PC14586 Demonstrates Meaningful Clinical Responses in TP53 Y220C Mutant Solid Tumors—Key Phase 1 Data Points from PYNNACLE Trial

Breaking Through an Unmet Need

PMV Pharmaceuticals unveiled critical Phase 1 findings from its PYNNACLE clinical trial, showing that PC14586, a precision oncology candidate designed to target TP53 Y220C mutations, delivered tangible therapeutic benefits across multiple advanced solid tumors. The late-breaking data, presented at the 2023 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, underscore why this investigational therapy has gained significant attention in the field.

For decades, p53 mutations have represented a major therapeutic vulnerability. Approximately half of all human cancers harbor p53 alterations, yet until now, no approved drugs could specifically address the TP53 Y220C variant—a mutation found in a subset of patients with limited treatment options. PC14586 addresses this gap by functioning as a first-in-class p53 reactivator.

How PC14586 Works: Targeting the Mutant Structure

The drug’s mechanism relies on a clever structural approach: PC14586 selectively binds to the specific pocket created by the TP53 Y220C mutation, essentially “correcting” the aberrant protein geometry and restoring its tumor-suppressing capabilities. This targeted pc14586 structure allows the mutant p53 protein to regain wild-type function, triggering apoptosis in cancer cells while minimizing off-target effects.

Clinical Results: Efficacy Across Tumor Types

Among 67 safety-evaluable patients treated at efficacious doses (1150 mg daily and above), meaningful disease responses emerged:

• Response rates: At the Recommended Phase 2 Dose of 2000 mg daily, the confirmed overall response rate reached 38% (6 of 16 evaluable patients); across the broader efficacious dose range, 34% of 38 patients showed response.
• Durable responses: The median duration of response was seven months, suggesting sustained clinical benefit rather than fleeting improvements.
• Tumor diversity: Confirmed responses were documented in multiple solid tumors, including ovarian, breast, prostate, small-cell lung, and endometrial cancers—all harboring TP53 Y220C mutations and KRAS wild-type status.

The patient population was heavily pretreated, with a median of three prior lines of systemic therapy (range 1-9), indicating PC14586 retained activity even in drug-resistant scenarios.

Safety Profile: Favorable Tolerability

Treatment-related adverse events were predominantly mild-to-moderate (Grade 1-2), with the most common side effects being nausea, vomiting, and elevated blood creatinine—each occurring in over 20% of patients. Critically, only 3% of patients discontinued due to adverse events, highlighting the tolerability advantage. Notably, gastrointestinal toxicity improved when PC14586 was co-administered with food, offering a simple mitigation strategy.

Phase 2 Strategy: Precision Patient Selection

Based on emerging Phase 1 efficacy patterns, PMV identified a refined Phase 2 patient population: those with TP53 Y220C-positive tumors and KRAS wild-type status. This population comprises approximately 90% of all patients with TP53 Y220C mutations, representing an optimal balance between therapeutic precision and addressable market size. The company plans to initiate a registrational Phase 2 trial in early 2024, marking a critical inflection point.

Clinical Significance

Dr. Alison M. Schram, Medical Oncologist at Memorial Sloan Kettering Cancer Center and PYNNACLE Study Investigator, emphasized: “Patients with TP53 Y220C mutations currently have no approved targeted therapies. Today’s safety and efficacy data suggest PC14586 could fulfill a substantial unmet medical need in advanced solid tumors.”

The FDA previously granted Fast Track designation to PC14586 for locally advanced or metastatic solid tumors with TP53 Y220C mutations, expediting regulatory review pathways.

Looking Ahead

These Phase 1 outcomes validate the therapeutic potential of p53-targeted precision oncology. As PC14586 advances into Phase 2 registration, the field awaits efficacy confirmation in the refined patient population—a pivotal step toward potentially becoming the first approved p53 reactivator therapy across multiple cancer types.