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A randomized phase II study of selinexor added to standard induction and consolidation chemotherapy in adults with acute myeloid leukemia (AML).

6512 Background: Preclinical and early clinical data suggest that inhibition of nuclear export by the XPOI inhibitor selinexor may enhance chemosensitivity in AML. We conducted a randomized phase II study evaluating the addition of selinexor to standard intensive induction and consolidation chemotherapy. Methods: This was an open-label, randomized (3:1) phase II trial in adults with newly diagnosed non-APL, AML. Good risk patients, those with FLT3 mutations or those with an indication for CPX-351 were excluded. Patients were assigned to standard induction with cytarabine and an anthracycline (7+3) followed by high-dose cytarabine (HDAC) consolidation (control arm) or the same regimen with the addition of selinexor (study arm). Selinexor was administered at a fixed dose of 60 mg orally on days 1, 3, 8, 10, 15, and 17 during induction and consolidation cycles. Randomization was not stratified. The primary endpoint was overall survival, analyzed in the intention-to-treat population. Secondary endpoints included overall response rate, complete remission with or without complete count recovery and safety. Results: A total of 57 patients were randomized (study arm n = 43; control arm n = 14). The study was discontinued early after results of the PARADIGM study raised concerns regarding the use of intensive chemotherapy in intermediate- and poor-risk AML patients. Baseline characteristics except for gender were generally balanced (Table 1). Median overall survival was 991 days in the study arm compared with 649 days in the control arm (log-rank p = 0.2267). Thirty-day mortality occurred in 5 patients (11.6%) in the study arm and 2 patients (14.3%) in the control arm. The response rate was 77% (33/43) in the study arm and 50% (7/14) in the control arm, corresponding to a risk ratio of 1.53 (95% CI, 1.01–4.57); this difference did not reach statistical significance by Fisher’s exact test (p = 0.09). The addition of selinexor was feasible, with early mortality rates consistent with intensive induction therapy and no unexpected safety signals observed. Conclusions: In this randomized phase II study, the addition of selinexor to standard induction and consolidation chemotherapy was associated with numerically higher response rates and longer median overall survival compared with chemotherapy alone. Small study size and early termination limit definitive conclusions. However, these findings suggest biological activity of nuclear export inhibition in AML and support further evaluation of selinexor-containing combinations. Clinical trial information: NCT02835222 . Characteristic Control arm (n = 14) Study arm (n = 43) Median age, years (range) 69 (22–75) 65 (24–73) Female sex, n (%) 11 (78.6%) 17 (39.5%) ELN 2022 Risk group  Good 5 (35.7%) 9 (20.9%)  Intermediate 3 (21.4%) 20 (46.5%)  Poor 6 (42.9%) 14 (32.6%)

Combinatorial drug repurposing of Valproic acid and Zebularine regulates Krüppel-like factor 4 and β-catenin expression in colon cancer cells

Colorectal cancer is the predominant and recurring cancer leading to the second largest cause of mortality, globally. Abnormal regulation of oncogenes and deactivation of tumor suppressor genes over an extended period were key mechanisms underlying colon tumorigenesis. As a result, an effective drug targeting these genes should be explored to combat this disease. We aim to explore the effects of Valproic acid (VPA), a histone deacetylase inhibitor (HDACi), and Zebularine (ZEB), DNA methyltransferase inhibitor, on the expression of the Krüppel-like factor 4 (KLF4) and CTNNB1 (β-catenin) in an early-stage colon cells (SW480 cells) and a late-stage colon cell (DLD-1 cells). Using several in-vitro assays including cell viability, proliferation assay, single cell imaging and analysis and molecular assays including qPCR, protein expression analysis, we have assessed the anticancer properties of both drugs, VPA and ZEB. The synergistic effect of VPA and ZEB could effectively inhibit the proliferation of colon cells than their independent doses. The gene expression profile revealed 2-fold increase in the expression of KLF4 in SW480 cells, with increase to about 22-fold in DLD-1 cells. Notably, CTNNB1 was downregulated than KLF4 in a dose dependent manner, potentially leading to antitumorigenic and anti-proliferative properties of the combinatorial drug. Cellular localization of KLF4 and CTNNB1 protein expression in cytoplasm and nucleus with morphological changes of the cancer cells revealed the onset of programmed cell death. qPCR analysis also showed the downregulation of KLF4 and CTNNB1 upon synergistic activity of ZEB and VPA treated colon cancer cells. Microscopic analysis confirmed the upregulation of KLF4 in ZEB treatment cells leading to DNA methylation. Finally, single cell image analysis has shown the reduced expression of both KLF4 and CTNNB1. Overall, the analysis confirmed that synergistic effect of ZEB and VPA served as a potential anti-colon cancer agent.

