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An open-label phase 1 study of DCC-2812 monotherapy in patients with advanced genitourinary cancers.

TPS4639 Background: The integrated stress response (ISR) is a major adaptive cellular response pathway that cancer cells depend on to survive in the context of oncogenic pathway activation and high proliferative demand. The ISR is tightly regulated by stress-sensing kinases, including general control nonderepressible 2 (GCN2). Under a controllable level of cellular stress, moderate activation of GCN2 promotes adaptation to nutrient and oxygen deficiency, supporting cancer cell survival. In contrast, excessive GCN2 activation in response to unresolvable stress leads to the induction of pro-apoptotic genes and cancer cell death, making pharmacologic activation of this pathway a promising therapeutic strategy. DCC-2812 is an investigational, potent, and selective activator of GCN2 and the ISR pathway in cancer cells. In preclinical studies, DCC-2812 upregulated the ISR pathway and demonstrated single-agent antitumor activity in a variety of cancer cell lines, including those of renal and urothelial origin. DCC-2812 also inhibited tumor growth in vivo in xenograft models of renal cell carcinoma (RCC) and urothelial cell carcinoma. Here, we describe an ongoing phase 1 study evaluating DCC-2812 as a monotherapy in patients with advanced genitourinary cancers. Methods: This is a multicenter, open-label, phase 1 dose-escalation study evaluating the safety and preliminary antitumor activity of DCC-2812 in adult patients (≥18 years) with histologically or cytologically confirmed advanced or metastatic RCC, urothelial cancer, or castration-resistant prostate cancer (NCT06966024). Eligible patients must have experienced disease progression on or be intolerant of standard-of-care therapies and must have adequate organ function as well as the ability to take oral medication. Individuals will be excluded if they received any anticancer therapy (other than luteinizing hormone–releasing hormone agonists/antagonists for prostate cancer) or investigational therapy within a specified timeframe prior to the first dose of DCC-2812, have impaired cardiac function, or had major surgery within 28 days of the first dose of DCC-2812. Enrolled patients will receive DCC-2812 orally in 28-day cycles. The primary outcome measures are the number of patients with dose-limiting toxicities during cycle 1, treatment-emergent adverse events (TEAEs) and serious adverse events, and dose modifications due to TEAEs. Secondary outcome measures include radiographic objective response rate and radiographic duration of response per Response Evaluation Criteria in Solid Tumors version 1.1 and Prostate Cancer Working Group 3 criteria, if applicable, as well as pharmacokinetics. The study is currently recruiting patients at multiple sites in the United States. Clinical trial information: NCT06966024 .

Association between pan-immune-inflammation value and clinical outcomes in critically ill patients with hyperlipidemia: An observational study

Background Hyperlipidemia contributes to immune-inflammatory imbalance and poor outcomes in critical illness. The pan-immune-inflammation value (PIV), derived from neutrophil, monocyte, platelet, and lymphocyte counts, may capture this burden, but its prognostic value in critically ill patients with hyperlipidemia is unclear. Methods We conducted a retrospective cohort study using MIMIC-IV (v3.1). Adults with a first ICU admission and ICD-coded hyperlipidemia, with complete blood counts within 24 h, were included. lnPIV (ln-transformed PIV) was analyzed as continuous and categorical (quartiles) exposures. Primary outcomes were 28-, 90-, and 180-day mortality; secondary outcomes included ICU and in-hospital mortality, acute kidney injury (AKI), and delirium. Survival, Cox regression, restricted cubic spline (RCS), and ROC analyses were applied. Results Among 12,408 patients (mean age 70 years; 38.6% female), 1,309 died in hospital. Higher lnPIV was independently associated with 28-day (HR = 1.14, 95% CI: 1.10–1.18), 90-day (HR = 1.15, 95% CI: 1.11–1.18), and 180-day mortality (HR = 1.13, 95% CI: 1.10–1.16; all P < 0.001). RCS analysis identified a threshold at PIV ≈ 172, above which mortality risk increased sharply. The highest quartile had significantly greater in-hospital mortality risk (OR = 1.85, 95% CI: 1.50–2.29). Adding PIV to the SOFA score significantly improved discrimination (AUC increased from 0.55 to 0.67, P < 0.001) and provided positive net benefit across clinically relevant threshold probabilities. lnPIV was also associated with AKI and delirium. Conclusion Elevated PIV is independently associated with mortality and adverse outcomes in critically ill patients with hyperlipidemia. As a simple and readily available composite marker, PIV may complement existing risk scores for early risk stratification in this vulnerable population.

Electron-beam irradiation–induced quasi-annealing enables enhanced thermoelectrics in commercial <i>n</i> -type Bi2Te2.7Se0.3

Commercial n-type Bi2Te2.7Se0.3 is widely employed for near-room-temperature thermoelectric (TE) applications; however, its TE performance remains inferior to that of p-type Bi0.5Sb1.5Te3, resulting in a pronounced p–n mismatch in Bi2Te3-based TE devices. Here, we report a simple, scalable, and composition-invariant post-treatment via high-energy electron-beam irradiation to enhance the TE performance of n-Bi2Te2.7Se0.3. The improvement originates from an irradiation-induced quasi-annealing effect associated with high-energy electron–electron-cloud interactions, whereby an appropriate dose enhances structural ordering, suppresses carrier scattering, and markedly enhances carrier mobility, thereby optimizing electrical transport. At an optimal dose of 400 kGy, the sample achieves a peak ZT of ∼1.35 at 353 K, a room-temperature ZT of ∼1.24, and an average ZTavg of ∼1.29 over 303–403 K. This work establishes electron-beam irradiation as an efficient and environmentally benign strategy for optimizing commercial n-type Bi2Te2.7Se0.3, offering practical implications for high-efficiency TE device applications.

