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Final results of a first-in-human study of the MC1R-targeting radiopharmaceutical ²²⁵ actinium MTI-201 ( ²²⁵ Ac-MTI-201) in metastatic uveal melanoma (mUM).

3099 Background: Prognosis in mUM is poor with limited efficacy of currently available therapies. The melanocortin-1 receptor (MC1R) is an attractive target for radiopharmaceutical therapy given high expression in UM. 225 Ac-MTI-201 is a novel alpha particle emitting MC1R bound radiopharmaceutical with high biostability, affinity, and MC1R-specific cytotoxicity with defined dosimetry and pharmacokinetics in pre-clinical studies. Methods: In this first-in-human study (NCT05496686) of a single IV dose of 225 Ac-MTI-201, we enrolled mUM patients (pts) who had disease progression on at least 1 prior therapy. Pts had adequate organ and functional status; prior radiotherapy to >25% of bone marrow was exclusionary. The primary objective was safety and toxicity of 225 Ac-MTI-201 with secondary endpoints of pharmacokinetics (PK) and clearance of 225 Ac-MTI-201, response rate, progression-free survival (PFS), and overall survival (OS). Up to 12 dose levels [from 4.7 microcurie (µCi) to 1327 µCi] for 225 Ac-MTI-201 were planned per a modified continual re-assessment method (CRM) with a cohort size of one based on dose limiting toxicity (DLT) assessment within 28 days of drug administration using CTCAE v5.0. Response was assessed by RECIST 1.1. Results: Sixteen pts (8 male, 8 female), median age 63 years (43, 84) have been treated. Median number of prior systemic regimens was 2 (0,4), 8 pts had prior liver directed treatment. Dose of 225 Ac-MTI-201 was escalated to level 6 (152 µCi) when one DLT (G4 thrombocytopenia and G4 neutropenia) was observed requiring de-escalation per CRM. A second DLT (G4 neutropenia) at level 5 (76 µCi) required expansions at levels 4 (38 µCi; n=5) and 5 (n=6) where all remaining pts were treated without further DLT with 1 pt currently pending final DLT assessment. Adverse events (AEs) were mostly G1-2 including leucopenia, lymphopenia, neutropenia, thrombocytopenia, anemia, nausea, fatigue and ↑ AST. Reversible myelosuppression [lymphopenia (7), neutropenia (5), thrombocytopenia (2)] was the most common > G3 AE. No non-hematological DLT was seen. Best response was stable disease (4/15; 27%); seen at dose levels 4 and 5. The median PFS was 2.30 months (95% CI: 1.84, 3.65); 6-month PFS was 0.07 (95% CI: 0.0, 0.26) and 12-month OS was 0.39 (95% CI: 0.13, 0.64). Median distribution phase half-life (n=15) was 6.19 minutes followed by a slower median elimination phase half-life of 74.06 minutes with significant positive correlation between fast and slow half-lives (Spearman = 0.696, p= 0.0039), independent of dose level. Conclusions: Single dose administration of 225 Ac-MTI-201 with dose escalation to 76 µCi appears safe and feasible in mUM. Disease stability in this difficult to treat population is encouraging and a multi-dose study of 225 Ac-MTI-201 in mUM is planned pending final pt DLT assessment. 225 Ac-MTI-201 has Orphan Drug designation for mUM. Clinical trial information: NCT05496686 .

Impact of organ-adjacent extracellular vesicle proteomics from uterine lavage on accurate detection and discrimination of ovarian cancer.

5581 Background: Survival in ovarian cancer (OvCA) exceeds 90% when disease is localized, yet most cases present at advanced stage and effective early detection remains elusive. Blood-based liquid biopsies may be limited by low tumor signal in early disease. We evaluated whether organ-adjacent sampling via uterine lavage extracellular vesicle (EV) proteomics combined with machine-learning (ML) classification could enable accurate detection of OvCA and clinically relevant discrimination from endometrial cancer (EndoCA). Methods: Uterine lavage samples were collected under IRB-approved protocols from women undergoing gynecologic evaluation for abnormal uterine bleeding and/or abnormal pelvic imaging. EVs were isolated using an affinity-based capture method and analyzed by liquid chromatography-tandem mass spectrometry. Protein features meeting predefined quality thresholds were analyzed using a novel ML pipeline incorporating entropy-based marker scoring and correlation filtering. Classifier performance was assessed using repeated random two-fold validation and receiver operating characteristic analysis. Results: Among 807 participants, diagnoses included OvCA (n=85), benign conditions (n=488), and EndoCA (n=234). An OvCA-versus-benign classifier derived from a 91-protein panel demonstrated strong discrimination (AUC >0.9). Across 100 validation splits, 83 of 85 OvCA cases were correctly classified, including all stage I cases (27/27). A separate 21-protein classifier distinguished OvCA from EndoCA with a sensitivity of 0.94 and specificity of 0.92. Conclusions: EV proteomic analysis of uterine lavage specimens enables accurate detection of ovarian cancer, including stage I disease, and reliably distinguishes OvCA from EndoCA in women undergoing gynecologic evaluation. These findings support further prospective clinical validation of organ-adjacent EV proteomics as a translational diagnostic strategy for earlier and more precise classification of gynecologic malignancies.

Aspirin use and survival outcomes in endometrial cancer.

