Abstract 750P
Background
M6223 is a human, intravenously (IV) administered, antagonistic, anti-TIGIT antibody.
Methods
This is a first-in-human dose escalation (DE) study of M6223 (NCT04457778) as monotherapy or combined with BA in pts ≥18 years with ECOG PS ≤1 and advanced solid tumours, for whom no known effective therapy is available. In monotherapy DE, pts received M6223 at 1 of 7 dose levels (DLs): 10‒1600 mg every two weeks (Q2W) or 2400 mg every three weeks (Q3W). In combination, pts received M6223 at 1 of 3 DLs (300, 900, 1600 mg Q2W) with BA 1200 mg IV Q2W. Doses were recommended by the SMC, supported by a Bayesian 2-parameter logistic regression model. The trial is ongoing and additional pts will be enrolled to receive monotherapy to collect biomarker data from paired biopsies (DL 2400 mg Q3W; DLs 900 and 1600 mg Q2W). Primary objectives are safety, tolerability, maximum tolerated dose, and recommended dose for expansion (RDE) of M6223 mono- and combination therapy (M6223 + BA). Secondary and exploratory objectives include pharmacokinetics (PK), clinical activity and biomarkers. We report preliminary interim data.
Results
By April 1, 2022, 24 pts (10 male, 14 female; age range: 24–78) had received M6223 and 17 (6 male, 11 female; age range: 34–80) had received M6223 + BA. To date, 2 DLTs have been observed: 1 with 900 mg M6223 (adrenal insufficiency) and 1 with 300 mg M6223 + BA (anaemia). 8/24 (33%) pts had experienced Grade ≥3 treatment (Tx)-emergent adverse events with M6223 and 12/17 (71%) with M6223 + BA. Across all doses, M6223 serum PK were dose-proportional. Tx-driven immunophenotype changes in peripheral blood were observed, including depletion of TIGIT+ regulatory T-cells. Blood TIGIT receptor occupancy (RO) was ≥95% at the RDE of 1600 mg for the Q2W regimen. Detectable M6223-anti-drug antibodies occurred in ≈20% of treated pts with no impact on PK or RO at doses ≤900 mg. 9/24 and 2/17 pts receiving M6223 and M6223 + BA, respectively, achieved clinical benefit (stable disease at first on-Tx assessment); 3/24 and 2/17 patients, respectively, were on Tx for ≥20 weeks.
Conclusions
M6223 ± BA had an acceptable safety profile with favourable PK and target modulation effect.
Clinical trial identification
NCT04457778.
Editorial acknowledgement
Medical writing assistance was provided by David Griffiths PhD, on behalf of Bioscript Stirling Ltd, Macclesfield, UK.
Legal entity responsible for the study
Merck Healthcare KGaA, Darmstadt, Germany.
Funding
Merck Healthcare KGaA, Darmstadt, Germany (CrossRef Funder ID: 10.13039/100009945).
Disclosure
L.L. Siu: Financial Interests, Personal, Advisory Role: Merck, AstraZeneca/MedImmune, Voroni Inc., Oncorus, GSK, Seattle Genetics, Arvinas, Navire, Janpix, Relay Therapeutics, Daiichi Sankyo/UCB Japan, Janssen, Hookipa Pharma, InterRNA, Tessa Therapeutics, Sanofi, Amgen; Financial Interests, Institutional, Research Grant: BMS, Genentech/Roche, GSK, Merck, Novartis, Pfizer, AstraZeneca, Boehringer Ingelheim, Bayer, Amgen, Astellas Pharma, Shattuck Labs, Symphogen, Avid, Mirati Therapeutics, Intensity Therapeutics, Karyopharm Therapeutics; Other, Personal and Institutional, Leadership Role, Recipient was an immediate family member: Treadwell Therapeutics; Other, Personal and Institutional, Stocks/Shares, Recipient was an immediate family member: Agios. M.A. Mckean: Financial Interests, Institutional, Research Grant: Alpine Immune Sciences, Arcus Biosciences, Arvinas, Ascentage