Rezatapopt Shows Promise Against Multiple Solid Tumors in PYNNACLE Phase 2 Trial

Rezatapopt (PC14586), a small molecule p53 reactivator, has been shown to yield responses in 8 types of tumors with a TP53 Y220C mutation including ovarian, lung, breast, endometrial, head and neck, colorectal, gallbladder, and ampullary carcinoma, according to interim data from the phase 2 PYNNACLE trial (NCT04585750).¹

As of the data cutoff date of August 4, 2025, an overall response rate (ORR) of 33% and median duration of response (DOR) of 6.2 months were observed across all tumor cohorts (n = 97). By cohort, the ORR was 43% in the ovarian cancer cohort (n = 44), 18% in breast cancer (n = 11), 60% in endometrial cancer (n = 5), 22% in lung cancer (n = 18), and 21% in other tumors (n = 19). In the ovarian cancer cohort, the median DOR was 7.6 months. These results support previous findings, where rezatapopt demonstrated preliminary efficacy in ovarian cancer during PYNNACLE’s phase 1 trial.

The safety results observed in the phase 2 portion were consistent with a previous phase 1 clinical trial, which demonstrated similar adverse events and an overall favorable safety profile.² The most common (over 15%) treatment-related adverse events (TRAEs) observed were nausea, fatigue, increased blood creatinine, and increased alanine aminotransferase. Grade 3 events were a minority of TRAEs (less than 6%). Only 3.7% of patients discontinued treatment due to TRAEs.

“These [p]hase 2 PYNNACLE interim trial data illustrate that rezatapopt, a first-in-class therapy, has the potential to harness the power of p53 to address cancers with high unmet need,” said Deepika Jalota, chief development officer of PMV Pharma, in a press release.¹

What is the Phase 2 PYNNACLE Study Evaluating?

The active PYNNACLE trial is a multicenter and multinational study spanning across 9 countries.³ A single-arm, open-label study, its objective is to assess the efficacy and safety of rezatapopt monotherapy in patients with advanced or metastatic solid tumors that have a TP53 Y220C mutation and are KRAS wild-type.^1,3

Phase 1 of the trial, which included 109 patients, assessed safety and tolerability and established the maximum tolerated dose of rezatapopt as monotherapy. Patients received at least one 2000 mg dose of rezatapopt daily, administered orally. A phase 1b portion assessed the safety and preliminary efficacy of rezatapopt plus pembrolizumab (Keytruda).³

In phase 2, which is ongoing and currently recruiting, 97 patients across 5 tumor-specific cohorts (ovarian, lung, breast, endometrial, and other solid tumors) have been treated with the same dosage in phase 1 as of the cutoff date. The primary end points of the study are ORR across all cohorts and in the ovarian cancer cohort. Secondary end points include measures of safety, pharmacokinetics, and quality of life.³ With an estimated completion of phase 2 by July 2026, continued data will be crucial to substantiating the promising trend of positive safety and efficacy exhibited by the interim results and in phase 1.

An update has also been provided by the sponsor regarding the planned regulatory timeline of rezatapopt, including submission of a new drug application (NDA) for platinum-resistant/-refractory ovarian cancer in early 2027.

“Looking ahead, we expect to complete enrollment in the [p]hase 2 portion of the PYNNACLE study by the first quarter of 2026 and plan to submit an NDA for the FDA for rezatapopt in the first quarter of 2027,” added Jalota in the press release.¹

REFERENCES:

1. PMV Pharmaceuticals Announces Promising Rezatapopt Monotherapy Interim Data From PYNNACLE Phase 2 Trial Across Multiple Solid Tumors With a TP53 Y220C Mutation. News release. PMV Pharmaceuticals. Published September 10, 2025. Accessed September 10, 2025. https://tinyurl.com/4k7b5aru

2. Dumbrava EE, Johnson ML, Tolcher AW, et al. First-in-human study of PC14586, a small molecule structural corrector of Y220C mutant p53, in patients with advanced solid tumors harboring a TP53 Y220C mutation. J Clin Oncol. 2022;40(16_suppl):3003-3003. doi:https://doi.org/10.1200/jco.2022.40.16_suppl.3003

3. The Evaluation of PC14586 in Patients With Advanced Solid Tumors Harboring a TP53 Y220C Mutation (PYNNACLE). ClinicalTrials.gov. Updated August 8, 2025. Accessed September 10, 2025. https://www.clinicaltrials.gov/study/NCT04585750