5621 Background: Given the worsening survival trends of endometrial cancer in the United States, further improvement in adjuvant treatment of this cancer is needed. Aspirin use has been shown to reduce cancer risk in multiple cancer types. A randomized controlled trial recently showed that aspirin therapy significantly improved overall survival in patients with colorectal cancer with PIK3CA mutations, a mutation that is seen in up to 50% of endometrial cancers. We therefore hypothesized that aspirin use may similarly improve survival in patients with endometrial cancer. Methods: We conducted a retrospective review of all patients with endometrial cancer treated at a single academic institution between 2014-2017. Demographics, clinicopathologic data, surgical and adjuvant treatment, and aspirin use were collected from the medical record. Proportional variables were compared using Fisher’s exact and Chi-square tests. Continuous variables were compared using t-tests and Mann-Whitney U-tests. Disease-specific survival (DSS, time from diagnosis to death due to cancer) was estimated using Kaplan-Meier plots, with log-rank and Cox proportional hazards analysis used to compare groups. Results: A total of 765 patients were included in the study. Most patients were white (92%), had Stage I disease (79.9%), had endometrioid histology (87.1%), and were mismatch repair (MMR) proficient (74.6%). Of the 765 patients, 243 (31.8%) were taking ASA at the time of their endometrial cancer diagnosis, while 522 (68.2%) were not. Patients taking aspirin at the time of diagnosis were significantly older than those who were not (66.2 vs 59.8, p<0.0001). Otherwise, there was no significant difference in BMI, stage, grade, histology, MMR status, or adjuvant treatment between the two groups. On multivariate analysis, aspirin use at diagnosis was significantly associated with improved DSS (HR 0.27 [0.10-0.64], p=0.0020) after adjusting for age, stage, grade, histology, MMR status, and adjuvant treatment. Conclusions: Aspirin use at the time of endometrial cancer diagnosis was associated with a significant improvement in DSS in our cohort. While retrospective, this data is promising as a potential improvement in therapy for patients with endometrial cancer. Additionally, this intervention would be inexpensive and easily accessible for all patients. Prospective data is needed to further evaluate the effect of aspirin on endometrial cancer outcomes.

Implementation of <i>DPYD</i> genotyping in response to FDA black box warning: Initial experience at a comprehensive cancer center.

e15139 Background: A subset of DPYD polymorphisms contribute to poor catabolism of fluoropyrimidines, resulting in increased risk of drug toxicity and even death. In 2025, the FDA recommended dihydropyrimidine dehydrogenase ( DPYD ) pharmacogenomic testing prior to fluoropyrimidine (FP) initiation. We describe implementation of mandatory DPYD testing into institutional workflow. Methods: DPYD pharmacogenomic testing was implemented 11/4/2025 at Memorial Sloan Kettering Cancer Center (MSK) prior to therapy with any FP using an in-house, CLIA and New York State approved blood-based assay. Testing of all 7 DPYD Tier 1 germline variants recommended by international professional societies was performed using a quantitative PCR-based approach (APIS Assay Technologies Ltd.) with results returned within 5 days from blood draw. We developed patient education materials, integrated New York State-required e-consent, notification to order testing, Genomic Indicator assignment, and hard stops preventing FP treatment verification and/or pharmacy release without DPYD results. A strategy for documenting exemptions and multidisciplinary communication was integrated into the Epic workflow. We describe implementation, detection rate, and treatment impact. Results: Among 604 tested patients, 27 (4.5%) harbored a DPYD polymorphism inclusive of patients with GI (n = 22), head and neck (n = 3), or breast (n = 2) cancers, with 20 receiving palliative intent treatment. Variants represented included c.1129-5923C &gt; G (n = 19); c.1905+1G &gt; A (n = 3), c.557A &gt; G (n = 3), and c.868A &gt; G (n = 2). 18 have had treatment modifications, 7 have had no treatment plan alteration and 2 are pending decisions. Among the 18 patients with altered treatment plans, 2 were prescribed non-FP regimens and 16 were administered FP dose-reductions ranging from 25-83% in dose-intensity for the first dose. Of the 16 who had dose-reduction, escalation after the first cycle was possible in 8 patients (4/8 to full dose). All patients tolerated therapy at initial and re-escalation doses without significant toxicity. Toxicities reported were dry mouth/lips (n = 2), diarrhea (n = 2), fatigue (n = 1), all grade 1 by CTCAE v5. Of the 7 patients where no treatment modification was initiated, 5 underwent testing in anticipation of future need for FP while 2 patients needed emergent treatment, both with intermediate DPYD activity who received full-dose therapy without exhibiting associated toxicity. Updated yield of universal DPYD testing and follow-up based on our experience through 4/2026 will be presented. Conclusions: MSK introduced mandatory e-consent and in-house DPYD testing prior to FP therapy in 11/2025. Polymorphisms were identified in 4.5% of the tested population and frequently led to treatment modifications. This implementation experience provides a framework for practices seeking to scale pharmacogenomic testing.

Induction failure (IF) as a prognostic marker in adult acute lymphoblastic leukemia (ALL).

6546 Background: Despite advances in the treatment of adult ALL, risk factors for IF and optimal management are poorly understood. We aimed to characterize patients (pts) with IF after therapy for newly diagnosed (nd)ALL and their outcomes. Methods: We performed a retrospective chart review of adult ndALL pts treated at Weill Cornell Medicine from 2012-2025. We defined IF as failure to achieve &lt; 5% bone marrow blasts, count recovery and extramedullary disease clearance after 1 cycle of induction. Fisher’s exact test was used for analysis of discrete variables and Wilcoxon rank-sum test for continuous ones. Results: Among 220 pts, 48.2% were female, mean age at diagnosis was 50.5 (18-87) yrs, 74.5% had B-cell ALL (of which 41.5% Ph+), with median follow-up 24.5 months. 34 pts (15.5%) had IF (22 B cell, 12 T cell). B-cell IF patients were more likely to have Ph-(77.3% vs 50%, p=0.0211) or Ph-like phenotype (13.6% vs 3.5%, p=0.0753). IF pts were more likely to have CNS disease at diagnosis (p= 0.034). There was no significant difference in baseline median white cell count (13.18 vs 9.60 p=0.4) or LDH (448 vs 517 p=0.17) in IF vs non-IF pts. IF was not associated with age, asparaginase-treatment, BMI, abnormal cytogenetics, pertinent mutations, or year of diagnosis. On multivariable logistic analysis controlling for age and lineage, CNS disease at diagnosis remained associated with IF (OR 2.81, p=0.0343). Overall survival (OS) was significantly worse in IF vs non-IF pts at 3-years (29.2% vs 66.8%, p = 0.0002). OS did not vary by CNS disease at diagnosis in IF pts. Of IF pts, 27/34 (79.4%) achieved CR with subsequent therapy (median time to CR 68.5 days, range 21-228), with improved survival vs the 7 pts (5 B cell, 2 T cell) who did not (p = 0.00001). 4/7 patients without CR died within 4 months, and none of these 7 patients received allo-SCT. In the 27 IF pts attaining later CR, there was a trend towards worse OS vs non-IF pts (1029 days vs not reached, p=0.0659), though importantly a subset of 10 pts who achieved minimal residual disease (MRD)-negativity had OS similar to the non-IF group (p=0.95). IF patients were more likely to receive allo-SCT than non-IF patients (51.4% vs 29.7%, p=0.0164). Receiving allo-SCT tended to be associated with improved survival in this group (p=0.0578) vs no allo-SCT. 16/22 B cell IF patients received blinatumomab and/or inotuzumab. These were not associated with MRD-negative status or allo-SCT, but did show a trend towards subsequent CR (p=0.1) and better OS (p=0.1119). Conclusions: In our single-center retrospective cohort of ALL pts, 15.5% had IF. 29.4% of these patients (4.5% of the total cohort) were able to achieve MRD- status with subsequent treatment, resulting in outcomes comparable to pts without IF. ALL-IF patients should be closely monitored for MRD and may benefit from early application of immunotherapeutic approaches and/or allo-SCT.

