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TREGCHECK 102: A study of tagmokitug (CHS-114) in combination with toripalimab and/or other treatments in participants with advanced solid tumors.
TPS2689 Background: Advanced solid tumors frequently exhibit resistance to standard therapies, including immune checkpoint inhibition. Intratumoral Tregs have been associated with immune suppression, tumor progression and anticancer resistance. Intratumoral Tregs preferentially express CCR8 and are abundant in many solid tumors (Plitas 2020; Plitas 2016; Kidani 2022). Tagmokitug is a novel, selective cytolytic anti-CCR8 mAb designed to deplete CCR8+ Tregs and remodel the tumor microenvironment to promote antitumor immunity. Preclinical and phase 1 clinical studies show tagmokitug can significantly deplete CCR8+ intratumoral Tregs, increase immune activation and has antitumor activity in combination with a PD-1 inhibitor (Wang 2026; Worden 2025; Kapoor 2025). These findings warrant evaluation of tagmokitug in combination with toripalimab, a PD-1 inhibitor, and/or other anticancer therapies across multiple tumor types. Methods: This multicenter, open-label, phase 1b/2a study evaluates tagmokitug in combination with toripalimab and/or other therapies in adults with advanced solid tumors in 4 cohorts: gastric, gastroesophageal junction (GEJ), and esophageal adenocarcinoma; second-line esophageal squamous cell carcinoma (ESCC); first-line ESCC; and advanced MSS/pMMR colorectal cancer. Eligible participants have histologically or cytologically confirmed advanced or metastatic solid tumors not amenable to curative therapy, measurable disease per RECIST v1.1, ECOG 0–1, and adequate organ function. Key exclusions include active autoimmune disease requiring systemic therapy, uncontrolled cardiovascular conditions, or other factors interfering with study participation. Tagmokitug is administered IV Q3W at pharmacologically active doses following toripalimab 240 mg IV and/or other anticancer therapies where indicated per protocol. Imaging assessments are performed every 6 weeks through week 24, every 9 weeks through week 51 and every 12 weeks through week 99. Patients continue treatment until disease progression, unacceptable toxicity, or withdrawal of consent. The primary objective is to evaluate the safety and tolerability of tagmokitug in combination with toripalimab and/or other anti-cancer therapies as measured by adverse events and laboratory abnormalities. Secondary endpoints include ORR, DOR, DCR, and PFS per RECIST v1.1, and assessment of PK and ADA. Exploratory endpoints include OS and biomarker analyses including evaluation of CCR8+ Tregs in tumors. Enrollment is ongoing. Approximately 150 participants are planned across all cohorts. Additional cohorts may be added based on emerging data. Clinical trial information: NCT06657144 .
Immune microenvironment signatures as prognostic biomarkers in gastroenteropancreatic neuroendocrine carcinoma (GEP-NEC).
4180 Background: GEP-NEC is an aggressive malignancy with rising incidence and limited therapeutic options. While immune checkpoint inhibitors (ICIs) have become standard of care in small cell lung cancer (SCLC), their role in GEP-NEC remains undefined. Characterizing immune cell signatures in the tumor microenvironment (TME) across different NEC histologies may help identify prognostic biomarkers and guide immunotherapy strategies. Methods: We included 4863 NEC tumors that underwent DNA (592-gene panel, whole exome) and RNA (whole transcriptome) sequencing at Caris Life Sciences. Composition of the TME was estimated from bulk RNA sequencing using QuanTIseq method. Overall survival (OS) and IO-associated OS (IO-OS) were derived from insurance claims and calculated from date of tumor biopsy (OS) or IO initiation (IO-OS) to last contact using Kaplan-Meier estimates and Cox proportional hazards models. Statistical significance was determined by Fishers Exact, Chi-square and Mann-Whitney U test with adjustments for multiple comparisons ( P < 0.05). Results: The cohort was comprised of small cell (SCNEC, n = 2320), large cell (LCNEC, 618), high-grade NEC (HGNEC, 414) and NEC not otherwise specified (NOS, 1511). Primary sites included lung (2642), pancreas (459), non-pancreatic GI (931) and other sites (831). SCNEC had lower Treg, M1 or M2 macrophage and neutrophils, and higher CD4+ T-, NK-, B- and dendritic-cell infiltration than other histologies, suggesting more lymphocyte-driven immune milieu with reduced myeloid-driven suppression. Compared with lung NEC, GEP-NEC demonstrated a more immunosuppressive TME, characterized by lower NK-, B- and dendritic-cell infiltration and higher Treg, M1/M2 macrophage and neutrophils—most pronounced in non-pancreatic GI primaries. Pancreatic NEC had reduced dendritic cells in LCNEC, HGNEC and NOS subtypes and higher neutrophils in HGNEC and NOS. Elevated B-cell infiltration was associated with improved OS in SCNEC of non-pancreatic GI (HR 0.56, 95%CI 0.37-0.85, P = 0.032) and lung (HR 0.81, 0.72-0.90, P = 0.001) origin. High M2 macrophage and NK-cell scores were associated with prolonged OS in NOS of non-pancreatic GI (M2: HR 0.35, 0.28-0.45, P < 0.001; NK: HR 0.32, 0.26-0.41, P < 0.001) and pancreas (M2: HR 0.46, 0.33-0.62, P < 0.001; NK: HR 0.64, 0.48-0.84, P = 0.010) origin. Among patients receiving ICIs (n = 1811, 910 with SCLC), only higher B-cell infiltration was associated with improved IO-OS in SCLC (HR 0.79, 0.68-0.92, P = 0.029); data was insufficient to analyze IO-OS for other histologic and anatomic subgroups. Conclusions: GEP-NEC exhibits a distinct and relatively immunosuppressive TME compared with lung NEC. B-cell, NK-cell, and macrophage signatures are prognostic across GEP-NEC subtypes. These findings support further evaluation of immune-based stratification and biomarker-driven therapeutic development in GEP-NEC.
