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Background As immune checkpoint inhibitors (ICIs) and antibody-drug conjugates (ADCs) become increasingly integrated into cancer care, it remains unknown whether a history of immune-related adverse events (irAEs) during ICI treatment predisposes patients to heightened toxicity or altered efficacy with subsequent ADC administration.Methods We conducted a multicenter retrospective study of patients treated with ≥1 cycle of ICIs followed by ≥1 cycle of ADCs between 2013 and 2025 across seven U.S. academic cancer centers. Patients receiving intervening therapies between ICIs and ADCs were excluded. irAEs and ADC-related adverse events (AEs) were graded per CTCAE v5.0. Multivariable Cox proportional hazards models, adjusted for age, sex, ECOG performance status, and line of therapy, were used to evaluate associations with overall survival (OS) and progression-free survival (PFS), with both prior irAE status and ADC-related AE status included as covariates within the same model. Survival was measured from the initiation of ADC therapy. Two-sided Fisher’s exact tests were used for categorical comparisons.Results Among 570 patients, the median age was 68.3 years (Q1-Q3: 59.7–75.1). The most common cancer types were urothelial (n=307; 53.9%) and breast (n=125; 21.9%). Pembrolizumab (n=386; 67.7%) and enfortumab vedotin (n=291; 51.1%) were the most frequently administered ICI and ADC, respectively. Any-grade irAEs occurred in 37.0% of patients and grade ≥3 in 14.9%. Any-grade ADC-related AEs occurred in 53.3% of patients and grade ≥3 in 16.7%. Prior irAEs were associated with a higher risk of grade ≥3 ADC-related AEs (odds ratio [OR] 1.7, 95% confidence interval (CI) 1.06–2.72; P=0.02), but not all-grade ADC-related AEs (OR 1.29, 95% CI 0.90–1.85; P=0.16). Patients who responded to ICIs were more likely to respond to ADCs (OR 1.82; 95% CI 1.16–2.88; P=0.008). In multivariable analyses, both prior irAEs (HR 0.66, 95% CI 0.53–0.83; P<0.001) and ADC-related AEs (HR 0.71, 95% CI 0.57–0.88; P=0.002) were independently associated with longer OS (table 1). ADC-related AEs were also associated with longer PFS (HR 0.69, 95% CI 0.54–0.87; P=0.002) on ADCs (table 2).Conclusions In the largest cohort to date of patients receiving sequential ICIs and ADCs, prior irAEs were associated with higher risk of severe ADC-related toxicity but also with significantly improved OS. These findings suggest a link between prior immune activation and therapeutic benefit on ADCs and highlight the need for close monitoring of patients with prior irAEs that receive subsequent ADC therapy.Ethics Approval The study was approved by the Institutional Review Board (IRB) at Dana-Farber Cancer Institute (Approval No. 24-139) and the IRBs of all participating institutions. All participants provided written informed consent prior to enrollment, in accordance with the Declaration of Helsinki and local regulatory requirements.Abstract 401 Table 1Multivariable cox model assessing the association of prior immune-related adverse events (irAEs) and adverse events (AEs) on antibody-drug conjugates (ADCs) with overall survival on ADCsBoth irAE status and ADC-related AE status were included as covariates in the same model. HR: hazard ratio; CI: confidence interval; ECOG PS: Eastern Cooperative Oncology Group Performance Status.Abstract 401 Table 2Multivariable cox model assessing the association of prior immune-related adverse events (irAEs) and adverse events (AEs) on antibody-drug conjugates (ADCs) with progression-free survival on ADCsBoth irAE status and ADC-related AE status were included as covariates in the same model. HR: hazard ratio; CI: confidence interval; ECOG PS: Eastern Cooperative Oncology Group Performance Status.