456MO - METEOR-1: A phase I study of the safety and efficacy of the protein arginine methyltransferase 5 (PRMT5) inhibitor GSK3326595 in advanced solid tumors

Background

PRMT5 methylates arginines in proteins important for tumor development. GSK3326595, a first-in-class selective PRMT5 inhibitor, suppressed tumor growth in animal models. METEOR-1 is a phase I, dose escalation/expansion, 3-part study in patients (pts) with relapsed/refractory solid tumors or non-Hodgkin lymphoma (NHL). Here we describe results from the part 2 dose expansion phase.

Methods

Eligible pts >18 years were enrolled in the following cohorts: triple-negative breast cancer (TNBC), metastatic transitional cell carcinoma of the urinary system (mTCC), glioblastoma multiforme (GBM), NHL, adenoid cystic carcinoma (ACC), hormone receptor-positive breast cancer (HR+BC), human papillomavirus positive solid tumors (HPV+), and non-small cell lung cancer (NSCLC). Pts were treated with 300 or 400 mg GSK3326595 once daily.

Results

In part 2, most pts had discontinued study treatment (211/218, 97%) at data cut off. There were 3/158 confirmed responses in pts with solid tumors (2 ACC and 1 HR+BC) and 3/29 responses in pts with NHL (efficacy evaluable population). Primary efficacy endpoint is shown in the table. Median time on treatment across cohorts was 1.87 (0–34.8) months. Treatment-related (tr) AEs occurred in 95% of pts; most common were fatigue (45%), anemia (41%), and nausea (39%); 51% of pts had a grade 3/4 trAE, which were mainly anemia (24%), thrombocytopenia (9%)/platelet count decrease (6%), and fatigue (8%). No grade 5 trAEs occurred. Seventy % of pts had dose interruption, 56% dose reduction, and 13% discontinued treatment due to any AE.

Conclusions

Some monotherapy efficacy was observed in a largely heavily pretreated population. Safety was consistent with that previously reported for GSK3326595. Toxicities were generally manageable, with a need for treatment interruption/reduction observed across cohorts. Longest median time on treatment were in the ACC cohorts. Table: 456MO

^a≥1 line of prior systemic therapy. Includes 1 PR from part 1 (400 mg) ACC pt and part 2 analyses per protocol. ^bN=14 efficacy evaluable pop. ^cConfirmed responses (CR or PR) based on RECIST 1.1 (solid tumors) or Lugano (NHL) criteria.

Clinical trial identification

NCT02783300.

Editorial acknowledgement

Editorial Assistance was provided by Sarah Hummasti, PhD of AOIC, LLC and was funded by GlaxoSmithKline.

Legal entity responsible for the study

GlaxoSmithKline.

Funding

GlaxoSmithKline.