High-dose furmonertinib in <i>EGFR</i> -mutant NSCLC with brain metastases after EGFR-TKI resistance.
e14028 Background: Patients with EGFR-mutant non–small cell lung cancer (NSCLC) who develop central nervous system (CNS) metastases after progression on prior EGFR tyrosine kinase inhibitors (EGFR-TKIs) represent a therapeutically challenging population. High-dose furmonertinib has been explored as a strategy to enhance CNS penetration and overcome resistance; however, its pooled efficacy and safety outcomes have not been systematically quantified. Methods: A single-arm meta-analysis was performed using random-effects models to pool proportions for extracranial and intracranial tumor responses and adverse events. Efficacy endpoints included objective response rate (ORR), disease control rate (DCR), complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD), assessed according to RECIST criteria. Safety outcomes included any-grade and grade ≥3 treatment-related adverse events (AEs). Results: A total of five studies with 285 patients were included. Extracranial efficacy was evaluable in 164 patients. The pooled extracranial ORR was 62% (95% CI, 41–79%), with a DCR of 84% (95% CI, 68–93%). CRs were uncommon (4%, 95% CI 1–10%), while PR and SD occurred in 29% (95% CI 13–54%) and 32% (95% CI 25–39%) of patients, respectively. Extracranial PD was observed in 16% (95% CI 7–32%). Intracranial responses were assessable in 90 patients. The pooled intracranial ORR was 53% (95% CI, 43–63%), and the intracranial DCR was 79% (95% CI, 51–93%). Intracranial CR was rare (1%, 95% CI 0–6%), whereas PR and SD were observed in 28% (95% CI 20–38%) and 19% (95% CI 12–28%), respectively. Intracranial PD occurred in 10% (95% CI 5–18%). High-dose furmonertinib demonstrated a manageable safety profile (Table 1). Elevated AST/ALT and rash were most common adverse events. Conclusions: The concordance between extracranial and intracranial disease control suggests that dose intensification may partially overcome pharmacokinetic limitations and resistance mechanisms that contribute to CNS progression after earlier-generation TKIs. Notably, the low rates of primary intracranial progression and infrequent grade ≥3 toxicities indicate that improved CNS exposure is achieved without a proportional increase in severe adverse events. These findings support the biological and clinical rationale for high-dose furmonertinib as a CNS-active salvage strategy in the post–EGFR-TKI resistance setting, particularly for patients with active or progressive brain metastases who have limited therapeutic options. Adverse event profiles across pooled studies. Adverse event Grade Pooled incidence % (95% CI) Elevated AST/ALT Any 10% (95% CI 4-22%) ≥3 3% (95% CI 1-8%) Elevated serum creatinine Any grade 7% (95% CI 2-22%) ≥3 1% (95% CI 0-6%) Oral mucositis Any grade 5% (95%CI 2-11%) ≥3 2% (95% CI 0-9%) Rash Any grade 16% (95% CI 1-77%) ≥3 3% (95% CI 0-27%)
Genomic landscape and precision therapeutics in polycythemia vera: Insights from the AACR Project GENIE.
6595 Background: Polycythemia vera (PV) is a myeloproliferative neoplasm associated with blood thickening and increased risk of life-threatening blood clots and bleeding. PV is rare and affects roughly 50 per 100,000 people in the US. PV is most commonly associated with a somatic mutation in the JAK2 gene and the mean age of diagnosis is 60. The JAK2 gene is critical for cell signaling, and cell maturation. Treatments for PV include immunotherapy, radiation and chemotherapy but this can only slow growth, underscoring the need to define molecular drivers for targeted therapies. Using the AACR GENIE database, this study characterizes the mutational landscape of PV to identify genetic markers and therapeutic targets. Methods: The American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) database was accessed from cBioPortal (v18.1-public) on November 20, 2025 to identify all patients with PV. The most common gene mutations, demographic correlations, and mutual exclusivities were analyzed using a two-sided T-test and non-parametric tests, with Benjamini-Hochberg false discovery rate (FDR) correction. Results: The cohort comprised 491 PV samples from 341 patients. The patient population consisted of adults(19-88 years old, n=341,100%). Males (n=171, 50.1%) were represented as equally as females (n=163, 47.8%), with some unknown cases (n=7, 2.1%). By race, the cohort consisted primarily of White (n=236, 69.2%), Black (n=13, 3.8%), and Asian (n=17, 5.0) patients, with the remaining patients (n=75, 22.0%) categorized as having an unspecified or other race. Of the samples derived from 90 tumors which were classified as primary (n=80, 16.3%) or metastatic (n=10, 2.0%), the most frequent somatic mutations were observed in JAK2 (87.17%, n=428), TERT2 (18.53%, n=91), DNMT3A (14.87%, n=73), ASXL1 (5.50%, n=27), and TP53 (3.05%, n=15). When stratified by sex, sex-associated mutational variability was observed. Specifically, mutations in NF1 (n=13, p < 0.001) were detected only in females. DNMT3A mutations occurred at a higher frequency in females compared to males (n=48 v. n=23; p < 0.001). AXSL1 mutations occur at a higher frequency in males compared to females (n=23 v. n=4; p < 0.001 ). Conclusions: To the best of our knowledge, this is the first GENIE database analysis of polycythemia vera, thus addressing a significant research gap regarding its genomic landscape. The predominance of JAK2 and TERT2 align with earlier descriptions in prior genetic profiling studies. Sex specific mutations underscore the importance of demographic-specific molecular features. Collectively, these findings suggest that JAK2 and TERT2 could serve as key genomic targets for the development of novel precision therapeutics. Further research is needed to validate these genomic associations and advance precision medicine approaches for patients with PV.
Age-stratified late outcomes following bispecific antibody therapy in multiple myeloma: A real-world 6-month landmark analysis.
7535 Background: Multiple myeloma (MM) predominantly affects older adults, with a median age at diagnosis of 69 years. Underrepresentation of older adults in clinical trials of Bispecific antibodies (BsAbs) and limited statistical power preclude definitive conclusions about treatment outcomes in this demographic. Some real-world studies report comparable outcomes for BsAbs in older and frail patients, but these are small and heterogeneous. Consequently, limited data exist on the safety and efficacy of BsAbs in older MM patients, especially late outcomes. To address this gap, we conducted a retrospective study comparing the post-6-month outcomes of BsAbs in older adults (≥65 years) with those in younger patients. Methods: We conducted a retrospective cohort study using the TriNetX Global Collaborative Network. We identified MM patients (ICD-10-CM: C90) aged ≥18 years who received any BsAbs (teclistamab, elranatamab, talquetamab, blinatumomab, epcoritamab, mosunetuzumab), stratified by age into two cohorts: (1) age ≥ 65 years (N =1913), and (2) age between 18 and 64 years (N =948). The index event was date of initial administration of BsAbs. Outcomes were analysed within a time window starting 180 days after index event, and patients with outcomes outside the window were excluded. Compared outcomes using Kaplan-Meier survival analysis. Calculated hazard ratios (HRs) and log-rank p-values. Results: After propensity score matching (1:1), each cohort had 736 patients. Median age was 75 years (maximum age 90 years) in cohort 1 vs 57 years in cohort 2. Female (41.7% vs 43.2%), White (60.6% vs 58.6%), African American (22.6% vs 23.4%). All comorbidities and prior therapies, including stem cell transplant (35.2% vs 35.1%), ide-cel CAR-T (6.3% vs 6.7%), and cilta-cel CAR-T (1.4% vs 1.4%), were balanced between groups. Median follow-up was 305.5 days in cohort 1 and 316 days in cohort 2. All-cause mortality did not differ significantly between groups (HR = 1.212, p = 0.229). ER visits (HR = 1.345), neutropenia (HR = 1.311), thrombocytopenia (HR = 1.559), sepsis (HR = 1.398), pneumonia (HR = 1.122), and opportunistic infections (HR = 1.119) were slightly higher, in contrast, anemia (HR = 0.841), blood transfusion (HR = 0.812), and hypogammaglobulinemia (HR = 0.927) were lower in the older cohort but none were statistically significant ( p > 0.05). Conclusions: In this large, real-world study, outcomes of BsAbs among patients aged ≥ 65 years were comparable to those of younger patients, without a significant increase in mortality or toxicities. Our findings, although retrospective, suggest that BsAbs can be safely administered in select patients aged ≥65 years, and advanced age should not, in itself, preclude treatment. Careful assessment and optimization of comorbidities and performance status could ensure that these patients benefit from effective treatments with minimal toxicity.