Pharma Group, Bayer, Bicycle Therapeutics, BioMed Valley Discoveries, BioNTech, Dragonfly Therapeutics , EMD Serono, Epizyme, Erasca, Exelixis, Foghorn Therapeutics, Genentech, Gilead Sciences, GSK, IDEAYA Biosciences, Ikena Oncology, ImmVira Pharma, Infinity Pharmaceuticals, Jacobio Pharmaceuticals, Kechow Pharma, Kezar Life Sciences, Kinnate BioPharma, MedImmune, Mereo BioPharma, Metabomed, Moderna, NBE Therapeutics, Nektar, Novartis, Oncorus, PACT Pharma, Pfizer, Plexxikon, Prelude Therapeutics, Pyramid Biosciences, Regeneron, Sapience Therapeutics, Scholar Rock, Seattle Genetics, Synthrox, Takeda Pharmaceuticals, Teneobio, Tempest Therapeutics, Tizona Therapeutics, TMUNITY Therapeutics, TopAlliance Biosciences, Xilio; Financial Interests, Institutional, Advisory Role: Astellas Pharma, AstraZeneca, BicycleTX Limited, Castle Biosciences, Eisai, Ideaya Biosciences, iTeos, Moderna, Pfizer, Regeneron Pharmaceuticals. A.W. Tolcher: Financial Interests, Personal and Institutional, Advisory Role: AbbVie Inc, Aclaris Therapeutics, Agenus, Inc, Asana Biosciences, Ascentage, Axlmmune, Bayer, Blu Print Oncology, Daiichi Sankyo, Inc, Gilde Healthcare Partners, HBM Partners, Idea Pharma, Immuneering, Immunomet Therapeutics, Inc., Impact Therapeutics US, Inc., Karma Oncology B.V., Lengo Therapeutics, Inc., Mekanistic Therapeutics, Menarini Ricerche, Mersana, Nanobiotix, Ocellaris Pharma, Inc. & Eli Lilly, Partner Therapeutics, Pfizer Inc., Pierre Fabre, Ryvu Therapeutics, Seattle Genetics, SK Life Science, Sotio Biotechnology Co., Spirea Limited Inc, Sunshine Guojian Pharmaceutical (Shanghai) Co., Ltd, Transcenta Therapeutics Inc., Trillium Therapeutics Inc., Zentails; Financial Interests, Personal and Institutional, Advisory Board: Adagene, Inc., Aro Biotherapeutics, Bioinvent, Boeringer Ingelheim International GmbH, Deka Biosciences, Eleven Bio, Elucida, EMD Serono/ Merck KGaA, Hiber Cell, Inc., Ikena Oncology, Immunome, Janssen Global Services, LLC, NBE Therapeutics, Pelican, Jazz, Pieris Pharma, PYXIS Oncology, Senti Biosciences, Vincerx, ZielBio, Inc., Zymeworks Biopharmaceuticals Inc., Mirati. A. Victor: Financial Interests, Personal and Institutional, Full or part-time Employment: Merck Healthcare KGaA, Darmstadt, Germany; Financial Interests, Personal, Stocks/Shares: Merck Healthcare KGaA, Darmstadt, Germany. T. Kitzing: Financial Interests, Personal and Institutional, Full or part-time Employment: Merck Healthcare KGaA, Darmstadt, Germany. V. Pierre: Financial Interests, Personal and Institutional, Full or part-time Employment: EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA. S. Gleicher: Financial Interests, Personal and Institutional, Full or part-time Employment: Merck Healthcare KGaA, Darmstadt, Germany. D.G. Holland: Financial Interests, Personal and Institutional, Full or part-time Employment: Merck Healthcare KGaA, Darmstadt, Germany. E. Richter: Financial Interests, Personal and Institutional, Full or part-time Employment: Merck Healthcare KGaA, Darmstadt, Germany. A. Naing: Non-Financial Interests, Personal, Advisory Role: Novartis, CytomX Therapeutics, OncoSec, STCube Pharmaceuticals Inc., Kymab, Takeda, CSL Behring, Horizon Pharma, Genome & Company, Immune-Onc, Deka Bioscience, Nouscom; Non-Financial Interests, Institutional, Funding: The Texas Medical Center Digestive Diseases Center, Jeffery Modell Foundation, Immune Deficiency Foundation, Baxalta US Inc., Chao Physician-Scientist Foundation.