Citations

Abstract Background NRG/RTOG 1010 evaluated trastuzumab added to trimodality therapy for HER2+ localized esophageal adenocarcinoma (EAC) management. Secondary PRO objectives assessed improvement in the FACT‐Esophageal Cancer Subscale (ECS), version 4, with trastuzumab, and if improved ECS correlated with pathologic complete response (pCR). Methods Patients were randomized to weekly paclitaxel/carboplatin/radiation (chemoradiation, CRT) followed by surgery ± trastuzumab (CRT + Tras). Disease‐free survival (DFS) was the primary end point. The projected PRO sample size of 158 patients, based on an 80% participation rate of the DFS primary endpoint sample size of 197 HER2+ patients, would provide ≥ 89% power to detect ≥25% increase in the proportion of CRT + Tras patients with ECS improvement from baseline to 6–8 weeks post‐CRT; one‐sided α = 0.05, using a χ 2 test. Improvement in ECS and its swallowing index (SI) and eating index (EI) was defined as 5‐, 2‐, and 2‐point increases, respectively, from baseline to 6–8 weeks post‐CRT. Univariate logistic regression was assessed if pCR was associated with improved ECS. Results From 2010 to 2015, 203 HER2+ patients were randomized and 194 were eligible. Of 171 PRO consenting patients, the ECS was completed by 162 (95%) at baseline, 108 (64%) 6–8 weeks, 82 (49%) 1 year, and 55 (33%) at 2 years. The proportion of patients with an improvement in 6–8 weeks ECS was higher on the CRT + Tras arm (46% vs. 38%), although not significantly different ( p = .39). There was no correlation between pCR and ECS scores at 1 year, with 39% and 37% of pCR and non‐pCR patients, respectively, having improved 1‐year ECS scores. Conclusions The addition of trastuzumab to CRT for localized HER2+ EAC did not improve PROs.

ABSTRACT Introduction Sodium‐glucose cotransporter‐2 inhibitors (SGLT2i), initially developed for type 2 diabetes, have shown promise in improving renal outcomes in patients with and without diabetes. However, their effect on lithium‐associated kidney dysfunction remains unknown. Methods This historical cohort study included patients from Mayo Clinic (2001–2023) with mood disorders who received lithium for ≥ 6 months and later used SGLT2i for ≥ 1 month. Data on SGLT2i use and lithium treatment were extracted from electronic health records. Serum creatinine values were used to calculate estimated glomerular filtration rate (eGFR) trajectories. Linear mixed‐effects models with piecewise linear splines were used to estimate eGFR slopes before and after SGLT2i initiation, adjusted for age and sex. Results Fifty‐six patients (mean age 57.4 years, 46.4% female), predominantly with bipolar disorder (87.5%), were included. The mean eGFR, measured nearest to SGLT2i initiation, was 77.9 ± 26.0 mL/min/1.73 m 2 , and the mean duration of SGLT2i use was 19.5 ± 17.8 months. Before SGLT2i initiation, eGFR declined at a rate of −1.43 mL/min/1.73 m 2 per year ( p < 0.001). After initiation, eGFR increased by 0.69 mL/min/1.73 m 2 per year, reflecting a + 2.13 change ( p = 0.025). Sensitivity analyses, including only patients on lithium at SGLT2i initiation ( n = 22) or who had > 1 year of SGLT2i use ( n = 29) showed similar, though non‐significant, changes in slopes. Conclusion SGLT2i treatment was associated with a significant improvement in eGFR trajectory in patients with mood disorders who received long‐term lithium therapy. These findings suggest a potential role for SGLT2is in mitigating lithium‐associated kidney dysfunction and highlight the need for randomized controlled trials in this population.

Abstract INTRODUCTION The tau positron emission tomography (PET) overlap index (OI) has shown promise in maximizing signal‐to‐noise for longitudinal tau PET imaging, particularly for early tau pathology, but requires validation against neuropathology. METHODS Fifty‐seven participants who underwent serial tau PET imaging (flortaucipir) and subsequent autopsy were included. Tau PET OI and standardized uptake value ratios (SUVRs) were compared across neuropathological diagnoses. RESULTS Tau PET OI showed greater concordance with neurofibrillary tangle (NFT) severity in the entorhinal cortex (a key region for Alzheimer's disease [AD] tauopathy) than SUVR, particularly in early Braak tangle stages (positivity: 52.2% for OI vs. 13.0% for SUVR). OI detected overlapping tau voxels that exhibited spatial correspondence with immunohistochemical and autoradiography measures of tau deposition across both AD and non‐AD tauopathies. DISCUSSION These findings demonstrate the enhanced capacity of OI in serial tau PET to robustly detect early and spatially localized tau pathology, supporting its application as a sensitive imaging metric in AD and select non‐AD tauopathies.

