher NRG1 detection rate in the DNA+RNA-NGS cohort (0.219%) compared to the DNA-NGS cohort (0.099%). Further analysis revealed that 36% (9/25) of patients in the DNA+RNA-NGS cohort harbored at least two NRG1 fusion variants, whereas only single fusions were detected in the DNA-NGS cohort. Among all identified fusion variants (n = 45), CD74 was the most frequent fusion partner (64.44%, 29/45), significantly higher than the 20%-30% reported in the literature, followed by ATP1B1 (17.78%, 8/45). Additionally, DNA+RNA-NGS identified a wider spectrum of fusion partners, while the relatively common partner ATP1B1 was not detected in the DNA-NGS cohort. Further examination of the breakpoints revealed that the NRG1 breakpoints were predominantly located in exon 5. Clinical characteristics analysis indicated that nearly all NRG1 fusion-positive patients were diagnosed with lung adenocarcinoma. Conclusions: In conclusion, DNA+RNA-NGS significantly enhances the detection capability of NRG1 fusions, providing critical insights for precision medicine.
The corticosteroid timing paradox in immune checkpoint inhibitor–treated solid tumors and its association with overall survival: A TriNetX retrospective cohort study.
11140 Background: Systemic corticosteroids are frequently used in patients receiving immune checkpoint inhibitors (ICIs) for symptom control and management of immune-related adverse events (irAEs). However, corticosteroids may impair antitumor immunity, and the impact of timing of corticosteroid exposure relative to ICI initiation on survival outcomes remains incompletely defined. We evaluated the association between corticosteroid timing and overall survival (OS) in a large real-world cohort of ICI-treated solid tumor patients. Methods: We conducted a retrospective cohort study using the TriNetX Global Collaborative Network, including adult patients (≥18 years) with solid tumors treated with ICIs. Patients were stratified based on systemic corticosteroid exposure into three groups: baseline use (−30 to 0 days before ICI initiation), early intercurrent use (1–56 days after ICI initiation), and late intercurrent use (57–180 days after ICI initiation). Patients without corticosteroid exposure served as controls. The primary outcome was overall survival (OS). Kaplan–Meier analysis and Cox proportional hazards models were used to estimate survival outcomes and hazard ratios (HRs) with 95% confidence intervals (CIs). Results: A total of 43,282 ICI-treated solid tumor patients were included. Baseline corticosteroid use was associated with significantly worse OS compared with no corticosteroid exposure (median OS 564 vs 900 days; HR 1.32, 95% CI 1.28–1.35; p < 0.0001). Similarly, early intercurrent corticosteroid use was associated with inferior OS (median OS 543 vs 907 days; HR 1.35, 95% CI 1.32–1.39; p < 0.0001). In contrast, late intercurrent corticosteroid use was not associated with a survival detriment compared with controls (median OS 617 vs 650 days; HR 0.99, 95% CI 0.97–1.02; p = 0.60). Conclusions: In this large real-world analysis, systemic corticosteroid exposure prior to or early during ICI therapy was associated with significantly worse overall survival, whereas corticosteroid use later during treatment did not adversely impact survival. These findings support a corticosteroid timing paradox, suggesting that early immunosuppression may impair ICI efficacy, while later corticosteroid use—often for irAE management—may be oncologically safe. Prospective studies are needed to further define optimal corticosteroid timing and indications in ICI-treated patients.
Comparative effectiveness and safety of axicabtagene ciloleucel versus lisocabtagene maraleucel in large B-cell lymphoma: A real-world target trial emulation.
