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Biologic factors limiting responsiveness to matched targeted therapies include genomic heterogeneity and complexity. Advanced tumors with unique molecular profiles can be studied by comprehensive genomic profiling (CGP) and enhance patient outcomes using principles of precision medicine. The clinical utility of CGP across all cancer types and different therapeutic interventions using overall survival (OS) and progression-free survival (PFS) data was studied in this systematic literature review. Randomized controlled, nonrandomized, and observational studies conducted in adult patients with advanced cancer, dated up to September 2022, were searched from PubMed and EMBASE databases following PRISMA guidelines. Of 14 CGP studies, 7 (50%) and 9 (64%) reported OS and PFS as an outcome, respectively. Improved OS and PFS were reported when CGP guided treatment decisions, but its clinical utility varied among cancer types. Treatments were assigned based on matching scores and with the involvement of molecular tumor board (MTB) enhanced OS and PFS. Patients following MTB recommendations had superior treatment outcomes compared with those on physician’s choice regimens. CGP clinically benefited patients with genomically matched therapies and yielded better clinical outcomes regardless of cancer type. Further, uniform clinical value-based ranking of actionable mutations can encourage oncologists to use CGP tests for patients.