Abstract 526P
Background
WEE1 tyrosine kinase is a critical component of the G2/M cell cycle checkpoint that phosphorylates CDK1 (p-CDK1), inducing cell cycle arrest in the presence of DNA damage to allow for DNA repair. Inhibition of WEE1 can induce mitotic catastrophe and apoptosis. ZN-c3 is a novel, selective inhibitor of WEE1 being evaluated in a phase 1 trial in patients with advanced solid tumors. Nonclinical and clinical pharmacodynamic (PD) and pharmacokinetic (PK) data are presented.
Methods
Biomarker assays using immunohistochemistry in formalin-fixed paraffin-embedded (FFPE) tissues were developed for p-CDK1, the DNA damage marker γH2AX, and the proliferation marker Ki67. A xenograft model of non-small cell lung cancer (A427) was used for preclinical PD studies. In humans, skin punch biopsies were obtained at baseline and after 15 days of treatment and tumor tissue biopsies were obtained at baseline and after 22 days of treatment.
Results
Anti-p-CDK1 antibodies were tested across a variety of FFPE normal and cancer tissues to evaluate their selectivity, specificity, and accuracy and a monoclonal antibody (10A11, CST) was selected for this biomarker assay. Tumor-bearing mice treated with ZN-c3 (80 mg/kg QD x 3) showed significant inhibition of p-CDK1 in tumors. In the phase 1 trial, skin punch biopsies (baseline and on-treatment) were obtained from 23 patients treated at the recommended phase 2 dose (RP2D) of 300 mg QD or higher; 18/23 patients (78.3%) showed target engagement (≥50% decrease in p-CDK1 levels), including 4/4 patients (100%) with confirmed radiographic partial responses following ZN-c3 treatment. The plasma levels of ZN-c3 and p-CDK1 inhibition in skin punch biopsies showed a clear correlation between drug exposure and WEE1 inhibition. Paired tumor tissue biopsies were obtained from 4 patients; evidence for WEE1 pathway modulation (decreased p-CDK1, increased γH2AX, or Ki67) was observed for 2/3 patients (66.7%) dosed at the RP2D or higher.
Conclusions
Target engagement by the WEE1 inhibitor ZN-c3 was demonstrated in skin and tumor tissue biopsies from patients treated at the RP2D or higher in a phase 1 trial. PK/PD analysis confirmed a correlation between ZN-c3 plasma levels and WEE1 pathway modulation.
Clinical trial identification
NCT04158336.
Editorial acknowledgement
Legal entity responsible for the study
Zentalis Pharmaceuticals.
Funding
Zentalis Pharmaceuticals.
Disclosure
P. Chalasani: Financial Interests, Personal, Advisory Board: Zentalis Parmaceuticals; Financial Interests, Personal, Advisory Board: Eli Lilly; Financial Interests, Personal, Advisory Board: Oncosec; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Institutional, Research Grant: Pfizer. A. Tolcher: Financial Interests, Personal, Advisory Role: AbbVie; Financial Interests, Personal, Advisory Role: Agenus; Financial Interests, Personal, Advisory Role: Asana Biosciences; Financial Interests, Personal, Advisory Role: Ascentage; Financial Interests, Personal, Advisory Role: AxImmune; Financial Interests, Personal, Advisory Role: Bayer; Financial Interests, Personal, Advisory Role: Gilde Healthcare Partners; Financial Interests, Personal, Advisory Role: HBM Partners; Financial Interests, Personal, Advisory Role: Immunomet Therapeutics; Financial Interests, Personal, Advisory Role: Karma Oncology; Financial Interests, Personal, Advisory Role: Mekanistic Therapeutics; Financial Interests, Personal, Advisory Role: Menarini Ricerche; Financial Interests, Personal, Advisory Role: Nanobiotix; Financial Interests, Personal, Advisory Role: Partner Therapeutics; Financial Interests, Personal, Advisory Role: Pfizer; Financial Interests, Personal, Advisory Role: Pierre Fabre; Financial Interests, Personal, Advisory Role: Ryvu Therapeutics; Financial Interests, Personal, Advisory Role: Seattle Genetics; Financial Interests, Personal, Advisory Role: Sotio Biotechnoogy; Financial Interests, Personal, Advisory Role: Spirea Limited; Financial Interests, Personal, Advisory Role: Transcenta Therapeutics; Financial Interests, Personal, Advisory Role: Trillium Therapeutics; Financial Interests, Personal, Advisory Board: