PMV Pharmaceuticals is advancing rezatapopt (PC14586) as a monotherapy in the phase 2 portion of the PYNNACLE trial (NCT04585750) for patients with TP53 Y220C-mutated and KRAS wild-type advanced solid tumors. This follows the discontinuation of the combination cohort of the study, which evaluated rezatapopt with pembrolizumab, due to dose-limiting toxicities (DLTs) and a lack of clinical benefit.
Rezatapopt Monotherapy in Solid Tumors
The ongoing registrational phase 2 trial is a multicenter, single-arm, tumor-agnostic study assessing rezatapopt monotherapy at a dose of 2000 mg once daily. The trial aims to enroll 114 patients across 5 cohorts, including those with ovarian, lung, breast, endometrial, and other solid tumors, across approximately 60 sites in the United States, Europe, and the Asia-Pacific region. The primary endpoint is overall response rate (ORR) per blinded independent central review. Interim data from the monotherapy portion of the trial is anticipated by mid-2025, with a new drug application (NDA) submission expected by the end of 2026. Prior phase 1 data showed a 38% ORR (n = 6) with rezatapopt at the 2000 mg dose, with a median duration of response of 7 months.
New Trial in AML/MDS
PMV Pharma is collaborating with The University of Texas MD Anderson Cancer Center and Memorial Sloan Kettering Cancer Center to initiate an investigator-initiated phase 1b study. This trial will evaluate 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. Enrollment is planned to begin in the first quarter of 2025.
According to Courtney DiNardo MD, MSCE, professor, Department of Leukemia, Division of Cancer Medicine, MD Anderson, there is a significant need for new treatments for patients with recurrent or refractory AML or MDS with a TP53 Y220C mutation, as this mutation is often associated with poorer prognosis and resistance to conventional therapies. Eytan M. Stein, MD, chief, Leukemia Service, MSK, commented that patients with p53-mutant AML currently lack effective standard-of-care options for long-term survival, highlighting the importance of this mutation-specific strategy.
Discontinuation of Combination Cohort
The discontinued combination portion of the PYNNACLE trial evaluated rezatapopt at a 500 mg once-daily dose in combination with pembrolizumab at 200 mg every 3 weeks. Nineteen patients were enrolled. The maximum tolerated dose (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 safety profile of the combination was consistent with each agent as monotherapy, and no new safety signals were observed; grade 4 and 5 adverse effects were not reported.
Mechanism of Action and Regulatory Status
Rezatapopt is designed to selectively bind to the pocket in the p53 Y220C-mutant protein, restoring wild-type tumor-suppressor function. The FDA previously granted Fast Track designation to rezatapopt for patients with locally advanced or metastatic solid tumors with a TP53 Y220C mutation.
David Mack, PhD, president and chief executive officer of PMV Pharma, expressed disappointment in discontinuing the combination arm but remains enthusiastic about the potential of rezatapopt as a monotherapy and in other settings.
