Khosla, Atulya Aman

e22677 Background: Lung cancer without tobacco exposure is a growing and preventable source of global morbidity driven by environmental and occupational exposures, with marked regional variation and unevenly addressed prevention strategies. Methods: Global Burden of Disease (GBD) 2023 estimates were used to quantify lung cancer disability-adjusted life years (DALYs) and age-standardized mortality rates (ASMRs) attributable to ambient particulate matter (PM2.5), household air pollution (HAP), residential radon, and occupational carcinogens across seven GBD super-regions from 1990–2023. Population attributable fractions (PAFs) and temporal trends were assessed, with sex-stratified analyses for radon and occupational exposures. Results: Air pollution accounted for the largest attributable lung cancer DALYs in low and middle-income regions, particularly South Asia, where PM2.5 (PAF 15.9%) and HAP (PAF 16.8%) together accounted for 32.7% of DALYs. In Sub-Saharan Africa, HAP alone accounted for 21.4%. Occupational carcinogens contributed the largest proportion in high-income regions (PAF 21.7%) and were associated with the highest DALY rate (230/100,000) and ASMR (13/100,000). From 1990–2023, HAP-attributable lung cancer burden declined across all regions (40–70%), consistent with transitions away from solid household fuels. In contrast, PM2.5-attributable DALY rates declined by 30–40% in high-income regions but increased by 40–50% in South Asia and the Middle East and North Africa. Radon- and occupational carcinogen–attributable burdens remained largely stable across most regions, although high-income regions experienced declines in radon (18.4%) and occupational carcinogen (32.1%) attributable DALY rates. Radon showed a modest male excess (male-to-female ratios 1.2–1.5), whereas occupational carcinogens demonstrated marked male predominance (often > 4). Conclusions: Despite substantial decrease in HAP related lung cancer burden, other modifiable factors including PM2.5, occupational carcinogen and radon exposure remain major contributors, specially in high-income regions where occupational exposures account for the largest PAF. These patterns suggest that reducing household energy exposure alone is insufficient. We need regional exposure targeted prevention strategies that extend beyond tobacco control and are relevant to oncology practice, survivorship and policy advocacy. Population-attributable fractions of lung cancer burden from environmental and occupational exposures across gbd super-regions. GBD Super-Region Air Pollution (PM2.5 + HAP) Residential Radon Occupational Carcinogens High-income 6.2 4.6 21.7 Central Europe, Eastern Europe & Central Asia 11.3 6.3 10.9 Latin America & Caribbean 12.5 4.1 11.9 North Africa & Middle East 21 3.7 12.7 South Asia 32.7 4.3 10 Sub-Saharan Africa 30.7 4.3 9.4 Southeast Asia, East Asia & Oceania 23.6 3.4 9.8

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.

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.

Abstract Objectives Understanding trends in end-of-life care for bladder cancer patients is essential in improving palliative care planning. This study analyzes trends in preferred place of death among bladder cancer patients in the United States from year 2000 to 2020. Methods Data from the CDC WONDER database were used to identify 293,906 deaths caused by bladder cancer. Further data on patient place of death, age, demographics, census geographic region, and year of death were recorded. Place of death was used as a proxy for preferred place of death. A multivariable binary logistic regression analysis was performed to determine associations between preferred place of death and other variables. Results At-home deaths were most common among individuals aged 75–84 years of age (42,644 deaths) and 85+ years of age (32,806 deaths). Hospice use was highest among the 75–84 age group (8,754 deaths) and 85+ age group (7,358 deaths). Nursing home deaths were highest in the 85+ age group (26,216 deaths), with significant age-related differences ( p < 0.001). In terms of racial variations, White individuals accounted for 93.6% of all deaths. Black individuals were less likely to utilize hospice care ( p < 0.001). Overall, race differences were significantly associated with place of death ( p < 0.001). The number of home deaths rose from 4,281 in 2000 to 8,554 in 2020, and hospice deaths also rose significantly during this time period. Interestingly, younger individuals were more likely to die in hospice compared to those aged 85 years or older, though the odds decreased with age. Black individuals had significantly lower odds of hospice use than White patients (OR = 0.699, p < 0.001) and hospice use increased annually by an average of 13.4% ( p < 0.001). Significance of results The results indicate that utilization of hospice care and home-based end-of-life care have risen in prominence though disparities are present across racial and regional groups. Further studies are needed to better understand potential barriers to end-of-life care among bladder cancer patients.

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.