Abstract Background White matter hyperintensities (WMH) are widely used to assess cerebral small vessel disease (SVD) but reflect late-stage injury. Diffusion MRI based biomarkers have been proposed to capture earlier SVD-related microstructural damage but their temporal progression relative to WMH and the risk factors associated with this progression have not been explored. Methods We analyzed longitudinal neuroimaging data from 2,047 participants from a population-based cohort study (aged 49-101 years, 47% female). Using multi-output nonlinear mixed-effects models, we characterized the temporal progression of WMH and four diffusion MRI based biomarkers: fractional anisotropy of the genu of the corpus callosum (Genu-FA), peak width of skeletonized mean diffusivity (PSMD), free water (FW), and Arteriolosclerosis-score (ARTS). Models incorporated participant-specific time shifts, correlations between biomarkers, and effects of risk factors (sex, education, APOE ε4 status, and cardiometabolic conditions). Results ARTS, Genu-FA, FW, and PSMD became abnormal in 50% of the study population 16, 12, 10, and 7 years before WMH, respectively. Global markers (ARTS, FW, PSMD, WMH) were correlated, indicating shared substrates of widespread white matter injury. Genu-FA, a vascular risk microstructural injury biomarker, was weakly coupled with WMH and had an earlier but more linear worsening across adulthood. Cardiometabolic conditions predicted earlier worsening of all biomarkers. Females showed earlier WMH, Genu-FA, and ARTS abnormalities whereas males exhibited earlier PSMD and FW abnormalities. Conclusions Diffusion MRI based biomarkers capture microstructural injury at least a decade before appearance of WMH, revealing a prolonged phase of early SVD and highlighting their potential for SVD prevention.

Background Antitumor immune responses induced by oncolytic immunotherapy (OI) are often followed by upregulation of programmed death-ligand 1 (PD-L1). As such, the combination of OI with blockade of the programmed cell death protein-1 (PD-1)/PD-L1 axis has demonstrated therapeutic activity in preclinical and clinical trials. The purpose of this study is to understand further the immune-mediated mechanism of interaction between oncolytic viruses and anti-PD-1 therapy. Methods Tumor cells and immune cells (splenocytes) were cultured separately, or in co-culture with vusolimogene oderparepvec, an oncolytic herpes simplex virus expressing the fusogenic gibbon-ape leukemia virus-fusogenic membrane glycoprotein protein (GALV) and granulocyte-macrophage colony-stimulating factor (GM-CSF), also known as RP1. Viral replication, interferon (IFN) responses and PD-L1 expression were analyzed using wild-type, IFNAR1, TNFAR1 and STING knockout splenocytes. In vivo studies evaluated immune cell infiltrates into the tumor following RP1 administration with anti-PD-1 therapy. Results RP1 replication was evident in tumor cells but not splenocytes. This was also accompanied by upregulated IFN expression in cultured splenocytes that was absent in cultured tumor cells. However, when these cell types were co-cultured, splenocytes mediated an interferon response to RP1 via STING that was transmitted to tumor cells in a non-touch-dependent manner. Tumor cells responded to these input signals via upregulation of cell surface major histocompatibility complex-I and PD-L1 through tumor intrinsic JAK-STAT signaling. In vivo, an IFN signature was observed following intratumoral injection of RP1, both in injected and non-injected tumors, which was further increased when combined with anti-PD-1 therapy. Marked upregulation of PD-L1 was observed in tumors injected with RP1 accompanied by the recruitment of CD11b+Ly6G+neutrophils into the tumor microenvironment, which stained positive for PD-L1. Conclusion Overall, the data demonstrate that RP1 remodels the tumor microenvironment through a combination of direct and indirect effects on both tumor and immune cells, resulting in an overall more inflamed phenotype.