Integrated CO ₂ Capture and Conversion Induced by Amines for Effective Electrocatalytic N‐Methylation

ABSTRACT N‐Methylation of amines is a crucial transformation for synthesizing valuable compounds. However, conventional N‐methylation methods often rely on hazardous reagents. The electroreduction of CO 2 as a sustainable C1 source presents an attractive alternative. Nevertheless, the direct electrochemical activation of CO 2 requires high overpotentials, often leading to a low Faradaic efficiency (FE). This study presents a CO 2 capture‒conversion pathway for the N‐methylation of amines. High concentrations of nucleophilic piperidine preferentially capture CO 2 , enabling spontaneous C─N coupling, as confirmed by 13 C nuclear magnetic resonance spectroscopy. Moreover, N ‐methyl piperidine (NMP) is produced through an electroreduction process. In situ Raman spectroscopy and theoretical calculations reveal the formation of a key piperidinium intermediate and provide insights into its role in subsequent electroreduction. This pathway effectively suppresses side reactions typical of CO 2 electroreduction, achieving a high NMP FE of 71.6% at −0.6 V versus Ag/AgCl. Furthermore, the CO 2 capture‒conversion pathway produces various N‐methylated amines, such as dimethylamine and 1‐methyl ethylenediamine, with excellent FEs, highlighting the generality and advantages of this approach.

Nanoparticles in ocular cancer: Diagnosis and treatment

In‐situ p‐Doping of Nanometer Tellurium‐based Oxide for Room‐Temperature CMOS Circuits (Adv. Mater. 36/2026)

Recent Advances on High‐Performance Inverted CsPbI ₃ Perovskite Solar Cells and Their Tandem Application

ABSTRACT Inverted CsPbI 3 perovskite solar cells (PSCs) have attracted more attention in single‐junction and tandem solar cells, owing to the optimal band‐gap, superior photothermal stability, and device architecture compatible with commercial bottom cells such as CuInSe 2 and silicon. However, their development is hindered by challenges including the complex phase transition process, interfacial energy‐level mismatch, unpassivated defects, and the suboptimal transport layer. A comprehensive understanding of the material characteristics, phase transition mechanisms, and interface state of CsPbI 3 is therefore essential to address these issues. In this review, we systematically examine the phase‐transition dynamics of CsPbI 3 and summarize recent advances in fabricating efficient and stable inverted CsPbI 3 PSCs, focusing on: (1) Regulation of the phase transition and bulk crystallization; (2) Management of interface energy‐level and defect passivation; (3) Selection of hole transport materials and their integration in tandem solar cells. Finally, we outline the remaining challenges and future perspectives to guide the development of high‐performance and operationally stable inverted inorganic perovskite‐based single‐junction and tandem photovoltaics.

3D‐Printable, Honeycomb‐Inspired Tissue‐Like Bioelectrodes for Patient‐Specific Neural Interface

ABSTRACT The unique gyral patterns of the human brain demand patient‐specific neural interfaces to achieve precise neuromodulation, mitigate adverse tissue responses, and optimize therapeutic efficacy and safety. One‐size‐fits‐all, conventional rigid electrocorticography (ECoG) electrodes, standardized for mass production through lithographic techniques, exhibit limited conformability to the brain's heterogeneous cortical topography. This mechanical mismatch results in poor electrode‐tissue contact, signal loss, and foreign body responses. To address these limitations, we present an integrated novel platform, synergizing MRI‐based anatomical mapping, finite element analysis (FEA)—optimized mechanical design, and direct ink writing (DIW) 3D printing to fabricate electrodes customized to individual gyral patterns. The resulting honeycomb‐inspired printable gel electrode (HiPGE) employs a bioinspired honeycomb architecture with ultra‐soft hydrogels, engineered to match the bending stiffness of brain tissue (0.1–10 kPa) while maintaining cost‐efficiency and long‐term durability. This mechanical congruence ensures exceptional cortical conformability and adaptive interfacing, circumventing the geometric and material limitations of traditional rigid electrodes. By combining patient‐specific design with scalable fabrication, our platform establishes a transformative framework for neural interface engineering, enhancing precision, biocompatibility, and functional performance in neuromodulation therapies and neuroprosthetic applications.

Investigating the utilization of LIME-enhanced AI and generated data for evaluating the risks associated with radial artery puncture procedures

Variants in glycine decarboxylase activate catabolic mechanisms of mitochondrial energy metabolism in the brain

Real-world outcomes of first-line enfortumab vedotin plus pembrolizumab in metastatic urothelial carcinoma.

e16595 Background: Metastatic urothelial carcinoma (mUC) is associated with poor prognosis. The approval of enfortumab vedotin plus pembrolizumab (EV+P) has established a new first-line standard of care. We report real-world outcomes of first-line EV+P, including efficacy, tolerability, and the impact of eligibility criteria. Methods: This retrospective cohort study included patients with advanced urothelial carcinoma treated with first-line EV+P at Alexandra Hospital since January 2024. Demographic, clinical, treatment, and safety data were collected from institutional records. Survival outcomes were estimated using Kaplan–Meier methods. Statistical analyses were performed with SPSS. Results: Sixty-two patients received first-line EV+P. Median age was 69.5 years (IQR 61.8–75.2); 12.7% had ECOG performance status (PS) ≥2, 38.1% had received prior (neo)adjuvant platinum-based chemotherapy, and 35.5% had de novo metastatic disease. Median follow-up was 13 months. At data cut-off, 36 patients (58.1%) had discontinued treatment, primarily due to disease progression. Disease control was achieved in 45 patients (72.6%), including complete response in 11 (17.7%), partial response in 22 (35.5%), and stable disease in 12 (19.4%). Median progression-free survival (mPFS) was 9.6 months (95% CI 7.1–12.2), and median overall survival (mOS) was 16.8 months (95% CI 12.9–20.6). Twenty-seven patients (43.5%) progressed on EV+P; 10 subsequently received platinum-based chemotherapy, achieving an mPFS of 6.1 months (95% CI 2.9–9.3). Eight patients did not meet EVITA eligibility criteria, mainly due to ECOG PS ≥2. These patients experienced rapid disease progression (mPFS 1.5 months, 95% CI 0.8–2.2), received no subsequent therapy, and had poor survival (mOS 3.9 months). Among EVITA-eligible patients (n = 54), mPFS was 13.2 months (95% CI 5.9–20.5), and mOS was not reached. Treatment-related adverse events occurred in 25 patients (40.3%), with grade ≥3 toxicity observed in 11 patients (17.7%). Pembrolizumab was permanently discontinued in 10 patients (16.0%) and EV in 13 patients (20.9%) due to toxicity. Treatment discontinuation for toxicity was associated with improved PFS and OS (p < 0.01) and remained significant on multivariable analysis adjusting for age, de novo metastatic disease, and EVITA eligibility (HR 0.32, 95% CI 0.12–0.89). Conclusions: Real-world first-line EV+P demonstrates meaningful clinical activity and manageable toxicity in mUC, with outcomes comparable to EV-302. Benefit appears independent of prior platinum exposure. Patients not meeting EVITA eligibility derive minimal benefit, highlighting the importance of appropriate patient selection.