Disclosure

S. Postel-Vinay: Financial Interests, Institutional, Research Grant, Laboratory research funding: AstraZeneca, Roche – IMCore, Boehringer Ingelheim; Financial Interests, Personal, Advisory Role, Consulting Fees: Merck KgA. A. Italiano: Financial Interests, Personal, Advisory Board: Bayer, Roche, Philips, CHUGAI, GSK; Financial Interests, Institutional, Invited Speaker: Bayer, AstraZeneca, Roche, MSD, IPSEN, MERCK. P. Martin Romano: Financial Interests, Institutional, Sponsor/Funding, For this study: GlaxoSmithKline; Financial Interests, Institutional, Principal Investigator: AbbVie, Adaptimmune, Adlai Nortye USA Inc, Aduro Biotech, Agios Pharmaceuticals, Amgen, Argen-X Bvba, Astex Pharmaceuticals, AstraZeneca Ab, Aveo, Basilea Pharmaceutica International Ltd, Bayer Healthcare Ag, Bbb Technologies Bv, Beigene, BicycleTx Ltd, Blueprint Medicines, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol Myers Squibb, Ca, Celgene Corporation, Chugai Pharmaceutical Co, Clovis Oncology, Cullinan-Apollo, Curevac, Daiichi Sankyo, Debiopharm, Eisai, Eisai Limited, Eli Lilly, Exelixis, Faron Pharmaceuticals Ltd, Forma Tharapeutics, Gamamabs, Genentech, GlaxoSmithKline, H3 Biomedicine, Hoffmann La Roche Ag, Imcheck Therapeutics, Innate Pharma, Institut De Recherche Pierre Fabre, Iris Servier, Iteos Belgium SA, Janssen-Cilag, Janssen Research Foundation, Kura Oncology, Kyowa Kirin Pharm. Dev, Lilly France, Loxo Oncology, Lytix Biopharma As, Medimmune, Menarini Ricerche, Merck Sharp & Dohme Chibret, Merrimack Pharmaceuticals, Merus, Millennium Pharmaceuticals, Molecular Partners Ag, Nanobiotix, Nektar Therapeutics, Novartis Pharma, Octimet Oncology Nv, OncoEthix, Oncopeptides, Orion Pharma, Ose Pharma, Pfizer, PharmaMar, Pierre Fabre, Medicament, Roche, Sanofi Aventis, Seattle Genetics, Sotio A.S, Syros Pharmaceuticals Inc, Taiho Pharmaceutical Company Ltd, Tesaro, Turning Point Therapeutics, Xencor; Financial Interests, Institutional, Research Grant: AstraZeneca, BMS, Boehringer Ingelheim, GlaxoSmithKline, INCA Pharma, Janssen-Cilag, Merck, Novartis, Pfizer, Roche, Sanofi; Non-Financial Interests, Institutional, Other, Supplied drug for study: AstraZeneca, Bayer, BMS, Boringher Ingelheim, GlaxoSmithKline, Medimmune, Merck, NH TherAGuiX, Pfizer; Non-Financial Interests, Institutional, : Roche. P.A. Cassier: Financial Interests, Personal, Advisory Board: Merck Serono/EMD, Roche, Amgen; Financial Interests, Personal, Invited Speaker: Amgen; Financial Interests, Personal, Other, Advisor: OSE immunotherapeutics; Financial Interests, Institutional, Invited Speaker: AbbVie, Amgen, Blueprint, Exelixis, GSK, Janssen, Novartis, Roche, Taiho, LOXO/Eli Lilly; Non-Financial Interests, Institutional, Product Samples: plexxikon, Novartis, MSD, AstraZeneca, GSK. L.L. Siu: Financial Interests, Institutional, Principal Investigator: Novartis, Bristol Myers Squibb, Pfizer, Boerhinger-Ingelheim, Roche/Genentech, Karyopharm, AstraZeneca/Medimmune, Merck, Celgene, Astellas, Bayer, AbbVie, Amgen, Symphogen, Intensity Therapeutics, Mirati, Shattucks; Financial Interests, Personal, Advisory Role, Consulting Fees: Merck, Pfizer, AstraZeneca, Roche, Symphogen, Seattle Genetics, GlaxoSmithKline, Voronoi, Arvinas, Tessa, Navire, Relay, Rubius, Janpix, Daiichi Sanyko, Coherus, Marengo, InteRNA; Non-Financial Interests, Personal, Advisory Role, Data Safety Monitoring Board: Mirati; Financial Interests, Personal and Institutional, Officer, Cofounder: Treadwell Therapeutics; Financial Interests, Personal, Stocks/Shares: Agios; Financial Interests, Institutional, Sponsor/Funding, Support for this trial: GlaxoSmithKline. I.S. Lossos: Financial Interests, Personal and Institutional, Research Grant: NHI