rezatapopt (PC14586) / PMV Pharma - LARVOL DELTA

Reactivating mutant p53 in T cells enhances anti-tumor activity in Acute Myeloid Leukemia (ASH 2025) - "T cells treated with the p53reactivator exhibited significantly decreased levels of exhaustion markers in both CD4 and CD8 subsets.Functional assessment using a real-time cell killing assay (InCuCyte) demonstrated that TP53 mutant CAR-T cells had significantly reduced anti-AML activity, which could be largely restored in vitro by PC14586.To evaluate in vivo efficacy of this approach, we employed a venetoclax-resistant patient-derivedxenograft (PDX) mouse model of AML. We recently reported TP53 mutations in T and NK cells from TP53 mutant AML patients (Li etal, ASH 2024). Our new findings establish reduced functionality of TP53 mutant T cells and enhanced anti-leukemia activity and improved therapeutic outcomes in vivo by pharmacological restoration of wild-typep53 by PC14586. A clinical trial of PC14586 (Rezatapopt, PMV Pharma) in p53-Y220C mutant AML isongoing (Senapathi, J. et al., ASH 2025)."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CD123 • CD4 • CD8 • IL3RA

Rezatapopt for advanced solid tumours with a TP53 Y220C mutation: Initial analysis of the PYNNACLE phase II study (ESMO Asia 2025) - P1/2 | "In this initial analysis of PYNNACLE phase 2, rezatapopt showed efficacy and manageable safety in heavily pre-treated pts with TP53 Y220C-mutated advanced solid tumors. Rezatapopt offers promising targeted treatment for solid tumors with a TP53 Y220C mutation. Table: LBA2 aEfficacy evaluable: Patients with 6 weeks of follow-up; patients discontinuing before 6 weeks are included."

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

Reactivation of p53 in TP53-Y220C Mutant AML: Mechanism of Action and Mechanism-Based Drug Combinations (ASH 2024) - "PC14586, in combination with venetoclax (VEN), can activate Bax and synergistically induced cell death in TP53-Y220C Molm13, primary patient samples, and PDX cells that did not respond to PC14586 as a single agent, and prolonged survival in Molm13 TP53-Y220C xenografted mice (p=0.0026). Both contribute to the diminished apoptogenic activity of PC14586 in TP53-Y220C AML cells, which can be overcome by combinations of PC14586 with MDM2 or/and Bcl-2 inhibitors. Clinical trials of PC14586 with VEN or VEN/HMA combinations are planned in TP53-Y220C AML/MDS."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Lymphoma • Oncology • BCL2L1 • CDKN1A • MCL1 • TP53

Selective Targeting of TP53-Y220C Mutant AML By PC14586 Results in TP53 Wild-Type Conformation and Synergistical Apoptosis Induction By Concomitant Inhibition of Xpo-1, MDM2, or Bcl-2 (ASH 2023) - P1/2 | "Mechanism-based combinations with XPO-1, MDM2, and Bcl-2 inhibitors induce massive apoptosis. PC14586 is presently in early clinical trials."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • BCL2 • CD34 • CDKN1A • 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

Rezatapopt New Drug Application submission for platinum resistant/refractory ovarian cancer planned in first quarter of 2027 (PMV Pharma Press Release)

FDA filing • Platinum resistant • Ovarian Cancer

Mutant p53 binds and controls estrogen receptor activity to drive endocrine resistance in ovarian cancer. (PubMed, Genes Dev) - "In this work, we show that missense mutant forms of p53, which occur in >60% of HGSOC, bind and inhibit ERα function and confer resistance to fulvestrant and elacestrant. Mechanistically, we show that mutant p53 predominantly inhibits one arm of the ERα pathway-the transactivation of jointly regulated ERα-SP1 target genes such as the mTOR regulator DEPTOR We show that silencing mutant p53 restores the ability of ERα to transactivate ERα-SP1 target genes and renders HGSOC markedly more sensitive to endocrine therapy. Consistent with this premise, we show that the p53 mutant Y220C refolding compound rezatapopt enhances fulvestrant response in a Y220C mutant cell line."