Clinical and molecular predictors of postoperative seizure outcomes in adult low-grade glioma.
e14084 Background: Seizures are a common presenting symptom in patients with low-grade glioma (LGG) and significantly impact quality of life. While surgical resection improves seizure control, the clinical and molecular factors predicting postoperative seizure outcomes remain incompletely defined. We performed a systematic review to evaluate predictors of postoperative seizure control in adult patients with LGG. Methods: A systematic review (PROSPERO: CRD420261295317) was conducted; PubMed, Embase, Scopus, and Cochrane Library were searched for studies evaluating clinical and molecular predictors of postoperative seizure outcomes in adults (≥18 years) with WHO grade II low-grade glioma undergoing surgical resection. Eligible studies reported seizure outcomes using standardized classifications (Engel or ILAE). Extracted data included demographic characteristics, seizure history, extent of resection (EOR), tumor location, molecular markers, follow-up duration, and effect estimates. Risk of bias was assessed qualitatively. Due to heterogeneity in study design and outcome reporting, quantitative synthesis was descriptive without meta-analysis. Results: Twenty-six retrospective studies comprising over 3,000 patients were included, with median or mean follow-up ranging from 3 months to 6 years. Postoperative seizure freedom (Engel class I or ILAE class I) was achieved in 65–83% of patients. Gross or near-total resection was the most consistent predictor of seizure freedom, with odds ratios (OR) ranging from 3.2 to 16.0 compared with subtotal resection (p < 0.05 across most multivariable models). Increasing EOR as a continuous variable independently predicted seizure freedom (adjusted OR per percentage increase 1.02–1.03; p ≤ 0.001). Molecular predictors associated with favorable seizure outcomes included 1p/19q codeletion (OR 3.2–4.7; p ≤ 0.004), while IDH mutation was associated with seizure presentation and postoperative seizure persistence in multicenter cohorts (OR 2.7–3.1; p < 0.001). Elevated Ki-67 expression was consistently associated with poorer seizure control (OR 0.07–0.38; p ≤ 0.02). Higher preoperative seizure frequency, longer seizure duration, and secondary generalized seizures were associated with worse postoperative seizure outcomes (OR 2.0–6.6; p ≤ 0.01). Overall risk of bias across studies was moderate. Conclusions: In adult patients with low-grade glioma, extent of resection is the strongest and most consistent predictor of postoperative seizure freedom. Molecular features, particularly 1p/19q codeletion and proliferative indices, provide additional prognostic value. These findings support aggressive yet safe surgical resection and highlight the role of integrated clinical–molecular risk stratification to optimize seizure outcomes in LGG.
<sup>68</sup> Ga-NODAGA-SNA014 whole-body PET imaging to detect Claudin18.2–positive pancreatic cancer lesions.
3065 Background: 68 Ga-labeled nanobody ( 68 Ga-NODAGA-SNA014) is a PET radiotracer based on a single-domain antibody. We conducted a first-in-human (FIH) evaluation of 68 Ga-NODAGA-SNA014 to characterize in vivo biodistribution, metabolism, radiation dosimetry, and safety, and to explore its ability to noninvasively quantify Claudin-18.2 (CLDN18.2) expression in patients with gastrointestinal cancers. Methods: 68 Ga-NODAGA-SNA014 was synthesized and first assessed preclinically in human pancreatic cancer cell lines and xenograft mouse models to evaluate affinity, specificity, and pharmacokinetics. We then performed a translational pilot study in 15 patients with pancreatic cancer imaged on a total-body (panoramic) PET/CT system. Whole-body biodistribution, organ dosimetry, and the association between lesion uptake and CLDN18.2 expression were analyzed and compared with 18 F-FDG, where available. Results: 68 Ga-NODAGA-SNA014 was produced reliably with favorable radiochemical characteristics. In preclinical studies, the tracer exhibited rapid blood clearance, high affinity for CLDN18.2, and specific uptake in CLDN18.2-positive cells and xenografts. In patients, physiologic uptake was highest in the stomach and kidneys, with mild uptake in the pancreas. Lesion uptake varied by CLDN18.2 expression level, and 68 Ga-NODAGA-SNA014 demonstrated more precise differentiation of CLDN18.2-high versus CLDN18.2-low lesions than 18 F-FDG. Conclusions: PET uptake (SUV) of 68 Ga-NODAGA-SNA014 correlated with CLDN18.2 expression, supporting its potential as a noninvasive companion diagnostic to guide and optimize CLDN18.2-targeted therapies.
Identification of high-grade neuroendocrine carcinoma (HGNEC) biology across tumor types through transcriptomic profiling and validation in lung cancer.
3121 Background: HGNECs, including small-cell (SC) and large-cell (LCNEC), are aggressive malignancies frequently misclassified due to subtle morphology and inconsistent use of neuroendocrine (NE) immunohistochemistry in routine pathology workflows. It is unclear if tumors with transcriptomic signatures reflecting HGNEC-like biology have inferior outcomes with conventional treatment. Leveraging a large real-world dataset, this study aims to identify transcriptomically defined HGNEC to improve upon morphology-based classification. Methods: 49,144 specimens underwent DNA and RNA sequencing at Caris Life Sciences. Using a previously reported framework, we developed a weighted, z-scored based HGNEC activity score (HAS) from 10,137 pathologically defined HG- and LG- NEC specimens and applied it to characterize NSCLC samples (without any pathologist assigned HGNEC diagnosis) further stratified by histology (n=39,007). Overall survival (OS) was obtained from insurance claims data and calculated from specimen biopsy to last contact using Kaplan-Meier and Cox proportional hazards estimates. Results: To identify a high-confidence HGNEC-like subpopulation, a HAS threshold (z-score>=3) was applied, classifying 0.2% squamous (sq) and 2.3% non-squamous (nsq) as HGNEC-like; this analysis is focused in nsq. Patient demographics, including age, gender, race, ethnicity, and smoking history, were similar between the HGNEC-like and non-HGNEC-like nsq cohorts. However, biopsies from lymph nodes (26 vs 11%) and brain (9.1 vs 5.6%) were more frequent, and lung (39 vs 56%) less frequent in HGNEC-like tumors (all p-adj<0.05). HGNEC-like tumors were associated with poor OS (HR:1.18, 95% CI:1.07–1.31, p<0.001). HGNEC-like tumors were more frequently PD-L1 negative (64% vs 47%), and were enriched for mutations in TP53 , PTEN and RB1 (OR: 1.7-14.1), as well as amplifications in MYC and CCNE (OR: 2.2-3.5), with lower odds of KRAS and EGFR mutations (OR:0.4-0.5, p-adj<0.05). Consistent with a highly proliferative phenotype, HGNEC-like tumors were enriched for MKI67 expression (1.4-fold) and higher cell-cycle and replication stress scores (1.5-fold) (all p-adj<0.05) . Gene set enrichment analysis revealed significant activation of neurodevelopmental programs (NES: 2.0-3.0, all p-adj<0.05) and negative enrichment of immune pathways (e.g antigen presentation) (NES: -3.0 to -1.5, all p-adj<0.05). Finally, transcriptomic expression of potentially actionable SCLC-directed targets, including DLL3 (10-fold), SEZ6 (3.7-fold), and SSTR2 (10-fold), were all higher in HGNEC-like tumors (all p-adj<0.05). Conclusions: We identify a transcriptomically defined HGNEC-like subset of NSCLC with inferior survival and targetable NEC biology, supporting transcriptomic stratification to inform clinical trial design and selection of SCLC-directed therapies.
