Rezatapopt Yields Responses Across TP53 Y220C-Mutated Solid Tumor Types

Rezatapopt achieved an ORR of 33% in all patients, and an ORR of 43% in patients with ovarian cancer, with 1 confirmed complete response.

Interim results from the phase 2 pivotal portion of the phase 1/2 PYNNACLE trial (NCT04585750) demonstrated that rezatapopt (PC14586) was efficacious and safe in patients with advanced solid tumors that were harboring a TP53 Y220C mutation, according to a press release from the developer, PMV Pharmaceuticals.¹

Across 8 tumor types, including ovarian, lung, endometrial, breast, head and neck, colorectal, gallbladder, and ampullary carcinoma, confirmed responses were reported in patients with TP53 Y220C mutations and KRAS wild type.

With a data cut-off date of August 4, 2025, the overall response rate (ORR) per investigator assessment was 33% (n = 32/97), including confirmed and unconfirmed responses, according to RECIST v1.1. In patients with ovarian cancer, the ORR was 43% (n = 19/44), with 1 confirmed complete response (CR), 17 confirmed partial responses (PRs), and 1 unconfirmed PR; in patients with breast cancer, the ORR was 18% (n = 2/11); in patients with endometrial cancer, the ORR was 60% (n = 3/5), with 1 unconfirmed PR; in patients with lung cancer, the ORR was 22% (n = 4/18 patients), with 3 unconfirmed PRs; and in patients with other solid tumors, the ORR was 21% (n = 4/19 patients).

Overall, the median time to response was 1.4 months, with a median duration of response of 6.2 months. Notably, the median time to response in the ovarian cohort was 1.3 months, with a median duration of response of 7.6 months.

As of the data cut-off, the patients with unconfirmed PRs remained on therapy with rezatapopt.

Additionally, the developer plans to enroll an additional 20 to 25 patients with platinum-resistant/refractory ovarian cancer who have received prior standard of care by the end of Q1 2026, with further plans to submit a new drug application to the FDA for platinum-resistant/refractory ovarian cancer by Q1 2027.

Previously, the FDA granted fast track designation to rezatapopt for the care of patients with locally advanced or metastatic solid tumors with a p53 Y220C mutation.

“These phase 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,” Deepika Jalota, PharmD, chief development officer of PMV Pharma, said in the press release.¹ “Since PMV Pharma’s inception, leveraging more than four decades of research experience, we have pioneered the discovery and development of small molecule therapeutics that are designed to selectively address this historically undruggable target. Today, we are one step closer to realizing our vision of developing therapies that reactivate specific mutant p53 proteins to restore their wild-type function.”

PYNNACLE is an open-label, multicenter study designed to evaluate rezatapopt in patients with TP53 Y220C-mutated advanced solid tumors. The phase 1 portion of the trial was designed to determine the maximum tolerated dose and recommended phase 2 dose (RP2D), and the phase 2 portion of the trial was a registrational, single-arm, expansion basket trial that evaluated the efficacy of rezatapopt at the RP2D in various tumor types.

A total of 109 patients were included in the safety population and received at least 1 dose of rezatapopt monotherapy at 2000 mg daily; the efficacy population included 97 patients who were treated with at least 1 dose of study drug and either had at least 1 post-baseline tumor assessment or discontinued early. The median number of prior lines of systemic therapy was 3 (range, 1-10).

Patients were permitted entry into the trial if they were 18 years or older or aged 12 to 17 years after safety review committee approval, with locally advanced or metastatic solid malignancy with a TP53 Y220C mutation, an ECOG performance status of 0 or 1, previous treatment with 1 or more lines of anticancer therapy and progressive disease, adequate organ function, and measurable disease per RECIST v1.1.²

Reasons for trial exclusion included anti-cancer therapy within 21 days or radiotherapy within 28 days of receiving the study drug, primary central nervous system tumor, history of leptomeningeal disease or spinal cord compression, and brain metastases, unless neurologically stable.

Regarding safety, treatment-related adverse events (TRAEs) were mainly grade 1 or 2; TRAEs occurring in more than 15% of patients were nausea, fatigue, blood creatinine increased, and alanine aminotransferase increased. Individual grade 3 TRAEs occurred at a rate less than 6%, with all events resolving on treatment; there were no discontinuations due to grade 3 alanine aminotransferase or aspartate aminotransferase elevations. TRAEs led to drug discontinuations in 3.7% of patients.

When rezatapopt was administered with food, an improvement in gastrointestinal tolerability was observed relative to the phase 1 data. The majority of lab abnormalities were transient and reversible.

“Looking ahead, we expect to complete enrollment in the Phase 2 portion of the PYNNACLE study by the first quarter of 2026 and plan to submit an NDA to the FDA for rezatapopt in the first quarter of 2027,” Jalota concluded.

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. September 10, 2025. Accessed September 10, 2025. https://tinyurl.com/4uxnj92t
2. The evaluation of PC14586 in patients with advanced solid tumors harboring a TP53 Y220C mutation (PYNNACLE). ClinicalTrials.gov. Updated August 6, 2025. Accessed September 10, 2025. https://tinyurl.com/5c9avhr3