Background: Liquid biopsies have enabled a transformation in the management of patients with cancer as they have the potential to detect, characterize, and monitor tumor burden. However, the increasing complexity involved in the integration of genomic data into clinical practice has presented challenges with the practical implementation of liquid biopsies in clinical cancer care. To address these challenges, multidisciplinary teams comprised of experts within oncology, genetics, pathology, and informatics have created Molecular Tumor Boards (MTBs), which can improve clinical outcomes for cancer patients by efficiently utilizing the technologies created by the rapidly expanding precision oncology industry. Nevertheless, there remains a gap in the optimal implementation and interpretation of these diagnostic findings to maximize patient outcomes and access to standard of care therapies and clinical trials. Methods: We instigated a prospective observational liquid biopsy-informed precision oncology study, in which patients with metastatic solid tumors will be matched with genotype-driven therapies via serial liquid biopsies (NCT05585684). Liquid biopsy-derived genotypes will be generated through a clinical NGS assay (PGDX Plasma Focus) and will be annotated by an automated ensemble approach for variant actionability assessment, developed by the Johns Hopkins MTB, followed by a treatment recommendation. Key eligibility criteria include patients ≥18 years old, with ECOG performance status of 0-1 and with metastatic disease that have relapsed or progressed after standard of care first-line therapies or patients for which first-line standard of care therapeutic options are not expected to yield a clinical response. The primary objectives of the trial focus on feasibility of the approach and evaluating the fraction of patients with actionable mutations, for which the MTB recommendation is enacted upon. Unique to this study, a recommendation to not pursue genotype-targeted therapy is equally considered for personalized clinical decision making. Secondary objectives are to investigate whether enacting upon MTB recommendations improves progression-free and overall survival and perform a comparative analysis with tumor-based NGS. Exploratory objectives are to determine if serial molecular profiling after initiation of systemic treatment is sufficient to determine therapeutic response, compare with RECIST radiographic response and determine whether changes in liquid biopsy dynamics correlate with progression-free and overall survival. This study will enroll 150 patients with solid tumors, including lung, esophageal, breast, and head and neck cancer and mesothelioma to evaluate the clinical utility of liquid biopsy genomic profiling. Patient accrual for this study initiated in February 2023. Clinical trial information: NCT05585684.