Leveraging EMR prompts to promote equitable clinical trial participation in gynecologic oncology: RE-AIM implementation results.
e23294 Background: Lack of diversity and low enrollment limit clinical trial success in gynecologic oncology. Providers represent an underutilized resource for trial recruitment. Methods: At a single urban academic institution, gyn onc clinic note templates for new and return visits were modified to include a clinical trial screening prompt (“This patient was considered for clinical trial:” yes/no). Implementation was guided by the RE-AIM framework. A retrospective pre- and post-implementation review evaluated provider screening and trial enrollment. Patients were identified using clinic location and ICD-10 codes for cervical, uterine, and ovarian cancers; all confirmed diagnoses were included. Collected variables included cancer status, age, sex, race/ethnicity, insurance, and provider type. Descriptive statistics summarized patient characteristics. Associations were assessed using Firth penalized logistic regression. Results: Screening increased significantly post-implementation (OR 3.63, 95% CI 1.92–7.12; p < 0.001). African American patients had higher odds than White patients (OR 3.88, 95% CI 1.28–19.1; p = 0.013), indicating improved equity. Screening was higher among recurrence visits versus at the time of new diagnoses (OR 7.22, 95% CI 3.74–14.0; p < 0.001) and lower among surveillance patients (OR 0.09, 95% CI 0.01–0.37; p < 0.001). Compared with ovarian cancer, cervical cancer had lower odds, while corpus uteri cancer showed no difference. Post-implementation, use of the tool was higher for new diagnoses (OR 1.71, 95% CI 1.08–2.71; p = 0.022) and recurrence (OR 4.53, 95% CI 2.27–9.34; p < 0.001) versus surveillance. Conclusions: EMR-based clinical trial prompts significantly increased screening in Gyn Onc clinics. Higher screening among African American patients suggests this low-cost intervention may reduce inequities. Variability by disease status and cancer type identifies targets for ongoing improvement. EMR-integrated prompts offer a scalable strategy to promote equitable trial access. Characteristic N Event N Event % OR 95% CI p-value Race/Ethnicity White 203 2 1.0% — — African American 706 32 4.5% 3.88 1.28, 19.11 0.013 Other 57 3 5.3% 5.18 0.98, 31.75 0.052 Hispanic 41 2 4.9% 5.10 0.77, 33.94 0.087 Unknown 20 2 10% 10.89 1.60, 74.47 0.018 Asian 16 0 0% 2.44 0.02, 31.70 0.606 Diagnosis Code C56.X: Malignant neoplasm of ovary 284 11 3.9% — — C54.X: Malignant neoplasm of corpus uteri 608 30 4.9% 1.25 0.64, 2.61 0.516 C53.X: Malignant neoplasm of cervix uteri 151 0 0% 0.08 0.00, 0.61 0.009 Cancer Status New diagnosis 526 19 3.6% — — Recurrence 98 21 21% 7.22 3.74, 14.04 <0.001 Surveillance 417 1 0.2% 0.09 0.01, 0.37 <0.001 Type of Insurance Private 430 18 4.2% — — Medicaid 156 5 3.2% 0.81 0.28, 2.01 0.664 Medicare 444 18 4.1% 0.97 0.50, 1.88 0.921 Self-pay 11 0 0% 0.97 0.01, 7.97 0.983 Other 2 0 0% 4.46 0.03, 57.45 0.418
Baseline body mass index (BMI) impact in advanced cholangiocarcinoma (CCA) treated with chemo-immunotherapy (Chemo-IO): Overall, sex-based, and site-specific analyses.
e16189 Background: Predictive and prognostic factors in advanced CCA remain limited. Although obesity is a recognized risk factor, an “obesity paradox” with improved outcomes in overweight patients (pts) has been reported in several solid tumors. In addition, sex-related differences in immune responses and tumor site biology may influence the efficacy of immune checkpoint inhibitors (ICI). We evaluated the impact of baseline BMI on outcomes in advanced CCA, overall, by sex and by tumor site. Methods: BMI (kg/m ² ) at initiation of first line (1L) therapy (tx) was recorded. Survival outcomes (overall survival [OS] and progression-free survival [PFS]) were evaluated according to BMI groups and assessed by Kaplan-Meier estimation. Pts were dichotomized as non-overweight (BMI < 25) versus overweight (BMI>25). Additional analyses were conducted using four BMI categories ( < 18.5, 18.5-24.9, 25-29.9 and >30) and further stratified by sex and tumor site. Results: A total of 72 pts were included: 33 (45.8%) males and 39 (54.2%) females. Median age was 66 years (IQR 58-72); median follow-up was 31.6 months (m) (95% CI 18.8-NR). The most common primary tumor site was intrahepatic CCA (iCCA) (37 pts, 51.3%), followed by perihilar CCA (15 pts, 20.8%), gallbladder (11 pts,15.3%) and distal CCA (9 pts, 12.5%). At diagnosis, 66 pts (91.7%) had metastatic disease and 8 (8.3%) locally advance disease. All pts received 1L platinum-gemcitabine plus ICI tx, with 65 pts (90.3%) had an ECOG PS of 0/1 at baseline. Overall, mPFS was 7.1 m (95% CI 6.1-8.6) and mOS was 11.6 m (95% CI 9.9-21.3). Thirty-one pts were overweight and 41 were non-overweight; obesity (BMI>30) was observed in 6 pts (8.3%). Overweight pts had significantly longer mPFS (8.6 vs 6.4 m; HR 0.58, 95% CI 0.28-0.81; p < 0.01), with no significant difference in mOS (12.5 vs 9.9 m; HR 0.56, 95% CI 0.41-1.30; p = 0.30). In analyses by four BMI categories, obesity was independently associated with improved mPFS (HR 0.20, 95% CI 0.05-0.87; p = 0.03). In sex-based subgroup analysis, improved mPFS in overweight pts was statistically significant in females (8.3 vs 5.7 m; HR 0.47, 95% CI 0.23-0.94; p = 0.03), whereas only a trend was observed in males (11.4 vs 6.6 m; HR 0.41, 95% CI 0.17-1.02; p = 0.05). No significant OS differences by BMI were observed in either sex. Overweight was also significantly associated with improved mPFS in iCCA (8 vs 6.1 m; HR 0.35, 95% CI 0.15-0.78; p < 0.01), with no impact on mOS. No significant associations were observed in extrahepatic CCA and gallbladder. Conclusions: Baseline overweight significantly improved PFS in advanced CCA pts treated with chemo-IO, particularly among obese pts, females and iCCA, without a significant impact on OS. Further studies are needed to determine whether BMI, sex, and tumor site may modulate ICI efficacy and guide treatment optimization in selected CCA pts.