Adagene; Financial Interests, Personal, Advisory Board: Aro Biotherapeutics; Financial Interests, Personal, Advisory Board: Bioinvent; Financial Interests, Personal, Advisory Board: Boehringer Ingelheim; Financial Interests, Personal, Advisory Board: Deka Biosciences; Financial Interests, Personal, Advisory Board: Eleven Bio; Financial Interests, Personal, Advisory Board: Elucida; Financial Interests, Personal, Advisory Board: EMD Serono; Financial Interests, Personal, Advisory Board: Immunome; Financial Interests, Personal, Advisory Board: NME Therapeutics; Financial Interests, Personal, Advisory Board: Pelican; Financial Interests, Personal, Advisory Board: Pieris Pharma; Financial Interests, Personal, Advisory Board: Pyxis Oncology; Financial Interests, Personal, Advisory Board: Vincerx; Financial Interests, Personal, Advisory Board: Zymeworks Biopharmaceuticals; Financial Interests, Personal, Other, IDMC: Mirati; Financial Interests, Personal, Full or part-time Employment: NEXT Oncology; Financial Interests, Personal, Stocks/Shares: Pyxis Oncology; Financial Interests, Institutional, Principal Investigator: AbbVie; Financial Interests, Institutional, Principal Investigator: ABL Bio; Financial Interests, Institutional, Principal Investigator: ADC Therapeutics; Financial Interests, Institutional, Principal Investigator: Agenus; Financial Interests, Institutional, Principal Investigator: Aminex Therapeutics; Financial Interests, Institutional, Principal Investigator: Amphivena Therapeutics; Financial Interests, Institutional, Principal Investigator: Apros Therapeutics; Financial Interests, Institutional, Principal Investigator: Arcellx; Financial Interests, Institutional, Principal Investigator: ARMO Biosciences; Financial Interests, Institutional, Principal Investigator: Arrys Therapeutics; Financial Interests, Institutional, Principal Investigator: Artios Pharma Limited; Financial Interests, Institutional, Principal Investigator: Asana BioSciences; Financial Interests, Institutional, Principal Investigator: Ascentage; Financial Interests, Institutional, Principal Investigator: Astex Pharmaceuticals; Financial Interests, Institutional, Principal Investigator: Basilea Pharmaceutica; Financial Interests, Institutional, Principal Investigator: BioInvent; Financial Interests, Institutional, Principal Investigator: BioNTech RNA Pharmaceuticals; Financial Interests, Institutional, Principal Investigator: Birdie Biopharmaceuticals; Financial Interests, Institutional, Principal Investigator: BJ Bioscience; Financial Interests, Institutional, Principal Investigator: Boehringer Ingelheim; Financial Interests, Institutional, Principal Investigator: Boston Biomedical; 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Financial Interests, Institutional, Principal Investigator: Samumed; Financial Interests, Institutional, Principal Investigator: Seattle Genetics; Financial Interests, Institutional, Principal Investigator: Spring Bank Pharmaceuticals; Financial Interests, Institutional, Principal Investigator: Sunshine Guojian Pharmaceutical; Financial Interests, Institutional, Principal Investigator: Symphogen; Financial Interests, Institutional, Principal Investigator: Syndax Pharmaceuticals; Financial Interests, Institutional, Principal Investigator: Synthorx; Financial Interests, Institutional, Principal Investigator: Takeda; Financial Interests, Institutional, Principal Investigator: Tizona Therapeutics; Financial Interests, Institutional, Principal Investigator: Zymeworks.F. Meric-Bernstam: Financial Interests, Personal, Advisory Role: AbbVie; Financial Interests, Personal, Advisory Role: Aduro BioTech Inc.; Financial Interests, Personal, Advisory Role: Alkermes; Financial Interests, Personal, Advisory Role: AstraZeneca; Financial Interests, Personal, Advisory Role: DebioPharm; Financial Interests, Personal, Advisory Role: eFFECTOR Therapeutics; Financial Interests, Personal, Advisory Role: F. Hoffman-La Roche Ltd.; Financial Interests, Personal, Advisory Role: Genentech Inc.; Financial Interests, Personal, Advisory Role: IBM Watson; Financial Interests, Personal, Advisory Role: Infinity Pharmaceuticals; Financial