Phase 1 Study of Rezatapopt, a p53 Reactivator, in TP53 Y220C-Mutated Tumors.

Rezatapopt is an investigational, first-in-class, oral, selective p53 reactivator that specifically binds to Y220C-mutated p53, which stabilizes p53 in its wild-type conformation and restores its functionality. In this phase 1, single-group, dose-escalation and dose-optimization study, we assigned heavily pretreated patients with locally advanced or metastatic solid tumors harboring a TP53 Y220C mutation to receive rezatapopt during continuous 21-day treatment cycles. The primary objectives were to determine the maximum tolerated dose and recommended phase 2 dose. Primary end points included dose-limiting toxic effects and adverse events. Secondary end points included preliminary efficacy and pharmacokinetic features. A total of 77 patients received rezatapopt at one of eight escalating doses: 150 mg, 300 mg, 600 mg, 1150 mg, 1500 mg, 2000 mg, or 2500 mg once daily or 1500 mg twice daily. 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. During the treatment period, 76 patients (99%) had at least one adverse event and 29 (38%) had an adverse event of grade 1 or 2. The most common adverse events were nausea (in 58% of patients), vomiting (in 44%), an increased blood creatinine level (in 39%), fatigue (in 39%), and anemia (in 36%). Treatment-related adverse events occurred in 67 patients (87%) and those of grade 1 or 2 in 48 (62%); 2 patients (3%) discontinued rezatapopt because of a treatment-related adverse event. Most gastrointestinal adverse events resolved with the treatment of symptoms and were less frequent when rezatapopt was given with food. Anemia was the most common adverse event of grade 3 or higher during the treatment period, occurring in 16% of patients. The overall response (complete or partial response) 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 once daily. Confirmed responses were seen across multiple tumor types, including ovarian and breast cancers. All patients with a response had a solid tumor that harbored TP53 Y220C and wild-type KRAS. In this phase 1 study involving heavily pretreated patients, the most common adverse events associated with rezatapopt were nausea and vomiting. Antitumor activity occurred across multiple tumor types, providing proof of concept for p53 reactivation. (Funded by PMV Pharmaceuticals; PYNNACLE ClinicalTrials.gov number, NCT04585750.).