11021 Background: Axicabtagene ciloleucel (axi-cel) and lisocabtagene maraleucel (liso-cel) are approved CD19-directed CAR T-cell therapies for large B-cell lymphoma (LBCL); however, comparative real-world evidence on their effectiveness and safety remains limited. We conducted a target trial emulation to compare the overall survival (OS), event-free survival (EFS), and safety outcomes between axi-cel vs liso-cel in routine clinical practice. Methods: Using de-identified electronic health record data from TriNetX (January 2017- December 2025), we emulated a two-arm target trial among adult patients with LBCL who received axi-cel or liso-cel. Index date (T 0 ) was defined as the date of CAR T-infusion. Patients with active severe infections at the index date or a history of cardiovascular and central nervous system involvement were excluded. Inverse probability of treatment weighting (IPTW) was used to balance the covariates, including age, sex, race, comorbidity, prior autologous stem cell transplantation, bridging therapy, and baseline inflammatory markers. OS was analyzed using IPTW Cox proportional hazards models. Event-free survival (EFS) was defined as a composite of death or initiation of subsequent systemic therapy (as a proxy for treatment failure). Cytokine release syndrome (CRS), and immune effector cell-associated neurotoxicity syndrome (ICANS) were evaluated. Hazard ratios (HRs) and 95% confidence intervals (CIs) were reported, and all analyses were conducted using R. Results: Among 1,311 eligible patients, 947 received axi-cel and 364 received liso-cel. In the unweighted cohort, patients treated with axi-cel were younger than those receiving liso-cel (median age 62 vs 72 years), with a similar sex distribution and a predominantly White population in both groups. After IPTW, baseline demographic, clinical, and laboratory characteristics were balanced between groups. OS did not differ significantly between axi-cel and liso-cel (HR 0.98; 95% CI, 0.71-1.36). Median OS was not reached in either group, with similar OS rates at 12 months (axi-cel: 78.1%, liso-cel: 80.3%) and 24 months (axi-cel: 71.3%, liso-cel: 71.4%). EFS was also comparable between treatments (HR 1.08; 95% CI, 0.82–1.44). No significant differences in CRS risk were observed within 90 days or overall follow-up (HR: 0.86; 95% CI, 0.66-1.11). Axi-cel was associated with a higher risk of ICANS within the first 90 days (HR 1.42; 95% CI, 1.00-2.01), although no significant difference was observed over longer follow-up. Conclusions: Axi-cel and liso-cel demonstrated comparable effectiveness in terms of OS and EFS. Safety profiles differed primarily in early neurotoxicity risk, while CRS incidence was similar between products. These findings provide real-world comparative evidence that may help to inform CAR T-cell therapy selection in clinical practice.
An AI-powered, human-in-the-loop, real-time registry platform to enable clinical trials, pragmatic studies, and prospective external control arms (ProECA) at scale in US community practices.
11058 Background: Drug development is requiring novel approaches such as prospective external controls to reduce development timelines and de-risk phase transitions. The majority of oncology patients in the US are seen at community oncology centers, many of which have limited clinical research infrastructure. The Kaleido registry was initiated to address these challenges through a hybrid operational technology model combining on-site staff, clinical note preparation, pre-visit abstraction, and automated workflows to facilitate pre-screening, data capture and research operations. Methods: The Kaleido registry enrolls patients at US community oncology practices with variable research infrastructure and is actively enabling seven studies. Real-time abstraction is performed prior to each patient visit across an expanding set of indications, including non-small cell lung cancer (NSCLC), colorectal cancer (CRC), prostate cancer, and myeloproliferative neoplasms, enabling standardized data collection and systematic/unbiased trial prescreening. An automated prescreening tool was developed and validated against manual chart review. Standardized draft notes are generated to reduce clinical documentation burden. A patient questionnaire captures social determinants of health (SDOH) and self-reported performance status. Results: As of 1/1 2026 more than 16,000 patients (60% female, median age 70 years, range 19-105) from 28 sites have been consented. Most common diagnoses are breast (29%), colorectal (9%), prostate (6%) and lung cancer (6%). 99% of approached patients filled out the patient questionnaire and missingness of race/ethnicity/education/marital status was <4%. Comprehensive biomarker testing exceeded 85% for patients with metastatic NSCLC. Time from specimen collection to NGS results (median 18 days, range 5-45) or PD-L1 (median 21 days, range 4-45) was a key driver of delays in evaluating trial-eligibility. Patients were consistently identified prior to starting next line of therapy. The model identified additional trial-eligible patients beyond standard workflows even at high-performing sites. In 2025, more than 500 patients were included in trials, ProECAs and pragmatic studies with enhanced data depth within the registry. Conclusions: The Kaleido registry demonstrates a scalable, integrated infrastructure for real time patient identification and comprehensive prospective data collection in the community setting. By facilitating community trial enrollment, pragmatic studies and prospective external controls while reducing operational burden of clinical teams, Kaleido has the potential to significantly accelerate drug development.
