691TiP - PYNNACLE phase II trial of rezatapopt (PC14586) in solid tumors with a TP53 Y220C mutation

Background

TP53, encoding p53, is one of the most frequently mutated genes across all cancers. TP53 mutations result in loss of p53 tumor suppressor function and tumor progression. Reactivation of wildtype p53 may be an effective therapeutic strategy; however, only a limited number of small molecules targeting mutated p53 have reached clinical trials. Rezatapopt (also known as PC14586) is a first-in-class, selective p53 reactivator specific to the TP53 Y220C mutation that restores wildtype p53 function. In Phase 1, rezatapopt showed single-agent efficacy and favorable safety in heavily pre-treated patients (pts) with solid tumors harboring a TP53 Y220C mutation (Schram A AACR-NCI-EORTC 2023 LBA25).

Trial design

PYNNACLE (NCT04585750; PMV-586-101) is a Phase 1/2 clinical trial of rezatapopt in pts with locally advanced or metastatic solid tumors harboring a TP53 Y220C mutation. PYNNACLE Phase 2 is an ongoing, global, pivotal, basket, single-arm, open-label, multicenter trial in pts with solid tumors (n=114) including ovarian (n=42), lung (n=18), breast (n=18), endometrial (n=18), and other (n=18) cancers. Eligible pts are aged ≥18 yrs (pts 12–17 yrs and ≥40 kg eligible in Australia, South Korea, and USA) with locally advanced or metastatic solid tumors harboring a TP53 Y220C mutation and KRAS wildtype. Key inclusion criteria include measurable disease at baseline (RECIST v1.1), progressive disease after ≥1 prior line of systemic therapy or ineligible for standard of care according to the investigator, ECOG performance status 0 or 1, and adequate organ function. Key exclusion criteria include KRAS single-nucleotide variant mutations, unstable brain metastases, and primary CNS tumors. Eligible pts receive rezatapopt 2000 mg orally once daily with food for continuous 21-day cycles. 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.

Clinical trial identification

NCT04585750.

Editorial acknowledgement

Editorial and medical writing support was provided by Lucretia Ramnath, PhD, and Danielle Lindley, PhD, of Nucleus Global.

Legal entity responsible for the study

PMV Pharmaceuticals, Inc.

Funding

PMV Pharmaceuticals, Inc.