Journal • Gynecologic Cancers • High Grade Serous Ovarian Cancer • Oncology • Ovarian Cancer • Solid Tumor • ER • TP53

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 | N=230 ➔ 300 | Trial completion date: Jul 2026 ➔ Dec 2027 | Trial primary completion date: Mar 2026 ➔ Aug 2026

Enrollment change • P53mut • Trial completion date • 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

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

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

Discovery of a Best-in-Class small molecule p53 Y220C reactivator: Breaking through the potency ceiling (AACR-NCI-EORTC 2025) - "First generation small molecule reactivators (PC14586), designed to bind to this pocket, to refold p53 and to restore its tumor-suppressive functions, have shown clinical efficacy in patients harboring the Y220C mutations...Here, we identified highly optimized p53 Y220C small molecule reactivator series with clear best-in-class potential. Comprehensive characterization and optimization are now ongoing to identify clinical development candidates with the ultimate goal of achieving superior efficacy at substantially lower doses, maximizing safety, and delivering meaningful benefits to patients with p53 Y220C mutations."

Oncology • Solid Tumor • CDKN1A

FMC-220, a highly potent and selective covalent activator of p53 Y220C, is broadly active in p53 Y220C containing PDX models across cancer indications (AACR-NCI-EORTC 2025) - "ChIPseq analysis demonstrated that FMC-220 delivers far more durable activation and ​persistent engagement of target gene promoters than noncovalent strategies such as rezatapopt (PC14586). In addition, FMC-220 combines effectively with other therapeutics including MDM2 inhibitors or DNA damaging agents. Together, these data demonstrate the promise of FMC-220, a first-in-class covalent activator of p53 Y220C, with the potential to deliver improved outcomes for patients with Y220C mutation positive tumors."

Oncology • KRAS • TP53

Rezatapopt New Drug Application submission for platinum-resistant/refractory ovarian cancer planned in first quarter of 2027 (GlobeNewswire)

Filing • Platinum resistant • Ovarian Cancer

PMV Pharmaceuticals Announces Updated Rezatapopt Monotherapy Interim Data From Ongoing PYNNACLE Phase 2 Trial Across Multiple Solid Tumors With a TP53 Y220C Mutation (GlobeNewswire) - "Data presented today as an oral presentation at 2025 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics. Confirmed responses observed in eight tumor types spanning ovarian, lung, breast, endometrial, head and neck, colorectal, gallbladder, and ampullary carcinoma. 34% overall response rate (ORR) observed among 103 evaluable patients across all cohorts with a median duration of response of 7.6 months. 46% ORR observed among 48 evaluable patients in ovarian cancer cohort with a median duration of response of 8.0 months."

P2 data • P53mut • Breast Cancer • Colorectal Cancer • Endometrial Cancer • Gallbladder Cancer • Head and Neck Cancer • Lung Cancer • Ovarian Cancer

Genomic alterations (GA) in TP53 including the targetable TP53 Y220C mutation in clinically advanced non-small cell lung cancer (CANSCLC) (ESMO 2025) - "Background Recent studies demonstrating the ability of drugs such as Rezatapopt to target a rare TP53 GA have spearheaded new interest in the TP53 genomic landscape and frequency of the targetable TP53 Y220C mutation...Future studies and post-hoc analysis should focus on its impact on treatment outcomes in the context of personalized regimes. Legal entity responsible for the study The authors."

Clinical • IO biomarker • Metastases • Tumor mutational burden • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK • BRAF • CCND1 • EGFR • HER-2 • KRAS • MTAP • PD-L1 • RET • ROS1 • SMARCA4 • STK11 • TP53

PMV Pharmaceuticals to Present Rezatapopt Pivotal Phase 2 Initial Analysis and Natural History Study Results at the 2025 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics (GlobeNewswire) - "Oral presentation to highlight initial data from ongoing pivotal Phase 2 study of rezatapopt...in patients with advanced solid tumors harboring a TP53 Y220C mutation."

P2 data • Solid Tumor

PMV Pharmaceuticals Announces Promising Rezatapopt Monotherapy Interim Data From PYNNACLE Phase 2 Trial Across Multiple Solid Tumors With a TP53 Y220C Mutation (GlobeNewswire) - "33% overall response rate (ORR) observed among 97 evaluable patients across all cohorts with a median duration of response of 6.2 months; 43% ORR observed among 44 evaluable patients in ovarian cancer cohort with a median duration of response of 7.6 months."

P2 data • P53mut • Platinum resistant • Ampullary Adenocarcinoma Intestinal Type • Colorectal Cancer • Endometrial Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Non Small Cell Lung Cancer • Ovarian Cancer • Small Cell Lung Cancer

PYNNACLE phase II clinical trial protocol: rezatapopt (PC14586) monotherapy in advanced or metastatic solid tumors with a TP53 Y220C mutation. (PubMed, Future Oncol) - P1/2 | "NCT04585750 (ClinicalTrials.gov)."