Beyond uveal melanoma: Genomic landscape and immunogenic profiles of <i>GNAQ</i> and <i>GNA11</i> mutations in metastatic solid tumors.
e15115 Background: Activating mutations in GNAQ and GNA11 are well-established oncogenic drivers in uveal melanoma (UM), typically occurring at the Q209 and R183 hotspots . However, their prevalence and genomic context across other metastatic solid tumors remain inadequately characterized . As targeted Gαq-pathway inhibitors enter clinical development, understanding the real-world distribution and immunogenic background of these mutations is essential for therapeutic stratification . Methods: We conducted a pan-cancer analysis of 5,416 patients with metastatic solid tumors who underwent comprehensive genomic profiling (TSO 500 or OCA Plus) at Samsung Medical Center between 2019 and 2025 . We analyzed mutational distribution, tumor mutational burden (TMB), microsatellite instability (MSI), and co-alterations to characterize the genomic landscape of GNAQ/11 -mutated tumors . Results: Mutations in GNAQ (N = 10) or GNA11 (N = 16) were identified in 26 patients (0.48%) . Outside of UM, these mutations were most frequent in colorectal cancer (38.5%), non-uveal melanoma (15.4%), gastric cancer (11.5%), and neuroendocrine tumors (7.7%) . A significant genomic dichotomy was observed between tumor types : Canonical hotspots (Q209, R183) were primarily associated with TMB-low and microsatellite stable (MSS) tumors, such as UM, where they act as primary drivers . Non-hotspot mutations (e.g., p.Gln88His, p.Ala231Val) were strongly linked to an immunogenic profile, with 42.3% of the total cohort being TMB-high (≥10 Mut/Mb) and 19.2% being MSI-high In colorectal cancer, 66.7% of GNA11 -mutated cases were MSI-high, suggesting these mutations likely represent bystander events arising from global genomic instability rather than isolated drivers . Frequent co-alterations included NOTCH3 (80%), FAT1 (70%), and TP53 (37.5–40%) . Conclusions: Our real-world analysis reveals that GNAQ/11 mutations are recurrent across various solid tumors beyond UM . The strong correlation between non-hotspot mutations and high TMB/MSI status indicates a distinct immunogenic subgroup . These findings underscore the importance of differentiating canonical hotspot drivers from bystander mutations to guide the selection between targeted Gαq-pathway inhibitors and immune checkpoint blockade in precision oncology .
Harnessing OMOP-CDM for multisite collaborations to measure cardiovascular risk factors and cardiovascular disease in the early survivorship period for children, adolescents, and young adults.
10009 Background: The Observational Medical Outcomes Partnership Common Data Model (OMOP-CDM) is an international effort to leverage data standards to cultivate multi-institutional collaborations and generate reproducible evidence using real-world data. Four institutions mapped their electronic health records data to the OMOP-CDM. Cardiovascular risk factors (CVRFs) and their impact on risk for cardiovascular disease (CVD) among survivors of childhood cancer merit further investigation into cardiotoxicity during the early survivorship period. Methods: Eligible patients from Seattle Children’s with at least one condition contained within the ancestor concept “malignant neoplastic disease” (concept ID 443392) and an index date defined as the initial administration of a medication contained within the ancestor concept “antineoplastic agents” (concept ID 21601387) were included. Clinically computable phenotypes from OMOP-CDM data were constructed in alignment with the Common Terminology Criteria for Adverse Events (version 6.0) for hypertension, diabetes, obesity, and hyperlipidemia within one year of the index date. The primary outcome was CVD, defined as the incidence of cardiomyopathy, heart failure, atrial fibrillation, and ventricular arrhythmias within 1-5 years of the index data. Results: Among 1195 survivors, the incidence rate of any CVD from non-cardiotoxic therapy was 0.11 per 100-person-years (95% Confidence Interval 0.04-0.25), compared to 0.43 (95% CI 0.25-0.71) and 1.6 (95% CI 0.08-7.88) for