Browse Articles

Modulating Interfacial Water Structure via Catalyst Engineering to Enhance Electrocatalytic Activity and Selectivity

ABSTRACT Renewable electricity‐driven electrocatalytic technology plays a crucial role in clean energy conversion and the realization of a net‐zero carbon emission future. Previous research has predominantly focused on regulating the adsorption behavior of reaction intermediates via catalyst engineering to enhance electrocatalytic performance. Such studies have only been centered on the solid phase at the solid–liquid interface. However, the effect of catalyst structural engineering on the liquid phase is equally crucial and has long been insufficiently emphasized. Interfacial water with unique structural configurations and dynamic properties has been shown to regulate critical steps in electrocatalytic reaction. Therefore, we are motivated to write this review, in order to systematically overview the research progress and key challenges in this area. This review first introduces the fundamental properties for interfacial water, including structural types and molecular orientation. Subsequently, a series of advanced experimental characterization techniques and computational methods are provided to detect interfacial water, which is crucial for obtaining accurate structural information. More importantly, we highlight various modulation strategies of the precise catalyst structure engineering to optimize interfacial water dynamics and boost electrocatalytic performance. Finally, we discuss the challenges and emerging perspectives in this fast‐developing field, providing valuable insights for guide future research directions.

Bayesian convolutional front-end based uncertainty-aware hybrid quantum–classical image classification

Functional evaluation of TRPC6 missense variants in cancer patients via molecular docking analysis compared with patch Clamp electrophysiology

Noninvasive imaging biomarkers for survival risk stratification with tarlatamab in ES-SCLC.

8020 Background: Subsequent treatment for extensive-stage small cell lung cancer (ES-SCLC) following platinum-etoposide chemotherapy +/- an immune checkpoint inhibitor was historically limited to alternative forms of chemotherapy with relatively poor clinical outcomes. Bispecific delta-like ligand 3 (DLL3)-targeting T-cell engagers, such as tarlatamab, have since demonstrated clinically meaningful activity with notable improvements in survival. Although there was a modest improvement in median progression-free survival (PFS) with tarlatamab in the phase 3 DeLLphi-304 trial, 20% of patients remained free from disease progression at 12 months. Unfortunately, conventional clinical factors and early radiographic responses are unable to distinguish transient from sustained benefit; thus underlying the need for validated biomarkers to identify patients likely to derive a durable response from tarlatamab. Methods: This study sought to evaluate whether radiomic texture and quantitative vessel tortuosity (QVT) metrics derived from baseline CT imaging are associated with PFS and overall survival (OS) in patients with ES-SCLC receiving tarlatamab.50 patients from Cleveland Clinic with ES-SCLC who received tarlatamab after front-line chemoimmunotherapy were included in this study. Radiomic texture and QVT features characterizing intratumoral heterogeneity and vascular architecture were extracted from CT scans obtained before the first dose of tarlatamab (median scan-to-treatment interval: 33.5 days). A least absolute shrinkage and selection operator Cox regression model with cross-validation identified prognostic features for PFS and OS. A radiomic risk score (RRS) was computed as a weighted linear combination of selected features, and patients were stratified into high- and low-risk groups using the median RRS. Cox regression and Kaplan–Meier analyses with log-rank testing evaluated associations with PFS and OS. Results: On univariable analysis, RRS was significantly associated with PFS (HR = 2.3, 95% CI 1.36–3.94, P = 0.0019) and OS (HR = 3.9, 95% CI 1.67–9.1, P = 0.0016). Kaplan–Meier analyses demonstrated significantly shorter PFS and OS in the high-risk group. In multivariable models adjusting for age, sex, race, smoking history, COPD, and prior lines of therapy, RRS remained the only factor independently associated with PFS (HR = 2.1, 95% CI 1.16–4.0, P = 0.014) and OS (HR = 5.87, 95% CI 2.0–17.0, P = 0.001). Conclusions: Baseline CT-derived radiomic and vascular features represent noninvasive biomarkers for predicting PFS and OS in patients with ES-SCLC receiving tarlatamab. Further validation of these novel features can improve patient selection, treatment sequencing, and optimized utilization of DLL3-targeted therapy in this unique cancer population with otherwise limited treatment options.

Phase I clinical trial evaluating dual-targeting CAR-T cells (KD-496) against CLDN18.2 and NKG2DL in advanced gastrointestinal cancers and pancreatic cancers.

4224 Background: Chimeric antigen receptor T-cell (CAR-T) therapy has shown limited efficacy in gastrointestinal (GI) cancers. Previous studies indicate that bispecific CAR-T cells incorporating tandem single-chain variable fragments (scFvs) demonstrate enhanced therapeutic indices compared to monospecific constructs. We developed novel bispecific CAR-T cells (KD-496) targeting both NKG2D ligands and CLDN18.2, demonstrating promising preclinical antitumor activity and safety profiles. Methods: We conducted an open-label, single-arm, "3+3" dose-escalation study (NCT06134960) in patients with treatment-refractory advanced GI cancers. Following lymphodepletion with fludarabine, cyclophosphamide, and nab-paclitaxel, subjects received a single KD-496 infusion at three dose levels: 1×10⁸ (DL1), 3×10⁸ (DL2), or 5×10⁸ (DL3) CAR-T cells. Primary endpoints included safety and toxicity; secondary endpoints comprised efficacy, pharmacokinetics, and immunogenicity. Results: Between March 2024 and October 2025 , seven subjects (age range: 43-73 years) received KD-496 treatment (n=3 at DL1; n=3 at DL2; n=1 at DL3). Only one Grade IV possibly treatment-related adverse events (TRAEs) is Neutrophil count decreased (14%); Grade III possibly treatment-related adverse events (TRAEs) included Neutrophil count decreased (14%); Alanine aminotransferase increased (14%); Elevated aspartate aminotransferase (14%); anemia (29%); and White blood cell decreased (57%). Cytokine release syndrome (CRS) occurred in seven subjects, with one case (17%) reaching grade 3; no grade 4/5 CRS or neurotoxicity was observed. The dual-antigen requirement effectively prevented on-target off-tumor toxicity, with no patients experiencing severe gastrointestinal adverse events. No dose-limiting toxicities or serious adverse events were reported. Among evaluable subjects: Those with gastric cancer (n=4), achieved an objective response rate (ORR) of 75%; Among three subjects with pancreatic cancer, disease control rate (DCR) of 66.7% overall; Achieved an objective response rate (ORR) of 33% overall. Notably, the ORR reached 100% for both gastric cancer and pancreatic cancer advanced subjects in the medium-dose group. Conclusions: These initial data demonstrate a favorable safety profile for KD-496 CAR-T cells targeting NKG2DL/CLDN18.2. The preliminary efficacy signals warrant further investigation of KD-496, particularly in gastric cancer and pancreatic cancer. Clinical trial information: NCT06134960 .