Disclosure

G. Lopes: Financial Interests, Personal, Stocks or ownership: Lucence Diagnostics, Xilis, Biomab, Morphometrix, CDR-Life; Financial Interests, Personal, Financially compensated role: Boehringer Ingelheim, Blueprint Medicines, AstraZeneca, Merck, Janssen; Financial Interests, Personal, Advisory Role: Pfizer, AstraZeneca; Financial Interests, Personal, Research Funding: AstraZeneca, Lucence, Lucence, Xilis, E.R. Squibb Sons, Llc; Financial Interests, Institutional, Research Funding: Merck Sharp & Dohme, EMD Serono, AstraZeneca, Blueprint Medicines, Tesaro, Bavarian Nordic, Novartis, G1 Therapeutics, adaptimmune, BMS, GSK, AbbVie, Rgenix, Pfizer, Roche, Genentech, Lilly, Janssen; Financial Interests, Personal, Other: Mirati Therapeutics, Boehringer Ingelheim, Pfizer, E.R. Squibb Sons, Llc, Janssen, Seattle Genetics, Celgene, Ibsen, Pharmacyclics, Merck, AstraZeneca, Seagen. A.B. El-Khoueiry: Financial Interests, Personal, Advisory Board: Exelixis, AstraZeneca, Genentech, Agenus, Tallac, ABL Bio, Senti Biosciences, Qurient; Financial Interests, Institutional, Funding: Fulgent, Astex, AstraZeneca; Financial Interests, Personal, Steering Committee Member: Merck, Genentech; Financial Interests, Personal, Coordinating PI: Genentech; Financial Interests, Institutional, Coordinating PI, trial; funding: Auransa; Non-Financial Interests, Principal Investigator: Agenus, Affimed, Bayer. E. Fontana: Financial Interests, Personal, Invited Speaker: Caris Life Science, Repair Therapeutics; Financial Interests, Personal, Other, Conference attendance: Sapience Pharma; Financial Interests, Personal, Invited Speaker, Conference Attendance: Bicycles Therapeutics; Financial Interests, Personal, Full or part-time Employment: Hospital Corporation of America (HCA) International; Financial Interests, Personal, Officer: EORTC; Financial Interests, Institutional, Coordinating PI: Repair Therapeutics, Amgen, Taiho Pharmaceutical; Financial Interests, Institutional, Local PI: Bicycle Therapeutics, Artios Pharma, Seagen, Nurix Therapeutics, BioNTech SE, Relay Therapeutics, Pfizer, Roche, Daiichi Sankyo, Gilead Science, Basilea Pharmaceutica, Jiangsu Hengrui Medicine, Mereo Biopharma, Hutchmed, Merus, Crescendo Biologics, GSK plc, BeiGene, Turning Point Therapeutics, Sapience Pharma, Arcus Bioscience, Exelixis, Nerviano Medica, Elipsees, Deciphera, Ribon Therapeutics. T.B. Karasic: Financial Interests, Personal, Other, Honoraria: Pfizer; Taiho Oncology; Elevar Therapeutics; Financial Interests, Personal, Advisory Role: Nucorion; Incyte; Synnovation Therapeutics; Financial Interests, Institutional, Research Funding: Taiho Pharmaceutical; Bristol Myers Squibb; PMV Pharma Replimune, Boehringer Ingelheim; ITotus Medicines; Incyte; Genentech; Xencor; Tempest Therapeutics Lilly; BioNTech SE. S. Kummar: Financial Interests, Personal, Advisory Board: Bayer, Gilead, Mundibiopharma, Springworks Therapeutics, HarbourBiomed, Oxford BioTherapeutics, BPGbio Therapeutics, XYOne Therapeutics, GI Innovation Inc.; Financial Interests, Personal, Advisory Board, Spouse: Cadila Pharmaceuticals; Financial Interests, Personal, Other, Chair, DSMC: Mirati; Financial Interests, Personal, Advisory Board, Consultant: Genome Insight; Financial Interests, Personal, Ownership Interest: Pahtomiq; Financial Interests, Personal, Ownership Interest, Spouse (co-founder): Arexeon; Financial Interests, Personal, Stocks/Shares: Fortress Biotech; Financial Interests, Personal, Other, co-founder: Pathomiq; Financial Interests, Institutional, Local PI, Trial funding: ADC Therapeutics, Pionyr Therapeutics, Eisai, Bristol Myers Squibb, Syndax, SeaGen, ORIC, EMD Serono, Genome & Company, Moderna, Amgen, ASTX Therapeutics, PMV Pharmaceuticals, Elevation Oncology, Gilead, Day One BioPharmaceuticals, Sillajen Inc.; Financial Interests, Institutional, Local PI, trial funding: 23&Me; Financial Interests, Institutional, Local PI, Trial Funding: Deciphera Pharmaceuticals Llc, AstraZeneca, Immunitas Therapeutics, Inc., Mirati Therapeutics Inc, Transcenta Therapeutics, Inc., Adanate, Inc, GV20 Therapeutics Llc, Blueprint Medicines Corp, Nuvectis Pharma, Inc., Fog Pharmaceuticals. P. Lorusso: Other, Personal, Advisory Board: ABL Bio, Actuate Therapeutics, Compass BADX, imCheck, Kineta, Kyowa Kirin Pharmaceutical Development, Inc, Mekanist, Mersana Therapeutics, Molecular Templates, NeuroTrials, P}zer, QED Therapeutics, Relay Therapeutics, Roivant Sciences, Scenic Biotech, Seagen Inc., STCube Pharmaceuticals, Stemline Therapeutics Inc., Zentalis Pharmaceuticals; Other, Personal, Advisory Role, grant reviewer and chair of the New Agents Committee: Cancer Research UK; Other, Personal, Other, Consultant, Was on a Scienti}c Advisory Board: F. Hozmann-La Roche; Other, Personal, Advisory Role: I-Mab; Other, Personal, Other, Data and Safety Monitoring: National Cancer Institute; Other, Personal, Advisory Board, Was on their advisory board: Qualigen. V. Gregorc: Financial Interests, Personal, Expert Testimony: BMS, Eli Lilly, MSD, Novartis; Financial Interests, Personal, Invited Speaker: BMS, Boehringer Ingelheim, MSD; Financial Interests, Personal, Advisory Board: Eli Lilly SPA; Financial Interests, Institutional, Invited Speaker: Sanofi. M. Millward: Financial Interests, Personal, Advisory Board: BeiGene Australia Pty Ltd, Bristol Myers Squibb Australia Pty Ltd, AstraZeneca Australia Pty Ltd, The Limbic, Eli Lilly Australia Pty Ltd, IQVIA Australia Pty Ltd; Financial Interests, Personal, Full or part-time Employment, Professor of Clinical Cancer Research: University of Western Australia; Financial Interests, Personal, Full or part-time Employment, Medical Oncology Director: Linear Clinical Research; Financial Interests, Institutional, Local PI, Trial payments to Institution: Bristol Myers Squibb, Genentech/Roche, BeiGene, Eli Lilly, Albion Laboratories, Akeso Biopharma, AbbVie, Five Prime Therapeutics, Dizal Pharma, Maxinovel, Amgen, Atridia, INXMED, Alpine Immune Sciences, Turning Point Therapeutics, IMPACT Therapeutics, Kinnate Biopharma, Rely Therapeutics, GenFleet Therapeutics, Vivace Therapeutics, Eucure Biopahrma, InventisBio, Cullinan Oncology, Tyra Biosciences, Axelia Oncology; Non-Financial Interests, Other, Scientific Advisory Committee member: Thoracic Oncology Group Australasia. S. Ponce Aix: Financial Interests, Institutional, Invited Speaker: Roche. D.L. Richardson: Other, Personal, Member of Board of Directors, not paid: SGO, National Ovarian Cancer Coalition ; Financial Interests, Personal and Institutional, Advisory Board: Mersana, AstraZeneca, GSK; Financial Interests, Personal, Advisory Board: ProfoundBio, Eisai, Daiichi Sankyo. A.I. Spira: Financial Interests, Personal, Other, Consulting or Advisory Role: Incyte, Mirati Therapeutics, Gritstone Oncology, Jazz Pharmaceuticals, Janssen Research & Development, Mersana, Gritstone Bio, Daiichi Sankyo/AstraZeneca, Array Biopharma, Blueprint Medicines, Regeneron, Lilly, Black Diamond Therapeutics, Sanofi; Financial Interests, Personal, Other, Consulting or Advisory Role/Honoraria: Amgen, Novartis, Takeda, AstraZeneca/MedImmune, Merck, Bristol Myers Squibb; Financial Interests, Personal, Other, Honoraria: CytomX Therapeutics, Janssen Oncology, Bayer; Financial Interests, Institutional, Officer, CEO: NEXT Oncology Virginia; Financial