National trends in non-melanoma skin cancer–related hospitalizations and in-hospital outcomes in the United States, 2018–2022.

e21552 Background: Non-melanoma skin cancers (NMSC) represent the most common malignancies in the United States and are predominantly managed in outpatient settings. However, a subset of patients require inpatient care for complex surgical management, advanced local disease, complications, or comorbidity-driven indications. Despite the high prevalence of NMSC, contemporary national data describing hospitalization burden, admission characteristics, outcomes, and resource utilization remain limited. Understanding inpatient patterns is important for contextualizing healthcare utilization and informing care delivery planning for this common malignancy. Methods: A serial cross-sectional analysis of the 2018–2022 Healthcare Cost and Utilization Project National Inpatient Sample was performed. Adult (≥18 years) hospitalizations with a principal diagnosis of non-melanoma skin cancer were included; all analyses were conducted at the hospitalization level. National estimates incorporated discharge-level survey weights with stratification and clustering to account for the complex sampling design. Outcomes included annual hospitalization volume, admission type (elective vs non-elective), in-hospital mortality, length of stay (LOS), and inflation-unadjusted hospitalization cost estimated using HCUP cost-to-charge ratios. Results: Among approximately 164.9 million weighted adult hospitalizations nationally, NMSC accounted for an estimated 22,930 weighted hospitalizations from 2018–2022 (unweighted n=4,586). Annual hospitalization volumes were stable across the study period. Overall in-hospital mortality was low at 1.40% (95% CI 1.07–1.81) without meaningful temporal variation. Most admissions were elective (68.6%; 95% CI 67.0–70.1), while 31.4% were non-elective. Mean LOS was 6.11 days (95% CI 5.85–6.37), and mean hospitalization cost was $31,104 (95% CI $29,415–$32,794). Conclusions: NMSC-related hospitalizations were uncommon relative to overall inpatient volume but were associated with prolonged LOS and substantial hospitalization costs despite low in-hospital mortality. The predominance of elective admissions and stable outcomes over time characterize contemporary inpatient NMSC care. These findings provide national benchmarks that contextualize inpatient resource utilization and inform healthcare planning for this highly prevalent malignancy.

HPV-stratified tissue factor expression and multi-omic correlates of overall survival after tisotumab vedotin in cervical cancer.

5537 Background: Cervical cancer (CxC) is heterogeneous, and the impact of HPV status on outcomes with tisotumab vedotin (TV; tissue factor [TF/F3]–targeted ADC) remains incompletely defined. We evaluated HPV-stratified associations between TF expression and real-world overall survival (OS) after TV and explored molecular correlates of long vs short survival. Methods: 274 CxC patients who received TV (HPV+, n=106; HPV-, n=45) underwent DNA and RNA sequencing. HPV16/18/31/33/45 status was determined from whole exome sequencing (WES). Real-world OS was calculated from first TV claim to death/last contact. Hazard ratio (HR) was estimated by Cox proportional hazards, with p-value using log-rank test. TFH was defined as TF (F3) expression (RNA-seq normalized expression) ≥ the cohort-specific median (median split) among TV-treated cases with available data. For transcriptomic comparisons, LS (long survival) and SS (short survival) were defined as above-median vs below-median OS after TV within each HPV stratum, respectively. Results: Among TV-treated patients with available TF/OS data, TFH vs TFL showed no statistically significant OS difference in the overall cohort (n=195; TFH n=98 vs TFL n=97; median OS 11.73 vs 9.79 months; HR 0.765; log-rank p=0.142) or in the HPV+ cohort (n=69; TFH n=35 vs TFL n=34; median OS 10.22 vs 10.35 months; HR 0.602; log-rank p=0.138). In contrast, in the HPV− cohort (n=27; TFH n=14 vs TFL n=13), TFH was associated with improved OS (median OS 21.81 vs 9.79 months; HR 0.251, 95% CI 0.065–0.977; log-rank p=0.032). Transcriptomic profiling suggested HPV-dependent survival: in HPV− patients, LS was enriched for cell-cycle/DDR, and energy metabolism pathways (e.g., p53 pathway NES 1.86; FDR-adjusted p&lt;0.0001), whereas in HPV+ patients, SS was enriched for inflammatory pathways (e.g., interferon-γ response NES −2.25; FDR-adjusted p&lt;0.0001; TNF–NFκB) and LS for tumor-intrinsic metabolic/drug-handling and coagulation-related pathways (e.g., Xenobiotic metabolism, NES 2.13, FDR-adjusted p=0.0021; Coagulation). In the HPV+ cohort, exploratory genomic correlates of survival included enrichment of ARID1A pathogenic mutations (3/18, 16.7% LS vs 0/41, 0% SS; p=0.0073) and AKT2 amplifications (2/17, 11.8% LS vs 0/39, 0% SS; p=0.0292), consistent with tumor-intrinsic pathway alterations in LS. Conclusions: TF expression and HPV status may interact in TV-treated cervical cancer. While TFH was not associated with OS in the overall or HPV+ cohorts, TFH was associated with improved OS in HPV− disease. HPV-stratified transcriptomic analyses further suggest distinct biological contexts of benefit and lack thereof, supporting the need to HPV-stratified biomarker analyses for evaluating TV benefit in CxC, potentially extending to other ADCs, and motivating validation in independent datasets.