The cost of inequity: Estimating the impact of delayed access to neoadjuvant pertuzumab in Canada.
e23060 Background: Pertuzumab, when used as a neoadjuvant treatment together with chemotherapy and trastuzumab for early-stage HER2-positive breast cancer, has been shown to significantly improve pathological complete response (pCR) rates, which predict for superior disease free survival outcomes at the patient level and avoidance of the need for postoperative chemotherapy (trastuzumab-emtansine), and allow for the use of anthracycline sparing chemotherapy backbones. Progression-free survival and disease-free survival were also improved. Despite these proven benefits and its adoption as a global standard of care, CADTH issued negative funding recommendations in 2015 and 2022. A recent positive recommendation ended a nearly decade-long inequity for Canadians. Methods: An analysis was conducted to estimate the impact of delayed treatment access on Canadian patients. An epidemiologic model was developed using Canadian breast cancer incidence and population growth data. Clinical outcomes were based on the NEOSPHERE trial, with scenario analyses conducted using alternate trials. The model examined a 10-year period (2015-2025), estimating the total number of eligible patients and those anticipated to achieve a pCR with pertuzumab-based regimens. Results: Our analysis estimates 10,154 Canadian breast cancer patients were eligible for neoadjuvant pertuzumab over the past decade. Consequently, an estimated 423-1,941 additional patients could have achieved a pCR and benefitted from access to pertuzumab during this unfunded period. Furthermore, potential long-term health system benefits from minimizing residual disease were not realized. Conclusions: This study highlights the implications of delayed funding on patients and the healthcare system, stressing the importance of ensuring equitable and timely access to innovative cancer treatments.
Real-world outcomes of doxorubicin and paclitaxel in advanced Kaposi sarcoma: A TriNetX retrospective cohort study.
11577 Background: For decades, pegylated liposomal doxorubicin (PLD) and paclitaxel have been standard antineoplastic therapies for advanced Kaposi sarcoma (KS). However, contemporary estimates of their efficacies remain limited. This limit is particularly profound in HIV-associated KS, where advances in antiretroviral therapy and supportive care reduce the relevance of historical outcomes. Methods: In January 2026, the TriNetX database (171 global healthcare organizations) was queried to identify patients with KS (ICD-10-CM code C46 and ICD-O-3 code 9140/3) who received doxorubicin or paclitaxel since 2010. Patients with a history of lymphoma, cervical cancer, anal cancer, or solid organ transplantation were excluded. We extracted demographics, overall survival (OS), and time to next-line treatment or death (TTNT-D) to obtain estimated progression-free survival (ePFS). Outcomes were measured from index treatment initiation (first recorded receipt of doxorubicin or paclitaxel after KS diagnosis). Lastly, HIV-based subgroup analyses were conducted with 1:1 propensity matching by age, sex, race, and prior antineoplastic treatments. Kaplan-Meier analysis was done with significance set at p<0.05. Results: We analyzed 935 KS patients treated with doxorubicin (including PLD) and 379 treated with paclitaxel. The patients treated with doxorubicin (median age: 45 years, 81.0% male, 48.3% HIV+) had 2- and 5-year OS of 77.5% and 70.0% and ePFS of 63.0% and 56.36% respectively. The patients treated with paclitaxel (median age: 50 years, 78.5% male, 42.7% HIV+) had 2- and 5-year OS of 71.3% and 62.4% and ePFS of 53.8% and 45.1% respectively. Within the doxorubicin cohort, HIV+ patients were younger (median age 40 vs 56 years), more often male (95.0% vs 64.7%), and had higher proportions of African American and Hispanic patients (36.4% and 14.7% vs 12.3% and 7.1%). A matched analysis of HIV+ vs. HIV- patients showed 2-year OS of 86.2% vs 71.7% (p=0.003) and 2-year ePFS of 74.85% vs 52.19% (p<0.0001). Within the paclitaxel cohort, HIV+ patients were also younger (median age 40 vs 64 years), more often male (96.5% vs 63.8%), and had higher proportions of African American and Hispanic patients (39.3% and 15.0% vs 9.0% and 5.0%). A matched analysis of HIV+ vs. HIV- patients showed 2-year OS of 60.3% vs 74.1% (p=0.151) and 2-year ePFS of 38.0% vs 57.7% (p=0.023). A matched analysis of doxorubicin vs. paclitaxel in HIV+ patients showed 2-year OS of 86.9% vs 73.0% (p=0.007) and ePFS of 77.7% vs 67.9% (p=0.069). Conclusions: This large real-world analysis provides a contemporary assessment of doxorubicin and paclitaxel in advanced KS. HIV+ status was associated with higher OS and ePFS in the doxorubicin cohort, whereas HIV- status was associated with higher ePFS in the paclitaxel cohort. Limitations include the retrospective design and imperfect reliability of TTNT-D as a surrogate for PFS.
Population pharmacokinetic analysis of raludotatug deruxtecan (R-DXd), a cadherin 6 (CDH6)–directed antibody–drug conjugate (ADC), in patients (pts) with advanced ovarian cancer (OC) or renal cell carcinoma (RCC).