Interests, Personal, Stocks/Shares: Eli Lilly; Financial Interests, Institutional, Local PI: LAM Therapeutics, Roche, AstraZeneca, Boehringer Ingelheim, Astellas Pharma, MedImmune, Novartis, Newlink Genetics, Incyte, AbbVie, Ignyta, Trovagene, Takeda, Macrogenics, CytomX Therapeutics, Astex Pharmaceuticals, Bristol Myers Squibb, Loxo, Arch Therapeutics, Gritstone, Plexxikon, Amgen, Daiichi Sankyo, ADCT, Janssen Oncology, Mirati Therapeutics, Rubius, Synthekine, Mersana, Blueprint Medicines, Kezar, Revolution Med, Regeneron, Loxo, Alkermes, Medikine, Black Diamond Therapeutics, Nalo Therapeutics, Scorpion Therapeutics, Arrivent Biopharma. D.S. Tan: Financial Interests, Personal, Invited Speaker: AstraZeneca, MSD, Merck Serono, Roche, Eisai, GSK, Takeda; Financial Interests, Personal, Advisory Board: AstraZeneca, Bayer, MSD, Eisai, Roche, Genmab, GSK, Boehringer Ingelheim; Financial Interests, Personal, Stocks/Shares: Asian Microbiome Library (AMiLi); Financial Interests, Institutional, Research Grant: Roche, Bayer, Karyopharm Therapeutics, AstraZeneca; Financial Interests, Institutional, Coordinating PI: AstraZeneca, Bergen Bio; Financial Interests, Institutional, Local PI: Zeria Pharmaceutical Co Ltd, Bayer, Byondis B.V.; Non-Financial Interests, Leadership Role, Ex society president: Gynecologic Cancer Group Singapore; Non-Financial Interests, Member of Board of Directors: Gynaecologic Cancer Intergroup (GCIG); Non-Financial Interests, Leadership Role, Ex- Chair: Asia-Pacific Gynecologic Oncology Trials Group (APGOT); Non-Financial Interests, Institutional, Product Samples, Research Study: MSD, Eisai, AstraZeneca, Cyclacel Pharmaceuticals. J.A. Thompson: Financial Interests, Personal, Other, Honoraria: Mabquest; Bristol Myers Squibb, Clinical Care Options; Regeneron; Financial Interests, Personal, Stocks or ownership: Alpine Immune Sciences; Financial Interests, Institutional, Advisory Board: Pfizer; PMV Pharma; Merck; Roche; Five Prime Therapeutics; Novartis; Trillium; Xencor; Other, Personal, Leadership Role, Chair - Immune Related Toxicity Guideline: NCCN. D. Uprety: Financial Interests, Personal, Advisory Board: Jazz Pharmaceuticals, AstraZeneca, Sanofi, Daiichi Sankyo. M. Fellous: Financial Interests, Institutional, Advisory Board: Relay Therapeutics; Financial Interests, Advisory Board: Mersana, Merus, PMV Pharmaceuticals, Schrodinger; Financial Interests, Steering Committee Member: Merus, Pfizer, Therapeutics; Financial Interests, Research Funding: AstraZeneca, ArQule, BeiGene, Springworks, Black Diamond Therapeutics, Elevation Oncology, Lilly, Merus, Northern Biologics, Pfizer, PMV Pharmaceuticals, Relay, Repare Therapeutics, Revolution Medicine, Surface Oncology; Financial Interests, Financially compensated role: PUMA, Repare Therapeutics; Financial Interests, Other: ASCO Conquer Cancer Foundation CDA, NCI P30CA008748 CCITLA, Cycle for Survival, MSKCC Support Grant [P30 CA008748]. Y.G. Qin: Financial Interests, Personal, Full or part-time Employment: PMV Pharma. E.E. Dumbrava: Financial Interests, Institutional, Other, Research/grant funding: Bayer HealthCare Pharmaceuticals, Immunocore Ltd, Amgen, Aileron Therapeutics, Compugen Ltd, Gilead, BOLT Therapeutics, Aprea Therapeutics, Bellicum, PMV Pharma, Triumvira, Seagen Inc, Mereo BioPharma 5 Inc, Sanofi, Rain Oncology, Astex Therapeutics, Sotio, Mersana Therapeutics, Poseida, Boehringer Ingelheim; Financial Interests, Personal, Invited Speaker: PMV Pharma; Financial Interests, Personal, Advisory Board: BOLT Therapeutics, Mersana Therapeutics, Orum Therapeutics, Summit Therapeutics. All other authors have declared no conflicts of interest.