PMV Pharmaceuticals, Inc. announced that preliminary results from the ongoing Phase 1/2 PYNNACLE study of PC14586 in patients with advanced solid tumors harboring a p53 Y220C mutation demonstrated anti-tumor efficacy across multiple tumor types with an acceptable safety profile. PC14586 is a first-in-class precision oncology small molecule investigational therapy that selectively targets the p53 Y220C mutation in solid tumors. The data were featured in an oral presentation at the 2022 American Society of Clinical Oncology (ASCO) annual meeting.

The presentation entitled, “First-in-human study of PC14586, a small molecule structural corrector of Y220C mutant p53, in patients with advanced solid tumors harboring a TP53 Y220C mutation,” was delivered by Ecaterina Ileana Dumbrava, M.D., Assistant Professor of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center. Safety: The most common treatment-emergent adverse events (>15%) included nausea, vomiting, AST increase, ALT increase, anemia, blood creatinine increase, and fatigue. The maximum tolerated dose (MTD) was reached at 1,500 mg twice daily.

Enrollment at doses below the MTD is ongoing to support the determination of a recommended Phase 2 dose. Efficacy: ORR assessed by investigators according to RECIST v1.1 was 32% (8/25) in patients receiving an initial total daily dose of 1,150 mg and above. Of the 8 responding patients, 6 have confirmed partial responses and 2 have unconfirmed partial responses, pending confirmation.

ORR was 24% (8/33) across all dose cohorts. Responses were observed across six distinct tumor types including breast, endometrial, prostate, pancreatic, ovarian, and small cell lung cancer. Best Response of stable disease or partial response was observed in 19/25 patients at doses =1,150 mg (76%).

PYNNACLE is an open-label, multicenter Phase 1/2 clinical study assessing safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of PC14586 in patients with advanced solid tumors harboring a p53 Y220C mutation. A total of 41 patients were enrolled as of May 10, 2022; 36 patients with measurable disease at baseline including 33 patients determined to be eligible for response evaluation. During the Phase 1 dose-escalation portion of the study, multiple dose levels of PC14586 were evaluated (150 mg QD, 300 mg QD, 600 mg QD, 1,150 mg QD, 1,500 mg QD, 2000 mg QD, 2,500 mg QD, and 1,500 mg BID).

Preliminary efficacy was assessed by RECIST v1.1. A recommended Phase 2 dose will be selected at the end of Phase 1. PC14586 is a first-in-class, small molecule p53 reactivator designed to selectively bind to the crevice present in the p53 Y220C mutant protein, hence, restoring the wild-type, or normal, p53 protein structure and tumor-suppressing function. PC14586 is being developed for the treatment of patients with locally advanced or metastatic solid tumors that have a p53 Y220C mutation. Fast Track designation has been granted by the Food and Drug Administration (FDA) for evaluating PC14586 for the treatment of patients with locally advanced or metastatic solid tumors that have a p53 Y220C mutation.