400TiP: PYNNACLE phase II assessing rezatapopt in patients with advanced solid tumors, including lung cancer, harboring a TP53 Y220C mutation.

Abstract

Background TP53 mutations are found in?>90% of small-cell lung cancers and 68% of non-small cell lung cancers. The TP53 Y220C mutation, occurring in ~1% of all lung cancers, is a missense mutation that destabilizes the p53 protein. Rezatapopt (also known as PC14586) is an investigational, first-in-class, p53 reactivator specific to the TP53 Y220C mutation that restores wildtype p53 function. In the phase I part of the PYNNACLE study, rezatapopt showed preliminary single-agent efficacy and favorable safety in heavily pre-treated patients. Here we describe the pivotal registrational Phase 2 part of the PYNNACLE study design. Trial design PYNNACLE (NCT04585750) is a Phase I/II clinical trial of rezatapopt in patients with locally advanced or metastatic solid tumors harboring a TP53 Y220C mutation. The Phase 2 part of PYNNACLE is an ongoing, global, single-arm, open-label, multicenter basket trial in patients with solid tumors (N = ~114; including lung cancer, n = ~18). Eligibility: adults aged >=18 years (>=21 years in Singapore) and adolescents aged 12-17 years (if weighing >=40 kg in Australia, South Korea, and the USA) with locally advanced or metastatic solid tumors that have a TP53 Y220C mutation and are KRAS wildtype (no KRAS single nucleotide variants [SNV]). Key inclusion criteria: confirmed advanced solid tumor with TP53 Y220C mutation, measurable disease at baseline (RECIST v1.1), progressive disease after >=1 prior line of systemic therapy or ineligible for standard of care therapy, ECOG performance status 0 or 1, and adequate organ function. Key exclusion criteria: KRAS SNV mutations, primary CNS tumors, and unstable brain metastases. Eligible patients will receive rezatapopt 2000mg orally once daily with food for continuous 21-day cycles. The primary endpoint is objective response rate as assessed by blinded independent central review; key secondary endpoints include time to response, duration of response, disease control rate, progression-free and overall survival, adverse events, pharmacokinetic parameters, and patient-reported outcomes. Patients will be followed until death, lost to follow-up, 2 years after last patient discontinuation, or end of study. Clinical trial identification NCT04585750 Editorial acknowledgement Editorial/medical writing support was provided by Lucretia Ramnath, PhD, and Danielle Lindley, PhD, of Nucleus Global Ltd, part of the Inizio group, funded by PMV Pharmaceuticals, Inc. Legal entity responsible for the study PMV Pharmaceuticals, Inc. Funding PMV Pharmaceuticals, Inc. Disclosure M.J. De Miguel: Financial Interests, Personal, Full or part-time Employment: HM Hospitals Group and START Program of Early Phase Clinical Drug Development in Oncology; Financial Interests, Personal, Invited Speaker: Janssen, MSD and Roche; Financial Interests, Personal, Advisory Board: Syneoshealth, MSD; Non-Financial Interests, Personal, Principal Investigator: MSD, Roche, PharmaMar, AZ, Genmab, Debio, GSK, HiFiBio, Replimune, Merck, Novartis, AbbVie, Achilles, Amunix, Arcus, Furmo, Biontech, Nektar, Catalym, Dizal, Genentech, Loxo, Lilly, Numab, Bayer, Chugai, Servier. E.E. Dumbrava: Financial Interests, Institutional, Research Grant: Bayer HealthCare Pharmaceuticals Inc, Immunocore LTD, Amgen, Aileron Therapeutics, Compugen Ltd, TRACON Pharmaceuticals Inc, Unum Therapeutics, Gilead Immunomedics, BOLT Therapeutics, Aprea Therapeutics, Bellicum Pharmaceuticals, PMV Pharma, Triumvira Imm; Financial Interests, Institutional, Advisory Board: BOLT Therapeutics, Mersana Therapeutics, Orum Therapeutics, Summit Therapeutics, Fate Therapeutics, PMV Pharma; Financial Interests, Institutional, Invited Speaker: PMV Pharma; Financial Interests, Institutional, Other, Travel, Accommodations, Expenses: ASCO, LFSA Association, Rain Oncology, Banner MD Anderson Cancer Center, Triumvira Immunologics. A. Body: Financial Interests, Institutional, Research Grant: BeiGene, Hanmi Pharma, Stingray Pharmaceuticals, Innovent, PMV Pharmaceuticals, Gilead, Vivace Therapeutics. A. Italiano: Financial Interests, Institutional, Advisory Board: Bayer, Boehringer Ingelheim, Daiichi Sankyo, Merck, MSD, Novartis, ROCHE; Financial Interests, Institutional, Research Grant: Bayer, BeiGene, BMS, Boehringer, Daiichi Sankyo, Invox Pharma, Merck, MSD, Novartis, PharmaMar, ROCHE. M.L. Johnson: Financial Interests, Institutional, Research Grant: AbbVie, Acerta, Adaptimmune, Amgen, Apexigen, Arcus