Substrate type effect on the structural, morphological and optical band gap of spray deposited CuO thin films

Revealing the Role of MOF and COF Reticular Chemistry in Solid State Batteries: From Electrode to Electrolyte Design

ABSTRACT Solid‐state batteries (SSBs) are considered next‐generation energy storage technologies due to their intrinsic safety and high energy density. However, their widespread commercial introduction is still hindered by slow ion transport and unstable interfaces. Reticular compounds, including metal‐organic frameworks (MOFs) and covalent organic frameworks (COFs), offer a growing toolset to address these limitations through ordered porosity, modular chemical functionality, and structural tunability. Solid electrolytes with directed ion pathways, mechanically flexible cathodes to stabilize high‐voltage chemistries, and anode interfaces that regulate ion flow and prevent dendritic growth can all be effectively engineered through reticular chemistry. This review first outlines the primary challenges of SSBs, subsequently conducting a critical role of reticular compounds within electrolytes, cathodes, and anodes, emphasizing the influence of reticular modulation strategies and the recent plethora in framework‐integrated batteries. Operando and multiscale characterizations are essential for elucidating these framework behaviors, and a dedicated section is also included to contextualize these design concepts and demonstrate how such modularity functions in practical SSBs. Finally, future directions are proposed to guide the systematic design of reticular compounds based SSBs, aiming to motivate the wider community in advancing safe, high‐performance, and scalable solid‐state energy storage systems.

Mechanical and tribological response of red brick dust filled hemp-epoxy composites using response surface methodology and machine learning approach

The Pof1 nicotinamide mononucleotide adenylyl transferase has a non-canonical role in NAD+ metabolism in the budding yeast Saccharomyces cerevisiae

Associations of autoimmune diseases with appendiceal cancer in a population-based study.

e16495 Background: Appendiceal cancer has a fast rising incidence, especially in younger adults. Causal factors of appendiceal cancers are unknown. There is immune dysregulation in appendiceal cancers, which is relevant given the significance of the appendix in mucosal immune regulation. We hypothesized that autoimmune and benign thyroid conditions, potentially including under-recognized autoimmune thyroiditis, are associated with appendiceal cancer. Methods: Using the All of Us Research Program (v8), a large, diverse U.S. cohort integrating electronic health record and survey data, we conducted a population-based study comparing adults with appendiceal adenocarcinoma to cancer-free controls. Autoimmune diseases were identified using ICD codes, and thyroid disorders were classified as autoimmune (Graves’ disease, Hashimoto’s thyroiditis) or benign (all other non-autoimmune thyroid disorders). Controls were adult participants with electronic health record and demographic data and no history of primary malignancy. Age- and sex-adjusted logistic regression estimated odds ratios (ORs). Results: Among 203 appendiceal cancer cases and 327,591 cancer-free controls, cases had a higher prevalence of any autoimmune disease (18.7% vs 10.2%, p&lt;0.001), inflammatory bowel disease (IBD), autoimmune thyroid disease, rheumatoid arthritis (RA), and benign thyroid disorders (32.5% vs 11.2%) (all p&lt;0.01). In age- and sex-adjusted analyses (Table), appendiceal cancer was associated with multiple immune-mediated conditions, most strongly IBD, as well as with non-autoimmune thyroid disorders. Additional associations were observed for RA, autoimmune thyroid disease, type 1 diabetes, and any autoimmune disease. Conclusions: Autoimmune diseases and non-autoimmune thyroid diseases are associated with appendiceal cancer in age- and sex-adjusted models in this cohort. Further investigation into immune-mediated and thyroid-related pathways contributing to the causal pathway of appendiceal cancer is essential, especially given other published data suggesting a parallel rapidly increasing incidence of these diseases. Prevalence and adjusted associations with appendiceal cancer. Condition Cases (%) Controls (%) Adjusted OR (95% CI) p-value Any autoimmune disease 38 (18.7%) 33,372 (10.2%) 1.92 (1.33-2.71) &lt;0.001 IBD ≤20 4,852 (1.5%) 3.82 (1.95-6.67) &lt;0.001 RA ≤20 8,030 (2.5%) 2.40 (1.29-4.07) 0.003 Type 1 diabetes ≤20 5,844 (1.8%) 2.24 (1.01-4.25) 0.026 Autoimmune thyroid disease ≤20 6,558 (2.0%) 2.37 (1.17-4.27) 0.008 Benign thyroid disorders 66 (32.5%) 36,814 (11.2%) 3.47 (2.54-4.72) &lt;0.001

FID-007 in combination with cetuximab in recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC).