Interests, Personal, Advisory Role: Jackson Laboratory; Financial Interests, Personal, Advisory Role: Kolon Life Science; Financial Interests, Personal, Advisory Role: OrigiMed; Financial Interests, Personal, Advisory Role: PACT Pharma; Financial Interests, Personal, Advisory Role: Parexel International; Financial Interests, Personal, Advisory Role: Pfizer Inc.; Financial Interests, Personal, Advisory Role: Samsung Bioepis; Financial Interests, Personal, Advisory Role: Seattle Genetics Inc.; Financial Interests, Personal, Advisory Role: Tyra Biosciences; Financial Interests, Personal, Advisory Role: Xencor; Financial Interests, Personal, Advisory Role: Zymeworks; Financial Interests, Personal, Advisory Board: Immunomedics; Financial Interests, Personal, Advisory Board: Inflection Biosciences; Financial Interests, Personal, Advisory Board: Mersana Therapeutics; Financial Interests, Personal, Advisory Board: Puma Biotechnology Inc.; Financial Interests, Personal, Advisory Board: Seattle Genetics; Financial Interests, Personal, Advisory Board: Silverback Therapeutics; Financial Interests, Personal, Advisory Board: Spectrum Pharmaceuticals; Financial Interests, Personal, Advisory Board: Zentalis Pharmaceuticals; Financial Interests, Personal, Invited Speaker: Chugai Biopharmaceuticals; Financial Interests, Personal, Full or part-time Employment: MD Anderson Cancer Center; Non-Financial Interests, Institutional, Principal Investigator: Aileron Therapeutics, Inc; Non-Financial Interests, Institutional, Principal Investigator: AstraZeneca; Non-Financial Interests, Institutional, Principal Investigator: Bayer Healthcare Pharmaceutical; Non-Financial Interests, Institutional, Principal Investigator: Calithera Biosciences Inc.; Non-Financial Interests, Institutional, Principal Investigator: Curis Inc.; Non-Financial Interests, Institutional, Principal Investigator: CytomX Therapeutics Inc.; Non-Financial Interests, Institutional, Principal Investigator: Daiichi Sankyo Co. Ltd.; Non-Financial Interests, Institutional, Principal Investigator: Debiopharm International; Non-Financial Interests, Institutional, Principal Investigator: eFFECTOR Therapeutics; Non-Financial Interests, Institutional, Principal Investigator: Genentech Inc.; Non-Financial Interests, Institutional, Principal Investigator: Guardant Health Inc.; Non-Financial Interests, Institutional, Principal Investigator: Klus Pharma; Non-Financial Interests, Institutional, Research Grant: Takeda Pharmaceutical; Non-Financial Interests, Institutional, Principal Investigator: Novartis; Non-Financial Interests, Institutional, Research Grant: Puma Biotechnology Inc.; Non-Financial Interests, Institutional, Principal Investigator: Taiho Pharmaceutical Co..H. Mamdani: Financial Interests, Personal, Advisory Role: Zentalis Parmaceuticals. P.R. de Jong: Financial Interests, Personal, Full or part-time Employment: Zentalis Parmaceuticals; Financial Interests, Personal, Stocks/Shares: Zentalis Parmaceuticals. K. Anderes: Financial Interests, Personal, Advisory Role: Zentalis Parmaceuticals. A.A. Samatar: Financial Interests, Personal, Full or part-time Employment: Zentalis Parmaceuticals; Financial Interests, Personal, Stocks/Shares: Zentalis Parmaceuticals. M. Sergeeva: Financial Interests, Personal, Advisory Role: Zentalis Parmaceuticals. M. Gazdoiu: Financial Interests, Personal, Full or part-time Employment: Zentalis Parmaceuticals; Financial Interests, Personal, Stocks/Shares: Zentalis Parmaceuticals. M.R. Viana: Financial Interests, Personal, Full or part-time Employment: Zentalis Parmaceuticals; Financial Interests, Personal, Stocks/Shares: Zentalis Parmaceuticals. P. Pultar: Financial Interests, Personal, Full or part-time Employment: Zentalis Parmaceuticals; Financial Interests, Personal, Stocks/Shares: Zentalis Parmaceuticals. D. Voliotis: Financial Interests, Personal, Full or part-time Employment: Zentalis Parmaceuticals; Financial Interests, Personal, Stocks/Shares: Zentalis Parmaceuticals. F. Donate: Financial Interests, Personal, Full or part-time Employment: Zentalis Parmaceuticals; Financial Interests, Personal, Stocks/Shares: Zentalis Parmaceuticals.