Rezatapopt Monotherapy Remains Under Study Following Discontinuation of Combination Cohort in TP53+ Solid Tumors

Courtney DiNardo, MD, MSCE

Enrollment is on track for the registrational phase 2 portion of the phase 1/2 PYNNACLE trial (NCT04585750) evaluating rezatapopt (PC14586) as monotherapy in patients with TP53 Y220C–mutated and KRAS wild-type advanced solid tumors, according to an update on the development of the first-in-class, small molecule p53 reactivator.¹

The update also indicated that due to dose-limiting toxicities (DLTs) and the lack of clinical benefit observed with pembrolizumab (Keytruda) plus rezatapopt in the phase 1b portion of the trial the combination cohort of the study will be discontinued.

Following the discontinuation of the combination cohort the company is collaborating with The University of Texas MD Anderson Cancer Center (MD Anderson) and Memorial Sloan Kettering Cancer Center (MSK) to launch an investigator-initiated phase 1b study. The trial will assess the safety, tolerability, pharmacokinetics, and preliminary efficacy of rezatapopt alone and in combination with azacitidine in approximately 25 patients with recurrent or refractory acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) harboring a TP53 Y220C mutation. Across both sites, enrollment is planned to begin in the first quarter of 2025.

“There is an important need for new treatment options for patients with recurrent or refractory AML or MDS harboring a TP53 Y220C mutation, as this mutation is often associated with poorer prognosis and resistance to conventional therapies” said Courtney DiNardo MD, MSCE, professor, Department of Leukemia, Division of Cancer Medicine, MD Anderson, in Houston, stated in a news release. “Based on proof-of-concept data demonstrating the ability of rezatapopt to selectively reactivate p53 in [patients with] locally advanced/metastatic solid tumor[s] with a TP53 Y220C mutation, we believe that rezatapopt in combination with azacitidine has the potential to significantly benefit this patient population.”

Rezatapopt is designed to selectively bind to the pocket in the p53 Y220C–mutant protein, restoring the wild-type tumor-suppressor function. The FDA previously granted fast track designation the agent for patients with locally advanced or metastatic solid tumors with a TP53 Y220C mutation.

“Patients with p53-mutant AML currently have no effective standard of care treatment options that lead to long-term survival, so this important trial using rezatapopt is the first step in developing a focused, mutation specific strategy, for this patient population,” Eytan M. Stein, MD, chief, Leukemia Service, MSK, in New York, New York, commented.

The multicenter, single-arm, registrational, tumor-agnostic trial will continue to assess rezatapopt as monotherapy at the recommended phase 2 dose (RP2D) of 2000 mg once daily in patients with TP53 Y220C–mutated and KRAS wild-type advanced solid tumors in the phase 2 portion of the study. The study is designed to enroll 114 patients across 5 cohorts, including ovarian, lung, breast, endometrial, and other solid tumors at approximately 60 sites. Overall response rate (ORR) per blinded independent central review will serve as the primary end point.

Across the United States, Europe, and Asia-Pacific regions, more than 75% of sites have been activated for treatment; the company plans to share data from the interim analysis of the monotherapy portion of the trial by mid-2025 and anticipates submitting a new drug application by the end of 2026.

Prior data from phase 1 demonstrated that the ORR with rezatapopt was 38% (n = 6) when patients were treated with the RP2D of 2000 mg. The median duration of response was 7 months.

The combination portion of the trial had been evaluating treatment with rezatapopt given at a 500 mg once-daily dose in combination with pembrolizumab at 200 mg every 3 weeks as the maximum tolerated dose (MTD). A total of 19 patients were enrolled in this portion of the trial.

The MTD was based on prior observed DLTs with the 1000-mg dose of rezatapopt plus pembrolizumab. DLTs included grade 2 and 3 aspartate aminotransferase increase, platelet count decrease, pancreatitis, dehydration, and rash. The combination’s safety profile was consistent with each agent as monotherapy and no new safety signals were observed; grade 4 and 5 adverse effects were not observed.

“While we are disappointed to discontinue enrollment of the trial evaluating rezatapopt in combination with pembrolizumab, we look forward to the initiation of the AML/MDS study and evaluating rezatapopt in other settings,” David Mack, PhD, president and chief executive officer of PMV Pharma explained. “I would like to thank the patients and investigators for their time and commitment to the phase 1b combination portion of the PYNNACLE study. We remain excited by the potential for rezatapopt as a monotherapy in patients with advanced solid tumors harboring a TP53 Y220C mutation and KRAS wild-type and look forward to providing interim data in the middle of next year.”

Reference

PMV Pharmaceuticals provides a progress update on PYNNACLE clinical trial. PMV Pharmaceuticals Inc. News release. October 23, 2024. Accessed October 28, 2024. https://ir.pmvpharma.com/news-releases/news-release-details/pmv-pharmaceuticals-provides-progress-update-pynnacle-clinical