5571 Background: R-DXd is a CDH6–directed ADC under clinical investigation for the treatment of pts with advanced or metastatic solid tumors, including platinum-resistant OC (PROC). This analysis was done to characterize the population pharmacokinetics (PopPK) of R-DXd and its small-molecule payload, DXd, in pts with OC or RCC. The analysis used data from two clinical studies of R-DXd: the first-in-human Ph 1 study in pts with OC or RCC (DS6000-A-U101; U101) and an ongoing global, randomized Ph 2/3 study in pts with PROC (REJOICE-Ovarian01). Methods: A joint PopPK model was developed for R-DXd and DXd, based on pooled data from the dose-escalation and -expansion parts of U101 (156 pts with OC and 23 with RCC; 1.6–9.6 mg/kg IV Q3W) and the dose-optimization primary analysis of REJOICE-Ovarian01 (107 pts with OC; 4.8, 5,6, or 6.4 mg/kg IV Q3W). The analysis was performed using nonlinear mixed-effects modeling in NONMEM (version 7.5.1). The effect of key intrinsic/extrinsic factors on the PK of R-DXd was explored through preliminary covariate analysis. Results: The PK of R-DXd and unconjugated DXd were adequately captured by the PopPK model. R-DXd displayed time-varying clearance, resulting in an elimination half-life of approximately 8 days after the first dose and 14 days at steady state. The overall PK profile supports a Q3W dosing interval. Consistent with findings from other mAbs and DXd-based ADCs, covariate analysis identified body weight (BW) as an influential covariate affecting R-DXd and DXd exposure, with the largest effect seen at the extremes of the BW distribution; pts with high BW (101 kg; 95 th percentile) showed 26% and 66% higher R-DXd and DXd steady state area under the concentration–time curve (AUC), respectively, relative to a reference pt (61 kg; median BW). Post-hoc estimates of R-DXd and DXd AUC by BW quartiles showed that exposure in pts in the highest BW quartile (>75 kg) trended higher yet remained within the range of pts with average BW (53–74 kg; 25 th –75 th percentile). Other baseline covariates did not have a clinically important effect on R-DXd or DXd AUC, with effects falling within the predefined range of 80–125% vs reference. These covariates were CDH6 expression (total % membrane staining at any intensity); R-DXd formulation; hepatic function (mild impairment vs normal); renal function (mild-to-moderate impairment vs normal); tumor size; albumin level; number of prior lines of therapy (1 vs 2–3 vs ≥4); tumor type (RCC vs OC); Asian vs non-Asian race. Conclusions: R-DXd 5.6 mg/kg IV Q3W, the recommended Ph 3 dose, does not appear to warrant adjustment for any of the patient-specific covariates and clinical characteristics investigated. These findings support the adequacy of this dose for the global population of pts with PROC being recruited in the Ph 3 part of REJOICE-Ovarian01.
Donafenib combined with anti–PD-1 antibody as adjuvant therapy for patients with hepatocellular carcinoma at high risk of recurrence after resection.
e16266 Background: A growing incidence of hepatocellular carcinoma and its high risk of recurrence after curative-intent treatment underscore the need for effective adjuvant treatment options. This study aimed to assess the efficacy of adjuvant donafenib with anti-PD-1 in patients with hepatocellular carcinoma (HCC) following radical resection. Methods: This single-center retrospective study enrolled primary HCC patients with high risk recurrence factors who underwent R0 resection at Hunan Provincial People's Hospital from October 2021 to November 2024. High-risk recurrence factors included: microvascular invasion (MVI), tumor diameter ≥5 cm, the number of tumors ≥ 2, satellite lesions and poor tumor differentiation (Edmondson stage III-IV). Patients received adjuvant therapy of donafenib combined with anti-PD-1 after surgery. Patients’ demographic characteristics, etiological characteristics, 1-year recurrence-free survival rate (RFSR), recurrence-free survival (RFS), overall survival (OS), and treatment-related safety were analyzed. Results: A total of 55 patients were enrolled with a median age of 58.9 years, 89.1% were male. Patients were classified as CNLC stage Ia/Ib/IIa/IIb/IIIa 12.7%/29.1%/9.1%/14.5%/34.5%. 50 patients (90.9%) were coinfected with HBV. All patients had an ECOG PS score of 0 and Child-Pugh grade A. Preoperative serum a-fetoprotein levels were ≥400 ng/mL in 30.9%. A total of 26 patients (47.3%) with MVI were pathologically reported after surgery, classified as M1 in 10 and M2 in 16. Additionally, 35 patients (63.6%) had a tumor diameter ≥5cm, 16 patients (29.1%) had had two or more tumors, and 14 patients (25.5%) had satellite lesions. Poorly differentiated tumors (Edmondson grade III-IV) were present in 38 patients (69.1%). 36 patients (65.5%) had more than one risk factor. The median follow up duration was 7.72 months (95% CI: 6.63-9.29), 6 patients experienced recurrence. The 6-month and 1-year recurrence-free survival rate was 91.6%（95% CI：84.0%-99.8%）, and 84.8% (95% CI: 73.8%-97.4%) respectively. The median RFS and OS were not reached. Patients with two or more tumors or satellite lesions exhibited higher rate of tumor recurrence after operation. Among all the patients who received adjuvant therapy, 47(85.5%) patients had at least one treatment-related adverse events (TRAE). TRAEs ≥Grade 3 occurred in 11 (20.0%) patients. Common TRAEs included platelet count decreased (40.0%), lymphocyte count decreased (27.3%), hand-foot syndrome (25.5%), white blood cell count decreased (21.8%). Conclusions: The combination of donafenib and anti-PD-1 antibody as adjuvant therapy demonstrated promising efficacy and was well tolerated in HCC patients with high risks of recurrence.
Genomic characterization of conventional, dedifferentiated, and mesenchymal chondrosarcoma: A 550-patient multicenter analysis.
11528 Background: The rarity of chondrosarcoma has historically impeded efforts and systematic genomic characterization. However, large, standardized, multi-center databases, such as the AACR Project GENIE, along with other, independent studies, have enabled genetic profiling of hundreds of patients with these cancers. Methods: The following datasets were accessed through cBioPortal: the GENIE Cohort v18.0; msk_impact_2017; metastatic_solid_tumors_mich_2017; pog570_bcgsc_2020; msk_ch_2020; msk_ch_ped_2021; sarcoma_msk_2022; sarcoma_mskcc_2022; mixed_kunga_msk_2022; msk_ctdna_vte_2024; and sarcoma_ucla_2024. These datasets included 550 unique patients: 453 conventional chondrosarcoma (CHS), 42 dedifferentiated chondrosarcoma (DDCHS), and 55 mesenchymal chondrosarcoma (MCHS). Mutational and structural variant data were also extracted from each data set and ranked by frequency. This ranked list of genes was then analyzed using g:Profiler enrichment analysis software. Dunn’s test with Benjamini-Hochberg correction following Kruskal-Wallis test was performed for statistical analysis. Results: The average age at biopsy was 52 for CHS, 63 for DDCHS, and 32 for MCHS. DDCHS displayed the greatest genomic instability, with significantly elevated mutation count and tumor mutation burden (TMB) compared to CHS and MCHS ( p < 0.001). Despite the higher TMB in DDCHS, the most frequently mutated genes were highly conserved between CHS and DDCHS, with six of the 20 most frequently mutated genes being shared between them. In contrast, MCHS shared only two of the 20 most frequently mutated genes with CHS and DDCHS. TP53 , IDH1 and -2 , and TERT were frequently mutated in both CHS and DDCHS. Enrichment analysis indicated that DNA repair pathways were among the most frequently altered in both diseases. These pathways, while still perturbed in MCHS, appeared less prominently, with genes involved in chromatin organization being frequently mutated. Moreover, Enrichment analysis of structurally variant genes in CHS also showed frequent alterations in chromatin organizing genes, along with genes involved in NOTCH signaling. While structural variant genes were not reported with enough frequency in DDCHS and MCHS to permit the analysis, the HEY1-NCOA2 fusion product was frequently detected in MCHS. Conclusions: The results of this multi-institutional bioinformatics survey confirms established observations that IDH1 and -2 mutations are the most common genetic alterations in CHS following TP53 . DDCHS bears a similar but more advanced mutational signature with greater genomic instability. MCHS harbors a distinct mutational profile defined by the characteristic HEY1-NCOA2 fusion. Despite these differences, all three subtypes share enrichment in mutations affecting genomic integrity pathways, suggesting this as a common feature of chondrosarcoma biology.