National trends and mortality burden of lung cancer with secondary brain and meningeal metastases among U.S. adults aged ≥ 55 years: A retrospective National Inpatient Sample analysis from 1999 to 2024.

e20695 Background: Lung cancer remains the leading cause of cancer-related mortality in the United States, with a substantial proportion of deaths attributable to distant metastases, most commonly involving the brain and cerebral meninges. Central nervous system involvement signifies advanced disease and is associated with high morbidity and poor survival. Characterizing long-term national mortality trends and demographic disparities is essential for informing oncologic care and public health strategies. This study examined U.S. mortality patterns where lung cancer was the underlying cause of death (UCOD) with secondary brain and meningeal metastasis. Methods: Mortality data from 1999–2024 were obtained from the CDC WONDER database for adults aged ≥55 years. Lung cancer was identified as the UCOD using ICD-10 codes C34.0–C34.9, with secondary malignant neoplasm of the brain and cerebral meninges identified as a multiple cause of death (C79.3). Age-adjusted mortality rates (AAMRs) per 100,000 population were calculated using the U.S. standard population and stratified by sex, race/ethnicity, age, state, U.S. Census region, and metropolitan status. Temporal trends were analyzed using Joinpoint regression, with statistical significance defined as p < 0.05. Results: Between 1999 and 2024, lung cancer with secondary brain and meningeal metastasis accounted for 193,506 deaths among U.S. adults aged ≥55 years. Overall mortality declined significantly, with AAMRs decreasing from 12.94 in 1999 to 9.30 in 2024 (AAPC: −1.20%). Mortality trends differed by sex; males experienced a significant decline (AAPC: −1.86%), whereas the decline among females was smaller and not statistically significant (AAPC: −0.49%). Metropolitan areas demonstrated a greater reduction in mortality (AAPC: −1.72%) compared with non-metropolitan regions, which exhibited a slower but significant decline (AAPC: −0.81%). A significant late-period increase was observed among non-Hispanic Black individuals (APC 2007–2024: +0.66%). Regionally, the Northeast experienced the most pronounced overall decline (AAPC: −2.19%). Conclusions: Over a 25-year period, lung cancer related mortality with secondary brain and meningeal metastases demonstrated an overall declining trend, despite a notable mid-period increase between 2013 and 2017 followed by a subsequent plateau. Despite overall improvements, mortality remained disproportionately higher among males, non-Hispanic White and Black populations, and residents of non-metropolitan regions. These findings highlight the persistent lethality and unequal burden of advanced lung cancer with CNS involvement, underscoring the need for earlier detection, improved CNS-directed therapies, and geographically targeted interventions to further reduce mortality.

Early-phase drug development in oncology: Geography of trials including US vs China.

e23049 Background: Early-phase oncology drug development is predominantly driven by industry sponsors and spans multiple regulatory regions. A characterization of clinical trial activity and features across different regions is important to understand the impact of recent regulatory shifts put in place to facilitate early-phase clinical trials and increase each region’s competitiveness in a global environment. We aim to analyze whether in the last 2 years early-phase oncology trials regional distribution has changed. Methods: We conducted a retrospective analysis of early phase (Phase I, I/II, II and II/III) interventional oncology trials registered on ClinicalTrials.gov (ct.gov) with start date between January 1st, 2024 and December 31st, 2025. Oncology trials were defined by certain keywords were filtered on ct.gov. Trial patterns were assessed using ct.gov reported characteristics, including geographic scope (single vs multi-country participation) and number of sites (small [1–5 sites], medium [6–10 sites], or large [ > 10 sites]). Regional comparisons were made focusing on China vs US. Comparisons across subgroups were evaluated using chi-square test for categorical variables, with an alpha level of 0.05. Results: Among 2,345 oncology trials meeting inclusion criteria, 1,713 (73.1%) were industry-sponsored, with comparable representation from China (50.5%) and the US (49.0%). Among industry-sponsored Phase I trials, the distribution of single-site versus multi-site designs differed markedly between China and the US (p < 0.00001), with trials including China more frequently single-country (242, 63.0%) and trials run in the US predominantly multi-country (195, 82.3%). Operational scale also differed significantly, with trials including China more commonly limited to small groups and trials including US more frequently expanding to medium and large site counts (China vs US; small 319 (79,4%) vs 142 (35,4%), medium 27(6.7%) vs 102(25.4%), large 25 (13%) vs 138 (34.4%)) (p < 0.00001). These regional design patterns persisted across development stages. More than 80% of US-based industry-sponsored trials were multi-country across all phases, whereas trials including China remained predominantly single-country, with increased multi-country participation observed only at the Phase II/III stage. The China–US difference in geographic scope remained highly significant when all trials were analyzed, including academic and hospital-led studies (p < 0.00001). Conclusions: Early-phase oncology trials demonstrate consistent regional differences in observable design patterns across development stages. Among industry-sponsored programs, trials including China and US differ markedly in geographic scope, operational scale and expansion strategy, with these patterns persisting across phase I and II trials. These findings describe distinct regional approaches to early-phase trial design.

