rezatapopt (PC14586) / PMV Pharma - LARVOL DELTA

The Evaluation of PC14586 in Patients With Advanced Solid Tumors Harboring a TP53 Y220C Mutation (PYNNACLE) (clinicaltrials.gov) - P1/2 | N=300 | Recruiting | Sponsor: PMV Pharmaceuticals, Inc | Trial primary completion date: Aug 2026 ➔ Dec 2026

P53mut • Trial primary completion date • Breast Cancer • Colorectal Cancer • Endometrial Cancer • Estrogen Receptor Positive Breast Cancer • Gallbladder Cancer • Head and Neck Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Positive Breast Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Prostate Cancer • Small Cell Lung Cancer • Solid Tumor • Triple Negative Breast Cancer • TP53

PYNNACLE PHASE 2 TRIAL ASSESSING SELECTIVE P53 REACTIVATOR REZATAPOPT: FOCUS ON TP53 Y220C-POSITIVE GYNECOLOGIC CANCERS (IGCS 2026) - P1/2 | "As of March 29, 2026, 141 patients received rezatapopt (ovarian cancer n=76; endometrial cancer n=9). For ovarian and endometrial cancer cohorts, median age was 66 (range 46–91) and 70 (62–74) years; ECOG score was 0/1; and median prior treatment lines was 4 (range 1–10) and 2 (0–7), respectively. For patients with ovarian cancer, 97.4% had high-grade serous cancer, 60.5% were platinum-resistant and 35.5% were platinum-refractory."

P2 data • Endometrial Cancer • Gynecologic Cancers • Oncology • Ovarian Cancer • TP53

Phase 1 Study of Rezatapopt, a p53 Reactivator, in TP53 Y220C-Mutated Tumors. (PubMed, N Engl J Med) - P1/2 | "In this phase 1 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. (Funded by PMV Pharmaceuticals; PYNNACLE ClinicalTrials.gov number, NCT04585750.)."

Journal • P1 data • Breast Cancer • Fatigue • Hematological Disorders • Oncology • Ovarian Cancer • Solid Tumor • KRAS • TP53

PMV Pharma Raises $50.8 Million to Fuel Cancer Drug Push (Yahoo Finance) - "The offering includes shares of common stock, pre-funded warrants, and accompanying warrants, with a combined public offering price of $1.21 per share and warrant combination. The financial move supports the company's ongoing research and anticipated regulatory submissions."

Financing • Ovarian Cancer

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. (ASCO 2022) - P1/2 | "Enrollment to a Phase 1 study is feasible in a TP53 mutation selective population. PC14586 is safe and tolerated up to 3000 mg daily. Preliminary efficacy was achieved in heavily pretreated pts."

Clinical • P1 data • Fatigue • Lung Cancer • Oncology • Solid Tumor • CTCs • TP53

Genomic and transcriptomic landscape of TP53 alterations in pediatric high-grade gliomas (EANO 2026) - "TP53 alterations play a central role in pHGG biology and clinical outcome, with distinct differences compared to adult gliomas. A higher proportion of truncating mutations in pediatric tumors suggests differences in TP53 functional inactivation. Notably, mutation-specific agents such as Rezatapopt, targeting the Y220C variant, may have limited applicability as this alteration was not observed in our cohort, while the modest clinical benefit observed with Eprenetapopt highlights the need for mutation-informed and age-specific therapeutic strategies."

Clinical • Tumor mutational burden • Brain Cancer • Glioma • High Grade Glioma • Oncology • Solid Tumor • ATRX • H3-3A • PDGFRA • TMB • TP53

Systematic Evaluation of Combination Strategies with Rezatapopt in p53 Y220C-Mutant Cancer Models. (PubMed, Mol Cancer Ther) - "While chemotherapy, bevacizumab, and MDM2 inhibitors showed in vivo efficacy, a high-throughput screen identified the phosphoinositide 3-kinase (PI3K)/ Protein Kinase B (AKT)/mechanistic target of rapamycin (mTOR) and mitogen-activated protein kinase pathways as top synergistic candidates. Validation confirmed that PI3Kα inhibition synergized with rezatapopt to deepen apoptosis and tumor growth inhibition in xenograft models. Thus, PI3K/mTOR pathway inhibition may represent a clinically actionable, conserved p53-reactivation vulnerability across diverse histologies harboring a TP53 Y220C mutation."

