rezatapopt (PC14586) / PMV Pharma - LARVOL DELTA

Leveraging p53 and MCL-1 as Therapeutic Targets in Small Cell Lung Cancer (IASLC-TTLC 2026) - "While chemoresistance is common after platinum-based strategies, lurbinectedin, or bispecific T-cell engagers, a need remains for novel therapeutic strategies in relapsed SCLC...APR-246 (0.39- 50 µM), rezatapopt (0.078-10 µM), or DMSO was added for 120 h, prior to evaluation of cell viability (CellTiter-Glo®)... MCL-1i with p53 reactivators is a promising therapeutic combination for SCLC, independent of NE subtype or TP53 alteration. Mechanistic understanding of how BAX/BAK homeostasis may regulate this response in SCLC is underway."

IO biomarker • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • ASCL1 • BCL2 • MDK

Rezatapopt, a selective p53 reactivator, in advanced or metastatic solid tumours with a TP53 Y220C mutation: interim efficacy results from patients with ovarian cancer in the phase 2 PYNNACLE trial (ESGO 2026) - "Median prior treatment lines was four (range: 1–10); 78.4% of patients had received prior bevacizumab. Conclusion In this interim analysis of the pivotal PYNNACLE Phase 2 trial, rezatapopt demonstrated clinically-meaningful efficacy and manageable safety in heavily pretreated patients with TP53 Y220C-mutated advanced ovarian cancer. Rezatapopt represents a promising targeted therapy for ovarian cancer harboring the TP53 Y220C mutation."

Clinical • Metastases • P2 data • High Grade Serous Ovarian Cancer • Oncology • Ovarian Cancer • Solid Tumor • HRD • KRAS • TP53

Clinical Focus: The rezatapopt Pathway (AD HOC NEWS) - "The clinical roadmap has a clear near-term objective: the company plans to complete patient enrollment for its study in platinum-resistant ovarian cancer by the close of this first quarter, specifically by the end of March 2026....PMV Pharmaceuticals currently aims to submit a New Drug Application (NDA) for this indication by the end of the first quarter of 2027. This timeline is supported by interim data from the PYNNACLE Phase 2 study, released in October 2025, which demonstrated clinical responses in various solid tumors harboring specific p53 mutations."

Enrollment status • FDA filing • P53mut • Platinum resistant • Ovarian Cancer

A Study to Investigate the Effects of Multiple Doses of Rezatapopt on the Pharmacokinetics of Metformin, Rosuvastatin, Repaglinide, and Midazolam in Patients With Advanced Solid Tumors Harboring a TP53 Y220C Mutation. (clinicaltrials.gov) - P1 | N=14 | Not yet recruiting | Sponsor: PMV Pharmaceuticals, Inc

New P1 trial • Prostate Cancer • Solid Tumor • TP53

Restoring Tumor Suppressor Function in TP53 Y220C–Mutant Cancers (LCC 2026) - "The presentation will also address emerging translational and early clinical observations from ongoing studies of rezatapopt in patients with advanced TP53 Y220C–mutant solid tumors. Together, these findings support a model in which precise structural correction of mutant p53 re-engages endogenous tumor suppressor programs, creating new therapeutic opportunities across tumor types."

Oncology • Solid Tumor • 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

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

The pivotal PYNNACLE Phase 2 trial assessing rezatapopt, a selective p53 reactivator, in patients with advanced or metastatic solid tumors harboring a TP53 Y220C mutation: Interim analysis of patients with ovarian cancer (SGO 2026) - No abstract available

Clinical • Metastases • P2 data • Oncology • Ovarian Cancer • Solid Tumor • TP53

Acquired on-target alterations drive clinical resistance to p53-Y220C reactivators. (PubMed, Cancer Discov) - "Functional modeling confirmed these double mutants eliminate p53 reactivation and target gene induction by rezatapopt. These findings establish a molecular framework for resistance to p53 Y220C reactivators and inform strategies to overcome resistance with next-generation agents."

Journal • Oncology • TP53

Have the gates been finally breached? PYNNACLE thinks so! @AliSchram @DrElkhoueiry Dr David Tan Rezatapopt/TP53 Y220C ORR 34% pantumor; 46% in ovarian ; rapid responses in ~1.3 months All responders ctDNA VAF ↓↓ ⏱ DoR ~7–8m GI AEs ↓↓ with food @oncodaily @MedwatchKate

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

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