Circulating kynurenine, tryptophan levels, and their ratio in lung cancer: A meta-analysis revealing subtype and outcome specific variations.

e20548 Background: Dysregulation of the kynurenine pathway driven by indoleamine 2,3-dioxygenase-1 (IDO1), contributes to immune escape in lung cancer. Circulating kynurenine (Kyn), tryptophan (Trp), and the kynurenine-to-tryptophan (Kyn:Trp) ratio have been proposed as non-invasive biomarkers; however, reported associations with lung cancer risk, subtype, and outcomes remain inconsistent. Methods: We searched the databases PubMed, Embase, and Scopus for studies published in this context from inception to December 1, 2025. Eligible studies reported circulating Kyn, Trp, or Kyn:Trp in lung cancer patients and controls. Standardized mean differences (SMDs) was used to generate a pooled comparison of biomarker levels between lung cancer and controls. Additionally, we pooled the odds ratios (ORs) of lung cancer incidence and hazard ratios (HRs) for mortality based on high biomarker levels. Results: 8 studies encompassing 6,600+ lung cancer patients and 7,000+ controls were included. Compared with controls, lung cancer patients exhibited significantly lower Trp levels (SMD −1.54, p < 0.00001) and higher Kyn/Trp ratios (SMD 0.48, p = 0.0008), while absolute Kyn levels did not differ significantly. High Kyn (OR 1.20) and high Kyn/Trp ratio (OR 1.43) were associated with increased odds of lung cancer. Subtype analysis revealed a strong association between elevated Kyn/Trp ratio and squamous cell carcinoma (SCC) (OR 2.21), but not adenocarcinoma or SCC. No significant association was observed between Kyn/Trp ratio and mortality. Conclusions: Lung cancer is characterized by systemic Trp depletion and increased Kyn pathway flux. The Kyn/Trp ratio emerges as a robust immune-metabolic biomarker, particularly relevant to SCC, supporting its potential utility in risk stratification and biological phenotyping. Study characteristics and patient demographics. Author and year Study location Study design No. of lung cancer patients Age and gender distribution Histological subtypes Proportion of active smokers Biomarker estimation method NOS score Chen et al. 2025 China Observational 195 51 (21-88)M:F: 61:39 AC: 77%SCC: 17% 20% HPLC 8 Chuang et al. 2013 Europe Case-control 893 59 (42-72)M:F: 62:38 AC: 32%SCC: 22%LCC: 7%SCLC: 16%Other: 23% 59% MS 9 Engin et al. 2009 Turkey Case-control 36 NRM:F: 31:5 NSCLC: 75%SCLC: 25% 11% HPLC 8 Huang et al. 2020 US/Europe/Australia/Asia Case-control 5,364 60 (44-72)M:F: 54:46 AC: 38.4%SCC: 15.5%SCLC: 9.2%LCC: 3.3%Other: 33.6% 47% MS 9 Zhao et al. 2014 China Case-control 27 60 (50-71)M:F: 18:19 NR NR AA analysis 7 Suzuki et al. 2009 Japan Cross-sectional 123 66.4 (10.1)M:F: 99:24 NSCLC: 88%SCLC: 12% NR MS 9 Creelan et al. 2013 USA Single-arm trial 33 62.4(7.9) ACC: 33%SCC: 30%Other: 36% 36% HPLC/MS 9 Mandarano et al. 2021 Italy Cohort 180 68 (38-84)M:F: 71:29 AC: 66%SCC: 34% 42% HPLC 9 https://ibb.co/2p8P3qp.

Fertility concerns, counseling, and preservation in AYA females with early-stage breast cancer: Chemotherapy receipt and timing.

