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Background Immune checkpoint inhibitors (ICIs) have transformed the treatment landscape for advanced non-small cell lung cancer (NSCLC), 1 yet ICI-associated immune-related adverse events (irAEs) remain a major clinical challenge.2 While clinical trials have characterized ICI-induced irAEs, real-world data on severe irAEs, particularly among older adults with more comorbidities and aggressive diseases, are limited.3 4 Moreover, the predictive accuracy of existing models has rarely been reported. This study aimed to identify risk factors for severe irAEs in a large cohort of older adults with advanced NSCLC.Methods A population-based retrospective cohort study was conducted using the SEER-Medicare database from January 2010 to December 2019. The study population comprised patients aged ≥65 years diagnosed with advanced NSCLC and treated with nivolumab, pembrolizumab, or atezolizumab from March 2015 to December 2018. Severe irAEs were identified using International Classification of Diseases (ICD) codes) requiring systemic corticosteroid/immunosuppressant within 14 days of irAE occurrence and ICI delay/discontinuation. 5–8 The onset of severe irAEs was described based on their occurrence in organ systems. The risk factors (patient- and county-level demographics, cancer-related characteristics, clinical and medication history) for severe irAEs were estimated using multivariable regression models that account for competing risks of death.9–10 Model performances were assessed using the time-dependent area under the receiver operating characteristic curve (AUC) and Brier score.11 Results Among 2,729 ICI-treated patients, 14.1%(n=387) experienced severe irAEs. The median time to severe irAE onset was 42 days(interquartile range [IQR]:14–121), with hematologic irAEs occurring earliest (median: 60 days;IQR:40–189) and cardiovascular irAEs latest (median: 228 days;IQR:56–490). Key predictors of severe irAEs included residence in non-metropolitan areas (Hazard Ratio, HR=2.61;95%CI:1.43–4.74), lower neighborhood education levels (e.g., high school only: HR=0.69; 95%CI:0.55–0.87), and prior prolonged hospitalization (HR=29.3; 95%CI:13.77–42.80). Treatment with PD-1 plus chemotherapy (HR=2.35; 95% CI:1.39–3.96) or pembrolizumab versus nivolumab (HR=2.46; 95%CI:1.13–5.36) ( figure 1) also conferred a higher risk. Prior recent immunosuppressant use strongly predicted irAEs (HR=7.37; 95% CI: 5.39–9.18). Additional risk factors included opioid use (HR=0.68; 95%CI:0.54–0.0.87) and longer time from diagnosis to ICI initiation (HR=1.50; 95% CI:1.31–1.60). The final model demonstrated good predictive accuracy (overall AUC=0.81) (figure 2) and calibration/discrimination ability (Brier score=0.14).Conclusions In a cohort of older adults with advanced NSCLC, geographic, socioeconomic, treatment-related, and clinical factors predicted the occurrence of severe irAEs. As ICIs become standard care for advanced NSCLC, recognizing these risks is vital to optimizing treatment outcomes.References Shiravand Y, Khodadadi F, Kashani SMA, Hosseini-Fard SR, Hosseini S, Sadeghirad H, et al. Immune checkpoint inhibitors in cancer therapy. Curr Oncol. 2022 May 1;29(5):3044.Johnson DB, Nebhan CA, Moslehi JJ, Balko JM. Immune-checkpoint inhibitors: long-term implications of toxicity. Nat Rev Clin Oncol. 2022 Apr 26;19(4):254–67.Hsiehchen D, Watters MK, Lu R, Xie Y, Gerber DE. Variation in the assessment of immune-related adverse event occurrence, grade, and timing in patients receiving immune checkpoint inhibitors. JAMA Netw Open. 2019 Sep 18;2(9):e1911519-e1911519.Das S, Johnson DB. Immune-related adverse events and anti-tumor efficacy of immune checkpoint inhibitors. J Immunother Cancer. 2019 Nov 15;7(1):306.Cook S, Samuel V, Meyers DE, Stukalin I, Litt I, Sangha R, et al. Immune-related adverse events and survival among patients with metastatic NSCLC treated with immune checkpoint inhibitors. JAMA Netw Open. 2024 Jan 2;7(1):e2352302.Watson AS, Goutam S, Stukalin I, Ewanchuk BW, Sander M, Meyers DE, et al. Association of immune-related adverse events, hospitalization, and therapy resumption with survival among patients with metastatic melanoma receiving single-agent or combination immunotherapy. JAMA Netw Open. 2022 Dec 8;5(12):e2245596.Brahmer JR, Abu-Sbeih H, Ascierto PA, Brufsky J, Cappelli LC, Cortazar FB, et al. Society for immunotherapy of cancer (SITC) clinical practice guideline on immune checkpoint inhibitor-related adverse events. J Immunother Cancer. 2021 Jun;9(6):e002435.Schneider BJ, Naidoo J, Santomasso BD, Lacchetti C, Adkins S, Anadkat M, et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: ASCO guideline update. J Clin Oncol Off J Am Soc Clin Oncol. 2021 Dec 20;39(36):4073–126.Austin PC, Lee DS, Fine JP. Introduction to the analysis of survival data in the presence of competing risks. Circulation. 2016 Feb 9;133(6):601–9.Schuster NA, Hoogendijk EO, Kok AAL, Twisk JWR, Heymans MW. Ignoring competing events in the analysis of survival data may lead to biased results: a nonmathematical illustration of competing risk analysis. J Clin Epidemiol. 2020 Jun;122:42–8.Collins GS, Dhiman P, Ma J, Schlussel MM, Archer L, Calster BV, et al. Evaluation of clinical prediction models (part 1): from development to external validation. 2024 Jan 8 [cited 2025 Jun 26];384(e074819). Available from: https://www.bmj.com/content/384/bmj-2023-074819Ethics Approval This study was approved by the University of Houston Institutional Review Board and conducted in accordance with all applicable guidelines and regulations. The analysis used de-identified data from the SEER-Medicare database. Informed consent was not required due to the retrospective nature of the study and use of de-identified data.Abstract 1051 Figure 1Cumulative incidence of severe irAE by immune checkpoint inhibitor typeAbstract 1051 Figure 2Model Area Under the Curve (AUC) at different time points (in days)