PMV Pharma announced encouraging interim results from the Phase 2 portion of its PYNNACLE trial, evaluating rezatapopt monotherapy in patients with advanced solid tumors harboring a TP53 Y220C mutation. The first-in-class p53 reactivator demonstrated a 33% overall response rate across multiple tumor types, with particularly strong efficacy in ovarian cancer patients.
Efficacy Results Across Multiple Tumor Types
Among 97 evaluable patients, confirmed responses were observed across eight tumor types, including ovarian, lung, breast, endometrial, head and neck, colorectal, gallbladder and ampullary carcinoma. The overall response rate reached 33%, with a median duration of response of 6.2 months.
The ovarian cancer cohort showed the strongest efficacy signals, achieving a 43% overall response rate among 44 patients. This included one complete response and 17 confirmed partial responses, with a median duration of response of 7.6 months. Endometrial cancer patients demonstrated a 60% response rate, while lung cancer and breast cancer cohorts reported 22% and 18% response rates respectively. Other solid tumors showed a 21% overall response rate.
Favorable Safety Profile
Safety data from 109 patients indicated that most treatment-related adverse events were Grade 1-2, with the most frequent events being nausea, fatigue, blood creatinine increased, and alanine aminotransferase increased occurring in more than 15% of patients. The rates of individual Grade 3 treatment-related adverse events were less than 6%, and all Grade 3 events resolved on treatment with no discontinuations due to Grade 3 AST/ALT elevations.
Rezatapopt administration with food led to improved gastrointestinal tolerability compared to Phase 1 data. Laboratory abnormalities were manageable, with the majority of cases being transient and reversible. The drug discontinuation rate due to treatment-related adverse events was 3.7%.
Regulatory Pathway and Timeline
Following a recent meeting with the U.S. Food and Drug Administration, PMV Pharma received feedback regarding the initial New Drug Application submission strategy for platinum resistant/refractory ovarian cancer. The company plans to enroll an additional 20-25 platinum resistant/refractory ovarian cancer patients who have received prior standard of care by the end of the first quarter of 2026. PMV Pharma expects to submit a New Drug Application for platinum resistant/refractory ovarian cancer by the end of the first quarter of 2027.
Mechanism and Development Background
Rezatapopt (PC14586) is designed to selectively bind to the pocket in the p53 Y220C mutant protein, restoring wild-type tumor-suppressor function. The U.S. Food and Drug Administration has granted Fast Track designation to rezatapopt for the treatment of patients with locally advanced or metastatic solid tumors with a p53 Y220C mutation.
"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," said Dr. Deepika Jalota, Chief Development Officer of PMV Pharma. "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."
The ongoing Phase 1/2 PYNNACLE clinical trial is a registrational, single arm, expansion basket clinical trial comprising five cohorts with the primary objective of evaluating the efficacy of rezatapopt at the recommended Phase 2 dose in patients with TP53 Y220C and KRAS wild-type advanced solid tumors.