1564 Background: Adolescent and young adult (AYA) females with early-stage ER-negative and/or HER2-positive breast cancer commonly receive chemotherapy to reduce risk of recurrence. Fertility concerns, counseling, and preservation may influence chemotherapy decisions and time to chemotherapy (TTC) initiation. Methods: We surveyed AYA survivors of stage I–III premenopausal ER-negative and/or HER2-positive breast cancer treated at Kaiser Permanente Northern and Southern California (2013-2022). Fertility concerns were defined as not having completed desired family size or being unsure about having completed desired family size at diagnosis. We summarized receipt of fertility counseling, receipt of chemotherapy, and use of oocyte/embryo cryopreservation for fertility preservation (FP). Among fertility-concerned patients who received chemotherapy, TTC (days from diagnosis) was assessed separately for neoadjuvant chemotherapy (NAC) vs for adjuvant chemotherapy (AdjC). Time to NAC was natural log–transformed and modeled with multivariable log-linear regression to estimate relative differences in TTC, adjusting for stage, study site, ER, HER2, age, and diagnosis year. Results: Of 363 respondents, 197 (54%) had fertility concerns at diagnosis; 183/197 (93%) received chemotherapy, similar to 153/166 (92%) among those without concerns (p=0.7). Of the concerned chemotherapy recipients, 45 (25%) saw a fertility specialist but did not pursue FP while 55 (30%) underwent FP. For the 112 fertility-concerned NAC recipients, FP was associated with longer TTC than no fertility specialist counseling (mean=41 vs. 30 days; adjusted ratio=1.39; 95% CI 1.15–1.69), whereas fertility specialist counseling without FP was not (mean= 31 vs. 30 days, adjusted ratio=1.04; 95% CI 0.86–1.25). For the 71 fertility-concerned AdjC recipients, TTC was similar for patients who did not see a fertility specialist (mean=63 days), those who froze oocytes/embryos (mean=65 days), and those who saw a fertility specialist but did not pursue FP (mean=69 days). Conclusions: In this AYA breast cancer cohort, there was no evidence that fertility concerns led patients to decline chemotherapy. FP was associated with a modest delay in NAC initiation (<2 weeks on average). Time to chemotherapy (TTC) among 183 AYA patients with ER− and/or HER2+ breast cancer and fertility concerns. Fertility-focused care N (n=183) Neoadjuvant chemotherapy (n=112) Mean TTC, days Relative difference in TTC, adjusted ratio (95%CI) Adjuvant chemotherapy (n=71) Mean TTC, days No fertility counseling from a specialist 83 (45%) 55 (49%) 29.6 Reference 28 (39%) 62.6 Received fertility counseling from a specialist No fertility preservation 45 (25%) 28 (25%) 30.7 1.04 (0.86,1.25) 17 (24%) 68.6 Fertility preservation 55 (30%) 29 (26%) 41.2 1.39 (1.15,1.69) 26 (37%) 64.6

Association of MET overexpression with patient outcomes in <i>EGFR</i> -mutant lung adenocarcinoma treated with first-line osimertinib.

e20757 Background: Activating EGFR mutations are present in up to 15-30% of lung adenocarcinoma patients, and are known genetic drivers that promote tumor cell growth and survival. Recently, EGFR-targeted therapies, including osimertinib +/- chemotherapy, lazertinib and amivantamab, have been shown to significantly improve overall survival. However, augmentation of MET signaling represents a bypass mechanism contributing to resistance to EGFR-targeted therapies. In this single-center retrospective cohort study, we evaluated the effect of MET overexpression at baseline on outcomes in patients with stage IV lung adenocarcinoma treated with first-line osimertinib. Methods: Among patients treated at NYU Perlmutter Cancer Center from 2019 to present, 51 patients with stage IV EGFR-mutant lung adenocarcinoma treated with first-line osimertinib and available tissue samples were selected. Samples were analyzed by immunohistochemistry (IHC) using the VENTANA MET (SP44) RxDx assay. MET expression was classified as high or low using a c-MET H-score ≥200 cutoff. Primary endpoints were progression-free survival (PFS), treatment response at 12 weeks, and overall survival (OS) as defined by RECIST v1.1. Data were analyzed in R by logistic regression and Cox-proportional hazard analysis to assess the association between MET expression and primary endpoints. Statistical significance was set at a threshold of p &lt; 0.05. Results: Cohort characteristics showed that most patients were female (80.4%), never-smokers (68.6%) with median age 64 years (range 38-87) at start of treatment. EGFR Exon 19 deletions were present in 58.8% of patients and Exon 21 L858R mutations in 41.2%. Median PFS was 11 months in the MET-high group and 15 months in the MET-low group (hazard ratio [HR] 1.07, 95% CI 0.70–1.62; log-rank p = 0.77). Treatment response at 12 weeks did not significantly differ between groups (odds ratio [OR] 1.03, 95% CI 0.49–2.16). Median OS was 32 months in both groups (HR 1.09, 95% CI 0.63–1.86; log-rank p = 0.76). Conclusions: In this retrospective cohort of EGFR-mutant lung adenocarcinoma patients treated with first-line osimertinib, MET overexpression by IHC was not associated with a statistically significant difference in PFS, treatment response, or OS. However, though not statistically significant, median PFS in the MET-high group was shorter by nearly 4 months compared to the MET-low group. These results are limited by small sample size and retrospective design, but support further evaluation of MET as a potential biomarker and target for upfront EGFR and MET targeting therapies in EGFR-mutant lung adenocarcinoma with concomitant MET alterations. Additionally, future studies with paired tissue for MET expression analysis before and after osimertinib treatment could be performed to assess the dynamic nature of MET expression post-osimertinib.

Development and validation of a multidimensional cfDNA assay for cancer detection and tissue-of-origin prediction.

