Jatwani, Karan

e20511 Background: Trop-2 ADCs have emerged as a novel therapeutic approach in NSCLC that is refractory to chemotherapy and immune checkpoint inhibitors. Comparative interpretation of the efficacy of multiple Trop-2 ADCs, including Sacituzumab tirumotecan (Sac-TMT), Datopotamab deruxtecan (Dato-DXd), and Sacituzumab govitecan (SG), is limited. We therefore conducted a systematic review, IPD survival analysis, and meta-analysis to evaluate the efficacy and PROs of Trop-2 ADCs compared with chemotherapy in NSCLC. Methods: A systematic search was conducted from inception to October 31, 2025, across PubMed, Scopus, Cochrane, and CT.gov. Clinical trials evaluating Overall Survival (OS) and Progression-free survival (PFS) in patients treated with Trop-2 ADC alone or compared with Chemotherapy were included. IPD were extracted from the Kaplan-Meier curves of clinical trials for reconstruction using the KMfromIPD website by MD Anderson, which stratified the data by treatment group. Outcomes included OS, PFS, and time to deterioration (TTD). The cumulative data were analyzed using R 4.5.1 and RStudio. RevMan version 5.4.1 was used for the meta-analysis of subgroups. Heterogeneity was assessed using the I 2 statistic. Results: Of 513 articles, 7 phase 1/2 single-arm and 4 randomized control trials were included, comprising 2,619 patients.Trop-2 ADCs were associated with improved OS (Median 15.6 vs 12.5 months; HR 0.78, 95% CI 0.69-0.88; p < 0.0001) and PFS (Median 5.5 vs 4.1 months; HR 0.66, 95% CI 0.59-0.74; p < 0.0001). Sac-TMT demonstrated the greatest OS benefit (OS 23.3 months; HR 0.40). Further drug classes are depicted in Table 1. PROs assessment showed TROP-2 ADCs were associated with longer time to deterioration in global quality of life and dyspnea-free survival compared to chemotherapy (HR 0.8 and 0.69), (p = 0.04 and p < 0.0001, respectively). Exploratory subgroup analysis showed improved OS among patients with actionable gene alteration (AGA) treated with Trop-2 ADCs (HR 0.58, p < 0.00001). However, no significant difference was observed in either treatment arm among patients without AGA (HR 0.89, p = 0.15). Conclusions: Trop-2 ADCs were associated with improved survival and PROs compared with chemotherapy in NSCLC, with variability across agents. Sac-TMT has shown higher OS and PFS. Dato Dxd had a favorable PFS; however, the OS was not superior to chemo. Furthermore, SG showed no favorable clinical outcomes compared with the chemo group. These findings support the continued development of Trop-2-directed therapies and highlight the need for prospective comparative trials and biomarker-driven patient selection. Drug N mOS (months) HR p- value mPFS (months) HR p- value Sac-TMT 386 23.32 0.4 <0.000001 7.5 0.5 <0.000001 Dato-DXd 486 13.2 0.95 0.55 5.02 0.71 <0.000001 SG 347 12.61 1.02 0.82 4.18 0.87 0.05

e16564 Background: Urothelial carcinoma (UC) predominantly affects older adults with a high burden of comorbidities, particularly chronic kidney disease (CKD), which affects 30–40% of patients at diagnosis and is more prevalent in advanced disease. Enfortumab vedotin plus pembrolizumab (EV+P) has become a frontline standard for advanced UC; however, patients with moderate-to-severe CKD were underrepresented in pivotal trials. Enfortumab vedotin targets Nectin-4 expressed in renal tubular epithelium, and immune checkpoint inhibitors are associated with immune-mediated nephrotoxicity, raising concern for renal vulnerability in patients with reduced renal reserve. Real-world data evaluating renal and clinical outcomes of EV+P in patients with baseline CKD are limited. Methods: We conducted a retrospective cohort study using the TriNetX Global Collaborative Network, identifying adult patients with UC treated with EV+P between January 2020 and December 2025. Baseline CKD status (stages 3–5; eGFR < 60 mL/min/1.73 m²) was determined by diagnostic codes and laboratory data obtained prior to EV+P initiation.Patients were stratified into CKD and non-CKD cohorts. Propensity score matching (1:1) was performed for demographics, comorbidities, laboratory values, and prior therapies. Outcomes assessed within 180 days of treatment initiation included overall survival (OS), major adverse kidney events (MAKE; composite of acute kidney injury, dialysis initiation or dependence, or death), and selected treatment-related toxicities. Kaplan–Meier and Cox proportional hazards models were used. Results: After matching, 386 patients were included in each cohort (median age 75 years), with well-balanced baseline characteristics (all post-matching standardized mean differences < 0.1). Prior to matching, patients with CKD had a higher burden of cardiovascular comorbidities. Baseline renal function differed by design, with lower mean eGFR and higher serum creatinine in the CKD cohort. Overall survival was similar between CKD and non-CKD cohorts (HR 0.96; 95% CI, 0.69–1.35; p = 0.83), with 180-day survival rates of 79.9% and 79.3%, respectively. Patients with CKD had a higher incidence of MAKE, reflected by lower 180-day event-free survival (49.4% vs 59.1%; HR 1.41; 95% CI, 1.13–1.76; p = 0.002). Treatment-related toxicities were also more frequent in the CKD cohort (HR 1.35; 95% CI, 1.05–1.74; p = 0.020), with a higher mean number of toxicity events (4.3 vs 3.4). Conclusions: In this large real-world analysis, EV+P use was associated with comparable short-term overall survival in UC patients with and without CKD but with higher rates of renal events and treatment-related toxicities among patients with baseline CKD. These findings support the use of EV+P in select UC patients with CKD, with close monitoring of renal function and treatment-related toxicity.

e13656 Background: Effective multidisciplinary cancer care is bottlenecked by the cognitive burden of synthesizing fragmented electronic health records across different specialties. Current AI tools often function as isolated chatbots rather than integrated workflow assistants. We developed and validated "OncoSphere AI," an Agentic AI multidisciplinary clinical workflow support tool designed to autonomously orchestrate the multidisciplinary review process by deconstructing complex cases into domain-specific insights. Methods: OncoSphere AI is a novel, multi-agent large language model–driven platform that simulates a multidisciplinary tumor board for cancer care. The architecture uses a parallel reasoning framework in which eight virtual specialty agents—Medical Oncology, Radiation Oncology, Surgical Oncology, Pathology, Radiology, Pharmacy, Clinical Research, and Nurse Navigation—independently analyze structured and unstructured patient data against specialty specific guidelines and contemporary peer-reviewed literature. System performance was assessed via built-in telemetry (task completion, latency, inter-agent agreement) and blinded review by eight expert oncologists using a structured survey to rate data extraction fidelity, guideline concordance, safety, and clinical utility compared with standard manual review. Results: The study cohort (n=20, median age 59.5 years; 55% female) had a median of 2.5 (range 0-7) prior lines of therapy and multiorgan metastatic disease (median: 2, range 1–4), including lung, breast, gastrointestinal (CRC, pancreatic, hepatobiliary), and genitourinary (prostate, renal) malignancies. OncoSphere AI demonstrated high workflow utility (mean rating: 4/5) and strong extraction fidelity, with more than 90% of biomarker extractions rated as a “perfect match” by expert reviewers. Operational efficiency gains were substantial with AI processing averaged 4.7 minutes per case versus 29.3 minutes for manual review, corresponding to an 84% reduction in time (p<0.001). System telemetry revealed adaptive compute behavior, with the platform autonomously allocating 1.73-fold more reasoning tokens to complex, refractory cases than to standard scenarios. Safety review identified only one critical contraindication issue in a heavily pretreated, multi-line setting. Conclusions: OncoSphere AI effectively automates the clinical “perception layer,” consistently transforming heterogeneous longitudinal data into decision-grade insights with high fidelity and marked time savings. By operating as a coordinated ensemble of domain-specialized AI agents rather than a single generic model, it offers a scalable approach to reduce physician cognitive burden and to standardize guideline-concordant care planning in diverse, heavily pretreated oncology populations.