Characterizing early oncology Orphan Drug Designation activity following expansion of the Orphan Drugs Exclusion.

e23050 Background: The Inflation Reduction Act (IRA) Medicare Drug Price Negotiation Program’s (DPNP) Orphan Drug Exclusion (ODE) was limited to orphan drugs designated only for “a single rare disease or condition” — generating concerns about the ODE’s impact on incentives for ongoing clinical development for rare disease treatments. The One Big Beautiful Bill Act, signed 7/4/25, expanded the ODE from drugs treating only a single rare disease to those treating “one or more rare diseases.” This expansion may preserve incentives for seeking additional orphan designations, which could particularly benefit rare cancer drug development. This study describes the characteristics of oncology drugs receiving a second orphan designation - and disease characteristics of those designations - following the ODE expansion. Methods: We obtained orphan designations granted from 7/5/2025-1/5/2026 from the orphan drug database maintained by the Food and Drug Administration (FDA). Oncology designations representing a second active designation for a given drug and manufacturer were identified by manual review (two PharmDs) using the FDA database and PharmaProjects. Drugs were excluded if FDA-approved for at least one nonorphan indication before 7/5/25. Drug modalities and dates of European Union (EU) orphan designations were obtained from PharmaProjects. US disease prevalence estimates were recorded from a targeted review of the SEER and cancer foundation websites as well as peer-reviewed literature. Drug and designation characteristics were summarized using descriptive statistics. Results: In the 6 months following ODE expansion, manufacturers of 15 orphan drugs received a second active designation. Drugs receiving a second active designation were more often biologics (n = 8, 53.3%) than small molecule drugs (n = 5, 33.3%). The two remaining drugs were a cell therapy (6.7%) and a cancer vaccine (6.7%). A total of 11 unique designations were received across 10 unique cancers, primarily (n = 8) solid tumor cancers. Over 1 million (estimated at approximately 1.15M) Americans are currently living with one of the 10 orphan-designated cancers. For the subset of designations that could be identified in PharmaProjects, all 14 (100%) were obtained in the US prior to the EU. Conclusions: Second orphan drug designations following ODE expansion were obtained by manufacturers of 15 orphan drugs across 10 unique cancers currently affecting approximately one million Americans. These second orphan designations were obtained earlier in the US than in the EU. These descriptive findings provide an early view of second orphan drug designations following the ODE expansion, which may preserve incentives for research into multiple rare diseases. Future research will explore additional characteristics and comparative findings.

Retrospective study of guideline concordance in cervical cancer screening surveillance by age, race, and ethnicity.

5525 Background: Nearly one in five new cervical cancer cases occur in individuals aged ≥ 65, with higher incidence among Black women compared to White women. Despite these disparities, evidence guiding screening and surveillance in older women is limited. This study evaluates guideline concordance for follow-up after abnormal cervical cancer screening and examines variation by age, race, and ethnicity. Methods: This retrospective cohort study assessed 1,861,906 cervical cancer screening results (2009-2024) from the TrinetX database. Included patients were female, ≥ 21 years old, and had an HPV test or pap smear. Guideline concordance (i.e., colposcopy within one year of high-risk cervical cancer screenings result) was assessed by running logistic regression models by age group, race, and ethnicity. Logistic regression assessed odds of concordant follow-up by age, race, and ethnicity, using women aged 30–39 and non-Hispanic White women as reference groups, respectively. Results: Guideline-concordant follow-up varied by age: 56.87% aged 21-29, 58.84% aged 30-39, 56.36% aged 40-49, 53.93% aged 50-65, and 45.80% aged 65+. Compared with women aged 30-39, both younger and older women were significantly less likely to receive guideline concordant follow-up. Women 65+ had 44% lower odds of concordant follow-up (OR= 0.56, 95% CI 0.53 to 0.60, p<.001). Guideline-concordant care also varied by race and ethnicity: 51.11% of non-Hispanic Black, 56.65% of non-Hispanic Asian, 60.36% of non-Hispanic White, 58.43% of non-Hispanic Other, and 51.71% of Hispanic patients. Compared to non-Hispanic White women, all other groups had significantly lower odds of follow-up, with non-Hispanic Black women having 30% lower odds (OR = 0.70, 95% CI 0.68 to 0.72, p<.001) and Hispanic women having 28% lower odds (OR= 0.72, 95% CI 0.71 to 0.74, p<.001) of concordant follow-up. Conclusions: Overall, the rate of guideline concordant follow-up after high-risk cervical cancer screening results was low (57.83%) and declined with age, with lowest rates among women ≥ 65 (45.80%). All other age groups had significantly lower odds of concordance than those 30-39, with those 65+ having the lowest odds of concordance. Significant disparities were also observed by race and ethnicity, particularly among non-Hispanic Black and Hispanic women. Further research is needed to assess the decreased surveillance rates after high-risk cervical cancer screening results at the population level and specific attention should be focused on groups who have been under-surveilled.

Machine learning (ML) model integrating cell death pathways as a prognostic and predictive biomarker for patients with melanoma.