Journal • Monotherapy • P2 data • Oncology • Solid Tumor • TP53

Regulatory Update: Rezatapopt (GlobeNewswire) - "PMV Pharma 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. The Company plans to submit an NDA for platinum resistant/refractory ovarian cancer by the end of the first quarter of 2027."

Enrollment status • FDA filing • Platinum resistant • Ovarian Cancer

PMV Pharmaceuticals Reports Second Quarter 2025 Financial Results and Corporate Highlights (GlobeNewswire) - "PMV Pharma will host an investor webinar on Wednesday, September 10, 2025 at 8:00 AM ET to review interim analysis data from the Phase 2 PYNNACLE clinical trial. This interim analysis will include data for approximately 65 patients who have had at least 18 weeks of follow-up, of which approximately 45% are in the ovarian cancer cohort....Research and development (R&D) expenses were $18.4 million for the quarter ended June 30, 2025, compared to $14.6 million for the quarter ended June 30, 2024. The increase in R&D expenses was primarily due to increased contractual research organization costs for the advancement of the rezatapopt program."

Commercial • P2 data • Ovarian Cancer

The roles of mutant p53 in reprogramming and inflammation in breast cancers. (PubMed, Cell Death Differ) - "Rezatapopt is an investigational small molecule p53 reactivator that binds specifically to the Y220C-mutant p53 protein without interacting with wild-type or other mutant p53 proteins...There are several wild type Tp53 regulated pathways that could play a role in reversing the inflammatory response and tumor growth observed in this patient case. This perspective explores the signal transduction pathways involved in this cancer mediated inflammation and the extensive reduction of detectable tumor tissue."

Journal • Review • Breast Cancer • Dermatitis • Oncology • Solid Tumor • Triple Negative Breast Cancer • TP53

Restoring p53 wild-type conformation in TP53-Y220C-mutant acute myeloid leukemia. (PubMed, Blood) - P1 | "Pharmacological inhibition of the BCL-2/BAX interaction with venetoclax fully compensates for this deficiency, induces massive cell death in AML cells and stem/progenitor cells in vitro and prolongs survival of TP53-Y220C AML xenografts in vivo. Collectively, we identified transcription-dependent and -independent mechanisms that limit the apoptogenic activities of reactivated conformational p53-WT and suggest approaches to optimize apoptosis induction in TP53-mutant leukemia. A clinical trial of PC14586 in TP53-Y220C AML/myelodysplastic syndromes has recently been initiated (NCT06616636)."

IO biomarker • Journal • P53WT • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • BCL2 • BCL2L1 • MCL1 • TP53

Rezatapopt: A promising small-molecule "refolder" specific for TP53Y220C mutant tumors. (PubMed, Neoplasia) - P1/2 | "achieve to enhance our understanding of the mechanisms and effects of p53-Y220C reactivator compounds and underscore the potential of targeting p53 mutants in cancer therapy [3]. Through this spotlight article, we aim to summarize the findings and emphasize the clinical implications of the study by Puzio-Kutler et al."

Journal • Oncology • Solid Tumor • TP53

TP53 genomic alterations including targetable TP53 Y220C mutation in clinically advanced breast cancer. (ASCO 2025) - "Funded by No funding sources reported Background: Recent studies demonstrating the ability of drugs such as Rezatapopt to target the TP53 Y220C mutation motivated us to assess the TP53 mutation landscape in clinically advanced breast cancer (CABC)... TP53 Y220C is a relatively rare event in CABC. The TP53 mutant group was associated with GA in tumor suppressor genes, including BRCA1, PTEN, and RB1, whereas the TP53wt group was associated with GA in pathways associated with endocrine resistance, including PIK3CA and ESR1. †Benjamini/Hochberg adjustment."

Clinical • IO biomarker • Metastases • Tumor mutational burden • Breast Cancer • HER2 Breast Cancer • Microsatellite Instability • Oncology • Solid Tumor • BRCA1 • BRCA2 • CCND1 • CDH1 • ER • HER-2 • HRD • MSI • PD-L1 • PIK3CA • PTEN • RB1 • TMB • TP53

PYNNACLE phase 2 clinical trial of rezatapopt in patients with advanced solid tumors harboring a TP53 Y220C mutation. (ASCO 2025) - P1/2 | "PYNNACLE Phase 1/2 basket study (NCT04585750).* Defined as no KRAS single nucleotide variant. BICR, blinded independent central review; ORR, objective response rate; RECIST v1.1, Response Evaluation Criteria in Solid Tumors Version 1.1."

Clinical • Metastases • P2 data • Brain Cancer • CNS Tumor • Oncology • Solid Tumor • KRAS • TP53