2028 Background: Patients with EGFR-mutated non–small cell lung cancer (NSCLC) frequently develop BM, and CNS progression is a common mode of failure on earlier-generation EGFR tyrosine kinase inhibitors (TKIs). After TKI failure in the setting of BM, optimal next-line systemic therapy remains uncertain, particularly regarding the comparative effectiveness of targeted escalation, immunotherapy (IO)-based regimens, and chemotherapy. Methods: We conducted a retrospective cohort study using the TriNetX Global Collaborative Network. We identified EGFR-mutated NSCLC patients treated with first- or second-generation EGFR TKIs who subsequently developed metachronous BM and initiated next-line systemic therapy between 2015 and 2025. Patients with leptomeningeal disease prior to earlier-generation TKI exposure were excluded. Treatment strategies were categorized as targeted escalation with osimertinib, IO-based therapy (immune checkpoint inhibitor with or without chemotherapy), or chemotherapy alone. The index date was defined as initiation of next-line systemic therapy. Propensity score matching was performed for pairwise comparisons. The primary endpoint was overall survival (OS) at 180 days. Restricted mean survival time (RMST) through 181 days was evaluated as a sensitivity analysis. Baseline covariate balance after matching was assessed using standardized mean differences, with values <0.10 indicating adequate balance. Results: After propensity score matching with adequate baseline balance, osimertinib was associated with significantly lower 180-day mortality compared with chemotherapy (24.5% vs 33.2%; hazard ratio [HR] 0.69, 95% CI 0.47–1.00). Comparisons between osimertinib and IO-based therapy showed numerically lower 180-day mortality with osimertinib (26.0% vs 32.6%; HR 0.79, 95% CI 0.54–1.15), but this difference did not reach statistical significance. Similarly, IO-based therapy was not associated with a statistically significant survival advantage compared with chemotherapy alone (31.7% vs 37.5%; HR 0.78, 95% CI 0.58–1.06). RMST analyses for death over 181 days were directionally consistent with hazard ratio–based results, with modest, non-significant differences in mean survival time. Conclusions: In EGFR-mutated NSCLC patients with metachronous brain metastases after earlier-generation TKI failure, targeted escalation with osimertinib was associated with significantly lower 180-day mortality compared with chemotherapy. IO-based approaches demonstrated intermediate, directionally favorable but non-significant outcomes relative to both osimertinib and chemotherapy. These real-world findings support guideline recommendations prioritizing next-generation TKIs and help inform systemic treatment sequencing in a CNS-enriched population where prospective data remain limited.