9561 Background: Established regulated non-apoptotic cell death mechanisms, including ferroptosis, necroptosis, and pyroptosis, can govern cancer cells' fate. Early reports suggest that these pathways can drive antitumor immune response, and may be associated with survival outcomes for pts treated with checkpoint blocker antibodies (ICB). We developed a ML model based on transcriptomic data (CDPS), integrating these 3 pathways, and interrogated its prognostic and predictive role in pts with melanoma. Methods: An ML score based on 148 non-redundant cell-death–related genes was developed and evaluated in patient-level data from TCGA-SKCM and validated in external cohorts of pts with melanoma (GSE65904, MEL-DFCI-2019, GSE98394, GSE54467). Prognostic performance was assessed using C-index, time-dependent ROC, Kaplan–Meier analysis, and univariable Cox models, with pts stratified by cohort-specific medians. Pathway activity was examined using gene set enrichment analysis (MSigDB Hallmark and Reactome gene sets; pathways were significant if FDR < 0.05). Immune infiltration was estimated with MCP-counter as per Cliff’delta (Mann-Whitney test p < 0.05). Predictive value was tested in pts treated with ICB (GSE78220, GSE91061, GSE168294), which also included on-treatment samples (GSE91061). Results: Across discovery and validation cohorts, a random survival forest model with ridge regression showed consistent prognostic performance (C-index range, 0.58-0.66). 7 genes emerged as dominant contributors during feature selection. The CDPS-high group showed a downregulation of MLKL and GSDMD (key mediators of necroptosis and pyroptosis, respectively), and an upregulation of SLC3A2 (a negative regulator of ferroptosis), suggesting suppression of these regulated cell-death pathways. Across all 5 cohorts, CDPS-high pts exhibited significantly worse overall survival (p < 0.05), corroborated by time-dependent ROC analyses at 1 (0.61 - 0.72), 3 (0.84 – 0.75), and 5 years (0.58-0.76). Functional pathway analyses revealed statistically significant positive enrichment of proliferative, anabolic, and DNA-repair signalling in the CDPS-high group and negative enrichment of immune-related pathways (FDR < 0.05). Similarly, CDPS-high tumors demonstrated broadly reduced innate and adaptive immune cell infiltration, indicating a less favorable tumor immune microenvironment (p < 0.05). CDPS was significantly lower in responders (R) vs non-responders ([NR], p = 0.04) in GSE168294. Notably, a decrease in CDPS levels was observed during treatment for R, whereas remained stable in NR (GSE91061). Conclusions: CDPS exhibited robust and consistent performance by combining selected programmed death pathways (ferroptosis, necroptosis, and pyroptosis), especially in pts treated with ICB. Future efforts will aim to validate CDPS in a prospective cohort of pts with melanoma.

Neoadjuvant adebrelimab combined with chemotherapy in locally advanced esophageal squamous cell carcinoma: A single-arm, phase II trial.

4090 Background: Neoadjuvant therapy is the standard treatment for patients with locally advanced resectable esophageal squamous cell carcinoma (ESCC). This study evaluated the efficacy and safety of adebrelimab (anti-PD-L1 antibody) combined with neoadjuvant chemotherapy and explored immune correlates associated with treatment response (ChiCTR2400085858). Methods: Patients with locally advanced ESCC (cT1b-T2N+M0 or cT3-4NanyM0) received three preoperative cycles of adebrelimab (1200 mg, IV, d1, Q3W) plus nab-paclitaxel (125 mg/m 2 , IV, d1, d8, Q3W) and carboplatin (AUC 5 mg/mL/min, IV, d1, Q3W). The primary endpoint was pathological complete response (pCR). Secondary endpoints included major pathological response (MPR), R0 resection rate, disease-free survival (DFS), overall survival (OS) and safety. PD-L1 expression was measured by immunohistochemistry using the combined positive score (CPS). Multiplex immunohistochemistry was performed to assess spatial immune microenvironment changes. Results: Forty-three patients were enrolled from October 2023 to June 2025. The median age was 61 years (range, 42-75), and 39 patients (91.0%) were male. Patients with cStage II/III/IVA were 6/16/22. Among the 35 patients who underwent surgery, all achieved R0 resection (100%), with pCR and MPR rates of 22.9% (8/35) and 45.7% (16/35), respectively. The median follow-up was 13.2 months (range 2.4-21.9), with 1-year DFS and OS estimates of 94.2% (95%Cl: 86.7%-100.0%) and 86.8% (95%Cl: 76.5%-98.4%). Patients with PD-L1 CPS ≥ 10 (57%, 20/35) demonstrated a higher pCR rate compared with those with PD-L1 CPS < 10 (43%, 15/35), specifically 30% (6/20) vs 13.3% (2/15). Multiplex immunohistochemistry revealed distinct spatial immune remodeling during neoadjuvant therapy. At baseline, PD-L1 expression was predominantly associated with CD11b⁺ myeloid cells in peritumoral regions and was enriched in good responders (TRG 0-1), accompanied by higher peritumoral CD3⁺ T-cell infiltration. Post-treatment analyses demonstrated divergent T-cell dynamics, with decreased peritumoral T-cell density in good responders (TRG 0-1) and increased infiltration in poor responders (TRG 2-3). Treatment-related adverse events were consistent with the known safety profile. The most common treatment-related grade 3/4 AEs were leukopenia (41.9%), alopecia (27.9%), thrombocytopenia (9.3%), anemia (7.0%), and hepatic dysfunction (2.3%). Conclusions: Neoadjuvant adebrelimab combined with chemotherapy demonstrated promising efficacy and manageable toxicity in patients with locally advanced ESCC. Myeloid-associated PD-L1 expression and treatment-induced T-cell redistribution may represent immune correlates of response and warrant further investigation. Clinical trial information: ChiCTR2400085858.

Overall survival (OS) in premenopausal ER+/PR+, HER2− breast cancer (BC) treated with endocrine therapy (ET) ± chemotherapy (CT): A National Cancer Database (NCDB) analysis.

