Citations

e20595 Background: Circadian regulation of immune function has been proposed as a modifier of immune checkpoint inhibitor (ICI) efficacy, with retrospective studies suggesting improved outcomes with earlier infusion timing. Whether these findings translate to routine oncology practice, where ICIs are administered across multiple lines, frequently combined with chemotherapy, and subject to treatment interruptions, remains uncertain. We evaluated the association between ICI infusion timing and overall survival (OS) in a real-world cohort of patients with non-small cell lung cancer (NSCLC). Methods: A retrospective cohort study included adults with NSCLC who received at least one line of ICI therapy at a community oncology center between January 2018 and December 2024. Infusion timing was defined at the patient level as morning-only ( < 1300 hours), evening-only (≥1300 hours), or mixed timing, reflecting receipt of infusions exclusively in different time-of-day categories across treatment lines. OS was measured from diagnosis to death or last follow-up. Kaplan-Meier and Cox proportional hazards models were used. Multivariable analyses adjusted for stage, ECOG performance status, body mass index, and premature ICI discontinuation. Line of therapy was excluded due to collinearity with mixed-timing classification and risk of immortal time bias. Results: A total of 127 patients were included (morning-only n = 77; mixed timing n = 36; evening-only n = 14). Staging data were available for 99.2%, and 94 deaths occurred. Median OS was 495 days for morning-only, 850 days for mixed timing, and 388 days for evening-only patients. Kaplan-Meier analysis showed no statistically significant OS differences across groups. In sensitivity analysis excluding patients with mixed infusion timing, morning-only and evening-only groups demonstrated overlapping survival curves, with no evidence of a time-of-day–specific survival advantage. In univariate analysis, mixed timing was associated with a borderline reduction in mortality compared with morning-only infusions (HR 0.63, 95% CI 0.39-1.00), while evening-only timing was not (HR 1.63, 95% CI 0.85-3.16). In multivariate analysis restricted to stage III-IV disease, infusion timing was not independently associated with OS. ECOG performance status, premature ICI discontinuation and advanced staging were the strongest predictors of mortality. Conclusions: In this real-world NSCLC cohort, ICI infusion timing was not independently associated with overall survival after adjustment for patient fitness and treatment continuity. These findings suggest that in pragmatic settings, clinical factors may outweigh subtle chronotherapy effects reported in more selected populations.

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

e20139 Background: Extensive-stage small cell lung cancer (ES-SCLC) frequently presents with brain metastases, affecting approximately 20% of the patients at diagnosis. The prognostic impact of baseline brain metastases on survival outcomes in patients treated with contemporary chemo-immunotherapy remains unclear, creating uncertainty in first-line treatment selection for this high-risk population. We conducted a systematic review and meta-analysis to evaluate the impact of baseline brain metastases on treatment outcomes in ES-SCLC. Methods: This PRISMA-compliant systematic review and meta-analysis was prospectively registered in PROSPERO. PubMed, Embase, Cochrane CENTRAL, and ClinicalTrials.gov were systematically searched from database inception through January 2026 to identify randomized controlled trials evaluating PD-1/PD-L1-based chemo-immunotherapy versus platinum-etoposide chemotherapy in adults with ES-SCLC. Two reviewers independently screened studies and extracted data, with discrepancies resolved by consensus. Hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS) were pooled separately for patients with baseline brain metastases (BM+) and without brain metastases (BM−) using random-effects models with Hartung–Knapp adjustment. Analyses were performed using R. Prespecified subgroup analyses were conducted based on follow-up duration and immunotherapy regimen. Results: Twelve randomized controlled trials were included. Among patients with baseline brain metastases (BM+), pooled OS from seven studies did not show a significant survival benefit (HR 0.84, 95% CI 0.66–1.08, I² = 0.0%, P = 0.145), nor did pooled PFS from five studies (HR 1.03, 95% CI 0.60–1.79, I² = 0.0%). Subgroup analyses revealed no significant heterogeneity. In contrast, among patients without baseline brain metastases (BM−), pooled OS from nine studies demonstrated a significant survival benefit (HR 0.72, 95% CI 0.69–0.76, I² = 0.0%, P < 0.001), with corresponding improvement in PFS (HR 0.70, 95% CI 0.60–0.82, I² = 0.0%). These findings indicate a differential treatment effect according to baseline brain metastasis status. Conclusions: First-line chemo-immunotherapy does not apprear to confer a significant survival benefit in ES-SCLC patients with baseline brain metastases, reflecting a differential treatment effect by brain metastasis status. These findings suggest that baseline brain metastases should be considered in treatment selection and future clinical trial design and highlight the need for optimized systemic strategies for this high-risk population.