TPS909 Background: BCG-Exposed NMIBC (a high grade recurrence within 24 months of prior BCG, but not meeting “unresponsive” criteria) is a large patient population with a critical need for more effective treatment strategies that prevent the development of BCG unresponsive disease/progression. The current standard of care is re-treatment with BCG alone, but only ~50% of patients derive clinical benefit. While intravesical gemcitabine (with or without docetaxel) is sometimes used, multiple retrospective studies have found that GemDoce is no better than re-treatment with BCG alone for patients with BCG-exposed NMIBC. A chemoimmunotherapy strategy of intravesical Gemcitabine with BCG (GemBCG) combines the two most effective, inexpensive, and commonly used treatments for NMIBC. Based on compelling biologic rationale and preclinical data, a phase I/II (n=52) trial was initiated of GemBCG in BCG-exposed NMIBC (NCT04179162). GemBCG has minimal side effects (3.8% [2/52] with Grade 3 TRAEs (no grade 4/5 seen) with similar side effects and tolerability to BCG alone. GemBCG has a outstanding early efficacy signal (6-month complete response of 97% [28/29] in patients with CIS, compared to ~50% 6-month complete response w/ BCG alone for BCG exposed CIS). GemBCG has promising preliminary longer term efficacy (18-month HG-RFS of 76% compared to ~45-55% reported with BCG alone, GemDoce, and recombinant BCG in BCG exposed NMIBC). Correlative studies support the hypothesis that the addition of gemcitabine to BCG can favorably modulate the tumor immune microenvironment. Methods: Based on the above rationale, we initiated the “GAIN” trial (A032303/ NCT07000084), a prospective, multicenter, open-label phase III study for patients with BCG-exposed NMIBC randomized to either: re-treatment with BCG only (Arm A, SOC) or Gemcitabine + BCG (GemBCG, Arm B). BCG-exposed NMIBC is defined as a high grade NMIBC (Ta, T1, Tis/CIS) that has recurred within 24 months of prior BCG, but NOT otherwise currently meeting BCG unresponsive NMIBC. The primary objective is to compare high grade recurrence-free survival (HG-RFS) between the two treatment arms. Notable aspects of the trial include: (1) the reduced burden on investigators and research teams due to the NCI’s new streamlined data initiative, (2) liberal inclusion/exclusion criteria and pragmatic design to improve generalizability of results, and (3) Cystoscopic biopsies/TURBT at week 13/month 3 for all participants (both CIS and “papillary only”) for multiple reasons including to allow for earlier detection of BCG unresponsive disease for patient safety, increased rigor of the trial, and objectively evaluate urinary biomarkers/urinary tumor DNA. Clinical trial information: NCT04179162 .

TPS577 Background: Pembrolizumab (pembro) for one year following resection of localized high risk clear cell renal cell carcinoma (ccRCC) in a phase 3 trial resulted in improvement in relapse-free survival and overall survival (Choueiri, NEJM 2024). However, 20% of patients still experienced a relapse within 2 years with no biomarker yet identified to predict who will respond to or needs adjuvant therapy. Addition of a tyrosine kinase inhibitor (TKI) to immunotherapy (IO) is a standard of care in metastatic ccRCC, but to date no studies have addressed the addition of a TKI to IO in the adjuvant setting. Subsequently, phase 3 STRIKE! was developed to explore the benefit of 6 months of tivozanib (tivo) added to pembro vs pembro alone in the adjuvant setting for resected high risk ccRCC. Methods: Eligible patients have an ECOG performance status ≤2 and a histologically confirmed diagnosis of RCC with clear cell component with or without sarcomatoid features after complete resection of the primary tumor, with pathology revealing pT2 grade 4 disease or any grade ≥ T3 or TxN1. Patients are also eligible if they developed metastasis within a year after resection and then underwent resection, definitive radiation or ablation of solid, isolated, soft tissue metastases (excluding brain and bone lesions) with no evidence of active disease (M1NED). Patients will be randomized 1:1 to intravenous pembro for 48 weeks with or without the addition of tivo 1.34 mg by mouth daily D1-21 q28D for 6 months stratified by stage (T2T3 vs T4/N1 vs M1NED) . With no limit on dose holds or interruptions of tivo, dose reductions of tivo to 0.89 mg D1-21 q28D or tivo 0.89 mg every other day are allowed. No dose reductions of pembro are permitted. Following baseline imaging to confirm no disease, imaging is performed every 12 weeks for first year, every 16 weeks for second year, every 24 weeks for third year and then annually until 5 years after registration or progression. The primary endpoint will be disease-free survival (DFS) as assessed by investigator, with secondary endpoints being overall survival, safety and tolerability. The study will enroll 1040 patients to detect a minimum detectable hazard ratio of 0.67 (24-month DFS 84% in experimental arm) with 90% power. Quality of life analysis will compare global quality of life and fatigue between the two arms. Imaging and specimens will be banked for future research. The study opened to accrual in April 2025 and at this time 106 patients have enrolled. Clinical trial information: NCT06661720 .