A national, patient-centered AI framework for equitable oncology clinical trial access: Early outcomes from the first 10 months of ACS ACTS.

e13573 Background: Less than 10% of eligible cancer patients enroll in clinical trials (CT) due to fragmented information, logistical barriers, and inequities in trial awareness and navigation. To address these challenges, the American Cancer Society (ACS) launched ACS ACTS (Access to Clinical Trials &amp; Support), a national, patient-centered program combining clinical trial education, health-related social needs (HRSN) screening, navigation, and artificial intelligence (AI)–enabled trial matching to reduce friction between trial interest and trial action. Methods: We conducted a descriptive analysis of the first 10 months of ACS ACTS, from launch on 2/23/25 to 12/31/25. Eligible participants (EP) included individuals of any age with any cancer type across all U.S. states &amp; territories, referred by patients, caregivers, or providers. Program components included trial education, HRSN screening, supportive services, AI-generated personalized trial matching (via Massive Bio–sourced interventional trials), and centralized prescreening hubs (CPH) for eligibility and site coordination. The AI platform employs a neurosymbolic, multi-agent, explainable architecture integrating rule-based eligibility reasoning with machine learning–based semantic extraction of clinical data to align patient characteristics with protocol-level inclusion &amp; exclusion criteria. Outcomes included reach, HRSN burden, AI matching throughput, trial matches, and downstream trial referral metrics. Results: 1,479 EP across over 30 cancer types and 48 states participated in the program, with representation from medically underserved and rural communities. 2,713 HRSNs were reported with 54% of EP reporting at least one unmet HRSN, most commonly financial, lodging, and emotional concerns. 66.7% of EP received CT education and HRSN support, and among them 75.0% elected to pursue CT matching, receiving AI-generated personalized trial lists with rapid turnaround. 1,591 partial or exact matches to trials were identified, with 99.9% of patients receiving at least one match. CPH completed for most matched EP and efficient triage to investigative sites. Early downstream outcomes demonstrated meaningful progression from trial awareness to site referral, with subsets advancing to trial screening and enrollment where confirmable. Conclusions: In its early national implementation, ACS ACTS demonstrates the feasibility of a scalable, patient-centered AI framework that integrates education, social needs support, AI-enabled trial matching, and centralized prescreening to reduce barriers to oncology CT participation. Early outcomes highlight substantial unmet social needs alongside strong demand for trial navigation and matching, particularly directly from patients. Ongoing analyses will examine impact on trial participation, equity, and patient engagement.

An SMS-enhanced supportive program to improve treatment management and communication during active cancer treatment.

e13714 Background: Patients undergoing active cancer treatment have high symptom burden and psychosocial distress that often go under-addressed between clinic visits. We implemented a prospective, SMS-based supportive care program to improve real-time communication and timely intervention by social workers. Methods: Adult patients receiving active cancer therapy enrolled in a text-messaging platform. Baseline measures included psychological distress (PHQ-4), quality of life (FACT-G), and cancer coping self-efficacy (CBI-B). For three months, patients received alternating weekly surveys: the Distress Thermometer and a 10-domain toxicity survey capturing symptom frequency, severity, and interference. Predefined thresholds triggered alerts to social workers. Patients could also send free-text SMS about symptoms, care coordination, practical needs, or emotional support. A secure provider dashboard allowed daily review and bidirectional SMS. Engagement and symptom reporting were summarized descriptively; Spearman correlations assessed associations between baseline factors and engagement. Results: We report the first three months for 116 patients. Demographics: 49.1% had high school education or less, 58.6% married, 41.4% retired. Baseline PHQ-4 mean = 2.6 (low distress); FACT-G mean = 51.9 (moderate QOL). Engagement was high: 100% sent ≥1 SMS; 56.6% sent ≥6 messages in three months. Distress: 57.4% (65/116) reported DT ≥4 at least once; among these, 69.2% reported DT ≥6. Toxicity reporting: 57.4% completed ≥1 toxicity survey; 51.4% of those reported at least one severe toxicity. In 36 patients with severe toxicity, common symptoms were fatigue (47.2%), muscle/joint pain (36.1%), insomnia (25.0%), and constipation (22.2%). Higher baseline distress correlated with more frequent distress reporting (ρ = 0.30, p = 0.01). Greater coping self-efficacy (CBI-B) and higher FACT-G correlated with more frequent toxicity reporting (ρ = 0.32, p &lt; 0.01; ρ = 0.26, p = 0.03). Qualitative analysis of patient-initiated SMS showed most messages concerned care coordination/navigation, medication management, and symptom/toxicity issues; others addressed practical needs, education, psychosocial support, and acknowledgments. Conclusions: An SMS-enhanced supportive care program is feasible and yields sustained patient engagement during active cancer treatment. Structured distress and toxicity monitoring identified meaningful symptom burden, and bidirectional messaging enabled timely supportive care. Baseline psychosocial factors differentially predicted engagement: higher coping self-efficacy and quality of life were associated with greater participation in proactive toxicity reporting.

