3140 Background: Several ADCs are FDA-approved for patients with advanced solid tumors; dozens more are in trials. Predictive biomarkers are lacking, with ADC target expression alone performing poorly across ADCs/tumor types. We previously described the development of ADC Treatment Response Scores (ADC-TRS)—a tissue-based multivariate gene-expression test combining individual ADC target expression with proliferation and adhesion—with high correlation of per-ADC/tumor type biomarker frequency (TRS-High) with corresponding clinical trial ORRs for 9 ADCs (PO1-14-04; SABCS 2023). Here we evaluated ADC-TRS in two cohorts of patients treated with approved ADCs. Methods: Adults with advanced solid tumors from an observational trial (NCT03061305) treated with an ADC with TRS results from FFPE tissue (collected prior to 1st ADC treatment) were eligible; HER2+ patients previously treated with trastuzumab or with hormonal therapy treatment between sample collection/first ADC treatment were excluded. Kaiser Permanente Northern California (KPNC; limited to breast [BR] and bladder [BL] cancer) patients and non-KPNC patient (pan-solid tumor) cohorts were analyzed separately. We evaluated whether treatment-matched ADC-TRS status (High or Low) was significantly associated with overall survival (OS) after ADC treatment initiation by Cox proportional hazards models (adjusting for age, indication, and years since tissue collection). Additional analyses in the non-KPNC cohort evaluated whether proliferation/adhesion-related gene expression provided information on outcomes beyond ADC target expression only and predictive/prognostic effect. Results: Patients treated with an approved ADC were included in the non-KPNC (n=72; 5 ADCs/9 tumor types); most frequent sacituzumab govitecan/BR [43%]) and KPNC (n=127; 3 ADCs/two tumor types; most frequent enfortumab vedotin/BL[50%]) cohorts, respectively. In both cohorts, ADC TRS status was significantly associated with OS (High vs. Low, median OS 22.8 vs. 8.7 months [mo.], aHR 0.15, p=0.005, and median OS 15.3 vs. 8.3 mo., aHR 0.58, p=0.011, respectively). In the non-KP cohort, ADC-TRS significantly improved model fit for OS beyond target gene expression alone (likelihood ratio test [LRT] p=0.0008). A predictive biomarker effect was confirmed by lack of ADC-TRS status association with OS from systemic chemotherapy start in indication-matched patients not treated with an ADC (n=126, aHR 0.43-2.79, p=0.11-1.0 for the 9 individual TRS). In a 15,108 patient pan-tumor cohort (regardless of treatment), 26.7% were ADC-TRS High for at least 1 approved ADC outside approved indications. Conclusions: Results support ADC-TRS as a multivariate gene-expression-based biomarker that predicts ADC OS across tumor types and targets. More than 25% of all patients with advanced solid tumors have a greater likelihood of being responsive to one or more approved ADCs outside of approved indications.