grant; Financial Interests, Personal, Advisory Board: Janssen Scientific, Verastem, Adaptive Biosciences . J.F. Hilton: Financial Interests, Personal, Advisory Board: Merck, Novartis, AstraZeneca, Pfizer, Eli Lilly; Financial Interests, Personal, Invited Speaker: Merck, Novartis; Financial Interests, Personal, Other, DSMC committee - relatlimab program: BMS; Financial Interests, Personal, Research Grant: GSK. M.A. Mckean: Financial Interests, Institutional, Advisory Board: Array BioPharma, AstraZeneca, MedPage Today, Pfizer, Regeneron; Financial Interests, Institutional, Research Grant: Acentage Pharma Group, Bicycle Therapeutics, Dragonfly Therapeutics, Epizyme, Exelixis, Genentech, GlaxoSmithKline, IDEAYA Biosciences, Ikena Oncology, Infinity Pharmaceuticals, Jacobio Pharmaceuticals, Moderna, NBE Therapeutics, Novartis, Oncorus, Plexxicon, Prelude Therapeutics, Regeneron, Sapience Therapeutics, Seattle Genetics, Tizona Therpeutics, TMUNITU Therapeutics, TopAlliance Biosciences. J. Strauss: Financial Interests, Institutional, Advisory Role, Consulting fee paid to institution: Binhui Biopharmaceuticals, Synlogic; Financial Interests, Personal, Leadership Role, Medical Director: Dialectic Therapeutics; Financial Interests, Personal, Stocks/Shares: AbbVie, Abbott Laboratories, Bristol Myers Squibb, Intuitive Surgical, Johnson & Johnson, Merck, Regeneron. G.S. Falchook: Financial Interests, Institutional, Sponsor/Funding, For the study: GlaxoSmithKline; Financial Interests, Institutional, Principal Investigator: GlaxoSmithKline; Financial Interests, Institutional, Other, Receipt for equipment, materials, and drugs: GlaxoSmithKline. M.J.A. de Jonge: Financial Interests, Institutional, Principal Investigator, Contract with Department of Medical Oncology for study conduct: ErasmusMC. F.L. Opdam: Financial Interests, Institutional, Principal Investigator: AstraZeneca, Boehringer Ingelheim, Cytovation, GlaxoSmithKline, InteRNA technologies, Merus, Pierre-Fabre, Taiho. D. Rasco: Financial Interests, Institutional, Research Grant: GlaxoSmithKline , Amgen, Mirati. J.S. Vermaat: Financial Interests, Institutional, Sponsor/Funding, For the study: GlaxoSmithKline. T. Crossman: Financial Interests, Personal, Full or part-time Employment: GlaxoSmithKline; Financial Interests, Personal, Stocks/Shares: GlaxoSmithKline . M. Zajac: Financial Interests, Personal, Stocks/Shares: GlaxoSmithKline; Financial Interests, Personal, Full or part-time Employment: GlaxoSmithKline. A. Hainline: Financial Interests, Institutional, Full or part-time Employment, Statistician for this study: GlaxoSmithKline. B. Kremer: Financial Interests, Personal, Full or part-time Employment: GlaxoSmithKline; Financial Interests, Personal, Stocks/Shares: GlaxoSmithKline. O. Barbash: Financial Interests, Personal, Full or part-time Employment: GlaxoSmithKline; Financial Interests, Personal, Stocks/Shares: GlaxoSmithKline. M.M. Gounder: Financial Interests, Personal, Advisory Role, Honoraria: Medscape, More Health, Physicians Education Resource, touchIME; Financial Interests, Personal, Advisory Role, Consulting: Athenex, Ayala, Bayer, Boehringer Ingelheim, Daiichi Sankyo, Epizyme, Karyopharm, Rain Therapeutics, Springworks Therapeutics, Tracon, TYME Technologies; Financial Interests, Personal and Institutional, Research Grant, (P30CA008748)—core grant (CCSG shared resources and core facility for MSKCC): National Cancer Institute, National Institutes of Health; Non-Financial Interests, Personal, Royalties, Patents with MSKCC (GODDESS PRO): Wolters Kluwer; Financial Interests, Personal, Other: Guidepoint, GLG, Third Bridge, Flatiron Health; Financial Interests, Institutional, Funding, For the study: GlaxoSmithKline.