Regorafenib in recurrent glioblastoma: Real-world outcomes from a Colombian cohort (REGOMA-COL).
2078 Background: Therapeutic options for recurrent glioblastoma (GBM) remain limited, with historically poor outcomes following first progression. The phase II REGOMA trial demonstrated an overall survival benefit of regorafenib compared with lomustine, prompting its adoption in selected patients. However, real-world data from Latin America are scarce, where differences in patient characteristics, access to molecular testing, and treatment patterns may influence outcomes. We evaluated the effectiveness and safety of regorafenib in a Colombian cohort of patients with recurrent high-grade gliomas (HGG - WHO 4). Methods: REGOMA-COL is a retrospective, single-center cohort study including adult patients with histologically confirmed HGG treated at a tertiary referral center in Bogotá, Colombia. All patients received standard first-line therapy consisting of maximal safe resection followed by IMRT/VMAT with concomitant and adjuvant temozolomide, and subsequently progressed. Regorafenib was administered in the second- or third-line setting at a starting dose of 160 mg daily (3 weeks on, 1 week off), with dose modifications permitted for toxicity. Survival outcomes were estimated using the Kaplan–Meier method. Adverse events were graded according to CTCAE v5.0. Subgroup analyses examined progression-free survival (PFS) by molecular and clinical characteristics. Results: Twenty-six patients were included. The median age at diagnosis was 49.3 years, and 80.8% had an ECOG performance status of 1. Most tumors were IDH–wild type (84.6%), and MGMT promoter methylation was present in 38.5%. Regorafenib was administered as second-line therapy in 53.8% of patients and as third-line therapy in 57.7%. Median PFS from regorafenib initiation was 4.9 months (95% CI 3.9–5.7), and median OS from regorafenib was 11.3 months (95% CI 9.3–13.2) (Figure 1). Disease control rate (DCR) with regorafenib was achieved in 69.2% of patients. Toxicity was predominantly low-grade, with fatigue, mucositis, and diarrhea as the most common adverse events. Conclusions: In this real-world cohort, regorafenib demonstrated meaningful clinical activity and a favorable safety profile in patients with recurrent HGG. Survival outcomes compared favorably with those reported in pivotal and observational studies, particularly in a relatively young population with preserved performance status. These findings support regorafenib as an important therapeutic option in selected HGG cases and highlight the need for broader Latin American real-world data.
Comparative toxicity profile of chimeric antigen receptor T-cell therapy versus bispecific T-cell engagers in multiple myeloma and B-cell lymphomas: A propensity-matched real-world analysis.
e19524 Background: Chimeric antigen receptor T-cell (CAR-T) therapy and bispecific T-cell engagers (BiTEs) are widely used T-cell–redirecting immunotherapies for multiple myeloma and B-cell lymphomas. However, their comparative real-world toxicity profiles have not been widely studied, particularly given differences in treatment intensity and patient selection. Methods: We conducted a retrospective cohort study using the TriNetX Global Collaborative Network, a federated database of de-identified electronic health records. Adult patients (≥18 years) with multiple myeloma or B-cell lymphoma treated with CAR-T therapy were compared with those treated with BiTE therapy. Propensity score matching (1:1) was performed on age, sex, race/ethnicity, diagnosis, prior stem cell transplantation, baseline cytopenias, and major comorbidities. Toxicity and healthcare utilization outcomes were assessed at 1, 2, and 5-year follow-up. Results: A total of 6,596 patients were identified (CAR-T: n = 480; BiTE: n = 6,116). After propensity score matching, 342 patients were included in each cohort. 342 patients were included in each cohort. In the matched population, mean age was 63.0 years in the CAR-T cohort and 64.5 years in the BiTE cohort, with a similar proportion of male patients (61.7% vs 61.1%). CAR-T therapy was associated with higher risks of neutropenia at 1 year (RR 2.92, 95% CI 2.02–4.22; p < 0.001), 2 years (RR 2.50, 95% CI 1.78–3.49; p < 0.001), and 5 years (RR 2.32, 95% CI 1.68–3.19; p < 0.001). Hospitalization was more frequent following CAR-T therapy at 1 year (RR 2.34, 95% CI 1.65–3.32; p < 0.001), 2 years (RR 2.24, 95% CI 1.59–3.16; p < 0.001), and 5 years (RR 2.16, 95% CI 1.55–3.01; p < 0.001). Thrombocytopenia occurred more commonly with CAR-T at 1 year (RR 1.48, 95% CI 1.02–2.15; p = 0.036) but not at later intervals, while anemia rates were comparable throughout follow-up. Immune-mediated toxicities were more common with CAR-T therapy, including cytokine release syndrome (RR 2.78, 95% CI 2.01–3.84; p < 0.001) and ICANS (RR 1.81, 95% CI 1.09–3.02; p = 0.021), with differences persisting through 5 years. Sepsis rates were similar between cohorts. Conclusions: In this real-world analysis, CAR-T therapy was associated with a higher burden of neutropenia, immune-mediated toxicity, and hospitalization compared with BiTE therapy across all follow-up intervals. Although prior studies report higher response rates with CAR-T therapy, these benefits must be weighed against its greater toxicity burden. These findings highlight meaningful safety differences between T-cell–redirecting therapies and underscore the importance of individualized treatment decisions in immunotherapy selection.
Bridging educational and research gaps among young oncologists in Latin America: Results from a multicenter survey.
