Rezatapopt (formerly PC14586), a novel p53 Y220C reactivator, is demonstrating potential as a tumor-agnostic therapy for advanced solid tumors harboring the TP53 Y220C mutation. This mutation, previously considered undruggable, is found in approximately 1% of all cancers and is more prevalent in ovarian cancer (approximately 3%). The ongoing phase 1/2 PYNNACLE study (NCT04585750) is evaluating the safety, tolerability, and efficacy of rezatapopt in this patient population.
Targeting p53 Y220C Mutation
The p53 Y220C mutation results in a loss of tumor suppressor function, promoting cancer growth and proliferation. Rezatapopt, an orally available small molecule, selectively binds to a pocket within the mutant p53 Y220C protein, stabilizing it in the wild-type conformation and restoring its activity. Preclinical studies have shown that rezatapopt inhibits tumor proliferation across Y220C-expressing cell lines, with increased sensitivity observed in the absence of RAS pathway mutations.
PYNNACLE Study Design and Early Findings
The PYNNACLE study is an open-label, multicenter trial assessing rezatapopt in patients with locally advanced or metastatic solid tumors with the TP53 Y220C mutation. Phase 1 of the study aimed to determine the recommended phase 2 dose (RP2D) and maximum tolerated dose (MTD) of rezatapopt, both as a monotherapy and in combination with pembrolizumab. Phase 2 is evaluating the efficacy of rezatapopt at the RP2D in specific cancer cohorts, including ovarian, lung, breast, and endometrial cancers, as well as other solid tumors.
Updated findings from the phase 1 portion of PYNNACLE, presented at the 2023 AACR-NCI-EORTC International Congress on Molecular Targets and Cancer Therapeutics, included data from 67 patients treated with rezatapopt monotherapy. Efficacy-evaluable patients (n = 38) treated at efficacious dose ranges (1150 mg daily to 1500 mg twice daily) achieved an overall response rate (ORR) of 34%. Notably, ORRs among patients with ovarian, breast, small cell lung, endometrial, and other cancers were 47%, 38%, 50%, 100%, and 8%, respectively.
Safety and Tolerability
Treatment-related adverse events (TRAEs) were primarily grade 1 or 2 in severity. The most common TRAEs were nausea (50.7%), vomiting (43.3%), and increased blood creatine (26.9%). Administering rezatapopt with food was found to mitigate gastrointestinal toxicities. The RP2D was determined to be 2000 mg daily.
Ovarian Cancer Subgroup Analysis
A phase 1 analysis focusing on a subgroup of patients with advanced ovarian cancer harboring the TP53 Y220C mutation was presented at the SGO Annual Meeting on Women’s Cancer in March 2024. Among 15 efficacy-evaluable patients treated with rezatapopt, 7 achieved a partial response (PR). The median duration of response (DOR) was 7 months, with treatment ongoing in 4 patients at the data cutoff.
Future Directions
The first patient has been dosed in the phase 2 portion of the PYNNACLE study. PMV Pharmaceuticals is optimistic about the potential for accelerated approval based on phase 2 results, pending discussions with the FDA. The ongoing phase 2 expansion aims to further clarify the expected response rate and identify specific diseases and genetic phenotypes for which rezatapopt is most effective.
