Abstract 488P
Background
We evaluated the EZH2 inhibitor PF-06821497 in an ongoing phase I trial (NCT03460977) in patients (pts) with SCLC, CRPC and FL.
Methods
In Part 1, PF-06821497 was dosed as oral monotherapy 2x daily (BID) in dose escalation (FL, CRPC, SCLC). For Part 2A PF-06821497 was dosed with enzalutamide + androgen deprivation therapy (E) (CRPC). A modified toxicity probability interval method was used to determine maximum tolerated dose. 1o objective: overall safety/determine monotherapy expansion dose (Part 1) and in combination (Part 2A). 2o objectives: pharmacokinetics (PK), pharmacodynamics (PD), anti-tumor activity.
Results
As of Sep 2021, 57 pts were dosed: n=25 (Parts 1A/B), n=32 (Part 2A). The mean age was 67 years. 1 pt with FL had a dose limiting toxicity of G4 thrombocytopenia. Overall the most common treatment related adverse events (TRAEs) were nausea (26.3%), fatigue (24.6%) and diarrhea (22.8%), the majority grade 1-2. Serious AEs occurred in 17 pts (1 treatment-related). In Part 2A, the most common TRAEs were fatigue (28.1%), decreased appetite, diarrhea (25.0% each), dysgeusia (21.9%). Among 15 Part 1 pts with FL there were 4 partial responses (PR). For Part 1 pts with CRPC (n=8), 2 had stable disease. For pts with SCLC (n=2), both had disease progression. All Part 2A pts with CRPC (n=32) had prior abiraterone and/or E; among evaluable pts (n=28), there were 4 objective responses (14.3%) (1 complete response [prior E] and 3 PRs [E naïve]). PSA reductions ≥50% occurred in 5 (17.9%) of 28 evaluable pts with CRPC (2 prior E, 3 E naïve). Median PFS was 8.7 mo (95% CI 4.0–17.0). Interim PK data reveals dose-dependent increases in drug exposure (AUCtau), and peak concentrations were rapidly achieved with multiple monotherapy dosing of 75–625 mg BID. Maximal decrease (≥75%) in H3K27me3 in peripheral granulocytes was achieved at all monotherapy doses and in E combination at 375 mg BID or higher.
Conclusions
PF-06821497 had a manageable safety profile, with evidence of EZH2 PD inhibition and durable objective tumor responses in pts with mCRPC and FL. A randomized trial in mCRPC is ongoing.
Clinical trial identification
NCT03460977 - First posted March 9, 2018.
Editorial acknowledgement
Medical writing support was provided by David Sunter, PhD of Engage Scientific Solutions, and was funded by Pfizer.
Legal entity responsible for the study
This study was sponsored by Pfizer.
Funding
This study was sponsored by Pfizer. Astellas Pharma Inc. provided enzalutamide for this study.
Disclosure
M. Schweizer: Financial Interests, Personal, Advisory Role, Consultant: Sanofi, AstraZeneca, PharmaIn , Resverlogix; Financial Interests, Institutional, Funding, Research funding: Zenith Epigenetics, Bristol Myers Squibb, Merck, Immunomedics, Janssen, AstraZeneca, Pfizer, Madison Vaccines, Hoffman-La Roche, Tmunity, SignalOne Bio , Ambrx, Inc. K.D. Penkov: Financial Interests, Personal, Research Grant, Grants/contracts: AstraZeneca, Janssen, Merck Sharp & Dohme, Nektar, Pfizer, Regeneron Pharmaceuticals, Hoffman-La Roche. A.W. Tolcher: Financial Interests, Institutional, Advisory Role, Consultant/advisory role: Nanobiotix, Pierre Fabre, Ascentage Pharma, AbbVie, EMD Serono, Bioinvent, Adagene, Agenus, Aximmune, Bayer, HMB