Singh, Rohit

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

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.