survivors treated with cardiotoxic therapy and cardiotoxic therapy plus targeted or immunotherapy, respectively. Validation of results and sharing of coding for multi-site meta-analysis is ongoing. Conclusions: OMOP-CDM represents a feasible approach to explore CVRFs and CVD in the early survivorship period among contemporary cohorts treated with traditional cardiotoxic chemotherapy, targeted therapy, and immunotherapy. CVD and CVRF among survivors. Non-cardiotoxic ChemotherapyN=677 Cardiotoxic chemotherapyN=493 Cardiotoxic and Targeted ImmunotherapyN=25 Age (in years) 6.6 (5.1) 8.6 (5.3) 9.4 (4.9) Cancer Type CNS 240 (35.5%) 0 (0.0%) 0 (0.0%) Hematologic 267 (39.4%) 285 (57.8%) 23 (92.0%) Solid Tumor 160 (23.6%) 208 (42.2%) 2 (8.0%) Sex (Female) 310 (45.8%) 243 (49.3%) 10 (40.0%) Race Asian 54 (8.0%) 36 (7.3%) 2 (8.0%) Black/African American 22 (3.2%) 13 (2.6%) 0 (0.0%) Hispanic 131 (19.4%) 101 (20.5%) 4 (16.0%) White 351 (51.8%) 259 (52.5%) 14 (56.0%) Other or Unknown 119 (17.6%) 84 (17.0%) 5 (20.0%) CVRFs (<1 year) Hypertension 111 (16.4%) 103 (20.9%) 5 (20.0%) Diabetes 100 (14.8%) 78 (15.8%) 8 (32.0%) Hyperlipidemia 87 (12.9%) 61 (12.4%) 8 (32.0%) Obesity 214 (31.6%) 143 (29.0%) 4 (16.0%) CVD (1-5 years) Any 2 (0.3%) 12 (2.4%) 1 (4.0%)
Definitive bladder/pelvic radiation after enfortumab vedotin–pembrolizumab for advanced urothelial carcinoma.
e16589 Background: Treatment with enfortumab vedotin and pembrolizumab (EV-P) is highly effective in patients (pts) with advanced urothelial carcinoma. The optimal local therapy for residual or oligoprogressive disease in the bladder after EV-P remains to be defined. Radiation (RT) to the bladder is highly effective in appropriately selected pts with muscle-invasive bladder cancer. Here, we report outcomes for pts receiving definitive bladder or pelvic RT after EV-P. Methods: A retrospective institutional database of pts treated with EV-P (n = 256) was reviewed to identify pts who received bladder or pelvic RT. RT-intent (consolidative, oligoprogressive, palliative) was coded. Investigator-assessed local control (LC), defined by recurrence at a RT-treated site, progression free survival (PFS), and overall survival (OS) were estimated from RT start. Treatment-related toxicity was retrospectively graded using CTCAE both acutely (within 3m of RT) and at 6-month intervals. Results: 36 pts received EV-P and RT to the bladder/pelvis. 24 were treated with definitive intent (for oligoprogression on/after EV-P or to consolidate non-growing residual disease). 7 were excluded from further analysis for RT given before EV-P, after intervening therapy, or > 1 year after EV-P. For the remaining 17 pts, 10 were treated for oligoprogression and 7 to consolidate residual disease. At diagnosis, 5 had M1b disease, 7 were M1a, 4 were N+M0, and 1 had N0M0 MIBC. Median follow-up was 11.7m. The median total duration of EV-P treatment was 4.1 months. All pts held EV during RT. RT was delivered to the bladder (n = 12, 4 with nodal coverage) or pelvic LNs alone (n = 5 patients); 7/17 received concurrent chemotherapy (all gemcitabine). After RT, 7/17 continued EV and/or P. LC at 12 and 24 months was 75%. 4/17 (24%) had local failure in the RT field at any time. After RT, median LC, PFS, and OS were 32.1 (95% CI NR-NR), 8.1 (95%CI 3.9-NR) and not reached (NR) (95%CI 11.9-NR) months. Median LC, PFS, and OS were not met for the consolidation patients and were 32.1, 3.9 and 11.9 months for oligoprogression pts. There were no Grade 3+ GU and 1 grade 3+ GI toxicities (a colo-vesical fistula in the context of disease progression with colonic invasion). Conclusions: Definitive bladder-pelvic RT after EV-P was well-tolerated with promising disease control, particularly in those patients receiving RT for residual non-progressing disease. Clinical outcomes and follow-up summary. Cohort Local Control Progression-Free Overall Survival All Patients 32.1 [NR to NR] 8.1 [3.9 to NR] NR [11.9 to NR] Consolidative NR [NR to NR] NR [NR to NR] NR [NR to NR] Oligoprogression 32.1 [NR to NR] 3.9 [2.2 to NR] 11.9 [8.4 to NR] NR: Not Reached; Values are Median [95% Confidence Interval] in months.