Journal • Preclinical • Oncology • PIK3CA

Targeting TP53 in triple-negative breast cancer: Molecular pathogenesis, therapeutic implications, and emerging pharmacological strategies. (PubMed, Bull Cancer) - "Key approaches include the pharmacological reactivation of mutant p53 using small molecules such as APR-246, COTI-2, and the mutation-specific reactivator rezatapopt (PC14586), which has shown significant clinical tumour reduction in Y220C-mutant patients. Recent clinical evidence further highlights the potential of combining epigenetic agents like decitabine with chemotherapy in TP53-mutant populations. Integrating TP53 mutation status into biomarker-driven treatment paradigms is a pivotal step toward achieving precision oncology and improving clinical outcomes for patients with TNBC."

Journal • Review • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • Triple Negative Breast Cancer • AURKB • CHEK1 • HER-2 • TP53

PMV Pharmaceuticals Announces Updated Promising Rezatapopt Monotherapy Interim Ovarian Cancer Data From PYNNACLE Phase 2 Pivotal Trial (GlobeNewswire) - "The efficacy population consisted of 76 patients enrolled as of the data cutoff date who either had ≥1 post-baseline tumor assessment or discontinued early. Overall response rate (ORR) of 46% (35/76 patients, including four confirmed complete responses, 29 confirmed partial responses, and two unconfirmed partial responses) per investigator assessment according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. The median time to response was 1.3 months and median duration of response was 10.0 months, based on confirmed responses only....The Company anticipates submitting an NDA in the first quarter of 2027....PMV plans to provide an update on all PYNNACLE Phase 2 pivotal trial cohorts at a medical conference in fourth quarter of 2026."

FDA filing • P2 data • Platinum resistant • Ovarian Cancer

Rezatapopt for locally advanced or metastatic solid tumors with a TP53 Y220C mutation: Initial analysis of the pivotal PYNNACLE Phase 2 trial (AACR-NCI-EORTC 2025) - P1/2 | "Pts were heavily pre-treated (median prior lines: 4 [range: 1–10]; 72.5% of pts had ≥3 prior lines) with 40 pts (78.4%) having received prior bevacizumab. In this initial analysis of the pivotal PYNNACLE Phase 2 trial, rezatapopt showed single-agent efficacy and manageable safety in heavily pre-treated pts with TP53 Y220C-mutated advanced solid tumors. Rezatapopt offers a potential targeted treatment approach for solid tumors with a TP53 Y220C mutation."

Late-breaking abstract • Metastases • P2 data • Breast Cancer • Endometrial Cancer • Lung Cancer • Oncology • Ovarian Cancer • Solid Tumor • KRAS • TP53

PYNNACLE phase II trial of rezatapopt (PC14586) in solid tumors with a TP53 Y220C mutation (ESMO 2024) - P1/2 | "Primary endpoint is objective response rate (ORR) assessed per BICR in the ovarian cancer cohort and across cohorts; key secondary endpoints include ORR per investigator, time to and duration of response, disease control rate, progression-free and overall survival, adverse event incidence, pharmacokinetic parameters, and pt-reported outcomes. Pts followed until lost to follow-up, death, two yrs after last pt discontinuation, or end of study."

P2 data • Brain Cancer • CNS Tumor • Oncology • Ovarian Cancer • Solid Tumor • KRAS • TP53

TP53 Y220C Mutations in Patients with Myeloid Malignancies (ASH 2023) - "A novel Y220C-targeted small molecule (PC14586) has shown preliminary efficacy and safety in patients with solid tumors (Dumbrava, E., ASCO 2022)... TP53 Y220C mutations are present in malignant blood disorders and are particularly more common in myelodysplastic syndromes and acute myeloid leukemia, with associated poor outcomes. Novel targeted therapies for this TP53 variant (Y220C) would be of interest for this patient population."

Clinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • Solid Tumor • DNMT3A • TET2 • TP53

PYNNACLE Phase 2 Monotherapy Update (The Manila Times) - "Enrollment of platinum-resistant/refractory ovarian cancer patients for the primary analysis in the Phase 2 monotherapy portion of the PYNNACLE clinical trial has been completed...PMV Pharma anticipates submitting an NDA for accelerated approval of rezatapopt as a treatment for platinum-resistant/refractory ovarian cancer patients with a TP53 Y220C mutation in the first quarter of 2027."

