In a historic first, the U.S. Food and Drug Administration (FDA) recently granted accelerated approval for a cancer treatment based on a common biomarker rather than histologic tumor origin. The FDA granted its first tissue/site–agnostic approval to pembrolizumab for adult and pediatric patients with unresectable or metastatic, microsatellite instability–high (MSI-H) or mismatch repair deficient (dMMR) solid tumors that have progressed after prior treatment. The approval was based on data from 149 patients with MSI-H or dMMR solid tumors enrolled across 5 uncontrolled, multi-cohort, multi-center, single-arm clinical trials (90 patients had colorectal cancer, and 59 patients were diagnosed with 1 of 14 other types of cancer). This paradigm-changing approval is at the intersection of precision medicine and immuno-oncology and creates unique challenges for all stakeholders: What demands will be placed on health economists to analyze smaller and smaller patient populations? How will these analyses be conducted in patients with highly variable clinical scenarios whose only commonality is a shared actionable mutation? What information will patients, providers, and payers need to become comfortable in this new reality? Through this symposium, we will ask key stakeholders to weigh in on a robust discussion that will include real-world evidence (RWE) beyond claims and medical records, prospective outcomes research beyond registries, linking patient-reported outcomes to clinical outcomes, and how RWE research studies can be designed to effectively capture the required clinical biomarker data to support such approvals in the future.