Neoadjuvant cadonilimab plus chemotherapy for locally advanced gastric/gastroesophageal junction cancer: A single-arm, phase II trial.
4100 Background: Cadonilimab plus chemotherapy is a promising treatment option in the first-line setting of gastric cancer; however, its activity in the neoadjuvant setting remains unclear. The study evaluated the efficacy and safety of cadonilimab plus chemotherapy in neoadjuvant treatment for locally advanced gastric or gastroesophageal junction (G/GEJ) cancer. Methods: Eligible patients with locally advanced G/GEJ cancer (cT3-4a N+ M0) were enrolled and treated with 3 cycles of SOX chemotherapy (oxaliplatin 130mg/m 2 , IV, d1; S-1 40-60 mg, PO, bid, d1-d14; q21d) plus cadonilimab (10mg/Kg IV, d1, q21d), followed by radical gastrectomy with D2 lymphadenectomy. The primary endpoint was pathological complete response (pCR) rate, and the secondary endpoints included R0 resection rate, major pathological response (MPR) rate, 2-year disease-free survival (DFS) rate, 2-year overall survival (OS) rate and safety. Moreover, a single-cell spatial proteomic atlas was constructed to identify the mechanisms of immune resistance in patients with G/GEJ cancer who received neoadjuvant cadonilimab combined with SOX chemotherapy. Results: From September 2023 to July 2024, 45 patients were screened, and 37 patients were enrolled in this study. The median age was 58 years (range 27–72). 26 (70.3%) patients had cT4a disease, and 32 (86.5%) patients had a primary tumor in the stomach. All patients underwent preoperative evaluation. Two (5.4%) patients refused surgery, and 35 (94.6%) patients underwent gastrectomy with D2 lymphadenectomy. pCR (TRG1a) was observed in nine patients (ITT set: 24.3% (95% CI: 11.8% to 41.2%); surgery set: 25.7% (95% CI: 12.5% to 43.3%)). The MPR (TRG1a/b) rate was 70.3% (95% CI: 53.0% to 84.1%). As of the cutoff date of January 1, 2026, the median follow-up time was 24.1 months (range 14.3-28.4). One patient who refused surgery died, and three patients in the surgery set relapsed. 2-year DFS and OS rates were 90.2% and 97.3, respectively. Most of the TRAEs were grade 1-2. Nine (24.3%) patients experienced grade 3-4 TRAEs. The most common grade 3-4 TRAEs were thrombocytopenia (n = 4, 10.8%) and rash (n = 2, 5.4%). Single-cell spatial atlas demonstrates that recurrence following cadonilimab combined with SOX chemotherapy in gastric cancer is associated with distinct spatial immune ecosystems, which is characterized by immune deserts or suppressive fibrotic–myeloid networks that spatially and functionally incapacitate CD8 T cells. Conclusions: Based on the encouraging pCR rate, survival outcome and manageable safety in this study, cadonilimab plus SOX chemotherapy is a promising neoadjuvant treatment option for patients with locally advanced gastric cancer. Moreover, targeting stromal and myeloid components may be necessary to unlock the full therapeutic potential of immune checkpoint blockade. Clinical trial information: NCT05948449 .
Early chemo-induced TME alterations as a predictor of response to PD-1 blockade in AVPC: Single-cell data from C3NIRA.