Biosciences, Array BioPharma, ArriVent BioPharma, Artios Pharma, AstraZeneca, Atreca, BeiGene, BerGenBio, BioAtla, Black Diamond, Boehringer Ingelheim, Bristol Myers Squibb, Calithera Biosciences, Carism. J. Kaczmar: Financial Interests, Institutional, Other, Consulting: PDS biotech Bicara therapeutics and EMD Serono. S. Kummar: Financial Interests, Institutional, Advisory Board: Springworks Therapeutics, SeaGen, Bayer, Genome & Company, HarbourBiomed, BPGbio Therapeutics, Oxford Biotherapeutics, Mundibiopharma, BPGbio, Inc., Gilead, Mirati; Fortress Biotech, Inc, GI Innovation Inc, XYone Therapeutics, Genome Insight, Aadi Bioscie; Financial Interests, Institutional, Other, co-founder: PathomIQ; Financial Interests, Institutional, Other, scientific advisor-spouse: Cadila Pharmaceuticals; Financial Interests, Institutional, Other, co-founder spouse: Arxeon. P.M. Lorusso: Financial Interests, Institutional, Advisory Board: AbbVie, Roche-Genentech, Takeda, SOTIO, Agenus, IQVIA, Pfizer, GSK, QED Therapeutics, AstraZeneca, EMD Serono, Kyowa Kirin Pharmaceutical Development, Kineta, Inc.: Advisory Boar, Zentalis Pharmaceuticals, Molecular Templates, ABL Bio, STCub. M. Millward: Financial Interests, Institutional, Advisory Role: Amgen Australia Pty Ltd, AstraZeneca Australia Pty Ltd, BeiGene Australia Pty Ltd, Bristol Myers Squibb Australia Pty Ltd, Eli Lilly Australia Pty Ltd, Guardant Health, IQVIA Australia Pty Ltd, Merck Pte Ltd, Pfizer Australia Pty Ltd, The Limbic.; Financial Interests, Institutional, Research Grant: Bristol Myers Squibb, Genentech/Roche, BeiGene, LOXO-Lilly, Akeso Biopharma, AbbVie, Maxinovel, Amgen, Atridia, INXMED, Alpine Immune Sciences, IMPACT Therapeutics, Kinnate Biopharma, Relay Therapeutics, GenFleet Therapeutics, Vivace Therapeutics, Eucure. I.L. Ray-Coquard: Financial Interests, Institutional, Other, Honoraria: Agenus, Blueprint, BMS, PharmaMar, Genmab, Pfizer, AstraZeneca, Roche, GSK, MSD, Deciphera, Mersena, Merck Sereno, Novartis, Amgen, Macrogenics, Tesaro and Clovis; Financial Interests, Institutional, Advisory Role: from AbbVie, Agenus, Advaxis, BMS, ESAI, Daiichi, PharmaMar, Genmab, Pfizer, AstraZeneca, Roche/Genentech, GSK, MSD, Deciphera, Mersana, Merck Sereno, Novartis, Amgen, Tesaro and Clovis; Financial Interests, Institutional, Research Grant: MSD, Roche, BMS, Novartis, AstraZeneca and Merck Sereno; Financial Interests, Institutional, Other, Travel Support: Roche, MSD, AstraZeneca and GSK. A. Spira: Financial Interests, Institutional, Research Grant: PMV Pharmaceuticals, Inc. D.S. Tan: Financial Interests, Institutional, Full or part-time Employment: National University Health System Singapore; Financial Interests, Institutional, Advisory Board: AstraZeneca, Bayer, BioNTech, Boehringer Ingelheim, Eisai, Genmab, GSK, MSD, PMV Pharma, Daiichi Sankyo and Roche; Asia Pacific Gynaecologic Oncology Trials Group (APGOT); Gynaecologic Cancer Group Singapore; GCIG; Financial Interests, Institutional, Invited Speaker: AstraZeneca, Eisai, GSK, Merck Serono, MSD, Roche, and Takeda; Financial Interests, Institutional, Stocks/Shares: Asian Microbiome Library (AMiLi); Financial Interests, Institutional, Research Grant: AstraZeneca, Bayer, Karyopharm Therapeutics, and Roche, MSD, Eisai, Bergen Bio, BioNTech, PMV Pharma, GSK, Sutro Pharma, Bayer, Byondis B.V. and Zeria Pharmaceutical Co Ltd, National Medical Research Council (NMRC), the Pangestu Family Foundation Gynaeco; Financial Interests, Institutional, Product Samples: AstraZeneca, Eisai, and MSD. J. A. Thompson: Financial Interests, Institutional, Research Grant: PMV Pharmaceuticals, Inc, University of Washington. Y. Qin: Other, Institutional, Full or part-time Employment: PMV Pharmaceuticals, Inc. M. Fellous: Other, Institutional, Full or part-time Employment: PMV Pharmaceuticals, Inc. A. Schram: Financial Interests, Institutional, Advisory Board: Relay Therapeutics, Mersana, Merus, PMV Pharma; Financial Interests, Institutional, Other, Consulting: Blueprint Bio, Flagship Pioneering, Redona Therapeutics; Financial Interests, Institutional, Other, Steering Committee: Merus, Pfizer. Research to Institution: AstraZeneca, ArQule, BeiGene/Springworks, Black Diamond, Therapeutics, Elevation Oncology, Kura, Lilly, Merus, Northern Biologics, Pfizer, PMV Pharma, Relay, Repare Therapeutics, Revolution Medicine, and Surface Onc; Financial Interests, Institutional, Research Grant: Merck KGaA.All other authors have declared no conflicts of interest.Copyright © 2025 International Association for the Study of Lung Cancer, Published by Elsevier Ltd