2036 Background: Patients with oncogene-driven metastatic non–small cell lung cancer (NSCLC) treated with CNS-penetrant tyrosine kinase inhibitors (TKIs) frequently develop brain metastases (BM) while continuing targeted therapy, and outcomes of adding local CNS-directed therapy in this setting are not well defined. We evaluated outcomes associated with local CNS therapy after post-TKI BM diagnosis. Methods: We conducted a retrospective cohort study using the TriNetX Global Collaborative Network. Adults with NSCLC treated with osimertinib or lorlatinib who subsequently had a coded diagnosis of BM (ICD-10 C79.31) at least 1 month after TKI initiation and evidence of continued TKI use were included. Patients were stratified by receipt of CNS-directed local therapy (SRS/SBRT or neurosurgery) within 3 months of the index BM diagnosis versus no local therapy. The primary outcome was all-cause mortality within 180 days of the index event. Secondary outcomes included hospitalization and systemic corticosteroid use. Cohorts were balanced using 1:1 propensity score matching on demographics, comorbidities, extracranial disease, laboratory values, and TKI exposure. Survival analyses were performed, and proportional hazards assumptions were validated using Schoenfeld residuals (p>0.05). Results: Among 1,157 eligible patients, 1,053 matched pairs were generated. Within 180 days of the index brain metastasis diagnosis, mortality was lower among patients who received local CNS therapy compared with those who did not (10.9% vs 18.1%), corresponding to a hazard ratio (HR) for death of 0.54 (95% CI 0.43–0.68; p<0.001). Survival probabilities at 180 days were 88.7% in the local therapy cohort and 80.2% in the no local therapy cohort. Hospitalization within 180 days occurred in 20.3% of patients receiving local therapy and 22.4% of those without local therapy (p=0.24), with a nonsignificant trend toward delayed hospitalization (HR 0.84, 95% CI 0.69–1.01). Systemic corticosteroid use was common and similar between groups (61.3% vs 59.4%; p=0.40), with no significant difference in time to steroid initiation. In an osimertinib-only sensitivity analysis, 180-day mortality was 10.5% among patients receiving local CNS therapy compared with 19.4% among those without local therapy (HR 0.48, 95% CI 0.37–0.61; p<0.001). Conclusions: In this multi-institutional real-world cohort of patients with NSCLC receiving osimertinib or lorlatinib who developed BM, receipt of local CNS-directed therapy within 3 months was associated with lower 6-month mortality compared with continuation of targeted therapy alone, with consistent findings in an osimertinib-only sensitivity analysis. These results suggest a potential survival benefit of local CNS intervention in selected patients, while acknowledging residual confounding related to intracranial disease burden and clinical indication.

58 Background: Skeletal-related events (SREs) are a common cause of morbidity and mortality in metastatic castration-resistant prostate cancer (mCRPC). These complications are managed using bone-modifying agents (BMAs), radiation therapy, and surgery, and lead to diminished quality of life irrespective of their castration status. We sought to evaluate the mortality trends for patients with PC and SREs in patients of >65 years from 1999 to 2023 using the CDC WONDER (Wide-ranging Online Data for Epidemiologic Research) database. Methods: The database was searched from January 1, 1999, to December 31, 2023. Mortality trends were assessed by identifying prostate cancer international classification of diseases-10th revision code (ICD-10 code C61) as the underlying cause of death in individuals aged >65 years, and (SREs) as contributing causes using the following ICD-10 codes: S02, S12, S22, S32, S42, S52, S62, S82, S92, T02, T08, T10, T12, T14.2, Y93.2, E55, M80, M81, M84.4. Joinpoint 5.0 software was used to analyze mortality trends. Results: From 1999 to 2023, a total of 3,231 deaths were reported. Trend analysis revealed a decline in overall mortality from 1999 to 2014, with an annual percentage change (APC) of -1.60 (CI: -2.6, -0.5; p = 0.005), followed by a significant increase in mortality from 2015 to 2023, with an APC of 5.30 (p = 0.0001). When stratified by age, individuals aged 65-69 showed an insignificant decline in mortality over the entire study period. For those aged 70-74, mortality significantly decreased from 1999 to 2014 (APC: -3.02, CI: -5.0, -0.9; p = 0.008), but experienced an exponential increase from 2014 to 2023 (APC: 14.07, CI: 8.7, 19.6; p = 0.00005). In the 75-79 age group, mortality significantly decreased from 1999 to 2011 (APC: -5.6, CI: -9.5, -1.6; p = 0.0091), followed by a robust increase from 2011 to 2023 (APC: 7.06, CI: 2.7, 11.5; p = 0.002). For individuals aged >80 years, the trend showed an insignificant decline in mortality from 1999 to 2023 (APC: -0.260, CI: -0.8, 0.3; p = 0.380). Conclusions: Our study revealed significant trends in prostate cancer mortality attributable to SREs, contributing to a sharp increase from 2015 to 2023. Age-stratified analysis revealed that substantial mortality is reported in patients aged 70-79, with the most pronounced rise occurring after 2014. These findings emphasize the growing burden of SREs in older prostate cancer patients, underscoring the need for targeted interventions along with a focus on patient-reported outcomes to improve survival and quality of life.