6020 Background: Paclitaxel is commonly used to treat HNSCC but is associated with infusion-related reactions and peripheral neuropathy (PN). Historically, the median progression-free survival (PFS) of standard of care, second line therapy for metastatic HNSCC is 2-3 months (mo). FID-007 is a novel nanoencapsulated paclitaxel utilizing a proprietary poly(2-ethyl-2-oxazoline) polymer excipient. This formulation overcomes the limited water solubility and pharmacodynamics of paclitaxel, enhancing both tumor penetration and retention. Methods: FID-007-003 is an ongoing phase 2, randomized, multicenter, open-label study. Patients must have progressed after anti-PD1/PD-L1 therapy and have not received &gt;1 line of prior therapy for R/M HNSCC. Prior cetuximab or taxane in the R/M setting were not allowed. Patients were stratified by p16 status and prior taxane exposure, and randomized 1:1 to one of two doses of FID-007 (Arm A: 75 mg/m 2 ; Arm B: 125 mg/m 2 ) IV on days 1, 8, and 15 in combination with cetuximab 500 mg/m 2 IV on days 1 and 15 every 28 days starting with Cycle 2. The primary endpoint was investigator-assessed objective response rate (ORR) by RECIST 1.1. Results: As of the preliminary data cut-off date of 20DEC2025, 45 patients were randomized and received ≥ 1 dose of FID-007; 42 patients were efficacy-evaluable (19 in Arm A, 23 in Arm B). Median age was 65 years (range 45-81), 62% (28/45) received prior platinum-based therapy and 67% (30/45) received 1 prior systemic therapy for R/M disease. The median cumulative dose of FID-007 was 825 mg/m 2 in Arm A and 1,450 mg/m 2 in Arm B. The median duration of treatment was 4 mo in Arm A and 4.3 mo in Arm B, with a median follow-up of 4.2 mo. The ORR/complete response (CR) rate was 60%/17% (58%/11% in Arm A, 61%/22% in Arm B), and the median PFS was 7.2 mo [6.7 mo in Arm A (2.0-12.8), and 7.2 mo in Arm B (4.0-NR)]. The median duration of response was 7.4 mo (7.4 mo in Arm A, NR in Arm B) with 56% (14/25) of responders continuing to respond at the time of data cut-off. The overall survival data are immature at present. Treatment-related adverse events (TRAEs) were mostly of grade 1-2. Grade 3-4 TRAEs occurring in ≥ 2 patients included neutropenia (3 in Arm A, 5 in Arm B), anemia (2 in Arm A, 4 in Arm B), leukopenia (3 in Arm B), acneiform dermatitis (2 in Arm A), maculo-papular rash and other rash (2 in Arm B). There was 1 Grade 5 TRAE: pneumonia (Arm B). Conclusions: FID-007, administered in combination with cetuximab, demonstrated clinically encouraging and durable anticancer activity at both doses tested in this population of pre-treated R/M HNSCC. Notably, the absence of infusion-related reactions and the lack of grade ≥ 3 PN, along with a tolerable safety profile potentially compares favorably with other taxanes, which may ultimately enable a longer treatment duration and lead to improved therapeutic outcomes. Clinical trial information: NCT06332092 .

Paclitaxel/cisplatin (TP) vs cisplatin/5-fluorouracil (PF) neoadjuvant chemoradiotherapy for locally advanced esophageal squamous cell carcinoma (ESCC): A randomized trial.

4084 Background: Neoadjuvant chemoradiotherapy (nCRT) followed by esophagectomy is standard treatment for patients with resectable locally advanced ESCC. A direct comparison of taxane/platinum nCRT versus PF nCRT in prospective randomized clinical trials has never been reported. Methods: This is a single-center, open-label, randomized phase II/III trial (registered as NCT0623737 at ClinicalTrial.gov). Patients with locally advanced ESCC (T3/4aN0M0 or T1-3N1-3M0 per AJCC 7 th ed.) were randomized 1:1 to TP (paclitaxel 50 mg/m2 weekly plus cisplatin 30 mg/m2 weekly for 5 weeks) or PF (cisplatin 75 mg/m2 day 1 plus 5-FU 1,000 mg/m2 days 1-4 on weeks 1 and 5) chemotherapy with concurrent radiotherapy 45 Gy/25 fractions. Esophagectomy was performed 6 to 10 weeks after completing CRT. Primary endpoint was pathological complete response (pCR) rate for phase II part. If significant pCR benefit of TP versus PF nCRT was found in phase II part, the trial would continue enrolment for the phase III part with overall survival as primary endpoint. Results: From Mar 2017 to Jul 2025, 128 patients were enrolled in the phase II part; 6 withdrew before treatment. The intention-to-treat (ITT) population included 122 patients (61 patients per arm); median age was 61 (35-77) years with TP and 58 (39-77) with PF; 90% and 89% were male, respectively. Esophagectomy was performed in 51/61 (84%) vs. 49/61 (80%), and R0 resection was achieved in 43/51 (84%) vs. 36/49 (73%) ( p =0.183), respectively. The pCR rate per ITT population was 23/61 (37.7%) with TP vs 17/61 (27.9%) with PF ( p =0.247). The difference of pCR rate did not meet the boundary to continue the trial to the phase III part. Median overall survival was 54 vs 43 months (HR 0.76; p =0.284) and median progression-free survival was 33 vs 25 months (HR 0.74; p =0.193) for TP vs PF. Median recurrence free survival was not reached in both arms. Grade 3-4 adverse events during nCRT occurred in 29/61 (47.5%) with TP and 40/61 (65.6%) with PF ( p =0.045); most common grade ≥3 events were leucopenia (23.0% vs 32.8%), esophagitis (11.5% vs 29.5%), and dysphagia (14.8% vs 27.9%). Postoperative 90-day mortality was 0% in both arms. Conclusions: TP-nCRT did not significantly improve pCR versus PF-nCRT in patients with locally advanced ESCC. Clinical trial information: NCT0623737 . Efficacy and safety outcomes for TP-nCRT versus PF-nCRT. TP PF Statistics ITT, n 61 61 - Resection, n (%) 51 (84) 49 (80) p =0.638 R0 resection rate (%) 43/51 (84) 36/49 (73) p =0.183 pCR (ITT) rate (%) 23/61 (37.7) 17/61 (27.9) p =0.247 pCR (resected population) rate (%) 23/51 (45.1) 17/49 (34.7) p =0.288 OS, median (mo) 54 43 HR 0.76; p =0.284 PFS, median (mo) 33 25 HR 0.74; p =0.193 Grade 3-4 AEs during nCRT, n (%) 29 (47.5%) 40 (65.6%) p =0.045 Postoperative 90-day mortality 0 0 -

Randomized phase II study of amivantamab + lazertinib versus afatinib in patients with uncommon/compound <i>EGFR</i> -mutated non-small cell lung cancer (WJOG17323L: AGEHA study).