Preclinical evaluation of CT03: A cardiosafe, first-in-class bifunctional MCL1 degrader for the treatment of hematological malignancies.

e15107 Background: MCL1, a crucial member of the Bcl2 family, acts as a key pro-survival factor that prevents apoptosis and drives therapeutic resistance in diverse human cancers. While MCL1 inhibitors have reached clinical stages, their development has been severely hindered by dose-limiting cardiac toxicities, characterized by significant elevations in cardiac troponin. Targeted protein degradation offers a transformative alternative by inducing proteasomal degradation of the target rather than mere inhibition. This approach provides superior selectivity, prolonged pharmacodynamic effects, and a significantly improved safety profile. We report the preclinical characterization of CT-03, a novel bifunctional compound designed to selectively degrade MCL1 for treating hematological malignancies. Methods: Ternary complex formation between CT-03, MCL1, and the recruited E3 ligase was validated using biophysical assays. Biological activity was evaluated across a broad panel of human cancer cell lines and primary cells to assess viability and MCL1 levels via Western blotting. Cardiosafety was specifically examined in human iPSC-derived cardiomyocytes. In vivo efficacy was tested in MV4-11 AML xenograft, both as monotherapy and in combination with venetoclax. Pharmacokinetics (PK), pharmacodynamics (PD), and safety were further evaluated in Cynomolgus macaques. Results: CT03 induced potent proteasomal degradation of MCL1, resulting in apoptosis with low nanomolar pIC₅₀ values (~9) in MV4-11, OPM2, and DMS114 cell lines. Importantly, CT-03 demonstrated a unique cardiosafe profile in human iPSC-derived cardiomyocytes, causing only transient MCL1 reduction. This stands in contrast to MCL1 inhibitors, which triggered a 6–15-fold compensatory upregulation of MCL1 persisting after washout—a mechanism linked to clinical cardiac toxicity. In vivo , CT03 showed robust anti-tumor activity and tumor growth inhibition. When combined with low-dose venetoclax (7.5 mpk), CT03 (5 mpk, 2 days on/5 days off) promoted tumor regression. In non-human primates, the compound exhibited a favorable PK/PD profile with effective MCL1 degradation and no evidence of cardiac toxicity or troponin elevation at exposures significantly exceeding predicted human efficacious doses. Conclusions: CT-03 is a highly potent bifunctional MCL1 degrader that achieves complete target coverage and demonstrates a superior safety margin compared to traditional inhibitors. By reducing MCL1 levels rather than inducing compensatory elevation, CT03 mitigates the risk of cardiac adverse events. These results support the clinical potential of CT03 as a promising therapy for high-risk MDS and R/R AML. The compound is currently undergoing IND/CTA-enabling studies, with a First-in-Human Phase 1 trial planned for 2026 to evaluate CT03 as monotherapy and in combination with venetoclax.

Impact of duration of bone-targeting agent on adverse events (AEs) and skeletal-related events (SRE) in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with radium-223 (Ra-223): Real-world experience from Princess Margaret Cancer Centre (PM).

e17052 Background: Bone-targeting agents (BTAs) are guidelines-recommended to reduce SREs in patients with mCRPC and bone metastases. Despite this, BTAs remain underutilized, and the optimal duration of therapy remains undefined. This knowledge gap is particular relevant for patients with mCRPC receiving Ra-223, who are at high risk for SREs. Methods: Patients with mCRPC and bone metastases treated with Ra-223 at PM between 2015 and 2024 were retrospectively reviewed. We evaluated the association between BTA duration (categorized as ≤2 versus &gt;2 years), BTA-related adverse events (AEs) leading to discontinuation, and SREs (defined as compression, pathological fracture, or bone metastases requiring radiotherapy or surgery). Results: Among 252 patients treated with Ra-223, 115 (45.6%) received BTAs with evaluable duration data. Ra-223 was administered for a median of 5 cycles (range 1-6). Median age was 73.6 years (range 51.5-93.4), median baseline PSA was 38.0 ng/mL (range 0.4-6277.0) and 65 patients (57.0%) presented with de novo metastases. All patients received prior androgen receptor pathway inhibitor therapy, 45.2% had prior Docetaxel. After a median follow-up of 20.4 months (range 1.2-60), median overall survival was 19.2 months (95%CI 16.6-23.3). Of 115 patients, 40 (34.8%) received zoledronic acid, 69 (60.0%) denosumab and 6 (5.2%) both. Median BTA duration was 20.4 months (range 0.3-115.2). BTA discontinuation occurred in 110 patients (95.7%), with AEs accounting for 37.2% (Table). Compared to ≤2 years, BTA duration &gt;2 years was associated with numerically higher but non-signficant rates of AEs leading to discontinuation (34.9% vs 40.4%). Numerically higher SREs rates (57.6% vs 65.3%) in patients who received BTAs &gt;2 years reflected a greater cumulative risk of SREs over time. Conclusions: In patients with mCRPC treated with Ra-223, BTAs were underutilized, BTA discontinuation due to AEs were frequent, while SRE rates remained high. Within the limitation of sample size, BTA duration &gt;2 years was associated with numerically higher but non-significant increase in AE-related discontinuation. These findings support BTA use beyond 2 years in selected high-risk patients, however highlight the need for AE management and future prospective studies to define the optimal BTA duration. BTA duration p -value Reason for BTA discontinuation ≤2yrsn=63 (%) &gt;2yrsn=47 (%) 0.74 AEs Hypocalcemia Anemia Osteonecrosis of jaw Bone pain Osteomyelitis Renal dysfunction 22 (34.9%) 11 (16.7%) 1 (1.5%) 4 (6.1%) 4 (6.1%) 1 (1.5%) 1 (1.5) 19 (40.4%) 7 (14.3%) 0 (0%) 5 (10.2%) 4 (8.2%) 3 (6.1%) 0 (0%) Disease progression / best supportive care 35 (55.6%) 21 (44.6%) Death 4 (6.3%) 4 (8.5%) Other 2 (3.2%) 3 (6.4%)

AI-assisted preoperative communication in prostate cancer: A prospective, single-blinded, randomized phase II trial.