5 Background: Penile cancer (PC) is often diagnosed late, which leads to advanced disease. Studies have reported that less than 18% of individuals with metastatic PC receive any kind of palliative therapy. Place of Death (PoD) is a crucial determinant of patient and caregiver preferences and the cost of caregiving at the end of life (EOL). We aimed to evaluate the trends in PoD for patients with PC in the U.S. from 2003 to 2023 based on the CDC WONDER (Wide-ranging Online Data for Epidemiologic Research) database. Methods: We analyzed data from January 01, 2003, to December 31, 2023. The data for deaths due to PC were pooled using the International Classification of Diseases-10th Revision code as C60 for malignant neoplasm of the penis. The inclusion criteria included patients aged > 25 years. PoD is defined as deaths at home and hospice (H&H) versus medical facilities. Average annual percentage change (AAPC) was calculated using the Joinpoint Regression Program, version 5.0.2. Results: The analysis demonstrated a total of n = 6,074 deaths from PC. A total of 52.1% of deaths, n = 3,167, were reported at H&H. The trend analysis demonstrates an exponential rise in H&H utilization from 34.4% in 2003 to 57.5% in 2023, AAPC [5.4284, CI (4.7-6.10, p < 0.000001]. A significant increase in the utilization of H&H is notable in both African Americans (AA), AAPC [2.8514, CI (1.0-4.7), p = 0.004], and the White population, AAPC [5.3497, CI (4.6-6.0); p < 0.000001]. However, a racial disparity is also noted, with 45.4% in AA, while the White population is at 52.5% deaths in H&H-based care. PC mortality in medical facilities has a 29.7% decline from 2003 to 2023. On age stratification, there was a significant increase in utilizing H&H as PoD for the 45-64 years cohort AAPC [4.29, CI (3.2, 5.2), p < 0.000001], similarly, with the older age group 65+ cohorts AAPC [6.26, CI (5.4, 7.0), p < 0.000001]. In contrast, the younger cohort deduced no significant trend AAPC [2.92, CI (-1.5, 7.6), p = 0.14]. Conclusions: This is the first study to our knowledge providing valuable insights into the evolving PoD preferences among PC patients in the U.S.The age-related trends underscore the importance of tailoring end-of-life care strategies to specific age cohorts. The findings emphasize the importance of policies promoting and supporting H&H care for PC patients. Targeted efforts are warranted to address notable disparities in PoD preferences among racial and age groups.

402 Background: Trastuzumab deruxtecan (T-DXd) is a HER2-targeted antibody-drug conjugate (ADC) with a cytotoxic payload. TDXd was approved in 2021 to be used in advanced gastric or GEJ cancers. Although given the recent approval, real-world evidence on efficacy and safety is limited. We sought to evaluate the efficacy and safety of T-DXd through a combined meta-analysis of clinical trials and real-world studies. Methods: A comprehensive search was conducted across PubMed, Embase, Scopus, and Clinicaltrials.gov databases. The original studies evaluating T-DXd in patients with metastatic/recurrent gastric/gastroesophageal junction (GEJ) cancers were included in the analysis. The pooled objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and the incidence of adverse events (AEs) were analyzed. A random-effects model was used for meta-analysis, and the heterogeneity of the data was evaluated by Chi-sq Q test and the I 2 statistic using OpenMeta [Analyst] (Tufts Medical Center, Boston, MA, USA). Results: This meta-analysis incorporated 8 studies (3 phase II clinical trials, 5 retrospective studies) comprising 915 patients with advanced HER2-positive gastric/GEJ cancer. The median patient age was 66.5 years (range: 27–89), with 75.4% males, 70.4% Asian, and 29.0% Caucasians. 77.9% had an ECOG performance status of 0–1, while 21.8% had ECOG ≥2. Histologically, 53.6% had intestinal and 22.9% diffuse-type adenocarcinoma. HER2 overexpression (IHC3+) was observed in 75.8% of evaluable cases, and 22.4% were IHC2+/FISH positive. 