TPS8676 Background: While EGFR tyrosine kinase inhibitors (TKIs) such as afatinib are standard treatments for patients with advanced non-small cell lung cancer (NSCLC) harboring uncommon or compound EGFR mutations (excluding exon 20 insertions and T790M), the duration of response is often limited, with a median progression-free survival (PFS) of approximately 8 to 10 months. Amivantamab is an EGFR mesenchymal–epithelial transition factor (MET) bispecific antibody with immune cell–directing activity that has multiple mechanisms of action as defined in preclinical models. For common EGFR mutated NSCLC, combination therapy with lazertinib has been approved in several countries based on its superiority in Phase III trial. Although a phase I study of amivantamab plus lazertinib combination therapy showed promising efficacy with a median PFS of 19.5 months in treatment-naïve patients with uncommon or compound EGFR mutations, this was a small-scale non-comparative study where efficacy was not the primary endpoint. The AGEHA study (WJOG17323L) is designed to prospectively evaluate whether amivantamab + lazertinib provides superior efficacy and acceptable safety compared to afatinib in patients with treatment-naïve, uncommon or compound EGFR mutated NSCLC. Methods: This multicenter, randomized, open-label, phase II trial is conducted by the West Japan Oncology Group (WJOG). Eligible patients are randomized in a 1:1 ratio to receive either combination therapy with amivantamab plus lazertinib in Arm A, or afatinib monotherapy in Arm B. The primary objective is to compare PFS between the two treatment arms. Secondary objectives include safety, overall response rate, and overall survival. Additionally, mandatory blood samples are collected at baseline and at the time of disease progression for comprehensive biomarker analysis using the Guardant Health platform to identify molecular predictors of response and resistance mechanisms, including approximately 740 gene alterations and methylation abnormalities. The target sample size is 70 patients (35 per arm). This study is designed with a one-sided alpha of 0.1 and a power of 80% to detect the superiority of amivantamab plus lazertinib over afatinib monotherapy. The primary analysis will compare PFS using a stratified log-rank test, and hazard ratios will be estimated using a Cox proportional hazards model. Key Eligibility Criteria: Patients must be histologically confirmed advanced or recurrent non-squamous NSCLC harboring uncommon or compound EGFR mutations, excluding exon 20 insertions and T790M. Participants must be treatment-naïve for advanced disease with an ECOG performance status of 0–1. Patient enrollment began in January 2026, with a recruitment period of two years and a total study duration of five years. Clinical trial information: jRCTs031250560 .

Predictors of biomarker-directed therapy utilization in metastatic colorectal cancer: A real-world analysis.

e15572 Background: The treatment landscape of metastatic colorectal cancer (mCRC) has evolved with identification of actionable biomarkers. However, despite inclusion of biomarker-directed therapies in NCCN guidelines, real-world uptake remains poorly defined. We evaluated predictors of receipt of biomarker-directed therapy in a large, real-world cohort of patients with BRAF V600E-mutated, KRAS G12C-mutated, and RAS/RAF wild-type (WT) mCRC. Methods: In this retrospective cohort study, we analyzed the Flatiron Health Research Database. Cohorts included patients with BRAF V600E-mutated, KRAS G12C-mutated, and RAS/RAF WT mCRC. The primary outcome was receipt of any NCCN-recommended biomarker-directed therapy at any line since FDA-approval. Univariable associations between demographic and clinical factors and therapy receipt were assessed within each cohort. Multivariable logistic regression estimated adjusted odds ratios (ORs) for treatment receipt, incorporating age, sex, baseline ECOG, primary tumor site, insurance, and stage. Results: A total of 12,226 patients were included. Among 1,336 patients with BRAF V600E, 26.2% (n = 350) received BRAF-targeted therapy. Treated patients were younger (median 66 vs 72 years, p &lt; 0.001) and had better performance status. In multivariable analysis, increasing age (OR 0.96 per year, p &lt; 0.001), ECOG 2 vs 0 (OR 0.60, p = 0.036), and ECOG 3 vs 0 (OR 0.19, p = 0.002) were independently associated with lower odds of therapy receipt. Race and tumor site were not associated with treatment receipt after adjustment. Among 93 patients with KRAS G12C, 10.8% (n = 10) received KRAS-targeted therapy. No significant predictors of receipt were identified, likely due to limited sample size. Among 10,797 patients with RAS/RAF WT mCRC, 44.5% (n = 4,803) received anti-EGFR targeted therapy. In multivariable analysis, older age (OR 0.98 per year, p &lt; 0.001) and worse performance status (ECOG 2 vs 0: OR 0.79, p = 0.006; ECOG 3 vs 0: OR 0.70, p = 0.021) were associated with lower odds of treatment receipt. Male sex (OR 1.27, p &lt; 0.001), rectal primary tumor site (OR 1.15, p = 0.008), Medicare insurance (OR 1.26, p = 0.003), and uninsured/self-pay status (OR 1.48, p &lt; 0.001) were associated with higher odds of receiving targeted therapy, while race, ethnicity, and SES were not independent predictors. Conclusions: Receipt of guideline-recommended biomarker-directed therapy was suboptimal, particularly for BRAF V600E and KRAS G12C mutations. Older age and worse performance status consistently predicted lower treatment receipt, suggesting clinical fitness drives the gap between biomarker identification and therapy. Notably, nearly three-quarters of patients with BRAF V600E mutations did not receive targeted therapy. These findings reveal underutilization of precision oncology in mCRC and highlight the need for interventions to improve access to therapy for eligible patients.