LBA630 Background: Enfortumab vedotin (EV) + pembrolizumab (pembro) is the established first-line standard of care for locally advanced/metastatic urothelial carcinoma and represents a novel neoadjuvant and adjuvant treatment strategy for patients with muscle-invasive bladder cancer (MIBC) who are ineligible for cisplatin-based chemotherapy. The randomized phase 3 KEYNOTE-B15/EV-304 study (NCT04700124) evaluates neoadjuvant and adjuvant EV + pembro followed by radical cystectomy plus pelvic lymph node dissection (RC + PLND) vs neoadjuvant chemotherapy followed by RC + PLND in participants (pts) with MIBC who are eligible for cisplatin-based therapy. Methods: Pts with clinical stage T2-T4aN0M0 or T1-T4aN1M0 MIBC (confirmed by central pathology and central imaging assessment) who were eligible for cisplatin-based chemotherapy and RC + PLND were randomized 1:1 to receive either 4 cycles neoadjuvant EV 1.25 mg/kg IV on days 1 and 8 + pembro 200 mg IV on day 1 Q3W, followed by RC + PLND, and adjuvant 5 cycles EV + 13 cycles pembro (EV + pembro arm) vs 4 cycles neoadjuvant gemcitabine 1000 mg/m 2 on days 1 and 8 + cisplatin 70 mg/m 2 on day 1 Q3W, followed by RC + PLND (cis + gem arm). The primary endpoint was event-free survival (EFS) by blinded independent central review. Key secondary endpoints were pathological complete response (pCR) rate by blinded central pathological review and overall survival (OS). Safety was a secondary endpoint; AEs of special interest were based on distinct prespecified lists for each drug. Results: A total of 405 and 403 pts were randomized to EV + pembro and cis + gem, respectively. Median time from randomization to the data cutoff date of October 27, 2025 was 33.6 months (range, 22.5–53.6). Baseline characteristics were generally balanced between groups. EV + pembro significantly improved EFS (median NR vs 48.5 mo; 24-mo estimated EFS rate 79.4% vs 66.2%; HR 0.53, 95% CI 0.41–0.70; 1-sided P <.0001), OS (median NR vs NR; 24-mo estimated OS rate 86.9% vs 81.3%; HR 0.65, 95% CI 0.48–0.89; 1-sided P =.0029), and pCR rate (55.8% vs 32.5%; estimated difference 23.4%, 95% CI 16.7–29.8; 1-sided P <.0001) vs cis + gem. Grade ≥3 treatment-emergent AEs occurred in 75.7% of pts with EV + pembro and 67.2% with cis + gem. Most common grade ≥3 drug-related AE of special interest for EV was skin reactions (14.1%); most common grade ≥3 AE of special interest for pembro was severe skin reactions (13.9%). Conclusions: Neoadjuvant and adjuvant EV + pembro significantly improved EFS, OS, and pCR rate compared with neoadjuvant gem + cis in pts with MIBC who were eligible for cisplatin-based chemotherapy. The safety profile of EV + pembro was consistent with prior experience with the combination. These results support EV + pembro as an effective perioperative treatment option in this setting. Clinical trial information: NCT04700124 .