5065 Background: Aggressive variant prostate cancer (AVPC) criteria enrich for androgen-indifferent disease that is highly aggressive and has limited therapeutic options. Single-agent immune checkpoint inhibitors have not demonstrated activity in prostate cancer patients. The C-COLA study (NCT03263650) showed that Cabazitaxel/Carboplatin (CabCarb) elicited inflammatory signaling in responsive patients with AVPC. Based on these findings, we hypothesized that chemotherapy-induced inflammation in the tumor microenvironment (TME) may prime tumors for immunotherapeutic approaches. Methods: The C3NIRA trial (NCT04592237) employed one cycle of CabCarb, followed by the addition of the PD-1 blocker Cetrelimab, from cycle 2 for up to 6 cycles of induction treatment in patients with AVPC. Among 120 enrolled men, 20 discontinued due to toxicities and 40 due to progression during induction. Sixty patients completed induction and were subsequently randomized to Niraparib maintenance with or without Cetrelimab. The 30 randomized to Niraparib with Cetrelimab had significantly longer progression free (PFS) and overall survivals than the 30 randomized to Niraparib alone. To investigate whether treatment-induced alterations in the TME could predict immunotherapy response, biopsies were obtained at baseline, and after cycles 1, 3 and 9 for single-cell RNA sequencing (scRNAseq). Results: scRNAseq analysis of tumor biopsies showed a high proportion of GZMK⁺ CD8⁺ T cells and CD8⁺ T effector memory clusters, and a low proportion in FOXP3 + CD4 + T regulatory cells, in the TME of responders (PFS≥10months) after cycle 1 of CabCarb, which was not seen in progressors. Similarly, SPP1⁺ macrophages scoring high immunosuppressive signatures were reduced in responders after CabCarb but not in progressors. Consistent with these suppressive and effector cell changes, LAG3 + TIGIT + CD8⁺ T exhausted cells gradually accumulated in progressors from baseline through CabCarb and Cetrelimab treatment, while remaining unchanged in responders over the same interval. Conclusions: One cycle of CabCarb induction altered the TME in a subset of AVPC tumors, with reduction of suppressive myeloid and T cell populations and expansion of anti-tumor effector cells associated with clinical responses. These early TME changes may predict benefit from the addition of PD-1 blockade and help refine patient selection for immune checkpoint inhibition. Ongoing analyses are identifying additional therapeutic vulnerabilities in the TME that can be targeted to further improve outcomes in men with AVPC. Clinical trial information: NCT04592237 .
EP4 Antagonist ONO-4578 Plus Nivolumab and Chemotherapy in HER2-Negative Unresectable Advanced or Recurrent Gastric or Gastroesophageal Junction Cancer
Purpose EP4, a key receptor in the PGE 2 axis, mediates tumor immunosuppression; the EP4 antagonist ONO-4578 plus nivolumab showed manageable safety, immune activation, and preliminary antitumor activity in previously treated gastric/gastroesophageal junction cancer (G/GEJC). This study explored whether ONO-4578 enhances the efficacy of nivolumab plus chemotherapy in unresectable advanced or recurrent G/GEJC. Patients and Methods This multicenter, double-blind, randomized phase 2 study enrolled chemotherapy-naïve patients with HER2-negative unresectable advanced or recurrent G/GEJC. Patients were randomized (2:1) to receive oral ONO-4578 or matching placebo, each in combination with nivolumab and oxaliplatin-based chemotherapy. The primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), and safety. Results At the data cutoff, 226 patients were randomized to the ONO-4578 group (n = 150) and the placebo group (n = 76). Adding ONO-4578 significantly improved PFS (hazard ratio of 0.67; 90% confidence interval, 0.48–0.92; p-value, 0.040 [prespecified two-sided α = 0.10]), with favorable OS at a prespecified analysis with limited follow-up (hazard ratio of 0.60; 95% confidence interval, 0.37–0.96) and ORR (62.0% vs 48.7%). Exploratory subgroup analyses suggested that ONO-4578 regimen provided greater benefit in PD-L1 CPS ≥1, whereas no clear benefit in CPS <1/indeterminate patients. In an extended follow-up exploratory OS analysis with a minimum follow-up of 16.1 months, OS numerically favored ONO-4578 regimen. Common treatment-emergent adverse events in the ONO-4578 group were diarrhoea (55.7% vs 45.3%), and anaemia (55.0% vs 34.7%). Conclusion This study demonstrated promising efficacy and acceptable safety of an ONO-4578 regimen as first-line treatment for HER2-negative unresectable advanced or recurrent G/GEJC. These findings warrant confirmation in a phase 3 trial.