VT3989 achieved a 32% overall response rate with 86% disease control in mesothelioma patients when optimal dosing and monitoring protocols were applied, marking the first successful clinical targeting of the Hippo-YAP-TEAD pathway. The oral TEAD palmitoylation inhibitor demonstrated manageable toxicities primarily involving reversible proteinuria and peripheral edema across 172 patients in this phase 1/2 trial. This breakthrough represents a significant advance in cancer therapeutics, as the Hippo pathway has long been considered "undruggable" despite its central role in organ size regulation and tumor suppression. The YAP-TEAD interaction drives aggressive tumor growth in mesothelioma and multiple other cancers, making this pathway an attractive but elusive therapeutic target. While promising, these interim results require validation in larger randomized trials, and the reversible kidney effects need long-term monitoring. The 10-month median progression-free survival in mesothelioma—a notoriously treatment-resistant cancer with few therapeutic options—suggests VT3989 could fill a critical unmet medical need. The FDA's orphan drug and fast-track designations reflect both the drug's potential and mesothelioma's status as a rare, lethal malignancy primarily linked to asbestos exposure.