519 Background: The comparative benefit of ET alone vs ET+CT in premenopausal women with stage I-III ER+/PR+, HER2- BC remains uncertain. Although Oncotype DX recurrence score (RS) guides CT use, management of premenopausal patients (pts) with low/intermediate RS remains challenging. The ongoing NRG-BR009 trial aims to clarify the relative benefit of CT but has faced accrual issues. To address this question, we evaluated OS difference by treatment among pts with N0 (n=0)/intermediate RS and N1 (n=1-3)/low-intermediate RS disease. Methods: NCDB data were analyzed for women <50 yrs with ER+/PR+, HER2−, stage I-III BC (2005-2022). Variables included tumor size, grade, nodal status (N0/N1), stage, lymphovascular invasion, Ki67, Charlson-Deyo comorbidity score (CCS), RS category (low=0-17, intermediate=18-30) and treatments (ET, CT, surgery, radiation [RT]). OS was compared between ET+CT vs ET only groups using the log-rank test. Multivariable Cox models (MVA) were conducted to identify predictors of OS. Results: Median age was 45 yrs (18-49) among 15591 enrolled pts. In N0/intermediate RS group, 3710 (42.5%) received ET+CT and 5022 (57.5%) received ET alone; 5-yr OS was 98.9% with ET+CT vs 98.7% with ET (p=0.40). In N1/low RS group, 1151 (26.2%) received ET+ CT and 3242 (73.8%) received only ET; 5-yr OS was 98.5% with ET+CT vs 98.6% with ET (p=0.85). In N1/intermediate RS, 1718 (69.7%) received ET+CT and 748 (30.3%) received only ET; 5-yr OS was 96.2% with ET+CT vs 95.0% with ET (p=0.28). On univariable analysis, ET+CT did not improve OS in the N0/intermediate RS, N1/low RS, or N1/intermediate RS groups (all p>0.05). MVA further confirmed ET+CT had no OS benefit compared to ET alone in all groups (all p>0.05, Table 1). Among N0/intermediate RS pts, grade 3 disease was associated with worse OS (p<0.05). In N1/low RS subjects, CCS=2 predicted worse OS (p<0.05). In N1/intermediate RS pts, stage III disease and lack of RT predicted worse OS (p<0.05). Conclusions: In premenopausal women with early-stage ER+/PR+, HER2- BC, ET+CT yielded similar OS to ET alone in low/intermediate RS pts. Limitations include inability to assess ovarian function suppression and invasive disease-free survival. Larger studies are needed to validate the above findings and to investigate whether CT could be safely omitted in low-intermediate risk pts. MVA for OS by RS and nodal status (HR, 95%CI). N0, intermediate RS N1, low RS N1, intermediate RS CCS (2 vs 0) 3.87 (0.52-29.00) 23.62 (4.63-120.46) 4.01 (0.43-37.77) Grade (3 vs 1) 7.39 (1.45-37.62) 2.26 (0.26-19.57) 1.64 (0.26-10.35) Stage (III vs I) 1.02 (0.21-4.99) n/a 11.77 (1.90-73.04) ET+CT vs ET 0.73 (0.33-1.62) 0.80 (0.25-2.51) 0.44 (0.14-1.35) RT (yes vs no) 1.02 (0.48-2.19) 2.89 (0.65-12.82) 0.22 (0.08-0.66)

Efficacy profile of nanoliposomal irinotecan + fluorouracil and leucovorin (nal-IRI+5-FU/LV) in gemcitabine-refractory metastatic pancreatic adenocarcinoma in elderly North American patients: A real-word experience.

e16382 Background: Second-line treatment options for metastatic pancreatic adenocarcinoma (mPDAC) remain limited. The NAPOLI-1 trial showed improved outcomes with nanoliposomal irinotecan (nal-IRI) + 5-fluorouracil and leucovorin (5-FU/LV) compared to standard therapy. However, only a small proportion of the enrolled patients who received nal-IRI+5-FU/LV were North American (19/417), many under the age of 65, raising concerns regarding the generalizability of results to this population. This study aimed to evaluate the real-world effectiveness of nal-IRI + 5-FU/LV in a mostly elderly North American population with gemcitabine-refractory mPDAC. Methods: This was a retrospective cohort study performed in a single cancer center in South Florida serving a predominantly elderly population. Medical records of patients with mPDAC who had received combination of nal-IRI+5-FU/LV after progression on gemcitabine-based therapy for mPDAC from October 1, 2015 to January 31, 2023 were analyzed. The primary outcome was overall mean survival (OS), defined as time from from initiation of nal-IRI+5-FU/LV to date of death or last known alive. Secondary outcomes included progression free survival (PFS), and CA 19-9 response. Survival outcomes were analyzed using Kaplan-Meier methods and compared using the log-rank test. Cox proportional hazards regression was performed to estimate hazard ratios (HR) and assess the impact of clinical and demographic factors on the survival outcomes. A p -value < 0.05 was considered statistically significant. Results: A total of 68 patients were included; 79.4% (54) were > 65 years old. Median OS was 5.7 months (CI: 4.5-6.7), and median PFS was 2.3 months (CI: 1.8-2.8) compared to 6.2 and 3.1 months, respectively in NAPOLI-1. CA 19-9 response was obtained in 70.3% of patients compared to 68% in NAPOLI-1. On cox proportional hazards model, when adjusted for clinical and demographic factors, age > 65 years (HR = 5.383, p < 0.0098), and anemia (HR = 13.161, p = 0.009) were independently associated with increased mortality. Conclusions: In this real-world cohort of predominantly elderly North American patients with gemcitabine-refractory mPDAC, nal-IRI + 5-FU/LV demonstrated clinically meaningful effectiveness in OS and PFS comparable to those reported in the NAPOLI-1 trial. These findings support nal-IRI + 5FU/LV therapy as a viable second-line treatment option for the underrepresented elderly North-American population that is routinely encountered in clinical practice. Advanced age and anemia at baseline were identified as independent predictors of mortality, highlighting the importance of patient selection and risk stratification.

Spatial transcriptome to identify biomarkers for endocrine sensitivity of hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) early breast cancer (EBC).

e12501 Background: Intratumor heterogeneity is associated with endocrine sensitivity in breast cancer. However, no relevant studies have elucidated the role of different regions within the tumor in regulating endocrine therapy (ET). The study aims to explore the intratumor heterogeneity and identify potential biomarkers associated with endocrine sensitivity in patients with HR+/HER2- EBC based on digital spatial profiling. Methods: Patients were stratified into the ET-resistant and ET-sensitive groups. A total of 111 spatially resolved regions in three tissue compartments defined by morphology markers [tumor (PANCK+), leucocytes (CD45+), and nonimmune stroma (CD45-/PANCK-)] were investigated. A designated panel comprising 235 ET-related genes was successfully constructed. Transcriptomic measurement, enrichment analyses, single-cell sequencing, and survival assessment were performed across three types of spatial regions. Results: A total of 27, 13, and 5 differentially expressed genes (DEGs) were identified when comparing the ET-resistant with the ET-sensitive group in PANCK+, CD45+, and CD45-/PANCK- regions. Biological processes were primarily associated with nuclear activities, cell cycle, and histone modification. Fourteen DEGs in the PANCK+ regions were significantly associated with disease-free survival (DFS), among which seven DEGs, including RAD51, KAT6A, SMARCE1, FGFR1, KDM4B, GREB1L, and CCNDBP1, were qualified to construct a model for predicting DFS. Patients with low-risk scores had a median DFS of 55.77 months, significantly longer than 21.67 months among those with high-risk scores (p=2.1e-4, HR=6.73, 95CI%=2.20-20.60). The AUC for 1-year, 3-year, and 5-year DFS was 0.98, 0.95, and 0.91, indicating its superior efficacy for predicting DFS in patients with HR+/HER2− EBC. In the CD45+ regions, MLH3 was the only DFS-related DEG, where high expression level of MLH3 led to a prolonged DFS (p=3.8e-5, HR=0.22, 95CI%=0.10-0.47). Similarly, in the CD45−/PANCK− regions, only HDAC7 upregulation was found to be significantly associated with longer DFS (p=9.2e-3, HR=0.39, 95CI%=0.18-0.81). Non-classical monocyte infiltration was significantly higher in the ET-sensitive group (p=0.03) in the CD45+ regions, and plasma cell infiltration was significantly higher in the ET-resistant group (p=0.01) in the CD45−/PANCK− regions. Conclusions: Our study has firstly demonstrated the intratumor heterogeneity of patients showing different responses to ET-based treatment, which may be helpful for disentangling the molecular mechanisms of endocrine resistance and stratifying patients who are responsive to ET.

