In a phase I trial (PYNNACLE) reported in The New England Journal of Medicine, Dumbrava et al described the toxicity and preliminary activity of rezatapopt in TP53 Y220C–mutated solid tumors. The agent is an investigational, first-in-class, oral, selective p53 reactivator that specifically binds to Y220C-mutated p53, stabilizing p53 in its wild-type conformation and restoring its functionality.
Study Details
In the study, 77 heavily pretreated patients with locally advanced or metastatic solid tumors received rezatapopt in continuous 21-day treatment cycles at one of eight escalating doses: 150, 300, 600, 1,150, 1,500, 2,000, or 2,500 mg once daily or 1,500 mg twice daily. The most common cancer types included ovarian cancer (30%), pancreatic cancer (18%), breast cancer (13%), and colon cancer (12%). The primary objectives were to identify maximum tolerated dose and recommended phase II dose.
Key Findings
The maximum tolerated dose was 1,500 mg twice daily; dose-limiting toxicity was reported in two patients at this dose, one with grade 3 increased alanine aminotransferase and aspartate aminotransferase and one with grade 3 acute kidney injury. A dose of 2,000 mg once daily was selected for the phase II dose.
The most commonly reported adverse events of any grade were nausea (58%), vomiting (44%), increased blood creatinine (39%), fatigue (39%), and anemia (36%). The most common grade 3 or 4 adverse events were anemia (15%), increased alanine aminotransferase (5%), increased aspartate aminotransferase (5%), and diarrhea (5%). Adverse events led to treatment discontinuation in 8% of patients. No treatment-related deaths were reported.
The objective response rate was 20% among all patients (all partial responses) and 30% among 46 patients with a KRAS wild-type tumor who had received a dose of at least 1,150 mg once daily. The median duration of response was 7.0 months (95% confidence interval = 2.8–10.6 months). Confirmed responses were observed across multiple tumor types, including ovarian and breast cancers.
The investigators concluded: “In this phase I study involving heavily pretreated patients, the most common adverse events associated with rezatapopt were nausea and vomiting. Antitumor activity occurred across multiple tumor types, providing proof-of-concept for p53 reactivation.”
Alison M. Schram, MD, of Memorial Sloan Kettering Cancer Center, New York, is the corresponding author for The New England Journal of Medicine article.
DISCLOSURE: The study was funded by PMV Pharmaceuticals. For full disclosures of the study authors, visit nejm.com.