TRUST: An MRI-based AI framework for non-invasive prediction of treatment response and prognosis in breast cancer.

e12556 Background: The tumor microenvironment (TME) plays a pivotal role in therapeutic response and prognosis in breast cancer. Although stromal tumor-infiltrating lymphocytes (sTILs) and tumor-stroma ratio (TSR) are established biomarkers, they capture immune infiltration and stromal architecture separately and are limited by biopsy sampling bias and invasiveness. We aimed to establish an integrated immune-stromal classification and develop a non-invasive, MRI-based artificial intelligence framework, the TILs-TSR Unification System (TRUST), to predict immune-stromal phenotypes and guide treatment stratification. Methods: sTILs and TSR were independently assessed to define four immune-stromal phenotypes: sTILs-high/TSR-high (HH), sTILs-high/TSR-low (HL), sTILs-low/TSR-high (LH), and sTILs-low/TSR-low (LL). These joint labels served as pathological ground truth for training TRUST using multiparametric MRI from a multicenter cohort of 687 patients across eight institutions. Model performance was evaluated in independent cohorts for neoadjuvant therapy (NAT; n = 351) response and disease-free survival (DFS; n = 190). Spatial proteomic profiling using PhenoCycler-Fusion was performed on tissue microarrays (n = 48) to characterize biological features across subtypes. Results: The integrated sTILs-TSR classification demonstrated stronger associations with NAT response and DFS than either metric alone. The HH subtype exhibited the highest pathological complete response (pCR) rate (78%), whereas the LL subtype showed the poorest prognosis. TRUST achieved high performance for tumor detection (AUC, 0.921; accuracy, 0.843) and immune-stromal phenotype prediction in training (AUC, 0.861; accuracy, 0.748) and validation cohorts (AUC, 0.821; accuracy, 0.721). Notably, in external cohorts (TNBC and Luminal subtypes), TRUST alone stratified pCR rates in neoadjuvant chemotherapy (73.0% vs. 10.1%) and chemoimmunotherapy with anti-PD-1 (67.8% vs. 14.3%) between predicted NAT-sensitive (HH) and NAT-resistant (LL) groups. TRUST also significantly stratified DFS, with no 3-year DFS events observed in the predicted HH group. Spatial proteomics revealed distinct immune-stromal architectures, characterized by enriched Granzyme B⁺ CD8⁺ T cells, abundant antigen-presenting cells, and close tumor-immune interactions in HH tumors, while LL tumors exhibited dominant myCAF-rich stroma, increased M2-like macrophages, and sparse CD8⁺ T-cell infiltration. Conclusions: The integrated sTILs-TSR classification provides superior prognostic and predictive value by capturing coordinated immune and stromal architecture. Leveraging multiparametric MRI and deep learning, TRUST establishes a biologically interpretable, non-invasive imaging biomarker that enables clinically actionable risk stratification and supports therapeutic escalation or de-escalation.

Combination of vemurafenib with cobimetinib in <i>BRAF</i> V600E/K mutated melanoma patients to normalize LDH and optimize immunotherapy with nivolumab and ipilimumab (COWBOY): A randomized, open-label phase 2 clinical trial.

9513 Background: Elevated levels of serum lactate dehydrogenase (LDH) in patients (pts) with metastatic melanoma are associated with reduced response to immune checkpoint inhibitors (ICIs). In a phase 2 trial, we investigated whether upfront reduction of tumor burden and normalization of LDH through six weeks of BRAF/MEK inhibitor (BRAF/MEKi) induction, prior to the initiation of ICIs, could improve response rates compared to standard first-line dual ICI. Methods: In this two-arm, multicenter, phase 2 trial, treatment naïve pts with unresectable stage III or stage IV BRAFV600E/K mutation-positive melanoma and elevated baseline LDH levels (&lt; 5x upper limit of normal) were randomized 1:1 (stratified by LDH) to one of two treatment arms. Arm A received 6 weeks of induction with vemurafenib 960 mg bid + cobimetinib 60 mg QD on a 21/7-day schedule, directly followed by four courses of ipilimumab 3 mg/kg q3wk (ipi3) plus nivolumab 1 mg/kg q3wk (nivo1). Arm B directly started with four courses of ipi3 + nivo1. Both arms received response-adapted nivolumab maintenance. The primary endpoint was to compare the best overall response rate (BORR) within 18 weeks from the start of treatment between two treatment arms, as assessed by RECIST 1.1. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and the rate of grade 3/4 toxicity. Exploratory endpoints focused on circulating tumor DNA dynamics (ctDNA), blood transcriptome, and tumor immunoprofiling. ClinicalTrials.gov identifier: NCT02968303. Results: Between 2017-2021, 71 pts were randomly assigned, 36 to arm A and 35 to arm B. The study was prematurely terminated due to slow patient accrual (planned accrual: 200 pts). The median follow-up time was 27.9 months (IQR 16.8-57.8). In arm A, the BOR was partial response (PR) in 75% of the pts (36.1% had an ongoing response after treatment switch), stable disease (SD) in 22.2%, and progressive disease (PD) in 2.8%. In arm B, 54.3% had PR, 22.9% SD, and 20% PD (1 pt was not evaluable). BRAF/MEKi induction prior to ICI was associated with a significantly shorter median PFS as compared with upfront dual ICI (4.4 months vs 25.0 months, HR 0.52, 95% CI 0.30-0.91; p=0.02). Median OS was also shorter in arm A (13.5 months), whereas the median OS was not reached in arm B (HR 0.38, 95% CI 0.19-0.68; p=0.002). Treatment-related grade ≥3 adverse events occurred in 25 of 36 pts (69%) in arm A and 15 of 35 pts (43%) in arm B. When combining both arms, pts with undetected ctDNA at 6-12 weeks after ICI initiation had significantly longer PFS than those with detected ctDNA (HR 2.05, 95% CI 1.05-4.0; p=0.03). Conclusions: BRAF/MEKi induction prior to dual ICI did not improve response rates to ICI and was associated with worse PFS and OS in pts with BRAFV600E/K mutated melanoma and elevated LDH compared to upfront dual ICI. Clinical trial information: NCT02968303 .