PDLIM2 expression and characteristics in KRAS- mutated lung adenocarcinoma.

e20561 Background: It has been shown that PDLIM2 is expressed at higher levels in normal lungs in comparison to cancerous lungs, where it modulates transcription factors as a tumor suppressor. PDLIM2 upregulates T-cell activation and antigen presentation but also downregulates resistance genes in malignant cells. Prior studies link expanded distant metastases and lung adenocarcinoma size to patients with simultaneous KRAS mutations, TP53 deletions, and decreased PDLIM2. This study investigates PDLIM2 expression amongst various patient populations, cancer characteristics, and disease trajectories. Methods: The study was IRB approved. From an initial 226 patient samples that underwent next generation sequencing, 196 samples were primary lung cancers. Patient charts were reviewed for KRAS, STK11, TP53, and NFE2L2 pathologic variants. Of the KRAS positive patients, 27 folders of RNA samples were analyzed for PDLIM2 expression using Salmon software. In total, 21 patients were analyzed, though exclusions were made for patients who did not meet specific categorical designations. We generated normalized ratios (NR) for PDLIM2 expression, collected patient demographic and clinical data and utilized T-tests and Kaplan-Meier curves for statistical analyses. Results: Despite the cohort size limiting statistical significance, meaningful trends emerged. 73% of ever smokers (n = 11/15) completely suppressed PDLIM2 compared to the 33% of never smokers (n = 2/6, p = 0.539). PDLIM2 expression was seen to decrease five-fold as tumor burden increased, with average NR of 0.026 in T1-T2 stage patients versus 0.005 in T3-T4 (p = 0.190). The decrease in metastasis was six-fold with an average NR of 0.035 in M0 patients compared to 0.006 in M1 patients (p = 0.345). TP53 mutated cancers displayed lower expression than those without (0.005 vs 0.022, p = 0.216). The only patient with an NFE2L2 mutation had a NR of 0. STK pathologic variants had an average NR 0.043 compared to 0.010 in patients without (p = 0.501). No statistically significant differences were observed in PDLIM2 expression according to patient age (p = 0.545), race (p = 0.735), or tumor location (p = 0.734). Kaplan-Meier curves for progression-free survival (PFS) did not exhibit a significant difference (p = 0.769). Overall survival (OS) data was not formally analyzed due to limited mortality events (n = 2). Conclusions: Overall, PDLIM2 expression may be a marker of aggressive tumor biology given its likely relation to tumor invasion, metastasis, KRAS and TP53 status, independent of patient demographics. There is also a strong likelihood of relation to tobacco exposure. Lastly, the association between NFE2L2 status and PDLIM2 expression raises the possibility that PDLIM2 is a mechanism by which patients with NFE2L2 mutations are insensitive to immune checkpoint inhibition. This study is limited by small sample size, indicating the need for larger studies to further investigate these patterns.

Comparative study between neoadjuvant hormone therapy plus CDK-4/6 inhibitors versus neoadjuvant chemotherapy for hormone receptor–positive breast cancer patients.

e12667 Background: Neoadjuvant Chemotherapy (NACT) has traditionally been employed in patients with operable and locally advanced breast cancer to downstage the primary tumour and to facilitate breast conservation and to provide in vivo assessment of treatment response. However, in HR+/HER2- breast cancer NACT response rates remains low with substantial chemotherapy related side effects. Given the evolving emphasis on treatment de-escalation, personalisation of therapy and avoidance of unnecessary chemotherapy in HR+/HER2- breast cancer there is a growing need to evaluate NAHT combined with CDK4/6 inhibitors can offer comparable surgical outcomes and treatment response in appropriately selected patients. Methods: This prospective, single-centre study included patients with non-metastatic HR+/HER2- breast cancer treated between January 2023 - November 2025. Eligible patients had operable or locally advanced disease and were planned for neoadjuvant systemic therapy following multidisciplinary discussion. Treatment plan was individualised with patients receiving either standard neoadjuvant chemotherapy (NACT) or neoadjuvant endocrine therapy combined with CDK-4,6 inhibitors (NAHT + CDK-4,6) for a duration of 4-6 months. Treatment response was assessed, followed by definitive breast and axillary surgery. Breast conservation (BCS) rates, changes in KI67, nodal down staging rates were analysed and compared between both treatment cohorts using appropriate statistical methods. Results: A total of 52 patients were included (NACT, n = 26; NAHT+CDK4,6, N = 26) with similar baseline clinicopathological characteristics. Breast conserving surgery (BCS) rates were identical in both groups (65.39%). In the NAHT + CDK-4,6 inhibitor cohort demonstrated higher response rates (19.23% vs 3.84%) and lower stable disease rates (19.23 vs 38.4%). Toxicity profiles differed between both groups: NAHT + CDK 4,6 inhibitors was predominantly associated with low grade, manageable side effects most commonly being diarrhoea and fatigue. No grade 4 toxicities were observed. In contrast, NACT was associated with fewer but more prominent side effects including grade III peripheral neuropathy. Conclusions: NAHT plus CDK-4,6 inhibitors achieved comparable breast conservation rates to NACT while demonstrating higher complete response rates and a more favourable toxicity profile in HR+HER2- breast cancer. These findings support NAHT + CDK-4,6 inhibitors as a feasible and effective chemotherapy sparing strategy in appropriately selected patients. Comparative response rates & BCS rates: NAHT+CDK-4,6 v/s NACT. SURGICAL OUTCOMES NAHT + CDK-4,6 NACT BCS (%) 65.39 65.39 MASTECTOMY (%) 34.61 34.61 RESPONSE RATES NAHT +CDK-4,6 NACT CR (%) 19.23 3.84 PR (%) 51.5 57.69 SD (%) 19.233 38.4