77.6% had primary gastric and 22.4% GEJ tumors. The median line of therapy was 3 (range: 2–11), with prior immune checkpoint inhibitor use in 31.8% and prior surgery in 44.5% .The pooled ORR was 47.7% (95% CI 43.0-52.4%) and DCR was 82.50% (79.40%–85.72%); PFS and OS were 4.92 and 9.86 months, respectively. Safety analysis revealed grade ≥3 AEs in 48.2% of patients, neutropenia (24.5%) being the most common. Treatment discontinuation due to adverse events occurred in 12.2%, and dose reductions were required in 21.5%. Patient-reported outcomes were not assessed in any of the studies. Conclusions: Our meta-analysis, encompassing both clinical trials and real-world data, confirms the encouraging efficacy of T-DXd in gastric/GEJ cancers, with a pooled ORR of 47.7% and a median PFS of 4.92 months, and supports its use as an early-line treatment in this challenging disease landscape. This analysis also highlights the significant incidence of grade ≥3 AEs, particularly neutropenia, which necessitates vigilant monitoring and proactive management. Future research should focus on optimizing patient selection, exploring combination therapies, and refining dosing strategies to maximize clinical benefit while mitigating toxicity.

Abstract Background: B-cell acute lymphoblastic leukemia (B-ALL) accounts for 0.3% of all new cancer cases and 0.2% of cancer-related deaths in the United States. While survival outcomes have improved over the years, further intensifying chemotherapy has offered diminishing returns. Blinatumomab, a bispecific T-cell engager targeting CD3 and CD19, has shown clinical benefit in minimal residual disease (MRD)-positive and relapsed/refractory settings. Its recent FDA approval for use in the consolidation phase of newly diagnosed Philadelphia chromosome–negative, CD19-positive B-ALL followed the landmark E1910 trial, which demonstrated a survival advantage when added to standard chemotherapy. We conducted a systematic review and meta-analysis to evaluate the efficacy and safety of blinatumomab in the consolidation phase across clinical trials and real-world studies. Methods: A comprehensive review was carried out on PubMed, Clinicaltrials.gov and Cochrane library from inception up to July 2025 using the terms “Blinatumomab” and “ALL”. Studies that evaluated response: overall response rate (ORR) and complete response (CR) and adverse events between Blinatumomab and control groups were included. Out of the 19 studies that met the inclusion criteria, 12 were clinical trials and 7 were observational studies. Open meta-analyst software was used to analyze the data. For single arm study, PLO (logit-transformed proportion) was used as a metric. Der Simonian-Laird random effects model was used to generate forest plots of pooled response rate estimates and 95% CI along with p-values and I2 statistics for heterogeneity. Results: A total of 824 patients were included (54.4% male, 45.6% female), with a median age of 48 years. The median follow-up across studies was 18.2 months (range, 3.4 to 92.8 months). Pooled ORR was 96.4% (95% CI, 93–98; p=0.955), and pooled CR was 92.7% (95% CI, 87–95; p&lt;0.001). TRAEs leading to treatment discontinuation occurred in 6.8% (95% CI, 2.5–11.2; p=0.004), dose reductions in 2.9% (95% CI, 0.2–5.6; p=0.069), and treatment-related mortality in 1.4% (95% CI, 0.4–2.3; p=0.256). There was moderate heterogeneity across studies for toxicity outcomes. Conclusion: Consolidation-phase blinatumomab is associated with high response rates and a favorable safety profile, reinforcing the survival gains observed in E1910 (3-year OS: 83% vs 65%). With low rates of treatment-limiting toxicity and mortality, our findings support the incorporation of blinatumomab into standard adult B-ALL consolidation regimens. These data suggest that this immunotherapeutic approach may help narrow the outcome gap between adult and pediatric ALL.