Rezatapopt is a first-in-class small molecule that selectively binds the pocket in the p53 Y220C mutant and restores its tumor-suppressor function.[1][2][3] A phase 1 study of the PYNNACLE clinical trial tested rezatapopt in 77 heavily pretreated patients with advanced solid tumors with the TP53 Y220C mutation.[2][4][5] The drug was generally well tolerated, with frequent adverse effects such as nausea and vomiting; toxic dose limits were rare.[2][4][5] Confirmed responses were observed in patients with TP53 Y220C mutation and wild-type KRAS in eight tumor types, including ovarian, lung, breast, endometrial, head and neck, colorectal, gallbladder, and ampullary carcinoma.[1][6] The overall response rate (ORR) was 34% (35/103 patients) by RECIST 1.1, including confirmed and unconfirmed responses.[1] Median length of response was 6.2 months.[6] Clinical and biomarker data confirm selective binding to the Y220C pocket and restoration of wild-type p53 function, providing proof of concept for this approach.[2][4][5]