e20030 Background: Recent studies suggested associations between higher serum Magnesium (Mg) level and better survival outcome in patients receiving immunotherapy, especially in small cell lung cancer (SCLC). However, the prognostic significance of Mg in extensive-stage (ES) SCLC treated with first-line chemoimmunotherapy remains unclear. We evaluated the association between baseline serum Mg and survival outcomes in ES-SCLC receiving platinum–etoposide plus PD-(L)1 blockade. Methods: We conducted a retrospective cohort study of adults with ES-SCLC treated with first-line platinum–etoposide plus atezolizumab or durvalumab at Mayo Clinic via Mayo Clinic Platform in 2018–2025. Baseline average serum Mg level was defined as the mean of all Mg labs from day −30 to day 0 relative to chemoimmunotherapy initiation and categorized as low ( < 1.7 mg/dL), normal (1.7-2.0 mg/dL), or high ( > 2.0 mg/dL) using clinical cutoff. Low and normal groups were combined a priori due to small low-Mg counts. The primary endpoint was overall survival (OS), estimated by KM and compared by log-rank test. OS was measured from chemoimmunotherapy initiation to death and censored at last follow-up. Multivariable Cox proportional hazards models adjusted for age, gender, ECOG, liver/brain metastases status, and smoking status. Results: The cohort included 214 patients, 124 (58%) were female; median age was 68 years; 49% had liver metastases and 30% had brain metastases. Median OS was 10.4 months (95% CI 7.6-15.9) among 99 patients with high serum Mg level, compared with 7.5 months (95% CI 6.7-10.7) in 115 patients with low or normal serum Mg level (Log-rank p = 0.126). High Mg was associated with a trend toward longer OS in unadjusted analyses (Hazard ratio [HR] 0.80, 95% CI 0.59-1.07, p = 0.129); however, the association was not statistically significant after multivariable adjustment (aHR 0.81, 95% CI 0.60-1.10, p = 0.180). Conclusions: Among patients with ES-SCLC treated with first-line platinum–etoposide plus PD-(L)1 blockade, higher baseline serum Mg was associated with numerically longer OS but was not independently associated with survival after multivariable adjustment. These findings suggest baseline serum Mg level may be associated with prognosis and warrant validation in larger cohorts. Baseline characteristics by baseline serum magnesium category in ES-SCLC treated with first-line chemoimmunotherapy. Variable Overall (N=214) High Mg >2.0 (n=99) Low/Normal Mg ≤2.0 (n=115) p value* Age, median (IQR) 68 (62, 74) 68 (61, 74) 69 (62, 75) 0.201 Female, n (%) 124 (58%) 57 (58%) 67 (58%) >0.999 ECOG ≥2, n (%) 58 (27.1%) 28 (28%) 30 (26%) 0.719 Liver metastases, n (%) 105 (49%) 49 (49%) 56 (49%) 0.648 Brain metastases, n (%) 65 (30%) 33 (33%) 32 (28%) 0.469 Ever smoker, n (%) 197 (92.1%) 90 (90.9%) 107 (93.0%) 0.974 *p values: Wilcoxon (age); χ²/Fisher (categorical).