Safety, tolerability, and efficacy of mesutoclax (ICP-248) in combination with azacitidine in patients with myeloid malignancies.

6506 Background: Venetoclax has been approved for the treatment of newly diagnosed acute myeloid leukemia (AML) in elderly or unfit pts but failed in the high-risk myelodysplastic syndromes (MDS). Mesutoclax is a novel, potent, highly selective BCL-2 inhibitor. It exhibits favorable pharmacokinetic profile without any major metabolites. Methods: ICP-CL-01205 (NCT06656494) is an ongoing, global, phase I study evaluating mesutoclax in combination with azacitidine (AZA) in pts with AML or MDS. In the dose escalation part, mesutoclax at100 mg, 125 mg, and 150 mg in combination with AZA were evaluated for safety and tolerability. 100 mg and 125 mg were selected as Recommended dose for expansion (RDE) for further evaluation. Antitumor activity in AML and MDS is assessed based on ELN 2017 and IWG 2006/2023 criteria, respectively. Herein, we report safety, tolerability and efficacy for mesutoclax with AZA in pts with AML and MDS in this phase 1 study. Results: As of January 12, 2026, a total of 59 pts were enrolled including 8 R/R AML, 39 TN AML and 12 TN MDS. The median age of AML and MDS pts was 65 (range: 23, 81) and 67 years (range: 54, 75), respectively. Adverse risk per 2017 ELN was identified in 51.1% AML pts. Azole prophylaxis and G-CSF treatment were used in 5% and 22% pts. Among the 35 evaluable TN AML pts, 30 (85.7%) achieved composite CR (cCR, CR+CRi) with central assessment of CR rate of 65.7% (23/35). Among those who achieved cCR, 86.7% (26/30) were MRD negative per flow cytometry. MRD negative in CR (CR MRD- ) was 60% (21/35). cCR was 75% in adverse risk per 2017 ELN classification. The DOR rate at 3-months was 91.7%. The 6-month OS rate was 94.1%. Among 10 response evaluable TN MDS pts, the overall response rate (ORR) per IWG 2006 criteria was 100%, including CR in 20%, marrow CR in 80%. The composite CR rate was 70% per IWG 2023 criteria including 30% CR even when most pts only received 1 cycle treatment. There were no DLT or TLS events. The most common (≥10%) grade ≥ 3 TEAEs in pooled analysis of 59 AML and MDS were neutrophil count decreased (62.7%), platelet count decreased (50.8%), anemia (33.9%), infection (16.9%), and lymphocyte count decreased (11.9%). There were 5.1% grade ≥ 3 febrile neutropenia and no TEAEs lead to dose discontinuation. SAEs were reported in 25.4% pts. For pts with TN AML, the median intervals between cycle 1 and cycle 2 initiation (requiring neutrophil ≥1*10 9 /l and platelet ≥ 100*10 9 /l) was 39 days and the median duration of grade 4 neutropenia and thrombocytopenia were 17 and 9 days, respectively. Conclusions: The combination of mesutoclax and azacitidine demonstrated a favorable safety profile and encouraging anti-tumor activity not only in AML but also in MDS pts, supporting its continued development for the treatment of myeloid malignancies. These preliminary results warrant further investigation in larger, randomized trials. Clinical trial information: NCT06656494 .

Preliminary efficacy and safety of intratumoral long-acting cisplatin-SRGel (TumoCure) in refractory locally advanced head and neck squamous cell carcinoma: Phase Ib CLPR-001.

6051 Background: Refractory LA-HNSCC progressing despite standard therapies is associated substantial locoregional disease driven morbidity and limited effective salvage therapies that achieve modest response rates and are poorly tolerated. Intratumoral (IT) therapies enabling high and durable drug exposure at the site of disease with minimal systemic toxicity may address this unmet need. TumoCure is a long acting injectable IT cisplatin formulation (100mg/mL) incorporated in SRGel, a solvent free biodegradable matrix designed to provide IT cisplatin release for up to 2 months, aiming to maximize locoregional cisplatin exposure with minimal systemic exposure. Methods: CLPR-001 is an open-label, multicenter Phase I/Ib study evaluating IT TumoCure in patients with chemo and/or radio resistant LA-HNSCC with no available curative or effective standard treatment options. TumoCure is administered as a single IT injection; individualized based on tumor dimensions to optimize IT dispersion. The primary endpoint is safety and tolerability. Secondary endpoints include locoregional response by RECIST v1.1, PK and QoL assessment. Results: Eight patients received IT TumoCure (5 males and 3 females) with a mean age of 66y. Patients were in average 7y from diagnosis and were heavily pretreated: 7/8 (87.5%) had prior surgery and 7/8 (87.5%) were platinum-resistant or refractory. The mean number of prior systemic treatment lines (including RT and IO) was 3. Target lesions reflected substantial locoregional tumor burden (longest diameter 30-98 mm). Administration was feasible across tumor sizes, with injection volumes of 0.4-1.0 mL. Treatment was generally well tolerated. Procedure related AEs were uncommon and limited to injection site pain. No systemic cisplatin related AEs were reported. Early clinical activity was observed, with 3 months best response of 45% and 37% reductions in tumor diameter and corresponding volumetric reductions of 75% and 36% respectively. Patients also experienced clinically meaningful improvement in tumor bulk related manifestations. Preliminary PK analyses demonstrated systemic platinum exposure at least one order of magnitude lower than historical systemic cisplatin exposure. Conclusions: In heavily pretreated, platinum-resistant/refractory patients, TumoCure treatment was safe and well tolerated. Early signals of tumor regression and improvement in tumor bulk-related symptoms were observed, supported by markedly reduced systemic platinum exposure. These findings support continued development of TumoCure as treatment for refractory LA-HNSCC. A subsequent study is planned to evaluate TumoCure + IMRT in cisplatin ineligible patients, addressing an unmet need where current chemoradiation regimens remain suboptimal, with the goal of improving outcome while minimizing toxicity. Clinical trial information: NCT05200650 .

