PMV Pharmaceuticals Updates on PYNNACLE Trial Progress

PMV Pharmaceuticals, a precision oncology company, has provided updates on the ongoing PYNNACLE clinical trial which is evaluating the effectiveness of rezatapopt in treating advanced solid tumors and blood cancers. This trial includes both Phase 2 monotherapy and Phase 1b combination therapy assessments.

In the Phase 2 monotherapy segment of the PYNNACLE trial, rezatapopt is being tested as a single-agent therapy. The trial is currently on schedule with more than 75% of clinical sites already activated across the United States, Europe, and Asia-Pacific. This phase involves a multi-center, single-arm trial that administers rezatapopt at a daily dose of 2000 mg to patients with TP53 Y220C and KRAS wild-typeKRAS advanced solid tumors. The primary goal is to evaluate the overall response rate, as reviewed by an independent central team, across five cohorts at around 60 different sites. PMV Pharmaceuticals aims to release interim analysis data by mid-2025 and hopes to submit a New Drug Application by the end of 2026.

Conversely, PMV has decided to stop further enrollment in the Phase 1b combination arm of the PYNNACLE trial, which combined rezatapopt with Merck’s anti-PD-1 therapy, KEYTRUDA (pembrolizumab). Initially, nineteen patients with advanced solid tumors containing the TP53 Y220C mutation were enrolled in this combination arm. However, the decision to halt enrollment was influenced by observed dose-limiting toxicities at a dose of 1000 mg of rezatapopt daily and 200 mg of pembrolizumab every three weeks. These toxicities included increases in AST, decreased platelet counts, pancreatitis, dehydration, and rash, although no severe adverse events were observed. The maximum tolerated dose was established at 500 mg of rezatapopt daily combined with 200 mg of pembrolizumab every three weeks. Patients treated at this dose did not show meaningful clinical benefits, prompting the discontinuation of the combination therapy arm.

Additionally, PMV Pharmaceuticals has announced a collaboration with MD Anderson Cancer Center (MDACC) and Memorial Sloan Kettering Cancer Center (MSK) to initiate a Phase 1b study. This new investigator-led study will focus on evaluating the safety, tolerability, pharmacokinetics, and initial efficacy of rezatapopt both as a standalone treatment and in combination with azacitidine. The study targets approximately 25 patients with recurrent or refractory acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) that carry the TP53 Y220C mutation. Enrollment for this study is anticipated to start in the first quarter of 2025, with participation at two sites.

Dr. Courtney DiNardo from MDACC highlighted the critical need for new treatments for patients with AML or MDS harboring the TP53 Y220C mutation, as these conditions are often resistant to conventional therapies. She expressed optimism about rezatapopt’s potential based on preliminary data showing its ability to reactivate p53 in solid tumor patients. Dr. Eytan M. Stein from MSK emphasized the lack of effective standard treatments for patients with p53 mutant AML, viewing this trial as an important step toward developing mutation-specific therapies.

David Mack, President and CEO of PMV Pharma, acknowledged the decision to discontinue the combination arm of the PYNNACLE trial but expressed enthusiasm for the upcoming AML/MDS study and other potential uses of rezatapopt. He expressed gratitude to the patients and investigators involved in the Phase 1b combination study and looked forward to future developments with rezatapopt as a monotherapy for advanced solid tumors carrying the TP53 Y220C mutation.

Rezatapopt, a p53 reactivator designed to bind specifically to the p53 Y220C mutant protein, is currently granted Fast Track designation by the FDA for treating patients with locally advanced or metastatic solid tumors with this mutation.