e20000 Background: Multimodal machine-learning (ML) models that fuse imaging, pathology, omics, and clinical data may improve overall-survival (OS) prediction in non–small-cell lung cancer (NSCLC) beyond staging-based tools. We systematically reviewed the design, performance, and methodological quality of these models. Methods: Following PRISMA 2020, we searched Ovid (MEDLINE/Embase/CENTRAL/CDSR), Scopus, IEEE Xplore, and arXiv (January 2017–July 2025). Eligible studies developed or validated ML models integrating ≥2 modalities to predict OS in adults with NSCLC and reported either time-to-event or fixed-horizon binary outcomes. Two reviewers independently screened, extracted, and assessed risk of bias using PROBAST with PROBAST-AI items. Due to heterogeneity, results were synthesized narratively. Results: We included 18 studies (2021–2025) with per-study sample sizes ranging from 115 to 2,898. Outcome framing: time-to-event OS only (n=11), fixed-horizon binary OS only (n=4), and both (n=3). Modalities most often used were clinical structured data (15/18), CT (12/18), PET (6/18), molecular omics (7/18), pathology whole-slide images (4/18), and EHR text (1/18). Fusion strategies clustered as early/concatenation (10/18), interaction-based (attention/bilinear/graph; 5/18), and late/score-level (3/18). For time-to-event OS, internal C-indices ranged 0.658–0.893, with the highest internal value 0.893 (CT+clinical). One study reported external C-index (0.678, pathology+genes). An additional study reported external time-dependent AUC 0.845 at 1-year for a PET/CT-genomics survival model (n=32). For binary OS, internal AUROCs were 0.802–0.888 (2–5-year horizons), and internal accuracies ranged 0.68–0.93 (1–5 years). External binary performance included accuracy 0.72 at 1-year in an immunotherapy cohort. Across studies, multimodal models typically outperformed the best single-modality comparator by ~+0.06 C-index or AUROC, though absolute gains varied. Risk of bias was frequently high in the analysis domain (internal-only validation, optimistic tuning, sparse calibration reporting); code/weights were publicly available in 5/18 studies. Conclusions: Multimodal ML models for NSCLC show consistent, modest improvements in OS discrimination versus single-modality approaches, with CT+clinical the most translationally pairing. However, independent validation, calibration, and transparency remain limited, constraining clinical adoption. Future work should prioritize multi-center datasets, standardized reporting, and open workflows.

8597 Background: Lorlatinib improves outcomes in NSCLC but commonly causes marked hyperlipidemia, prompting initiation of lipid-lowering therapy (LLT). Beyond lipid control, LLT may be associated with vascular events; however, its association with thromboembolism, healthcare utilization, and mortality among lorlatinib-treated patients has not been characterized in real-world cohorts. Methods: Using TriNetX, we identified adults with NSCLC who received lorlatinib (index = first lorlatinib record). Patients were grouped by early LLT initiation within 30 days of index versus no LLT within 30 days. LLT included statins, ezetimibe, PCSK9 inhibitors, or fibrates. Cohorts were balanced 1:1 using propensity score matching on demographics and baseline comorbidities. Outcomes were assessed through 365 days; patients with prior outcome documentation were excluded. Results: After matching, 387 patients per cohort were analyzed. Early LLT was associated with lower all-cause mortality at 365 days (16.1% vs 26.4%; risk ratio [RR] 0.61, 95% CI 0.46-0.81; p=0.0004) and improved time to death (hazard ratio 0.60, 95% CI 0.44-0.82). Early LLT was also associated with lower venous thromboembolism (6.2% vs 12.1%; RR 0.51, 95% CI 0.30-0.86; p=0.0093) and fewer inpatient hospitalizations (14.6% vs 23.6%; RR 0.62, 