5024 Background: To evaluate whether AI-assisted preoperative communication reduced patient anxiety, and physician workload compared with standard preoperative communication in patients undergoing radical prostatectomy. Methods: We conducted a prospective, randomized, single-blinded, phase II trial in newly diagnosed prostate cancer patients undergoing radical surgery, excluding those with severe psychiatric or cognitive disorders. Upon hospital admission, patients were randomized at the room level to receive either standard or AI-assisted preoperative communication. After baseline assessment, the AI-assisted group received individualized responses generated by a locally deployed large language model–based AI system prior to routine physician-led face-to-face preoperative communication, while physicians remained blinded to group allocation. The primary outcomes were patient anxiety (GAD-7) and physician workload (NASA-TLX). Comparisons were conducted using non-parametric rank-sum tests. The trial was registered at ClinicalTrials.gov (NCT07082049). Results: Between April and November 2025, 268 patients were randomized to the control group (n = 130) or the AI-assisted group (n = 138). A total of 3,507 questions were collected (avg. 13.08 per patient). After routine preoperative communication, patients in the AI-assisted group reported lower anxiety levels than those in the control group (GAD-7 median [IQR], 3.5 [2.5–5.0] vs. 7.5 [6.5–9.0]; P &lt; 0.001). Physician workload was also reduced in the AI-assisted group, as reflected by lower NASA-TLX scores (median [IQR], 37.0 [27.0–46.0] vs. 54.0 [35.0–73.0]; P &lt; 0.001), accompanied by a substantial reduction in preoperative communication time (12.60 vs. 21.90 minutes; P &lt; 0.001). Patients in the AI-assisted group reported more favorable emotional status, lower negative illness perceptions, and higher satisfaction, while exploratory analyses indicated that AI-assisted communication alone improved anxiety, emotional status, and disease-related perceptions prior to physician face-to-face preoperative communication. The observed reductions in physician workload and communication time suggest potential applicability in resource-constrained clinical settings where clinical manpower and consultation time are limited. Conclusions: AI-assisted preoperative communication reduced patient anxiety, and physician workload compared with standard communication, supporting its role as a supplementary approach to routine preoperative care in prostate cancer, including settings involving older adults and limited clinical resources. Clinical trial information: NCT07082049 .

Tumor cell-intrinsic programs of metabolic adaptation and immune evasion in colorectal cancer liver metastases (CRCLMs).

3554 Background: CRCLMs account for the majority of colorectal cancer (CRC)-related mortality and represent a key site of immunotherapy resistance. The tumor cell-intrinsic molecular programs enabling adaptation to the liver microenvironment and immune evasion remain poorly defined. Methods: We performed spatial whole transcriptomic analysis of 189 patient-matched primary CRC and CRCLM samples from two independent cohorts (Cohort 1 = 47; Cohort 2 = 141). Samples were represented using tissue microarrays and analyzed using the GeoMx Digital Spatial Profiling (DSP) platform. Two ROIs (tumor cell [CK] and stroma [DAPI]) were analyzed per sample, with analyses focused on tumor cells. Differential expression analyses were conducted independently within each cohort. Results were integrated using Fisher’s combined probability method for batch-aware meta-analysis. Expression of selected transcripts in tumor and matched non-tumor tissue in TCGA and associated survival outcomes were evaluated using the GEPIA2 webtool. Gene set enrichment analysis (GSEA) was applied to identify consistently altered biological pathways. Exploratory LASSO regression using normalized expression values identified gene sets distinguishing liver metastases from primary tumors. Results: We identified multiple genes consistently enriched in malignant cells from CRCLM compared to primary CRC. Prioritized genes include MMP10 (logFC = 0.41, p = 0.007), KRT17 (logFC = 0.87, p &lt; 0.001) and PLA2G2A (logFC = 0.72, p = 0.002), all showing higher tumor expression relative to normal tissue, association with unfavorable survival, and translational relevance (Table 1). GSEA revealed enrichment of acute-phase response (NES = 1.86, FDR = 0.003), complement activation (NES = 1.81, FDR = 0.002) and xenobiotic metabolism (NES = 1.71, FDR = 0.006) in liver metastases, together with reduced antigen processing and presentation (NES = -1.78, FDR = 0.012). Exploratory LASSO regression yielded cohort-specific gene signatures with limited gene-level overlap but convergence on shared biological programs distinguishing CRCLM from primary CRC, including epithelial and metabolic pathways. Of note, PLA2G2A was among the selected features in an independent cohort, reinforcing its association with CRCLM. Conclusions: We identified tumor cell-intrinsic programs in CRCLMs consistent with cellular metabolic adaptations and immune evasion with potential relevance in disease progression and treatment resistance. Our analyses also identified genes, including MMP10, KRT17, and PLA2G2A, as potential therapeutic vulnerabilities in CRCLMs for future investigation. Prioritized liver metastasis-enriched genes. Gene Translational Relevance MMP10 Enzymatic target; inhibitor scaffolds exist KRT17 Tumor-specific biomarker/pathway proxy PLA2G2A Enzymatic target; pathway inhibition feasible

Phase III study of multidisciplinary therapy combining local ablative therapy with immune-checkpoint inhibitors for patients with synchronous oligometastatic NSCLC (J-OLIGO: WJOG20924L).

TPS8667 Background: The standard of care for stage IV non-small cell lung cancer (NSCLC) patients without actionable driver mutations is immune-checkpoint inhibitors (ICIs) with or without platinum-based chemotherapy. For patients with synchronous oligometastatic disease, local ablative therapy (LAT) to all lesions, including primary sites, may improve survival based on several randomized phase II trials. Furthermore, combining LAT with ICIs may enhance anti-tumor immune responses by reducing tumor burden. However, a recent large phase II/III study failed to demonstrate a survival benefit for adding LAT to systemic therapy in patients with synchronous or induced oligometastatic NSCLC. Consequently, it remains unclear whether LAT provides a survival benefit in synchronous oligometastatic NSCLC. Based on the promising results from our preceding phase II trial (TRAP-OLIGO; WJOG11118L), we initiated this phase III trial to definitively evaluate the benefit of adding LAT to pembrolizumab plus platinum-based chemotherapy specifically for synchronous oligometastatic NSCLC. Methods: J-OLIGO is a multicenter, open-label, randomized phase III intergroup trial. Eligible patients have untreated stage IV NSCLC, ECOG PS 0-1, 1–3 metastases, and no actionable driver mutations. During the induction phase, patients receive 4 cycles of pembrolizumab plus platinum-based chemotherapy. Patients who achieve disease control with induction therapy and remain eligible for LAT to all residual lesions are randomized (1:1) to either the LAT group (Intervention) or the standard group (Control). The feasibility and appropriateness of LAT for each patient are evaluated by a multidisciplinary tumor board, consisting of medical oncologists, radiation oncologists, and thoracic surgeons, to ensure definitive treatment of all viable lesions. The LAT group receives definitive surgery and/or definitive radiotherapy to all sites, followed by maintenance pembrolizumab (±pemetrexed). Stratification factors include number of metastases, PD-L1 TPS, histology, and induction response. The primary endpoint is overall survival (OS), defined as the time from randomization. Secondary endpoints include progression-free survival (PFS), objective response rate (ORR), and the safety. Based on results from previous studies, the study has 80% power to detect a hazard ratio of 0.55 for OS (median OS: 20 vs. 36 months) with a one-sided alpha of 0.05. The target sample size is 150 patients for primary registration and 100 for secondary registration. Accrual began in October 2025 and is planned for 4 years, followed by a 4-year follow-up period. This trial is supported by the Japan Agency for Medical Research and Development (AMED) under the Project for Innovative Cancer Research. Clinical trial information: jRCTs041250114.