10531 Background: Early detection remains a major unmet need in oncology, and multi-cancer early detection assays that analyze circulating cell-free DNA features have shown promise for detecting multiple cancers with high specificity and tissue-of-origin prediction. Here, we leverage whole-genome sequencing (WGS) to extract multiple cfDNA features (genomic, fragmentomic, and estimated methylation) from a single assay to enable multi-cancer early detection and tissue-of-origin (TOO) localization. Methods: Plasma samples were collected in a multicenter, prospective case-control study. From 5× low-pass WGS data, multiple cfDNA feature sets were extracted, including fragmentomic, genomic, and inferred epigenetic features. Machine learning models were trained for cancer detection (healthy vs. cancer) and tissue-of-origin (TOO) classification. The training set included 3,577 healthy and 3,578 cancer participants, and the independent validation set included 2,384 healthy and 2,386 cancer participants. Cancer cases spanned 56 cancer types, grouped into 21 cancer classes. Results: Age and sex are evenly distributed across healthy and cancer samples in both the training and validation datasets (Table 1). At 99% specificity, cancer detection sensitivity increased with stage and was consistent between training and validation cohorts: Stage I: 70.66% vs 70.89%, Stage II: 80.41% vs 80.27%, Stage III: 89.89% vs 88.58%, and Stage IV: 92.23% vs 91.76%. Across tumor types, sensitivity at 99% specificity varied substantially, ranging from 57.43% (Thyroid tumor) and 63.87% (Kidney cancer) to 95.96% (Lymphoma) and 99.07% (Liver/Biliary cancer). Tissue-of-origin prediction achieved high accuracy in machine-learning predicted cancer-positive samples (Top-1/Top-2: 0.75/0.89 in training; 0.75/0.88 in validation). Conclusions: We developed a cost-efficient blood test (CanScan Pro) using multidimensional cfDNA features from low-pass WGS and machine learning that detects cancers at 99% specificity, with sensitivity increasing by stage and similar performance in training and validation cohorts. The model predicts tissue of origin with high accuracy, which may help guide downstream diagnostic evaluation following a positive result and thereby enhance real-world clinical utility. Patient characteristics. Train Valid Healthy Cancer Healthy Cancer (N=3577) (N=3578) (N=2384) (N=2386) Age Mean (SD) 57.8 (6.46) 57.7 (14.74) 58.1 (6.63) 57.2 (15.00) Median [Min, Max] 57.0 [45.0 ,76.0] 60.0 [11.0 ,91.0] 57.0 [45.0 ,76.0] 59.0 [11.0 ,92.0] Sex F 2018 (56.4%) 1655 (46.3%) 1355 (56.8%) 1101 (46.1%) M 1559 (43.6%) 1923 (53.7%) 1029 (43.2%) 1285 (53.9%) Stage TNM - 3577 (100%) 0 (0%) 2384 (100%) 0 (0%) I 0 (0%) 1060 (29.6%) 0 (0%) 718 (30.1%) II 0 (0%) 883 (24.7%) 0 (0%) 588 (24.6%) III 0 (0%) 811 (22.7%) 0 (0%) 534 (22.4%) IV 0 (0%) 824 (23.0%) 0 (0%) 546 (22.9%)

ABBV-706 as monotherapy and in combination with budigalimab in patients with relapsed/refractory (R/R) small cell lung cancer (SCLC).

8008 Background: SCLC is an aggressive cancer with poor prognosis and limited treatment options. Seizure-related 6 homolog (SEZ6) is overexpressed in SCLC. ABBV-706 is a SEZ6-targeting antibody-drug conjugate with topoisomerase 1-inhibitor payload. Here we report updated data from a phase 1 study (NCT05599984) evaluating ABBV-706 in patients (pts) with R/R SCLC as monotherapy or in combination with budigalimab (Budi), an anti-PD-1 immune checkpoint inhibitor (CPI). Methods: The study enrolled pts ≥18 years old with R/R SCLC and Eastern Cooperative Oncology Group performance score ≤1. Pts received either ABBV-706 monotherapy every 3 weeks (Q3W), or in combination with 375 mg Budi Q3W. Results: As of Sept. 27, 2025, 124 pts received ABBV-706 monotherapy. Of these, 41 received the recommended phase 3 dose (1.8 mg/kg), with 17 receiving ABBV-706 as a second-line (2L) therapy. Overall, median age was 64 years, and most pts (65%) received at least 2L of prior treatment. The safety profile was comparable with previously reported data. Median follow-up (mFU) was 16.2 months, and median overall survival (mOS) overall (N=124) and among pts receiving 1.8 mg/kg as 2L (n=17) was 11.3 and 14.3 months, respectively. The 15-month OS estimates for the same cohorts were 40% and 50%, respectively. As of Sept. 27, 2025, 11 pts received ABBV-706 (1.8 mg/kg Q3W) + Budi as 2L treatment. Median age was 68 years. No new safety signals were detected as compared to monotherapy, and there were no reports of pneumonitis. Treatment-related adverse events (TRAEs) occurred in 91% of pts, most commonly gastrointestinal (64%) and hematological (64%). TRAEs grade ≥3 occurred in 46% of pts, with anemia (27%) and neutrophil count decreased (18%) being most common. TRAEs led to treatment discontinuation, interruption, or dose reduction in 0%, 64%, and 36% of pts, respectively. No treatment-related deaths were reported. mFU was 9.1 months. Detailed efficacy endpoints are shown in the Table. Conclusions: ABBV-706 monotherapy shows promising OS benefit in a heavily pretreated pt population with R/R SCLC and is combinable with a CPI. Clinical trial information: NCT05599984 . Efficacy of ABBV-706 in R/R SCLC. MonotherapyTotal(N=124) Monotherapy1.8 mg/kg (n=41) Monotherapy1.8 mg/kg as 2L(n=17) ABBV-706 1.8 mg/kg + Budi(n=11) Best overall response, a,b n (%) Complete response 3 (2) 3 (7) 2 (12) 0 Partial response c 64 (52) 20 (50) 12 (71) 6 (55) Stable disease 46 (37) 16 (39) 2 (12) 3 (27) Progressive disease 6 (5) 1 (2) 1 (6) 1 (9) NE/not assessed 5 (4) 1 (2) 0 1 (9) Objective response rate a (%) 52 56 82 55 Median duration of response, months 5.3 d 5.9 e 6.6 f 6.7 g Median progression-free survival, months 5.4 6.4 6.8 8.1 mOS, months 11.3 12.4 14.3 NE OS estimate at 15 months, % 40 44 50 NE a Confirmed by investigator per RECIST v1.1. b Percentages may exceed 100% due to rounding. c Includes 2 pts with unconfirmed partial response and ongoing treatment. d n=65. e n=23. f n=14. g n=6.