Partners, Mekanistic, NBE Therapeutics, Pelican, Immunome, Gilde Healthcare Partners, Immunomet, Mirati Therapeutics, Pieris, Aro Biotherapeutics, Asana, Elucida, Partner Therapeutics, Ryvu Therapeutics, Sotio, Eleven Bio, Zymeworks, Mersana, Trillium Therapeutics, Boeringer Ingelheim International GmbH, Janssen Global Services, LLC, Aclaris Therapeutics, Blu Print Oncology, Daiichi Sankyo, Inc., IDEA Pharma, Immuneering, Impact Therapeutics US, Inc., Karma Oncology, Lengo Therapeutics, Menarini Ricerche, Seattle Genetics, SK Life Sciences, Sunshine Guojian, Transcenta Therapeutics, Zentalis, Transgene, Deka Biosciences, Hiber Cell, Inc., Ikena Oncology, Jazz Pharmaceuticals, PYXIS Oncology, Vincerx Pharma, ZielBio, Senti Biosciences, Ocellaris Pharma, Lilly; Financial Interests, Personal, Advisory Role, Consultant/advisory role: Spirea Limited Inc.; Financial Interests, Institutional, Funding, Research Funding: AbbVie, Pfizer, Syndax, Asana Biosciences, ADC Therapeutics, Adagene, Aminex, Ascentage Pharma, Arrys, CStone Pharmaceuticals, Deciphera, GlaxoSmithKline, Inhibrx, Innate Pharma, Kiromic, Mersana, Naturewise, NextCure, Nitto BioPharma, Pieris Pharmaceuticals, Symphogen, Tizona Therapeutics, Inc., Zymeworks, Agenus, Amphivena, Astex, Boehringer Ingelheim, Basilea, eFFECTOR Therapeutics, EMD Serono, Gilead Sciences, KeChow, K Group Beta, Janssen Research & Development, Merck Sharp & Dohme, ORIC Pharmaceuticals, Samumed, Spring Bank, Seattle Genetics, Sunshine Guojian, Synthorx, BioInvent International AB; Financial Interests, Institutional, : Birdie Biopharmaceuticals. A.D. Choudhury: Financial Interests, Personal, Advisory Role, Consultant/Honoria: Clovis, Dendreon, Bayer, Eli Lilly, AstraZeneca, Astellas, Blue Earth, Janssen; Financial Interests, Institutional, Funding, Research funding: Bayer. R. Aljumaily: Financial Interests, Personal, Advisory Role, Consultant: Regeneron, AstraZeneca. E. Calvo: Financial Interests, Personal, Advisory Role, Consultant/advisory role: Nanobiotix, Janssen-Cilag, PsiOxus Therapeutics, Seattle Genetics, Roche/Genentech, Amcure, TargImmune Therapeutics, Servier, Bristol-Myers Squibb, PharmaMar, Alkermes, Amunix, Adcendo, Anaveon, AstraZeneca/MedImmune, BeiGene, Chugai Pharma, MonTa, MedSIR, MSD Oncology, Nouscom, Novartis, OncoDNA, Sanofi, Syneos Health, T-Knife, Boehringer Ingelheim; Financial Interests, Personal, Other, Honoraria: HM Hospitales Group; Financial Interests, Personal, Funding, Research Funding: BeiGene, START, Achilles; Financial Interests, Personal, Stocks/Shares: START, Oncoart Associated; Financial Interests, Personal, Leadership Role: START; Other, Personal, Other, President and Founder of Foundation: INTHEOS. J.T. Hamm: Financial Interests, Institutional, Funding, Research funding: F. Hoffman-LaRoche Ltd., National Surgical Adjuvant Breast and Bowel project, GBG Forschungs GmbH Neu-Isenburg, AstraZeneca, Seattle Genetics Inc., EMD Serono Inc., EpicentRx (formerly RadioRx), NRG Oncology, Genmab, Astellas Pharma Global Development Inc, IntraImmuSG Pte Ltd (IISG), Exact Sciences Corporation, OncoC4 Inc., Nucleix Inc., Pfizer, Agentus Therapeutics, Boston Biomedical Inc., Novocure, Deciphera Pharmaceuticals LLC., AbbVie, Boehringer Ingelheim, Astellas Pharma