Background: Immunotherapy has revolutionized oncology care, but clinical response to immune checkpoint inhibitors (ICIs) remains unpredictable, and treatment carries substantial risks and costs. The EpiSwitch® CiRT blood test is a novel 3D genomic assay that stratifies patients by probability of ICI benefit using a binary, blood-based classification: high (HPRR) or low (LPRR) probability of response. Methods: This interim analysis of the ongoing PROWES prospective real-world evidence study evaluates the clinical utility of CiRT in 205 patients with advanced solid tumors. The primary endpoint was treatment decision impact, assessed by pre/post-test physician surveys. Secondary endpoints included treatment avoidance, time to ICI initiation, concordance with clinical response, early discontinuation rates, and exploratory health economic modeling. Longitudinal use, resistance monitoring, and equity analysis by social determinants of health (SDoH) were also explored. Results: CiRT results influenced clinical decision-making in a majority of cases. LPRR status was associated with higher rates of treatment avoidance and early discontinuation due to immune-related adverse events (IrAEs). In contrast, HPRR patients experienced greater clinical benefit and longer ICI exposure. CiRT classification was not associated with short-term imaging-based response outcomes, supporting its role as an independent predictor. Given that ICI therapy and supportive care can cost more than $850,000 per patient, CiRT offers potential value in avoiding ineffective treatment and associated toxicities. Conclusions: CiRT demonstrates meaningful clinical utility as a non-invasive, predictive tool for guiding immunotherapy decisions across tumor types. It enables more precise treatment selection, improves patient outcomes, and supports value-based cancer care.