Enrollment status • FDA filing • Platinum resistant • Ovarian Cancer

DFT design of PO4@C60 nanohybrid unveils superelectrophilic molecular metamorphosis with molecular dynamics exhibiting therapeutic potential against p53 cancer mutant Y220C. (PubMed, RSC Adv) - "Comparative molecular docking reveals that POC exhibits a strong binding affinity of -11.5 kcal mol-1, outperforming the docking scores of pristine C60 and reported stabilizers MB710 and Rezatapopt...Thermodynamic evaluation using MM/PBSA and MM/GBSA yields binding free energies of -38.78 kcal mol-1 and -43.73 kcal mol-1, respectively, with an acceptable in-silico toxicity profile. These insights position this superelectrophilic nanohybrid as a promising candidate for restoring the pro-apoptotic function of the p53 tumor suppressor."

Journal • Oncology • TP53

Discovery of an Indole-Based p53-Y220C Reactivator with In Vivo Antitumor Activity via Structure-Guided Design. (PubMed, J Med Chem) - "Although the clinical advancement of PC14586 validates this target, the scarcity of structurally distinct correctors limits exploration of this chemical space...Despite rapid metabolic clearance and the need for intraperitoneal dosing, D2 achieved 59.2% tumor growth inhibition in a xenograft model. Although further pharmacokinetic optimization is required, D2 serves as an alternative structural template for future medicinal chemistry efforts."

Journal • Preclinical • Oncology

Rezatapopt for locally advanced or metastatic solid tumors with a TP53 Y220C mutation: Initial analysis of the pivotal PYNNACLE Phase 2 trial* (AACR-NCI-EORTC 2025) - P1/2 | "Pts were heavily pre-treated (median prior lines: 4 [range: 1–10]; 72.5% of pts had ≥3 prior lines) with 40 pts (78.4%) having received prior bevacizumab. In this initial analysis of the pivotal PYNNACLE Phase 2 trial, rezatapopt showed single-agent efficacy and manageable safety in heavily pre-treated pts with TP53 Y220C-mutated advanced solid tumors. Rezatapopt offers a potential targeted treatment approach for solid tumors with a TP53 Y220C mutation."

Metastases • P2 data • Breast Cancer • Endometrial Cancer • Lung Cancer • Oncology • Ovarian Cancer • Solid Tumor • KRAS • TP53

Revisiting p53 as a therapeutic target: emerging clinical evidence in gynecologic oncology. (PubMed, Int J Gynecol Cancer) - No abstract available

Journal • Gynecologic Cancers • High Grade Serous Ovarian Cancer • Oncology • Ovarian Cancer • Solid Tumor

PYNNACLE Phase 2 Monotherapy Update (GlobeNewswire) - "Enrollment is on track in the Phase 2 monotherapy portion of the PYNNACLE clinical trial. The multicenter, single-arm, registrational Phase 2 study is assessing rezatapopt as monotherapy at a dose of 2000 mg once-daily in patients with TP53 Y220C advanced solid tumors; PMV Pharma anticipates submitting a New Drug Application (NDA) for rezatapopt in platinum-resistant/refractory ovarian cancer patients with a TP53 Y220C mutation in the first quarter of 2027."

Enrollment status • FDA filing • Platinum resistant • Colorectal Cancer • Endometrial Cancer • Estrogen Receptor Positive Breast Cancer • Gallbladder Cancer • Head and Neck Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Non Small Cell Lung Cancer • Ovarian Cancer • Prostate Cancer • Small Cell Lung Cancer • Solid Tumor • Triple Negative Breast Cancer

Discovery of a Best-in-Class small molecule p53 Y220C reactivator: Breaking through the potency ceiling (AACR 2026) - "The first-generation small molecule reactivator (PC14586, Rezatapopt), designed to bind to this pocket, to refold p53 and to restore its tumor-suppressive functions, has shown clinical efficacy in patients harboring the Y220C mutations.However, this first-generation compound is limited by modest potency, necessitating high dosing in patients. In line with their superior cellular activity and in combination with optimized key ADME, safety parameters, and favorable in vivo PK profiles across species, our leads reach similar efficacy in vivo as PC145586 at much lower exposure.In conclusion, we have identified unique p53 Y220C small molecule reactivators with clear best-in-class cellular potency and favorable drug-like properties. We are currently further profiling these leads as potential drug candidates to achieve superior efficacy at substantially lower doses, maximizing the safety window to ultimately deliver better outcomes to cancer patients with p53 Y220C mutations."

