Rezatapopt Elicits Responses in Several Solid Tumors Harboring a TP53 Y220C Mutation

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Rezatapopt induced responses in patients with solid tumors—such as ovarian, lung, breast, endometrial, head and neck, colorectal, gallbladder, and ampullary carcinoma—and a TP53 Y220C mutation, according to interim data from the phase 2 PYNNACLE study (NCT04585750).1

At the data cutoff date of August 4, 2025, the agent elicited an investigator-assessed objective response rate (ORR) of 33% by RECIST v1.1 criteria, which comprised confirmed and unconfirmed responses. Across cohorts, the median time to response (TTR) was 1.4 months and the median duration of response (DOR) was 6.2 months.

When broken down by cohort, the ORR achieved by those with ovarian cancer (n = 44) was 43%, which included 1 confirmed complete response, 17 confirmed partial responses (PRs), and 1 unconfirmed PR (uPR). The median TTR was 1.3 months, and the median DOR was 7.6 months. In those with breast cancer (n = 11), the ORR was 18%. This rate was 60% in those with endometrial cancer (n = 5), which included 1 uPR. In those with lung cancer (n = 18), the ORR was 22%, and this included 3 uPRs. In other solid tumors (n = 19), the ORR with the agent was 21%. After the data cutoff, those with uPRs remain on treatment.

In terms of safety, most treatment-related adverse effects (AEs) were grade 1 or 2, and the most common toxicities were nausea, fatigue, increased blood creatinine, and increased alanine aminotransferase levels. Grade 3 TRAEs occurred in under 6% of patients and all resolved. TRAEs resulted in treatment discontinuation for 3.7% of patients.

“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, stated in a news release. “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.”

What Is the Design of the PYNNACLE Study?

The phase 2 study includes patients with locally advanced or metastatic solid tumors harboring a TP53 Y220C mutation who are at least 12 years of age, were previously treated, and have an ECOG performance status up to 1.2 For phase 2 specifically, patients were at least 18 years of age and had KRAS wild-type disease; adolescents between the ages of 12 and 17 years were permitted if they weighed at least 40 kg and were from Australia, South Korea, and United States only.

The trial is comprised of 2 parts. The phase 1 dose-escalation portion that is active but not enrolling and seeks to determine the maximum tolerated dose of rezatapopt and the recommended phase 2 dose, as well as to examine pharmacokinetics (PK), safety, and preliminary efficacy. The phase 2 dose-expansion is evaluating efficacy, safety, PK, and quality of life when rezatapopt is being evaluated at a once-daily dose of 2000 mg with food.

The global, single-arm, open-label, multicenter, phase 2 basket trial (n = ~114) comprises several planned cohorts, including ovarian cancer (cohort 1; n = ~42), lung cancer (cohort 2; n = ~18), breast cancer (cohort 3; n = ~18), endometrial cancer (cohort 4; n = ~18), and all other solid tumors (cohort 5; n = ~18). This portion of the trial includes those at least 18 years of age for all global sites except for Singapore (adults aged ≥ 21 years), and also adolescents between the ages of 12 and 17 years if weighing at least 40 kg and from Australia, South Korea, and the United States. These patients have locally advanced or metastatic solid tumors, an ECOG performance status of 0 or 1, acceptable organ function, measurable disease by RECIST 1.1 criteria at baseline, documented TP53 Y220C mutation, and KRAS wild-type disease. They also were previously treated with at least 1 line of systemic therapy or were not candidates for standard-of-care treatment.

If patients had KRAS single-nucleotide variant mutations, unstable brain metastases, primary central nervous system tumors, heart conditions, uncontrolled infections, or a history of leptomeningeal disease, spinal cord compression, organ transplant or gastrointestinal disease that may impact absorption of the drug, they were excluded.

The primary end points were ORR by blinded independent central review (BICR) assessment and RECIST 1.1 criteria across cohorts and specifically in cohort 1. Secondary end points included investigator-assessed ORR by RECIST 1.1 criteria across all cohorts and in cohort 1 only; TTR, DOR, and disease control rate at 6, 12, 18, and 24 weeks across all cohorts and in cohort 1 only; and BICR- and investigator-assessed progression-free survival and overall survival in all cohorts and in cohort 1 only. Investigators are also examining safety, plasma PK parameters, and patient-reported outcomes.

In a past interview, Ecaterina Dumbrava, MD, an associate professor in the Department of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center, discussed the rationale for clinical development of rezatapopt in PYNNACLE.3 She underscored: “All patients with ovarian cancer have a TP53 mutation, so developing drugs that are able to restore the normal TP53 wild-type function is essential.”

Previously, in October 2024, it was reported that because of dose-limiting toxicities and the lack of clinical benefit observed with rezatapopt plus pembrolizumab (Keytruda) in the phase 1b portion of the trial, the combination cohort of the study would be discontinued.4 PMV Pharmaceuticals also announced that they would be collaborating with The University of Texas MD Anderson Cancer Center and Memorial Sloan Kettering Cancer Center to launch an investigator-initiated phase 1b study that would evaluate rezatapopt in combination with azacitidine in patients with recurrent or refractory acute myeloid leukemia and myelodysplastic syndrome.

What Is Next for Rezatapopt?

PMV Pharmaceuticals reported that they received feedback from the FDA regarding an initial new drug application (NDA) for platinum-resistant or -refractory ovarian cancer.1 They shared plans to enroll an additional 20 to 25 patients with this disease who previously received standard treatment by the first quarter of 2026. NDA submission seeking the use of rezatapopt in this population is estimated for the first quarter of 2027.

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. September 10, 2025. Accessed September 12, 2025. https://ir.pmvpharma.com/news-releases/news-release-details/pmv-pharmaceuticals-announces-promising-rezatapopt-monotherapy
  2. Schram AM, Frenel J-S, Johnson ML, etal. PYNNACLE phase 2 clinical trial of rezatapopt in patients with advanced solid tumors harboring a TP53 Y220C mutation. J Clin Oncol. 2025;43(suppl 16):TPS11581. doi:10.1200/JCO.2025.43.16_suppl.TPS11581
  3. Dumbrava EI. Dr Dumbrava on the rationale for evaluating rezatapopt in TP53 Y220C–mutated ovarian cancer. OncLive.com. April 8, 2025. Accessed September 11, 2025. https://www.onclive.com/view/dr-dumbrava-on-the-rationale-for-evaluating-rezatapopt-in-tp53-y220c-mutated-ovarian-cancer
  4. PMV Pharmaceuticals provides a progress update on PYNNACLE clinical trial. PMV Pharmaceuticals Inc. News release. October 23, 2024. Accessed September 11, 2025. https://ir.pmvpharma.com/news-releases/news-release-details/pmv-pharmaceuticals-provides-progress-update-pynnacle-clinical
  5. Kummar S. Kummar on the investigation of rezatapopt in TP53 Y220C–mutated advanced solid tumors. OncLive. May 9, 2024. Accessed September 11, 2025. https://www.onclive.com/view/kummar-on-the-investigation-of-rezatapopt-in-tp53-y220c-mutated-advanced-solid-tumors

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