Declined or refused?: Electronic health record documentation of patients who do not proceed with recommended care by provider characteristics.

e13725 Background: Labeling a patient as "refusing" care can be stigmatizing; alternative terms more accurately and neutrally capture a patient's barriers, preferences, and decision-making. This study investigates if the use of “refused” as opposed to “declined” to describe these scenarios in cancer care electronic health record (EHR) notes varies by provider training and demographic characteristics. Methods: We developed a natural language processing model to identify documentation of “refusing” and “declining” care from a population of nearly 200,000 EHR notes of patients with cancer from 2022-2023 in a large upper Midwest health system containing both academic and community sites. Provider information was abstracted from publicly available licensing data. Providers in cancer treatment specialties (e.g. medical oncology, radiation oncology, surgical subspecialties) were included if they wrote a minimum of three notes between 2022-2023 that described a patient “refusing” or “declining” care. The percentage of notes containing “refuse” terminology per provider was analyzed by univariate linear regression models with provider characteristic predictors (age, gender, specialty, type [physician/NP/PA], time since training completion, and geographic region of terminal training [physician/PA only]). Results: 247 providers were represented: 68.8% physicians, 15.4% PAs, and 15.8% NPs. Mean age and time since training completion were 44 and 11 years, respectively. Provider gender was 56.7% female and 43.3% male. Medical oncology/hematology (46.2%), radiation oncology (9.3%), and general surgery (9.3%) specialties were most common, and the majority completed training in the Midwest (119, 57.2%). Average use of refusal language varied significantly by medical specialty: Compared to medical oncology/hematology (25.2%), use was highest among those in general surgery (39.0%, p = 0.02) and lowest among those in gynecologic oncology (6.9%, p = 0.01). Use of refusal language was also higher among male providers than female providers (29.8% vs. 20.0%, p = 0.003). Conclusions: Provider specialty and gender were associated with differing frequency of refusal language use in cancer care notes. This suggests that provider lived experiences, training, and/or specialty-specific culture or resources may play a role in the way stigmatizing language is used in EHR notes as well as its potential impact on patients and other providers.

Nanosponges: A comprehensive analysis on drug delivery systems for the treatment of diverse diseases

Predictors of real-world progression-free survival (rwPFS) in patients (pts) with epithelial ovarian cancer (EOC) treated with first-line maintenance (1LM) niraparib (nir): Post hoc analysis of the 1NSPIRE chart review study.

e17556 Background: The retrospective, US-based multicenter 1NSPIRE chart review study reported a median rwPFS of 21.7 mo in pts with EOC treated with 1LM nir (N=218). This post hoc analysis of 1NSPIRE used machine learning methods to identify factors associated with rwPFS. Methods: Eligible adults with EOC who initiated 1LM nir (index; nir initiation date) between 01Apr2020–01Apr2023 were followed from index to earliest of death, loss to follow-up, or start of data collection (site-specific initiation visit date). Univariable Cox regression analyses were used to identify characteristics associated with rwPFS. Variables with statistically ( P &lt;0.15) or clinically (hazard ratio &lt;0.5 or &gt;2.0) significant results were first included in multivariable analyses. Variables independently associated with rwPFS were then identified by least absolute shrinkage and selection operator (LASSO) and stepwise selection. Predictors of longer rwPFS were identified by survival tree analysis. Results: Univariable analyses showed that age, BRCA/ homologous recombination deficiency (HRD) status or HRD status alone, type of cytoreductive surgery (CRS), residual disease (RD) status, neoadjuvant chemotherapy (CT), number of cycles/duration of and best response to first-line (1L) CT, cancer antigen 125 (CA-125) level at nir initiation, hypertension, and starting nir dose were associated with rwPFS. LASSO and stepwise selection (Table) identified BRCA -mutated ( BRCA m) status, no RD, and normalized CA-125 level to be significantly associated with rwPFS. Survival tree analysis identified CA-125 level, BRCA /HRD, and RD status as the top predictors of longer rwPFS. Conclusions: BRCA m/HRD status, no RD, and normalized CA-125 level at nir initiation were associated with longer rwPFS among pts with EOC who received 1LM nir. These findings align with clinical expectation but should be interpreted with caution due to small covariate subgroups. Covariates n Hazard ratio a (95% CI) P value ComorbiditiesHypertension 89 1.05 (0.69–1.60) 0.81 BRCA /HRD status BRCA mHRd and BRCA wt/ BRCA unkHRp BRCA wt and HRDunk 22495058 13.28 (1.31–8.20)4.07 (1.64–10.07)2.23 (0.91–5.46) 0.01&lt;0.010.08 Type of CRSPrimary onlyInterval only 77102 11.56 (0.83–2.93) 0.17 HRD status closest to nir startNoneVisibleUnknown 1064132 11.67 (1.03–2.71)1.59 (0.88–2.90) 0.040.13 Duration of 1L CT, mo 179 1.02 (0.81–1.29) 0.87 Best response after 1L CTCompletePartialStable 1193723 11.41 (0.83–2.41)0.79 (0.40–1.58) 0.200.51 CA-125 level at nir startNormalized (≤35 U/mL)Elevated (&gt;35 U/mL) 15821 12.25 (1.23–4.13) &lt;0.01 Analysis cohort (N=179). a Higher numbers indicate higher risk of progression. HRd, homologous recombination deficient; HRp, homologous recombination proficient; nir, niraparib; unk, unknown; wt, wild-type.