9032 Background: Strengthening oncology research capacity in LATAM is critical to improving regional cancer outcomes. Early-career oncologists play a central role in clinical research, yet structural barriers limit their engagement. Data on educational access, research opportunities, and training needs in LATAM remain limited. This study describes research involvement among early-career oncologists and assesses access to training, mentorship, and career development opportunities, and key barriers to education and research participation. Methods: An international, cross-sectional, web-based survey was conducted between Nov/2025 and Jan/2026 among early-career oncologists in LATAM (<40 years or <10 years post-training). Data included demographics and professional development indicators related to research and training. Results: A total of 105 surveys were included and were mainly from Colombia 37.1%, Mexico 23.8%, Argentina 8.6%, and other LATAM countries 30.5%; 58.1% were female. Most were ≤40 years 84.8%, with 43.8% aged 30–35; 19.0% were in training and 55.2% early career. 19% reported no research involvement; 71.4% dedicated <25% of professional time to research, and only 9.5% ≥26%. Most participants (80.0%) received no research-related compensation. Although 51.4% reported access to educational opportunities, only 29.5% perceived adequate access to clinical research. Institutional encouragement was reported by 23.8%, and 39.0% had a clear career development plan. Main training barriers were cost (63.8%), clinical workload (61.9%), and limited institutional support (49.5%). The leading unmet educational need was clinical trials and research methodology (83.8%), followed by precision medicine (64.8%) and leadership/oncology management (57.1%). Overall, 68.6% had prior research exposure—mainly as collaborators (43.8%)—while only 21.9% reported principal investigator experience. Key research barriers included limited clinical time (58.1%), lack of funding (48.6%), and restricted research networks (42.9%). Only 37.1% reported an active mentor; institutional mentorship was available to 22.9%, and formal leadership training to 30.5%. Despite high motivation, structural barriers—including limited protected time, funding, mentorship, and institutional support—restrict research engagement among young oncologists in LATAM. Clinical trials and research methodology as unmet needs underscores a gap between educational access and effective research capacity development. Conclusions: Young oncologists in LATAM face limited opportunities for active research participation. Structural barriers—including workload, funding, restricted networks, and limited mentorship—hinder progression toward independent research and leadership roles, underscoring the need for programs that expand participation pathways beyond education.
Influence of pharmacologic ALDH2 activation on alcohol-driven tumor progression in ALDH2-deficient esophageal squamous cell carcinoma models.
e15171 Background: Esophageal squamous cell carcinoma (ESCC) is highly prevalent in East Asia and strongly linked to alcohol consumption. Aldehyde dehydrogenase 2 (ALDH2) deficiency, common in East Asian populations, leads to acetaldehyde accumulation, a WHO Group I carcinogen, and is a major genetic risk factor for ESCC. However, how ALDH2-deficient tumors biologically adapt to chronic alcohol exposure and whether pharmacologic ALDH2 activation can mitigate tumor progression remain unclear. Methods: We investigated alcohol-associated tumor phenotypes using ESCC cell lines with distinct ALDH2 status: ALDH2-deficient KYSE510 and ALDH2–wild-type KYSE270. Cells were treated with ethanol with or without ALDH2 activators (Alda-1, Alda-64). Cell viability (MTT, CCK-8), clonogenicity, apoptosis signaling, and epithelial–mesenchymal transition (EMT) markers were assessed. In vivo, subcutaneous tumors were established using MOC1 cells in mice stratified by ALDH2 genotype and alcohol exposure, followed by treatment with Alda-1 or Alda-64. Results: ALDH2 activators were non-cytotoxic and enabled evaluation under physiologic alcohol exposure ( < 2% ethanol). In ALDH2-deficient KYSE510 cells, ALDH2 activator treatment increased ALDH2 protein expression, a response not observed in ALDH2–wild-type KYSE270 cells. KYSE510 cells demonstrated enhanced alcohol tolerance, reduced apoptosis-related signaling, and phenotypic adaptation consistent with metabolic reprogramming, whereas KYSE270 cells retained alcohol responsiveness, highlighting intertumoral heterogeneity. ALDH2 activation modulated malignant phenotypes under alcohol exposure. Alda-64 was associated with decreased N-cadherin and increased E-cadherin expression, suggesting suppression of EMT-related progression. In vivo, alcohol-fed ALDH2-mutant mice showed significantly accelerated tumor growth compared with other groups, demonstrating a synergistic effect of ALDH2 deficiency and alcohol exposure. Notably, Alda-64 treatment reduced tumor volume by approximately 20–30% in ALDH2-mutant alcohol-exposed mice compared with Alda-1 and control groups, indicating a selective antitumor effect in the high-risk genetic and environmental context. Conclusions: ALDH2 deficiency drives adaptive tumor survival and progression under alcohol exposure and contributes to biologically aggressive ESCC phenotypes. Pharmacologic ALDH2 activation, particularly with Alda-64, attenuates alcohol-driven tumor progression and EMT-associated changes. These findings support ALDH2 as a metabolism-based therapeutic target and provide a precision prevention and treatment rationale for alcohol-associated ESCC.
Outcomes of CD-19–directed CAR-T therapy in patients with primary and secondary central nervous system lymphoma: A multi-center observational study.
2038 Background: CD-19 directed chimeric antigen receptor T-Cell (CAR-T) therapies have been approved for the treatment of diffuse large B-Cell lymphoma; however, patients with primary central nervous system (CNS) lymphoma were excluded from pivotal registration trials. Although early-phase trials and meta-analysis suggest promising efficacy in CNS lymphoma, existing data remain limited by small sample sizes. We conducted a large, multicenter observational study evaluating outcomes of CD19-directed CAR-T therapy in patients with primary or secondary CNS lymphoma. Methods: This study utilized the TriNetX database, encompassing over 110 healthcare organizations, to evaluate outcomes of adults with a diagnosis of primary or secondary CNS lymphoma prior to receiving CAR T therapy between 2019 and 2025. Outcomes were assessed from the time of CAR-T infusion. The outcomes analyzed were 1-year overall survival, as well as development of cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), treatment with tocilizumab, and risk of infection within 100 days post-CAR-T infusion. Kaplan-Meier estimated event rates were used to assess the primary outcomes. Results: We identified 155 patients with a diagnosis of primary or secondary lymphoma who received CD-19 directed CAR-T therapy. The median age at CAR-T infusion was 63 years. The cohort was predominately male (57%) and white (87%). A majority of the cohort, 80%, received Fludarabine/ Cyclophosphamide for lymphodepletion chemotherapy; 16% received Bendamustine. Most patients received axicabtagene ciloleucel (n=78), followed by lisocabtagene maraleucel (n=56), and tisagenlecleucel (n=21). The Kaplan–Meier estimated overall survival at one and three years was 63.9% and 46.9%, respectively. The estimated cumulative risk for CRS and ICANs post-CAR-T infusion was 58.7% and 26.5% respectively – 49.0% were treated with tocilizumab. The risk of infection by day 100 post-CAR-T infusion was 43.2%. Conclusions: CNS lymphomas have been associated with limited overall survival and represent an unmet need, necessitating the emergence of new therapeutic strategies. Our findings support the efficacy and safety of CAR-T in this population. To our knowledge, this is the largest single observational study of patients with CNS lymphoma treated with CAR-T. Outcome Time Point Rate (%)(n = 155) Overall Survival 1 years 63.9% 3 years 46.9% CRS 60 days 58.7% ICANS 60 days 26.5% Tocilizumab Use 60 days 49.0% Any Infection 100 days 43.2%