95% CI 0.40-0.97; p=0.0320). Emergency department visits were numerically lower (8.3% vs 13.9%; RR 0.59, 95% CI 0.35-1.00; p=0.0467). No significant differences were observed for acute kidney injury or major adverse cardiovascular events. Conclusions: In a real-world propensity-matched cohort of lorlatinib-treated NSCLC patients, LLT initiated within 30 days was associated with lower 1-year mortality, venous thromboembolism, and hospitalization. Given the frequency of lorlatinib-associated dyslipidemia, these findings support early lipid monitoring and timely LLT initiation in practice. Prospective studies are warranted to confirm these associations. 365-day outcomes after matching. Outcome Early LLT (n=387) No early LLT (n=387) RR (95% CI) HR (95% CI) p All-cause mortality 16.1% 26.4% 0.608 (0.458-0.806) 0.597 (0.435-0.818) 0.0004; log-rank 0.001 Venous thromboembolism 6.2% 12.1% 0.509 (0.302-0.857) — 0.0093 Inpatient hospitalization 14.6% 23.6% 0.619 (0.396-0.967) — 0.0320 ED visit 8.3% 13.9% 0.593 (0.352-1.001) — 0.0467 Acute kidney injury 5.4% 7.1% 0.769 (0.429-1.378) — 0.3758 MACE 4.6% 4.6% 1.006 (0.511-1.979) — 0.9868

8598 Background: Immune checkpoint inhibitors (ICI) have become a cornerstone of treatment for lung cancer. Glucagon-like peptide-1 receptor agonists (GLP-1 RA) have been associated with improved outcomes in cancer patients in prior studies; however, their impact on outcomes among lung cancer patients receiving immunotherapy remains limited. Methods: We conducted a retrospective cohort study using the TriNetX real-world data platform. Adult patients with lung cancer treated with ICIs, including PD-1, PD-L1, or CTLA-4 inhibitors, were included. Patients were stratified based on exposure to GLP-1 RA. Propensity score matching (1:1) was performed to balance baseline demographics and comorbidities, including type 2 diabetes mellitus and body mass index. Primary outcomes included all-cause mortality, intensive care unit (ICU) admission, and hospitalization. Secondary outcomes included immune-related pneumonitis, colitis/enteritis, cachexia, and major adverse cardiovascular events (MACE). Results: After matching, 2,013 patients were included in each group, with a median follow-up of 372 days in the GLP-1 RA group and 383 days in the non-GLP-1 RA group. Mean age was 66.8 and 67.2 years, respectively, and approximately 50% of patients were male. Most patients were White (77.2% vs 71.8%), followed by Black (14.1% vs 14.0%) and Asian (2.1% vs 1.8%). GLP-1 RA use was associated with a significantly lower all-cause mortality rate compared with non-use (35.7% vs. 53.4%; p < 0.0001), with a hazard ratio of 0.65 (95% CI, 0.59–0.71). Significant reductions were also observed in ICU admissions (22.8% vs 29.0%; p = 0.0001), hospitalizations (64.1% vs 71.8%; p = 0.0001), pneumonitis (5.2% vs 6.8%; p = 0.0457), and MACE (19.9% vs 25.3%; p = 0.0026). No significant differences were observed in colitis/enteritis (9.3% vs 9.4%; p = 0.9704) or cachexia (8.0% vs 9.8%; p = 0.0650). In a subgroup analysis of lung cancer patients not receiving ICI, GLP-1 RA use was similarly associated with lower mortality, ICU admission, hospitalization, and MACE, without differences in immune-related toxicities. Conclusions: GLP-1 RA use among lung cancer patients was associated with improved survival, reduced healthcare utilization, and fewer selected adverse events in patients receiving ICI therapy. These associations likely reflect established metabolic and cardiovascular benefits of GLP-1 RA and may also involve antitumor mechanisms suggested in prior studies. Residual confounding related to healthcare access and socioeconomic factors cannot be fully excluded and should be considered when interpreting these findings. Prospective studies are warranted to validate these observations and clarify underlying biological mechanisms.