Oncology • Solid Tumor • CDKN1A

Highly potent and mutant-selective p53 Y220C reactivators with best-in-class potential (AACR 2026) - "Background: The tumor suppressor p53, encoded by the TP53 gene, is a transcription factor that regulates genes involved in DNA repair, cell cycle arrest, senescence, and apoptosis. The significantly improved potency of the novel p53 reactivators described here offers the opportunity to restore p53 function in less sensitive patient populations and meaningfully improve upon the clinical response profile of rezatapopt."

Oncology • Solid Tumor • KRAS

NTS071-101: A phase 1/2a study to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of NTS071 in patients with advanced solid tumors harboring a TP53 Y220C mutation (AACR 2026) - "In preclinical studies, NTS071 has demonstrated superior in vitro potency, favorable ADME/T profile, and enhanced in vivo antitumor efficacy versus PC14586 (an investigational drug with the same targeting mechanism). Exploratory objectives are to evaluate the correlations between NTS071's pharmacodynamic profiles, efficacy outcomes, and relevant biomarkers.Summary: The first-in-human trial of NTS071 marks a critical milestone in advancing such precision oncology therapies for those patients with limited treatment options and poor prognosis. The first patient for NTS071-101 enrolled in August 2025, with active recruitment continuing in both the U.S. and China."

Clinical • First-in-human • Metastases • P1/2 data • PK/PD data • Oncology • Solid Tumor • TP53

Discovery of SY-14556, a highly potent and selective small molecule reactivator of p53 Y220C mutant with differentiated preclinical profile (AACR 2026) - "Pharmacologic stabilization and reactivation of the Y220C mutant to a wild-type-like conformation is a validated therapeutic strategy, as demonstrated by the clinical activity of PC14586 (rezatapopt). In conclusion, SY-14556 is a best-in class p53-Y220C reactivator with robust preclinical efficacy and safety. These data support its advancement into clinical trials for p53 Y220C-mutant solid tumors."

Preclinical • Oncology • Solid Tumor • CDKN1A

Rezatapopt and KRAS inhibitors for the treatment of TP53 Y220C and KRAS mutant cancers (AACR 2026) - "SRB assay showed that both MRTX1133 (KRAS G12D inhibitor) or daraxonrasib (RMC-6236, pan-RAS inhibitor) were synergistic with rezatapopt in two TP53 Y220C and KRAS G12D cell lines. Rezatapopt combined with KRAS inhibition increased antitumor activity. Further studies are needed to understand the mechanism of synergy."

Colorectal Cancer • Oncology • Solid Tumor • KRAS

Rezatapopt Shows Activity in Pretreated Ovarian Cancer With TP53 Mutation (Cure Today) - "Rezatapopt, an investigational targeted therapy, led to tumor shrinkage and lasting responses in patients with advanced ovarian cancer whose tumors carry a TP53 Y220C mutation, according to findings presented at the 2026 SGO Annual Meeting on Women’s Cancer...In the phase 2 PYNNACLE trial, 44.4% of patients experienced tumor shrinkage, also called an overall response rate. This included 1.4% of patients whose cancer was no longer detectable and 43.1% who had partial tumor shrinkage. An additional 31.9% of patients had stable disease, meaning their cancer did not grow, while 6.9% experienced disease progression...Many patients had large reductions, with 85% showing at least a 50% decrease and 60% showing a reduction of at least 90%."

P2 data • Platinum resistant • Ovarian Cancer

GS-P-328, a brain-penetrant small molecule p53 Y220C reactivator for tumors harboring p53 Y220C mutation (AACR 2024) - "The initial clinical evaluation of PC14586 that can restore missense-mutant p53 protein has seen efficacy in patients harboring p53 Y220C mutation even though there is still room for improvement. GS-P-328 has a favorable ADME profile in rodents, dogs and NHPs, as well as a much better safety profile. GS-P-328 is now under IND-enabling study and P1 study is planned in early 2025."

Lung Cancer • Oncology • Solid Tumor • CDKN1A • MDM2