US Inc., Medimmune LLC. V. Moreno Garcia: Financial Interests, Personal, Advisory Role, Consultant: Roche, Bayer, BMS, Basilea; Financial Interests, Institutional, Advisory Role, Consultant: Janssen; Financial Interests, Institutional, Funding: AbbVie, AceaBio, Adaptimmune, ADC Therapeutics, Aduro, Agenus, Amcure, Amgen, Astellas, AstraZeneca , Bayer, Beigene, BioInvent International AB, BMS, Boehringer, Boston, Celgene, Daichii Sankyo, DEBIOPHARM, Eisai, e-Therapeutics, Exelisis, Forma Therapeutics, Genmab, GSK, Harpoon, Hutchison, Immutep, Incyte, Inovio, Iovance, Janssen, Kyowa Kirin, Lilly, Loxo, MedSir, Menarini, Merck, Merus, Millennium, MSD, Nanobiotix, Nektar, Novartis, Odonate Therapeutics, Pfizer, PharmaMar, Principia, PsiOxus, Puma, Regeneron, Rigontec, Roche, Sanofi, Sierra Oncology, Synthon, Taiho, Takeda, Tesaro, Transgene, Turning Point Therapeutics, Upshersmith. V. Vorobyev: Financial Interests, Personal, Advisory Role, Consultant: Janssen, Roche, AstraZeneca, BeiGene, Takeda, Novartis, Gilead, Sanofi, MSD, AbbVie; Financial Interests, Personal, Speaker’s Bureau: Janssen, Roche, AstraZeneca, Amgen, Beigene, Novartis, Takeda, Sanofi, AbbVie, Biocad. S. Billotte: Financial Interests, Personal, Full or part-time Employment: Pfizer Inc.; Financial Interests, Personal, Stocks/Shares: Pfizer Inc. T. Bowler, J. Chen, T. Lin, L. Liu, A. Maity, S. Sharma: Financial Interests, Personal, Full or part-time Employment: Pfizer Inc.; Financial Interests, Personal, Stocks/Shares: Pfizer Inc. M.L. Johnson: Financial Interests, Personal, Advisory Role: AbbVie, Amgen, Astellas, AstraZeneca, Axelia Oncology, Black Diamond, Boehringer Ingelheim, Bristol-Myers Squibb, Calithera Biosciences, Checkpoint Therapeutics, CytomX Therapeutics, Daiichi Sankyo, EcoR1, Editas Medicine, Eisai, EMD Serono, G1 Therapeutics, Genentech / Roche, Genmab, Genocea Biosciences, GlaxoSmithKline, Gritstone Oncology, Ideaya Biosciences, iTeos, Janssen, Lilly, Merck, Mirati Therapeutics, Novartis, Oncorus, Regeneron Pharmaceuticals, Ribon Therapeutics, Sanofi-Aventis, Turning Point Therapeutics, WindMIL; Financial Interests, Institutional, Funding, Research Funding: AbbVie, Acerta, Adaptimmune, Amgen, Apexigen, Arcus Biosciences, Array BioPharma, Artios Pharma, AstraZeneca, Atreca, BeiGene, BerGenBio, BioAtla, Boehringer Ingelheim, Calithera Biosciences, Checkpoint Therapeutics, Corvus Pharmaceuticals, Curis, CytomX, Daiichi Sankyo, Dracen Pharmaceuticals, Dynavax, Lilly, Elicio Therapeutics, EMD Serono, Erasca, Exelixis, Fate Therapeutics, Genentech/Roche, Genmab, Genocea Biosciences, GlaxoSmithKline, Gritstone Oncology, Guardant Health, Harpoon, Helsinn Healthcare SA, Hengrui Therapeutics, Hutchison MediPharma, IDEAYA Biosciences, IGM Biosciences, Immunocore, Incyte, Janssen, Jounce Therapeutics, Kadmon Pharmaceuticals, Loxo Oncology, Lycera, Memorial Sloan-Kettering, Merck, Merus, Mirati Therapeutics, NeoImmune Tech, Neovia Oncology, Novartis, Numab Therapeutics, Nuvalent, OncoMed Pharmaceuticals, Pfizer, PMV Pharmaceuticals, RasCal Therapeutics, Regeneron Pharmaceuticals, Relay Therapeutics, Revolution Medicines, Ribon Therapeutics; Financial Interests, Institutional, : Rubius Therapeutics. All other authors have declared no conflicts of interest.