8534 Background: Immunotherapy (IO) has transformed treatment for non–small cell lung cancer (NSCLC), but not all patients (pts) benefit, underscoring the need for predictive biomarkers to guide IO versus chemotherapy (Ch). CheckMate 227 (CM227; NCT02477826) showed a survival benefit of first-line nivolumab plus ipilimumab (nivo+ipi) over Ch in stage IV NSCLC. CD8⁺ T cells are key mediators of antitumor immunity and are associated with IO benefit. We developed an artificial intelligence (AI)–based pipeline (VIGOR-CD8) that predicts spatial CD8⁺ immune signatures from routine baseline H&E whole-slide images using histopathology foundation model embeddings (H-Optimus-0) and virtual gene expression modeling (HE2Gene), and evaluated its ability to identify pts who do and do not derive IO benefit over Ch in CM227. Methods: 1,598 pts with advanced NSCLC were analyzed, including multi-institutional retrospective cohorts (n = 487; 65 for patch-level CD8⁺ prediction and overall survival (OS), 422 for patient-level OS) and a blinded CM227 validation subset (n = 1,111). For orthogonal validation, 86,470 H&E patches were co-registered with quantitative CD8⁺ immunofluorescence. H-Optimus-0 and HE2Gene immune-related embeddings were used to train a random forest classifier to predict patch-level CD8⁺ probability. Patch-level probabilities were aggregated into a patient-level CD8⁺ signature and dichotomized into biomarker-positive (B⁺) and biomarker-negative (B⁻) groups by the training-set median. Cox models assessed the impact of VIGOR-CD8 on OS. In CM227, prognostic and predictive utility were evaluated using treatment-specific analyses; investigators were blinded to outcomes, and models were trained on independent, non-overlapping cohorts. Results: VIGOR-CD8 was associated with longer OS in the testing cohort (n = 422; HR 0.68, 95% CI 0.53–0.87, p = 0.00163) and CM227 (n = 1,111; HR 0.8, 95% CI 0.67–0.96, p = 0.016), irrespective of treatment type and PD-L1 expression. Among pts with evaluable PD-L1, B⁺ pts treated with nivo+ipi had superior OS versus Ch (n = 617; HR 0.72, 95% CI 0.58–0.90, p = 0.003), while in B⁻ pts there was no significant OS difference between treatment arms (n = 130; HR 1.18, 95% CI 0.79–1.75, p = 0.436), supporting a predictive rather than purely prognostic role for VIGOR-CD8. Conclusions: An AI-derived CD8⁺ immune signature from routine baseline H&E slides was associated with favorable OS in CM227 and predicted differential benefit from nivo+ipi versus Ch. VIGOR-CD8 may help identify advanced NSCLC pts most likely to benefit from first-line dual IO, but further validation in independent and prospective trials is warranted.

8519 Background: Non-classical mutations (NCM) of epidermal growth factor receptor (EGFR) represent a broad group of oncogenic mutations in non-small cell lung cancer (NSCLC), often associated with resistance to osimertinib (e.g., P-loop and αC-helix compressing [PACC] mutations). Patients (pts) with NCM have inferior clinical outcomes with a high incidence of CNS metastases (CNSm). Silevertinib (BDTX-1535) is a fourth-generation, covalent EGFR TKI with high CNS penetrance targeting both EGFR classical mutations and NCM. The antitumor activity and safety of silevertinib in pts with advanced NSCLC were evaluated in a Phase 2 trial (NCT05256290). Methods: Pts with advanced EGFR NCM NSCLC who received no prior systemic therapy were enrolled (Cohort 3) based on a local molecular test. Silevertinib 200 mg was administered orally once daily. The primary endpoint of objective response rate (ORR) was assessed using RECIST v1.1. CNS ORR was assessed using Response Assessment in Neuro-Oncology for Brain Metastases (RANO-BM) in pts with no prior CNS therapy. Secondary endpoints include progression-free survival (PFS), duration of response (DOR), disease control rate (DCR), and safety. Results: From February 2024 to July 2025, 43 pts with 35 unique NCMs (including 25 pts with PACC mutations) were enrolled in Cohort 3: median age 70.0 years, 72% female, 74% white, and 42% never smoked cigarettes. As of November 3, 2025, median follow-up was 7.2 months. ORR by RECIST v1.1 is shown in the table. Sixteen pts (37%) had CNSm, including 7 pts (16%) with measurable CNS disease. RANO-BM CNS response was 86% (n=6/7). Complete clearance of EGFR VAF ctDNA was observed in 21/26 (81%) evaluable pts. Serious treatment-related adverse events (TRAEs) were reported in 5 pts (12%), and 4 pts (9%) discontinued treatment due to TRAEs. The most common TRAEs included rash (19%, grade 3), diarrhea (19%, grade 3), stomatitis (9%, grade 3), and paronychia (5%, grade 3). While 77% of pts had a dose reduction, 19/22 (86%) patients with a radiographic response maintained or deepened their response after dose reduction, including all patients with CNS response. Conclusions: Silevertinib demonstrated robust antitumor activity in treatment-naïve pts with a broad spectrum of NCM EGFR driver mutations with high intracranial activity in pts with brain metastases. The safety profile was consistent with the known AEs of the EGFR TKI class. Clinical trial information: NCT05256290 . Data as of November 3, 2025 N ORR n (%) 95% CI DCR n (%) 95% CI ITT Population * 43 26 (60) (44.4, 75.0) 39 (91) (77.9, 97.4) PACC mutations 25 14 (56) (34.9, 75.6) 22 (88) (68.8, 97.5) Compound mutations † 16 11 (69) (41.3, 89.0) 15 (94) (69.8, 99.8) *No pts with classical (E746_A750del or L858R) mutations were enrolled. † Presence of ≥ 2 NCMs. As of December 27, 2025, the 6-month PFS rate was 86% overall and 80% in pts with CNSm; available PFS and DOR data will be presented.

