Multicenter phase 1 trial of the p53 reactivator rezatapopt for TP53 Y220C-mutated tumors

Rezatapopt is an investigational, first-in-class, selective p53 reactivator that specifically binds to Y220C-mutated p53, thus stabilizing p53 in its wild-type conformation and restoring its functionality. The multicenter phase 1 PYNNACLE trial in the USA evaluated rezatapopt in 77 heavily pretreated patients with locally advanced or metastatic solid tumors harboring a TP53 Y220C mutation. In the dose escalation phase, the maximum tolerated dose was 1500 mg twice daily; on the basis of safety, efficacy, and pharmacokinetic data, 2000 mg once daily with food was selected as the recommended phase 2 dose (primary objective). Almost all patients (99%) had at least one adverse event, and 38% had an adverse event of grade 1 or 2 (primary endpoint). Treatment-related adverse events occurred in 87% of patients and those of grade 1 or 2 in 62%; two patients (3%) discontinued rezatapopt because of a treatment-related adverse event. The overall response rate was 20% among all patients and 30% among those who had a KRAS wild-type tumor and received a dose of at least 1150 mg daily. Confirmed response were seen across multiple tumor types. All patients with a response had a solid tumor that harbored TP53 Y220C and wild-type KRAS. The authors conclude that these data provide proof of concept for p53 reactivation.