Real-world comparison of atezolizumab/bevacizumab vs durvalumab/tremelimumab in decompensated hepatocellular carcinoma.

e16159 Background: Pivotal trials established atezolizumab-bevacizumab and durvalumab-tremelimumab as first-line therapies for unresectable hepatocellular carcinoma (HCC). Atezolizumab plus bevacizumab demonstrated superior survival outcomes compared to sorafenib for unresectable HCC in the IMbrave150 trial in 2020, while durvalumab plus tremelimumab showed superior survival in the HIMALAYA trial in 2022. However, data on head-to-head comparison of these two combinations as first-line systemic therapy for the patient with decompensated HCC are limited. This study aims to compare survival outcomes between these two treatment regimens in decompensated HCC patients to address a critical gap in the current literature, as decompensated patients have largely been excluded from clinical trials. Methods: This retrospective study utilized electronic health records from 146 U.S. healthcare organizations within the TriNetX Network. Adults aged ≥21 years diagnosed with decompensated HCC receiving atezolizumab/bevacizumab and durvalumab/tremelimumab from 10/21/2022 to 8/20/2024 were included. The comparison group received atezolizumab/bevacizumab, and the control group received durvalumab/tremelimumab. The primary outcome was all-cause mortality. A 1:1 propensity score matching was conducted to balance baseline characteristics (age, gender, race/ethnicity, lab results including liver function tests, platelet counts, INR, gamma glutamyl transferase, alpha-fetoprotein, and underlying liver diseases). Kaplan–Meier survival analysis and Cox regression was used to estimate the mortality risk. Subgroup analysis was stratified by HCC etiology. Results: A total of 302 and 664 patients received durvalumab/tremelimumab, atezolizumab/bevacizumab, respectively. After propensity matching, 253 patients per group were included. Median OS was 283 days with durvalumab/tremelimumab and 391 days with atezolizumab/bevacizumab. The two treatment regimens showed no significant difference in survival (hazard ratio [HR]: 0.875, 95% confidence intervals [CI] 0.696–1.101, p=0.254). Subgroup analyses demonstrated no significant differences in survival between the two groups of patients in MASLD (HR: 0.698, 95% CI: 0.468–1.040), alcohol associated liver disease (HR: 0.821, 95% CI: 0.603–1.118), and chronic viral hepatitis (HR: 0.852, 95% CI: 0.596–1.219). Conclusions: There was no statistically significant difference in survival outcomes between atezolizumab plus bevacizumab and durvalumab plus tremelimumab in patients with decompensated advanced HCC. These results support current real-world practice in which both regimens may be considered viable first-line treatment options in this high-risk population with liver decompensation.

Association of solid tumor patients’ characteristics and cure expectations with their portal-reported health-related values.

e24114 Background: Patient portals are an efficient, valid method of assessing patients’ health-related values (HRVs) to inform oncology teams’ care delivery. But patient-level factors influencing these HRVs (e.g., communication preferences, hopes, concerns, sources of strength) are unknown. Methods: A random sample of HRV portal questionnaire responses (200 of 852 solid tumor outpatients responding from 7/2023-7/2024 at a dedicated cancer center) coded for thematic content were analyzed descriptively (e.g., HRV code frequencies) alongside patient characteristics and questionnaire responses on cure expectations (patient Likert scale rating of the likelihood of cancer treatment to cure their cancer). Results: 200 patients were median age 66, 52% male, 75% White; 68% married/partnered, with median 16 months between first medical oncology visit and HRV questionnaire response, and intestinal [42%], pancreas [20%], and genitourinary cancers [12%]), 78% at advanced (metastatic) stage. Of treatment expectations reported by 150 patients (57% on active treatment; 57% expecting cure), no significant differences were found in HRV codes, in advanced or early-stage patients, based on cure expectations. Patients with advanced vs localized stage were more likely to report valuing communication with the medical team (27% v 11%, p = 0.03) and less likely a desire to live as a source of strength (3% v 16%, p = 0.009) or a hope to keep working (1% v 11%, p = 0.009). Unmarried vs married patients reported friends as sources of strength (30% v 17%, p = 0.04), preferences for independence (13% v 1%, p = 0.002) and negativity/pessimism (5% v 0%, p = 0.03) more often. While faith was more frequently reported as a source of strength in religious vs non-religious patients (38% v 13%, p = 0.01), non-religious patients more often reported strength from their own identity/autonomy (10% v 2%, p = 0.047) and concerns of burdening others (20% v 6%, p = 0.02). Patients with less (vs more) time from initial visit to HRV portal response were more likely to identify family, and friends, as sources of strength (73% v 57%, p = 0.03, 29% v 13%, p = 0.009, respectively) and less likely the medical team (15% v 30%, p = 0.02); they also reported concerns about dying (28% v 14%, p = 0.02) and hopes for a return to physical normalcy (15% v 4%, p = 0.02) more frequently and hope for a happy/positive emotional state (5% v 15%, p = 0.03) less frequently. Conclusions: Patient-level factors (e.g., marital status, stage, religion, time since initial oncology visit) are associated with HRVs elicited via patient portal questionnaire. Identifying such factors may help clinicians deliver care that is concordant with patients’ HRVs and define appropriate care goals. Ongoing research is evaluating large-scale implementation of portal-enabled elicitation of patients’ HRVs to normalize and systematize communication informing person-centered oncology care.

DAREON-8: Updated efficacy and safety from a phase I dose-escalation/expansion trial of first-line (1L) obrixtamig plus chemotherapy and atezolizumab in extensive-stage small cell lung carcinoma (ES-SCLC).