8077 Background: Small cell lung cancer (SCLC) is an aggressive malignancy with poor prognosis. This study evaluates national trends in surgical management of early-stage SCLC using the National Cancer Database (NCDB), aiming to identify factors associated with improved outcomes and assess the survival benefit of surgical resection. Methods: Patients diagnosed with clinical stage T1–T3 N0 M0 SCLC between 2004 and 2022 were identified from the NCDB. Exclusions included non-SCLC histologies, advanced or missing staging, non-lobectomy surgeries, and incomplete survival data. Propensity score matching (1:1) was used to balance surgical and non-surgical cohorts based on demographic, clinical, and socioeconomic variables. Kaplan-Meier and Cox regression analyses were used to evaluate overall survival, stratified by T stage. Results: Among 17,762 patients with early-stage SCLC, 3,234 (18.2%) underwent lobectomy with mediastinal lymph node dissection. Surgical rates increased from 5% in 2004, 17% in 2013 to 24% in 2021. Surgery was more common in T1 (26.5%) than T2 (11.4%) or T3 (4.6%) disease. After matching, surgery was associated with improved survival across all T stages, with no significant interaction between T stage and surgical benefit (p=0.43). Older age, male sex, and higher comorbidity scores predicted worse outcomes. Among surgical patients, 2.3% received neoadjuvant therapy and 71.6% received adjuvant treatment. Systemic therapy-both neoadjuvant (HR 0.63) and adjuvant (HR 0.69)-was significantly associated with improved survival. Conclusions: Lobectomy remains underutilized in early-stage SCLC but is linked to significantly improved survival. Albeit small patient's number, neoadjuvant systemic therapy further enhanced survival, supporting broader use of surgery and multimodal treatment in appropriately selected patients Univariable results 1 Multivariable results 2 Characteristic No. deaths Person-months HR (95% CI) p-value HR (95% CI) p-value Charlson score <0.001 <0.001 0 761 77727 1.00 (ref) 1.00 (ref) 1 623 60483 1.06 (0.95,1.18) 1.07 (0.96,1.20) 2 or more 350 27025 1.30 (1.15,1.48) 1.30 (1.13,1.48) Clinical T-stage 0.011 0.014 cT1N0M0 1266 124916 1.00 (ref) 1.00 (ref) cT2N0M0 406 33924 1.18 (1.06,1.32) 1.20 (1.06,1.35) cT3N0M0 62 6393 0.96 (0.75,1.24) 1.00 (0.76,1.31) Residual disease <0.001 <0.001 No residual tumor 1626 158838 1.00 (ref) 1.00 (ref) Residual tumor 92 4699 1.91 (1.55,2.36) 1.91 (1.52,2.40) Neoadjuvant systemic treatment 0.253 0.034 No 1629 154116 1.00 (ref) 1.00 (ref) Yes 30 3495 0.81 (0.56,1.16) 0.63 (0.41,0.97) Adjuvant radiation 0.067 <0.001 No 1209 118925 1.00 (ref) 1.00 (ref) Yes 452 40471 1.11 (0.99,1.23) 1.33 (1.18,1.51) Adjuvant systemic treatment <0.001 <0.001 No 563 44045 1.00 (ref) 1.00 (ref) Yes 1096 113566 0.75 (0.68,0.83) 0.69 (0.62,0.78)