Rezatapopt Shows Early Promise in TP53 Y220C-Mutant Tumors in PYNNACLE Phase II Trial
Rezatapopt is a first-in-class p53 reactivator specifically targeting the TP53 Y220C mutation, designed to restore wild-type p53 function by stabilizing the mutated protein and inducing tumor suppressor activity.
The PYNNACLE phase II clinical trial is a single-arm, multicenter, basket trial assessing rezatapopt monotherapy at 2000 mg daily in patients with locally advanced or metastatic solid tumors harboring TP53 Y220C mutations and wild-type KRAS.
Interim results from PYNNACLE showed an overall response rate (ORR) of 33% across 97 efficacy-assessed patients with multiple tumor types including ovarian, lung, breast, and others.
Ovarian cancer patients demonstrated a 43% ORR with one complete response and 17 partial responses, showing particularly notable efficacy.
Median time to response was approximately 1.4 months, with a median duration of response around 6.2 months; in ovarian cancer, duration extended to 7.6 months.
Rezatapopt was generally well tolerated with mainly grade 1 or 2 treatment-related adverse events like nausea and fatigue, with low discontinuation rates due to side effects.
The FDA has granted fast track designation to rezatapopt, reflecting its potential to address an unmet need in TP53 Y220C-mutant advanced solid tumors.
Enrollment for PYNNACLE phase II started in March 2024 and is expected to complete by the end of 2025, with plans for NDA submission in early 2027.