Early vs late survival patterns of chemoimmunotherapy compared with immune checkpoint inhibitor monotherapy in non–small cell lung cancer.

e20603 Background: Immune checkpoint inhibitors (ICIs) have improved long-term outcomes in multiple cancers, and ICI trials often suggest durable benefit in a subset of patients. In first-line non–small cell lung cancer (NSCLC), ICIs are administered either as ICI monotherapy or combined with chemotherapy. Although chemotherapy is generally believed to improve early disease control, its impact on longer-term survival remains unclear. We assessed whether the relative effect of chemoimmunotherapy versus ICI monotherapy differs between early and later time periods. Methods: We reviewed pivotal first-line NSCLC trials of FDA-approved ICIs reporting long-term overall survival (OS) outcomes. Eligible arms were categorized as ICI-only regimens versus ICI plus chemotherapy; six ICI-only and six combination arms were included. Published Kaplan–Meier curves were digitized and individual patient data (IPD) were reconstructed using an IPD-from-KM approach. OS was estimated using Kaplan–Meier methods. To compare early versus later treatment effects, we performed a piecewise Cox analysis with a prespecified cutoff at 12 months, estimating hazard ratios (HRs) for 0–12 months and &gt; 12 months. We also evaluated the PD-L1 ≥50% subgroup where available. Results: A total of 2,054 patients in the ICI-only arms and 1,902 patients in the ICI plus chemotherapy arms were analyzed. In the overall population, the HR for chemoimmunotherapy versus ICI monotherapy was 0.98 (95% CI, 0.89–1.09) during 0–12 months and 1.24 (95% CI, 1.13–1.37) during &gt; 12 months, indicating a neutral early effect with a later disadvantage. In the PD-L1 ≥50% subgroup, the corresponding HRs were 0.84 (95% CI, 0.66–1.06) during 0–12 months and 1.11 (95% CI, 0.91–1.35) during &gt; 12 months, suggesting a more favorable early effect that diminished and trended toward harm in the later period. Conclusions: In this reconstructed-IPD, cross-trial analysis of first-line NSCLC ICI trials, the relative effect of chemoimmunotherapy versus ICI monotherapy appeared time-dependent, with attenuation and potential reversal beyond 12 months. These findings support evaluating early and late survival phases separately when interpreting chemoimmunotherapy outcomes.

Outcomes and clinicopathological characteristics of patients with metaplastic breast cancer at the National Cancer Institute Mexico between 2016-2020.

e12747 Background: Metaplastic breast cancer is a rare histological subtype (&lt; 1%) with dismissal prognosis and few studies regarding patient outcomes and characteristics. Information in Latin America is scarce, therefore our primary objective was to determine Survival Outcomes and Clinicopathological characteristics in a Tertiary Cancer Center in Mexico. Methods: This was a prospective cohort of metaplastic breast cancer patients between 2016-2020 at the National Cancer Institute in Mexico City whether they went to primary systemic therapy or not. For descriptive statistics we used frequencies and proportions. A Kaplan-Meier analysis was performed for Overall Survival, Progression-Free Survival and Recurrence-Free Survival outcomes. Results: The most relevant clinicopathological characteristics are presented in Table 1. Median tumor size was 4.3cm (1-30); 48% underwent neoadjuvant chemotherapy of which 8% (1) had ypT0, 58% (7) ypN0. In upfront surgery patients, 63% (7) were pT1-pT2, and 55% (6) were pN1-pN2. 67% (28) had mastectomy and 48% (13) had axillary dissection. Median follow-up was 67 months (51-82), there were 8 deaths (median survival not reached), 2 recurrences (median recurrence 28 months) and 1 progression. Conclusions: Metaplastic breast cancer in this population consisted of high grade tumors, advanced stages, predominantly triple negative breast cancers and no HER2+ subtypes. 70% of patients had a ductal component, with 52% of nodal disease at presentation. This is an interesting finding since nodal disease in these tumors is not usually reported. Median survival was not reached with a follow-up of more than 5 years, which gives insight on the prognosis of a rare breast cancer subtype in the largest cohort reported in Mexico so far. Clinicopathological characteristics of patients with metaplastic breast cancer. % (n) Age 52 (39-79)* Clinical StageIIIIIIIV 12 (3)19 (5)54 (14)15 (4) T Stage1234 19 (5)26 (7)18 (5)37 (10) Nodal StagecN 0cN 1cN 2cN 3 48 (13)19 (5)26 (7)7 (2) Subtype HR+HER2-HR-HER2-HER2+ 33 (9)67 (18)0 (0) GradeIIIIIIN/A 4 (1)11 (3)56 (15)30 (8) Ductal componentYesNoN/A 70 (19)26 (7)4 (1) Neoadjuvant ChemotherapyYesNoN/A 48 (13)48 (13)4 (1) Adjuvant ChemotherapyYesNoN/A 70 (19)26 (7)4 (1) *Median (range).

Long-term sex-specific trends in heart, pericardial, and mediastinal tumors: A population-based analysis (1975–2022).

e22604 Background: Heart, pericardial, and mediastinal tumors are rare neoplasms with potential sex-specific disparities. Despite their clinical significance, long-term temporal trends stratified by sex remain poorly characterized. Methods: We conducted a population-based analysis using data from the Surveillance, Epidemiology, and End Results (SEER) database, evaluating annual case counts from 1975 to 2022, stratified by sex. Temporal trends in total, male, and female cases were assessed using linear regression models. Results: A total of 657 cases were reported over the study period (445 males; 212 females). Total case counts showed a significant upward trend, increasing by 1.25 cases per year (p &lt; 0.001, R² = 0.59). Male cases increased by 0.85 cases/year (p &lt; 0.001), nearly twice the increase observed in females (0.40 cases/year, p &lt; 0.001). Male predominance persisted throughout the study period, with both sexes showing a gradual upward trend, reflecting a consistent sex disparity in these tumors. Conclusions: The occurrence of heart, pericardial, and mediastinal tumors has increased steadily over the past five decades, disproportionately affecting males. These findings highlight persistent sex-based disparities and underscore the need for further sex-specific research to elucidate underlying risk factors and inform targeted surveillance and early detection strategies.