Correlation of presurgical circulating tumor DNA (ctDNA) levels with pathologic (p) stage and lymph node (LN) burden in localized colon cancer.

3048 Background: Accurate preoperative staging is vital for tailoring neoadjuvant therapy (NAT) in localized colon cancer. However, clinical staging often diverges from pathological findings due to limitations of imaging modalities in assessing pathologic LN (pLN) involvement and inter-observer variability. This study evaluated the association between presurgical ctDNA levels, microsatellite instability (MSI) status, and pLN burden across pStages I–III in colon cancer. Methods: This retrospective study included patients (pts) with pStage I-III colon cancer from the GALAXY study with available presurgical ctDNA levels (mean tumor molecules/mL; MTM/mL) assessed by a personalized tumor-informed assay (Signatera, Natera, Inc). Key exclusions included receipt of NAT, inconsistent pLN classification, pN1c disease, and missing MSI status. Conditional inference tree modeling was used to hierarchically evaluate clinicopathologic and molecular risk factors for their association with presurgical ctDNA levels. Results: Of the 3,473 pts (14.4%, 43.1% and 42.5% with pStage I, II and III, respectively) included, 90.2% had microsatellite stable (MSS) tumors. The conditional inference tree partitioned the cohort into five subgroups of distinct presurgical ctDNA level distributions defined by pStage, pLN burden, and MSI status, and demonstrated the pStage to be the strongest determinant of presurgical ctDNA levels. pStage I pts had uniformly low MTM/mL. In contrast, pStage II–III pts had higher and more variable MTM/mL levels, which were stratified by pLN burden and further differentiated by MSI status within each nodal category. Presurgical ctDNA levels were significantly higher in pLN-positive vs pLN-negative pts (median 2.52 vs 1.23 MTM/mL, p &lt;0.0001) and in pStage IIB-III vs pStage I-IIA pts (median 2.64 vs 1 MTM/mL, p &lt;0.0001). While presurgical ctDNA levels did not differ significantly based on MSI status alone, within both MSS and MSI-H subgroups, they were significantly higher in pLN-positive pts vs pLN-negative pts (MSI-H: median 4.40 vs 1.19 MTM/mL; MSS: median 2.41 vs 1.25 MTM/mL). Similar results were observed when grouped based on pStage I/II vs III. Specifically among pLN-positive pts, presurgical ctDNA levels increased with higher pLN burden (MSI-H: median 15.13 vs 3.75 MTM/mL for ≥4 vs 1-3 LN, p=0.049; MSS: median 3.70 vs 1.96 MTM/mL for ≥4 vs 1-3 LN, p&lt;0.0001). Conclusions: Presurgical ctDNA levels reflect a hierarchical interplay of pathologic stage, lymph node burden, and MSI status rather than any single clinicopathologic factor. High presurgical ctDNA levels reliably correlated with pStage and pLN positivity in localized colon cancer, supporting the development of models incorporating presurgical ctDNA quantification to better select pts for NAT and their evaluation in prospective trials. Clinical trial information: 000039205.

Impact of artificial intelligence on inter-reader variability in breast ultrasound interpretation: An international multireader multicase study.

e12552 Background: Artificial intelligence (AI) has been developed as a promising assistive tool for improving diagnostic accuracy and reducing inter-reader variability in breast ultrasound interpretation. However, evidence regarding the practical impact of AI assistance on diagnostic consistency remains limited. This study aimed to evaluate the impact of AI-assisted breast ultrasound interpretation on diagnostic performance and inter-reader agreement in a multicenter, multinational setting. Methods: Between Sep 2024 and Mar 2025, 148 breast ultrasound cases were collected from Korea, Hong Kong, and Kazakhstan. The images were analyzed using an AI ultrasound system (CadAI-B), and all data were uploaded to a web-based scoring platform. Ground truth was established by three board-certified radiologists, while seven international junior physicians served as readers. Each reader evaluated in two phases: a pre-AI phase and, after a one-month washout period, an AI-assisted post-AI phase. The post-AI phase consisted of three sequential steps providing increasing levels of AI support: measurements and BI-RADS lexicons (post-AI 1), additional AI maps and malignancy scores (post-AI 2), and final BI-RADS categories (post-AI 3). Diagnostic performance and mean probability of malignancy (POM) were compared between phases, and inter-reader variability was assessed using Randolph’s free-marginal Fleiss’ kappa. Results: Mean AUC, sensitivity, and specificity were 0.816, 94.2%, and 27.7% in pre-AI phase, and 0.811, 98.8%, and 16.5% in post-AI phase, respectively. Inter-reader variability in POM was high in the pre-AI phase but was markedly reduced in the post-AI phase across all sub-phases. This trend was consistently observed in both benign (n = 84) and malignant (n = 64) cases. Among the BI-RADS descriptors, shape, orientation, and posterior features demonstrated substantial inter-reader agreement (kappa values &gt; 0.81). Especially, margin—showing the lowest agreement in pre-AI phase—improved from a kappa value of 0.2897 to 0.6871, reaching the level of substantial agreement. Conclusions: AI-assisted breast ultrasound interpretation could reduce inter-reader variability, thereby improving diagnostic consistency and reliability. These findings provide strong evidence supporting the clinical impact of AI-based decision support systems, particularly in establishing a more standardized reading environment for reader groups with heterogeneous levels of experience. Strength of agreement and inter-reader variability of breast ultrasound descriptors in pre-AI and post-AI phases. Descriptor Pre-AI Post-AI 1 Post-AI 2 Post-AI 3 Shape 0.4826 0.8345 0.8345 0.8345 Orientation 0.4659 0.8867 0.8867 0.8867 Margin 0.2897 0.6919 0.6887 0.6871 Echo Pattern 0.5232 0.7161 0.7161 0.7161 Posterior Features 0.5281 0.8275 0.8202 0.8134

