Rezatapopt Restores Mutant p53, Yields 38% ORR in Heavily Pretreated TP53 Y220C-Mutated Metastatic Breast Cancer

Rezatapopt (PC14586) is an oral, first-in-class small-molecule that binds the p53 Y220C pocket, refolding the mutant protein into a wild-type conformation and reactivating tumor-suppressor function. In the Phase 1 PYNNACLE trial (NCT04585750), nine women with advanced breast cancer carrying the TP53 Y220C mutation (median 4 prior regimens; 4 TNBC) received rezatapopt 150 mg QD–1 500 mg BID. Among eight RECIST-evaluable patients, confirmed partial responses occurred in 3 (37.5%), four achieved stable disease, and tumor shrinkage was seen in all (-2% to -55%). Treatment-related events were mostly grade 1/2 nausea (51%), vomiting (43%), and creatinine rise (27%); no grade ≥3 GI events were reported when dosing with food. These results compare favorably with the <10% ORR typically seen with single-agent chemotherapy in this refractory setting, and they are agnostic to hormone/HER2 status.

https://aacrjournals.org/clincancerres/article/31/12_Supplement/P3-12-27/752943/Abstract-P3-12-27-Phase-1-Analysis-from-the