rezatapopt (PC14586) / PMV Pharma - LARVOL DELTA

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

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

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

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

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

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 | Recruiting | Sponsor: PMV Pharmaceuticals, Inc | Not yet recruiting ➔ Recruiting

Enrollment open • Oncology • Prostate Cancer • Solid Tumor • TP53

Really extraordinary to see TP53-targeted therapy with rezatapopt showing a 20% response rate. Rezatopopt targets TP53 Y220C mutations (~1% of solid tumors). Interestingly, activity does not appear to extend to KRAS-mutant tumors.

PYNNACLE Phase 2 Monotherapy Update (The Manila Times) - "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."

Enrollment status • 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 • Triple Negative Breast Cancer

On March 2, 2026, the U.S. Food and Drug Administration (FDA) granted Orphan Drug Designation (ODD) to rezatapopt for the treatment of TP53 Y220C positive ovarian cancer, fallopian tube cancer, and primary peritoneal cancer (The Manila Times)

Orphan drug • Fallopian Tube Cancer • Ovarian Cancer • Peritoneal Cancer

New findings from the rezatapopt PYNNACLE Phase 2 trial in ovarian cancer were presented at the 2026 European Society of Gynecologic Oncology Congress, demonstrating robust and consistent ORRs across key ovarian cancer subgroups. (The Manila Times) - "The ORR subgroup data included those with platinum-resistant, platinum-refractory disease, prior systemic therapies and folate receptor alpha status, that provide further evidence of the broad efficacy of rezatapopt within ovarian cancer patients; After the September 4, 2025 data cut-off, among the 48 evaluable patients in the ovarian cancer cohort, a 50% ORR was observed with 23 confirmed responses and one unconfirmed partial response."

P2 data • Platinum resistant • Ovarian Cancer

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

"Pioneering" p53 Reactivator Shows Proof-of-Concept in Phase I Trial. (PubMed, Cancer Discov) - "Findings from a phase I study show that the p53 reactivator rezatapopt is safe and can elicit responses in patients with a range of solid tumors containing the Y220C mutation. Although the drug was ineffective in tumors with KRAS mutations, and whether the strategy can be applied to more common missense mutations remains unclear, the findings offer proof of concept for p53 reactivation."

Journal • P1 data • Oncology • Solid Tumor • KRAS

Targeting the p53 cancer mutants Y220C, Y220N, and Y220S with the small-molecule stabilizer rezatapopt. (PubMed, Cell Death Dis) - "The Y220N mutant, despite exhibiting high-nanomolar affinity for rezatapopt and substantial stabilization, did not show noticeable effects in cells at the concentrations tested, as rezatapopt binding resulted in only partial compensation for the mutation-induced loss of stability, for which we provide a structural explanation. Our data suggest that the development of clinical pan-Y220C/N/S reactivators, which could benefit an additional 10,000 patients per year, is challenging but not impossible."

Journal • Biliary Cancer • Oncology • TP53

PMV Pharmaceuticals (PMVP) Publishes Positive Phase 1 Results for Rezatapopt (Gurufocus) - "The results showed that rezatapopt was generally well-received, with infrequent dose-limiting toxicities, supporting the choice of the recommended dose for Phase 2. Objective responses were noted in different tumor types, indicating its effective binding to the Y220C mutation and restoring the tumor-suppressing abilities of the p53 protein."

P1 data • Colorectal 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 • Triple Negative Breast Cancer

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...New approaches with p53 reactivators, APR-246 and rezatapopt, can stabilize the conformation of mutant p53 to induce apoptosis... 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 • MCL1 • MDK

The impact of p53 mutation on tumor immune evasion: mechanistic insights and clinical implications. (PubMed, Front Immunol) - P1/2, P1b/2, P3 | "Therapeutic approaches include Mtp53 reactivators (e.g., APR-246, PC14586), degraders, synthetic lethal strategies, and neoantigen vaccines. Its combination with pembrolizumab (NCT04383938) demonstrated acceptable safety (immune-related adverse events in ∼12%) but limited efficacy, underscoring the need for biomarker-guided, precision-based combinations. Thus, a multidimensional biomarker platform is urgently needed-one integrating TP53 mutation subtypes (e.g., R175H vs. nonsense mutations), dynamic ctDNA monitoring (VAF ≥ 0.01%), tumor immune microenvironment (TIME) features (e.g., TILs, MDSCs), and spatial multi-omics-to enable precise molecular stratification and personalized intervention in Mtp53-driven cancers."

IO biomarker • Journal • P53mut • Review • Breast Cancer • Colorectal Cancer • Lung Cancer • Metabolic Disorders • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • Triple Negative Breast Cancer • 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

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