First-in-human novel bispecific epitope anti-CD5 nanobody CAR-T cells for refractory or relapsed T-cell malignancies.

7015 Background: Refractory/relapse (r/r) aggressive T-cell lymphomas have poor prognosis with 5-year PFS of 20~30%, meanwhile CAR-T therapy brings new hope to this progressive disease. We previously reported allogeneic humanized CD5 CAR-T (huCD5 CAR) therapy achieved 100% ORR in r/r acute T lymphoblastic leukemia/lymphoma (T-ALL) patients. However, huCD5 CAR-T exhibit insufficient expansion activity, necessitating the optimization of CAR-T structure. Here, we developed a llama-derived nanobody-based bispecific epitope anti-CD5 CAR (NbCD5 CAR) construct, and evaluated its efficacy and safety in r/r T-ALL and T-cell non-Hodgkin’s Lymphoma (T-NHL). Methods: llama-derived nanobody library was utilized to screen for CD5-specific nanobodies. The efficacy was then examined in NSG mice inoculated with Jurkat cell line. Tumor burden was assessed by flow cytometry and bioluminescent imaging. Finally, the efficacy and safety of the NbCAR vector were evaluated in the trials of r/r T-ALL (NCT07070323) and r/r T-NHL (NCT07022964). Results: We selected the NbCD5 CAR-T cells with superior cytotoxicity against T-cell lines compared to huCD5 CAR-T constructs. Then we determined its efficacy in NSG mice inoculated with Jurkat cell line. On day 7 post-tumor inoculation, mice received either Mock-T, huCD5 CAR-T or NbCD5 CAR-T cells. We observed that the NbCD5 CAR completely controlled tumor burden in mice and showed superior efficacy compared to huCD5 CAR. Then we proceed to the clinical trials containing 5 cases of T-ALL and 9 cases of T-NHL. In the T-ALL cohort, 3 patients have history of allo SCT, 4 patients received prior CD7 CAR-T therapy. All patients have infused 1.0×10 6 /kg NbCD5 CAR-T cells. The adverse events (AEs) included grade 1 CRS (5/5), grade 2 ICANS (1/5), and grade 1~2 GVHD (2/5). All patients achieved CR at day 30 evaluation. In the median follow-up time of 80 days, 2 patients bridged to allo SCT, 1 patient relapsed at day 45 and died shortly thereafter. In the T-NHL cohort, 9 patients aged 30 to 64 have failed of at least 2 lines of chemotherapy, and 1 patient had history of auto SCT. The patients have received 1.0×10 6 /kg NbCD5 CAR-T cells. All patients had grade 1-2 CRS, no ICANS was reported. Notably, EBV reactivation (5/9) was observed, including Grade 3-5 EBV reactivation (3/9). The ORR was 66.7% at day 30, 2 patients failed to respond for CAR-T expansion failure or weak CD5 expression. The CAR-T expansion was reached its peak at day 12 (range: 11-17), with the clearance of CD5 + T cells in blood. In the median follow-up time of 94 days, 5 patients bridged to allo SCT. Conclusions: We optimized the nanobody NbCD5 CAR construct and showed superior cytotoxicity in vitro and in vivo . We also got preliminary safety and efficacy profiles in r/r T-ALL and T-NHL. This clinical trial is still ongoing, and long-term efficacy and clinical complication of CD5 CAR-T cell therapy still require further investigation. Clinical trial information: NCT07070323 , NCT07022964 .

Cancer outcome among adolescents in Canada.