98 Background: Circulating tumor DNA (ctDNA) monitoring provides an additional clinical tool for assessing treatment response and emerging resistance. We evaluated the real-world (RW) use and results of FoundationOne Monitor (F1Monitor), a tissue-free ctDNA monitoring assay, in patients (pts) with prostate cancer (PCa). Methods: The clinical laboratory developed test, F1Monitor, was available to physicians in a limited pilot with full discretion of test eligibility, timing, and frequency. Therapy type was a non-mandatory field on the order form. CtDNA was detected and quantified by ctDNA tumor fraction (TF); variants were tracked with variant allele frequency (VAF), and the origin [tumor somatic (TS), germline, or clonal hematopoiesis (CH)] was predicted algorithmically. Results: F1Monitor was ordered by 28 physicians for 215 pts with PCa. Therapy data were known for 156 pts: ADT+ androgen receptor pathway inhibitor (ARPI, N = 69/156 pts, 44%), ADT alone (N = 32, 21%), ADT + chemotherapy (chemo, N = 20,13%), ADT + radioligand therapy (RLT, N = 17, 11%), and others (N = 18). Median follow-up was 188 days. Longitudinal testing (≥2 tests) occurred in 64 pts, often (N = 37) when the first test was ctDNA TF positive (+). Median cadence for serial testing (≥3 tests, N = 31) was 42 days (IQR: 35, 59). ctDNA TF was + at any timepoint in 50% (107/215) of pts overall and 53% (82/156) of pts known to be on therapy, trending higher in pts on ADT+chemo (80%) and ADT+RLT (65%). Median and maximum ctDNA TF values were 11% (IQR: 0.9,37.8%) and 89% respectively. Lowest ctDNA TF and reportable TS VAF quantified were 0.13% and 0.04%, respectively. ctDNA TF longitudinal changes were observed in 67% (43/64) of pts: 92% of pts on ADT+chemo, 69% on ADT+RLT, 59% on ADT+ARPI, and 38% of pts on ADT alone. Among pts with ≥2 tests, 39% (25/64) had ctDNA TF increase, including 6/27 (22%) pts that were ctDNA TF negative (-) on the first test. Of pts with ≥2 tests and any ctDNA TF+ result, 35% cleared ctDNA TF in later tests. 33% of pts were persistently ctDNA TF -. Each test reported an average of 5 alterations: ~2 TS short variants, copy number variants, or rearrangements, and ~2 predicted CH variants. HRR variants were detected in 37% (80/215) of pts (31 with ≥2 tests) : persistent in 20 pts, cleared in 7, and newly emerging in 14. At least 50% of alterations in CHEK2 and ATM were predicted CH. Alterations in PI3K pathway genes were detected in 20% (43/215) of pts: (16 with ≥2 tests) persistent in 6 pts, cleared in 5, and newly emerging in 5. Conclusions: In this RW pilot of tissue-free ctDNA monitoring in PCa, F1Monitor demonstrated high sensitivity in clinical practice, detecting ctDNA TF as low as 0.13% and TS VAF as low as 0.04% while distinguishing tumor-derived from predicted CH variants. Importantly, ctDNA TF was + in 53% of pts while on therapy with observed longitudinal changes for 67% of pts, supporting potential utility of ctDNA for monitoring treatment response and emerging resistance.

TPS290 Background: Landmark randomized trials established the survival benefit of adding D to ADT in mCSPC. Building on this foundation, subsequent trials (PEACE-1 and ARASENS) demonstrated further survival improvements when androgen receptor pathway inhibitors (ARPI) were added to the ADT + D backbone. However, the independent contribution of D within the triplet regimen remains unclear given lack of prospective evaluation. Additionally, tumor suppressor gene (TSG) alterations involving TP53, PTEN, and RB1 are frequently observed in PC and are associated with aggressive biology and poor outcomes, providing an opportunity to enhance prognostic accuracy and optimize selection of candidates for treatment intensification. We hypothesize that adding D to ADT plus A will improve survival compared to ADT + A in mCSPC and stratification by TSG status may identify different treatment effects across molecular subgroups. Methods: ASPIRE is an open-label, two-arm, randomized phase 3 study to assess the benefit of D added to ADT plus A for patients with mCSPC. Eligible patients include those with confirmed adenocarcinoma of the prostate with evidence of distant metastatic disease on conventional imaging and are appropriate to receive D. Patients with metachronous low-volume disease or PSMA-PET only disease are excluded. Candidates must have next-generation sequencing (NGS) results from a CLIA-certified tissue test available for TSG status stratification at registration. Eligible patients will receive ADT plus A (240 mg PO daily) +/- D for up to 6 cycles until progression of disease by PCWG3/RECIST version 1.1 criteria. Prior therapy with ADT (with or without ARPI) initiated within 120 days before registration is permitted. The primary endpoint is overall survival (OS). Secondary endpoints include OS by TSG status; radiographic progression-free survival (rPFS); time to castration resistance; symptomatic skeletal event–free survival; time to worsening of disease-related symptoms (NCCN-FACT FPSI-17); safety and tolerability (CTCAE v5.0); PSA90 response at 6 weeks and 6 months; time to PSA progression; and objective response rate in patients with measurable disease. The study will enroll 1200 patients and is currently actively accruing patients. Clinical trial information: NCT06931340 .