8089 Background: Obrixtamig (BI 764532) is a DLL3/CD3 IgG-like T-cell engager that has shown promising efficacy in ES-SCLC, as monotherapy and in combination with other agents. Due to the aggressiveness of ES-SCLC, early initiation of optimal 1L induction therapy is critical, as many patients (pts) may not reach treatment maintenance. We report updated efficacy and safety data from the ongoing Phase I DAREON-8 (NCT06077500) dose-escalation/expansion trial investigating 1L obrixtamig + induction SoC (carboplatin + etoposide + atezolizumab) and maintenance obrixtamig + atezolizumab in pts with ES-SCLC. Methods: Obrixtamig was given IV as step-up dosing followed by target dose (Part A: 3 dose levels [10, 30, 60 mg] guided by a BLRM with overdose control; Part B: selected target dose) + SoC (given per label). After 4 cycles of obrixtamig + SoC, obrixtamig + atezolizumab was continued until disease progression or another reason requiring discontinuation. Primary endpoint: DLTs; secondary endpoints included PFS, DoR, and ORR (RECIST v1.1; investigator assessed). Results: As of Dec 17, 2025, 46 pts were treated (Part A/B: n=28/18); 44 pts received ≥1 dose of obrixtamig. Median cycles of obrixtamig: 10 (range: 1–21); median age: 69 yrs (range: 34–76); ECOG PS 0/1: 27%/73%; brain metastasis: 16%. MTD was not reached in Part A; the study continued in Part B with the highest dose level (60 mg). Key efficacy data are in the table. Confirmed ORR: 73% (95% CI: 58–84); DCR: 91% (95% CI: 79–96). mDoR: NC; mPFS: NC; 6- and 9-month PFS rates (95% CI): 76% (62–90), and 61% (44–79), respectively. In the 60 mg cohort, confirmed ORR: 76% (95% CI: 58–88); mDoR and mPFS: NC. Most common G≥3 AEs were cytopenias and were almost wholly related to chemotherapy. Most common obrixtamig-related AE: cytokine release syndrome (52%). SoC discontinuations due to TRAEs: n=2 (G2 asthenia, G2 decreased platelets, G3 anemia). Obrixtamig discontinuations due to TRAEs: n=1 (G2 asthenia). Conclusions: Obrixtamig + SoC demonstrated encouraging efficacy, supporting obrixtamig as a combination partner for 1L SoC. The combination showed a safety profile consistent with individual agents, supporting the favorable tolerability of obrixtamig in combination regimens. Updated safety data are consistent with previous findings (Peters S et al, Ann Oncol 2025;36: S1466–7), and results warrant further development in Phase III trials. Clinical trial information: NCT06077500 . Best confirmed response, n (%) Obrixtamig 60 mg, n=29* Total (obrixtamig 10‒60 mg), N=44* CR / PR 4 (14) / 18 (62) 4 (9) / 28 (64) SD 4 (14) 8 (18) PD 0 (0) 1 (2) NE/missing 3 (10) 3 (7) ORR, % (95% CI) 76 (58–88) 73 (58–84) DCR, % (95% CI) 90 (74–96) 91 (79–96) Median PFS, months (95% CI) NC (NC–NC) NC (7.2–NC) 6-/9-month PFS rate, % (95% CI) 84 (69–98) / 78 (60–95) 76 (62–90) / 61 (44–79) *Efficacy-evaluable population.

Avatrombopag for chemotherapy-induced thrombocytopenia in gastrointestinal malignancies (ACT-GI): A multicenter, U.S., randomized, double-blind, placebo-controlled clinical trial.

3580 Background: Chemotherapy-induced thrombocytopenia (CIT) is a frequent complication of chemotherapy. Persistent CIT (not adequately resolved by day 1 of the following cycle) may lead to reduction or delay in treatment. There are no FDA approved therapies for CIT. Aim: To evaluate the safety and efficacy of avatrombopag (AVA), an oral thrombopoietin receptor agonist, to treat persistent CIT and prevent its recurrence in GI cancer. Methods: ACT-GI (NCT05772546) was a multicenter, randomized, double-blind, placebo-controlled, investigator-initiated trial of GI cancer patients with persistent CIT (platelets [Plt] <85×10 9 /L on day 1 of a scheduled chemotherapy cycle). Patients were randomized 1:1 to AVA 40 mg daily or placebo and treated for two on-study phases. In the lead-in phase, patients were treated up to 2 weeks while chemotherapy was held. Patients proceeded to the on-cycle phase and resumed chemotherapy only if their Plt recovered to ≥100×10 9 /L. In the on-cycle phase, patients received a single full-dose chemotherapy cycle with continued study drug. The primary endpoint was successful correction of CIT and prevention of recurrence (achieving Plt ≥100×10 9 /L within the lead-in period AND prevention of CIT recurrence (Plt ≥100×10 9 /L) at end of the cycle). Results: Efficacy: ACT-GI was closed to enrollment by the DSMB, for overwhelming efficacy, at a prespecified interim analysis when 20 patients in each arm completed the double-blind period. 16 of 23 patients (70%; 95% CI 47% to 87%) in the AVA arm achieved the primary endpoint versus 4/24 patients (17%; 95% CI 5% to 37%) in the placebo arm (Z=3.67, P<0.001). 74% and 88% of patients had stage IV cancer in AVA and placebo arms, respectively. 44/47 patients completed study drug; 2 discontinuations were due to physician decision and 1 was due to an adverse event. Plt improvement to ≥100×10 9 /L during lead-in was achieved by 83% of patients in the AVA arm vs. 46% of patients in the placebo arm. The median (IQR) Plt at the end of the on-cycle treatment period was 157 (136-202) in the AVA arm vs 72 (68-134) in the placebo arm. In the AVA arm there were two clinically relevant bleeding events (intestinal stoma site bleed at Plt 105×10 9 /L and intracranial hemorrhage). No patient received platelet transfusion. Safety: AEs and serious AEs (SAEs) occurred in 74% and 13% of patients in the AVA arm and 46% and 0% of patients in the placebo arm, respectively. No SAEs were study drug-related. There were no treatment-related AEs leading to death or discontinuation of study drug. Conclusions: In this randomized, placebo-controlled trial, AVA demonstrated safety, tolerability, and efficacy in treatment and prevention of persistent CIT in GI cancers. These findings are promising for a common, serious condition that prevents delivery of full-dose, on-time cancer-directed therapy. Clinical trial information: NCT05772546 .