Real-world efficacy and safety outcomes of older adult patients on enfortumab vedotin for urothelial carcinoma.

e13767 Background: The treatment landscape for advanced urothelial carcinoma (aUC) has undergone a significant transformation since the FDA approval of enfortumab vedotin (EV) in 2019. Although results from pivotal trials have been practice-changing, older adults were underrepresented in these studies, and data including these patients remains limited. This study compares efficacy and safety outcomes between patients aged ≥70 years and those aged &lt; 70 years receiving EV therapy using real-world data. Methods: This single-center, retrospective cohort study reviewed patients with aUC who received at least one dose of EV (alone or with pembrolizumab) in any line of treatment between 12/01/2019 and 08/01/2025 at the Huntsman Cancer Institute. Primary endpoints include overall survival (OS) and progression free survival (PFS) stratified by age group. Additional outcomes include incidence and reasons for dose modification, relative dose intensity (RDI), and frequency of treatment-related toxicities. Progression and incidence/severity of toxicities were determined by the primary treating physician and collected via electronic medical record documentation. RDI was calculated using the total delivered dose divided by the total standard dose multiplied by 100. Median OS and PFS were estimated using Kaplan-Meier methods and compared using Cox regression, adjusting for sex, de novo metastatic disease, pre-existing diabetes and baseline neutrophil-to-lymphocyte ratio. Other outcomes were presented descriptively. Results: 84 adult patients with a median age of 71.6 years were included. Baseline characteristics were similar across age groups, except for higher male predominance and baseline HbA1c levels in those 70 and older. OS and PFS did not significantly differ in both unadjusted and adjusted analysis, with HR 0.89 (95%CI 0.49, 1.61) and HR 1.06 (95%CI 0.61, 1.85), respectively, among patients aged ≥70 years compared to &lt; 70 years. Patients aged ≥70 years started at a reduced dose (1 mg/kg) more frequently than those &lt; 70 years (33.3% vs 10.3%, p = 0.012). Fewer older patients maintained RDI ≥80% throughout therapy (80% vs 94.9%, p = 0.044). Dose delays and cancellations were more common in &lt; 70 years group (74.4% vs 53.3%, p=0.046), while patients ≥70 years old more often required dose reduction (48.9% vs 30.8%, p=0.071). Overall, toxicity was the most common reason for dose modification. Grade 2+ neuropathy (28.9% vs 25.6%, p = 0.74) and dermatologic toxicity (24.4% vs 17.9%, p = 0.47) did not differ significantly between patients aged ≥70 years compared to &lt; 70 years, respectively. Conclusions: This study provides real-world evidence on efficacy, dosing, and tolerability of EV therapy in older adults with aUC. Older patients with aUC receiving EV therapy achieved similar outcomes to younger patients, supporting the use of individualized dosing strategies in this population.

Impact of prior chemotherapy (CT) on dabrafenib plus trametinib (D + T) outcomes in <i>BRAF</i> ^V600E –mutated metastatic non–small cell lung cancer (NSCLC): A post hoc analysis.

e20666 Background: The Phase II study (NCT01336634) evaluated the BRAF inhibitor, dabrafenib with the MEK inhibitor, trametinib, in patients with BRAF V600E–mutant metastatic stage IV NSCLC. In this exploratory post hoc analysis, we examined outcomes according to the duration of prior CT exposure before D + T initiation. Methods: This post hoc analysis included adult patients with metastatic stage IV, BRAF V600E–mutated NSCLC from sub-cohort B in the NCT01336634 study who received D + T as second-line therapy after prior systemic CT. Patients were further stratified by duration of prior CT exposure (≤4 weeks vs &gt;4 weeks). Dabrafenib 150 mg twice daily and trametinib 2 mg once daily were administered orally. Progression-free survival (PFS) and overall survival (OS) were estimated using Kaplan–Meier methods and compared descriptively. PFS and OS were calculated from the date of D + T initiation (day 1). Results: A total of 38 patients received D + T as second-line therapy in sub-cohort B. The mean duration of prior CT was 3.0 months (SD = 4.0, n = 37), with a median of 2.1 months (Q1–Q3: 0.8–2.8; range: 0.0–21.4). Overall, 11 patients (28.9%) had ≤4-weeks of prior CT, and 26 (68.4%) had &gt;4 weeks; data was missing for 1 patient. In patients who received ≤4 weeks of prior CT before starting D + T had numerically longer PFS than those with &gt;4 weeks, by both investigator assessment (median PFS 19.3 vs 9.7 months, p = 0.101; PFS events: 7 vs 23) and independent review (58.1 vs 7.7 months, p = 0.123; PFS events: 6 vs 23). A numerically longer median OS was also observed in the ≤4-week group compared with the &gt;4-week group (55.2 vs 19.2 months, p = 0.388; OS events: 8 vs 21). Median follow-up was 18.2 months overall, 55.2 months in the ≤4-week subgroup, and 17.0 months in the &gt;4-week subgroup. Conclusions: This exploratory, hypothesis-generating analysis suggests that, in patients with BRAF V600E–mutated metastatic NSCLC treated with second-line D + T, shorter prior CT exposure (≤4 weeks) was associated with a trend toward numerically longer PFS and OS compared with longer exposure (&gt;4 weeks). These findings, derived from a small sample size, post hoc design, and limited number of events, support further evaluation in prospective studies. Future analyses using start of prior CT as time zero may help assess potential lead-time effects. Clinical trial information: NCT01336634 .