10024 Background: Adolescents and young adults (AYA) with cancer, commonly defined as patients aged 15–39 years at diagnosis, experience higher morbidity and mortality compared with other age groups. In this study, we compared outcomes of adolescents with newly diagnosed cancer treated at Canadian pediatric oncology centers with those of younger children. Methods: We conducted a retrospective cohort study using the population-based CYP-C database, including children aged 1–18 years with newly diagnosed cancer across Canada (2015–2020). Event-free survival (EFS) and overall survival (OS) were compared between adolescents (15–18 years) and younger children (1 to &lt;15 years) across cancer subtypes using Kaplan–Meier analyses and univariable and multivariable Cox proportional hazards models. Results: Of the 6,794 patients, adolescents aged 15–18 years comprised 16% (n=1,075) of the cohort. Median age at diagnosis was 16 years (IQR: 15.7–17.2), and among those with solid tumors, 26% (n=150) had metastatic disease at diagnosis. The most frequent adolescent cancers were Hodgkin lymphoma (20%), gliomas and other glioneuronal tumors (12%), acute lymphoblastic leukemia (11%), osteosarcoma (6%), thyroid carcinoma (6%), malignant extracranial germ cell tumors (5%), and Ewing sarcoma (4%). Adolescents with leukemia had comparable 5-year EFS (71% vs. 79%; p=0.06) and OS (83% vs. 89%; p=0.07) to younger children, as did those with non-central nervous system (CNS) solid tumors for EFS (65% vs. 65%; p=0.55) and OS (74% vs. 75%; p=0.23). Among patients with sarcomas, adolescents had similar 5-year EFS (50.7% vs. 52.0%, p=0.55) and OS (55.6 vs. 59.7%, p=0.14) to younger children. Adolescents with CNS tumors had superior EFS (83% vs. 66%; p=0.005) and OS (89% vs. 73%; p=0.006), primarily driven by ependymoma and choroid plexus tumors, and other gliomas/glioneuronal tumors excluding pilocytic astrocytoma. Conclusions: Although AYA with cancer are often reported to have poorer outcomes, adolescents aged 15–18 years treated exclusively in Canadian pediatric oncology centers did not have inferior outcomes to younger children, underscoring the effectiveness of pediatric treatment approaches. 5-year EFS and 5-year OS of adolescents (≥15 years-old) vs. younger children (1 to &lt; 15 years old) across major cancer categories. - Adolescents 5-year EFS (%) [95% CI] Younger children 5-year EFS (%) [95% CI] p-value Adolescents 5-year OS (%) [95% CI] Younger children 5-year OS (%) [95% CI] p-value All cancers 76.4 [72.8-79.9] 72.6 [70.8-74.3] 0.12 84.7 [81.4-87.4] 81.1 [79.6-82.7] 0.13 Leukemias 71.2 [58.7-80.5] 79.0 [75.8-81.9] 0.06 83.2 [73.3-89.7] 88.6 [86.2-90.6] 0.07 Lymphomas 88.5 [82.6-92.5] 87.3 [82.6-90.7] 0.63 96.2 [91.9-98.3] 95.5 [92.7-97.3] 0.50 Non-CNS solid tumors 65.4 [58.6-71.3] 65.2 [61.8-68.3] 0.55 73.5 [66.7-79.0] 74.8 [71.5-77.9] 0.23 CNS tumors 83.1 [74.2-89.1] 66.3 [62.5-69.8] 0.005 89.1 [82.0-93.5] 72.5 [68.8-75.9] 0.006

Overall survival differences by treatment setting in older adults with classical Hodgkin lymphoma: A National Cancer Database analysis.

e19037 Background: Classical Hodgkin lymphoma (cHL) has high cure rates in younger patients but worse outcomes in older adults. Five-year overall survival (OS) in elderly patients ranges from 49–65%, compared with nearly 90% in younger cohorts. These disparities are attributed to higher relapse rates, treatment-related mortality and intolerance. Despite this, data examining outcomes in elderly cHL patients remain limited. We evaluated the impact of treatment setting on survival in cHL patients aged &gt; 75 years. To our knowledge, this is first analysis comparing characteristics and survival between older patients treated at academic cancer programs (ACP) versus community cancer programs (CCP). Methods: We performed a retrospective analysis of U.S. patients with cHL from 2004–2022 using the National Cancer Database (NCDB). Demographic, clinical, and survival data were compared between ACP and CCP. ACP included academic and NCI-designated centers; CCP included community, comprehensive community, and integrated network programs. Kaplan-Meier and Cox models compared OS, adjusting for age, race/ethnicity, insurance status, Charlson-Deyo score, and distance from facility. Results: Among 9,330 patients, 49% were treated at ACPs and 51% at CCPs. Sex distribution was similar (49% female, 51% male), with median age 80 years. Most patients were non-Hispanic (NH) and predominantly White. ACP treated more Hispanic patients (8.7% vs 7.3%, p = 0.02), while CCPs treated more NH patients (88% vs 87%, p &lt; 0.001). Medicare was the most common insurance type (ACP 85%, CCP 88%, p &lt; 0.001), followed by private insurance (9% vs 8%, p &lt; 0.001). Charlson-Deyo score ≥2 was present in 12% of both groups. More patients with Stage III–IV disease were treated at ACP (55% vs 51%, p = 0.005). Median time to treatment was 25 days for ACPs and 26 days for CCP. More ACP patients underwent treatment than CCP patients (58% vs 54%, p &lt; 0.001). Median time from diagnosis to last contact or death was 21 months at ACPs versus 14 months at CCP (p &lt; 0.001). Two and five-year survival for ACP vs CCP was 52% vs 47% and 35% vs 32%, respectively. Median survival time was 2.25 years for ACP and 1.57 years for CCP, with a statistically significant overall survival advantage for ACP (p &lt; 0.001). Conclusions: Among patients aged ≥75 years with cHL, treatment at ACP was associated with a statistically significant improvement in OS compared with CCP (log-rank p &lt; 0.001), despite a higher proportion of advanced-stage disease at ACP. These differences occurred alongside higher treatment rates and longer follow-up at ACP. While outcomes for older adults with cHL remain inferior to those of younger patients, this analysis suggests that treatment setting is an important system-level factor influencing survival. Further studies are needed to identify modifiable components of care delivery and optimize treatment strategies for this high-risk population.