Survival outcomes by insurance coverage in non-Hodgkin lymphoma (NHL): Experience from two academic centers and a safety-net health system.

e19058 Background: The impact of insurance coverage on survival in NHL has been described, but it remains unclear how this relationship varies by care setting. We compared overall survival (OS) among NHL patients treated at two academic medical centers participating in the Lymphoma Epidemiology of Outcomes (LEO) Cohort Study (Emory University Hospital, GA; MD Anderson Cancer Center, TX) and at the Harris Health System (HHS), a safety-net system providing charity care to low-income uninsured and underinsured residents of Harris County, TX. Methods: We analyzed patients diagnosed between 2015 and 2025 at two LEO centers (N=2,864) and at HHS (N=726). We examined 5-year OS by care setting, insurance type, and NHL subtype (indolent: follicular lymphoma, marginal zone lymphoma; aggressive: diffuse large B-cell lymphoma, Burkitt/lymphoblastic lymphoma). We conducted separate Cox proportional hazards models for academic centers and HHS to assess associations between insurance coverage and OS. Covariates included age, sex, race/ethnicity, year of diagnosis, ZIP-level income, and NHL subtype. Results: At academic centers, 8% of patients were Black and 18% were Hispanic; at HHS, 18% were Black and 68% were Hispanic. Mean ZIP-level income was higher at academic centers ($106,916) than at HHS ($74,458). Across NHL subtypes and insurance categories, 5-year OS was higher among patients treated at academic centers than HHS for both indolent NHL (92% vs. 90%) and aggressive NHL (77% vs. 63%). At academic centers, OS was highest among privately insured patients (indolent: 96%; aggressive: 84%), followed by uninsured patients (89%; 78%) and Medicare beneficiaries (89%; 73%), and lowest among Medicaid patients (not reportable due to few observations; 62%). At HHS, OS was highest among privately insured patients (not reportable; 67%), followed by uninsured patients (93%; 66%), and lowest among Medicare beneficiaries (74%; 39%) and Medicaid patients (72%; 59%). In adjusted Cox models, Medicaid coverage was associated with poorer OS compared with private insurance at both academic centers (HR 4.03, p=0.025) and HHS (HR 2.23, p=0.009). Uninsured status was associated with poorer OS compared with private insurance at academic centers (HR 2.78, p=0.018) but not at HHS. Medicare coverage was associated with better OS than private insurance at academic centers (HR 0.51, p=0.001) but not at HHS. Conclusions: Insurance-related survival differences in NHL varied by care setting. Medicaid coverage was associated with poorer OS across both settings, identifying Medicaid patients as a persistently high-risk group. In contrast, uninsured patients had poorer OS at academic centers but not at HHS, suggesting that safety-net charity care may attenuate survival disparities among uninsured patients.

Intracranial efficacy of tarlatamab versus chemotherapy (CTx) as second-line (2L) treatment for small cell lung cancer (SCLC): DeLLphi-304 phase 3 post hoc analysis.

8006 Background: Brain metastases (BM) are common in patients (pts) with SCLC and are associated with poor outcomes. Tarlatamab, a bispecific T-cell engager (BiTE) immunotherapy, demonstrated superior overall survival versus CTx in pts with SCLC following progression on or after platinum-based CTx in the DeLLphi-304 study, including pts with history of BM (prior or current) at baseline (OS HR 0.45 [95% CI: 0.31–0.65]). Here we compare the intracranial efficacy of tarlatamab vs CTx. Methods: Pts were randomized 1:1 to receive tarlatamab or CTx (topotecan, lurbinectedin or amrubicin) as 2L treatment for SCLC. Pts with stable asymptomatic brain metastases were eligible; prior CNS treatment was required until protocol amendment 3. Baseline brain imaging by contrast enhanced MRI was mandatory for all pts at screening and repeated at all subsequent imaging assessments for pts with a history of BM at baseline. A post hoc analysis on intracranial efficacy was performed by BICR per mRANO-BM. Given that most pts had prior CNS treatment, specified outcomes were CR, non-CR/non-PD, and PD. Results: BM at baseline were present in 98/254 pts (39%) in the tarlatamab arm and 99/255 (39%) in the CTx arm, of whom 75/98 (77%) and 69/99 (70%) had prior CNS treatment, respectively. A CNS full analysis set (FAS) was specified to include pts who had both a baseline scan and ≥ 1 postbaseline scan (tarlatamab-67; CTx-56 pts). In pts in FAS, treatment with tarlatamab resulted in longer CNS PFS than CTx (median: 6.5 mos vs 4.2 mos; HR, 0.40 [95% CI: 0.24–0.66]; Table). CNS tumor shrinkage of ≥30% was observed in 56% of pts with tarlatamab vs 38% with CTx. CNS complete response was observed in 15% of pts with tarlatamab vs 5% with CTx, with longer CNS duration of complete response (DOCR) (not estimable [NE] vs 3.6 mo) and longer CNS duration of disease control (DODC) (8.2 vs 5.2 mo) for pts in the tarlatamab arm. Pts with BM at baseline had longer OS with tarlatamab vs CTx (median OS: 13.9 vs 6.8 mos; HR, 0.51 [95% CI: 0.34–0.74]). In pts with BM at baseline, treatment-emergent adverse events (TEAEs) of any grade (gr)/gr 3/gr 4/gr 5 occurred in 99%/38%/9%/7% for tarlatamab vs 100%/38%/40%/10% for CTx. In pts treated with tarlatamab, the incidence of CRS and ICANS was 54% and 9% in pts with BM at baseline vs 58% and 4% in pts without BM at baseline, respectively. Conclusions: Tarlatamab demonstrated increased intracranial efficacy with longer CNS PFS and OS vs CTx in pts with stable, treated and untreated asymptomatic BM. These results affirm tarlatamab as the 2L standard of care for SCLC, even in pts with BM. Clinical trial information: NCT05740566 . Tarlatamabn = 67 CTxn = 56 CNS PFS, mos (95% CI) 6.5 (4.3, 13.7) 4.2 (2.9, 5.5) CNS Complete Response, n (%) 10 (15%) 3 (5%) CNS DOCR, mos (95% CI) NE (2.9, NE) 3.6 (3.1, NE) CNS DODC, mos (95% CI) 8.2 (6.3, NE) 5.2 (4.2, 6.2) CNS tumor shrinkage of ≥30%, % (n/N) a 56% (9/16) 38% (5/13) a Assessed in pts with ≥1 lesion that was ≥ 10 mm.