Abstract 742P
Background
Lymphocyte activation gene 3 (LAG-3) is a cell-surface immune checkpoint receptor that negatively regulates cell activation and proliferation. INCAGN02385 is a humanized Fc-engineered IgG1κ monoclonal antibody with selective and potent LAG-3 antagonist action against LAG-3 binding to MHC class II, leading to enhanced TCR signaling and cytokine secretion of activated T cells. This study primarily aims to determine safety and tolerability and define the MTD or PAD of INCAGN02385 monotherapy.
Methods
This phase 1, multicenter, open-label, dose-escalation study enrolled patients (pts) with advanced solid tumors who failed available therapies, were intolerant to treatment, or refused noncurative standard treatment. A 3+3 dose-escalation design was used; pts received intravenous INCAGN02385 Q2W at 1 of 5 dose levels (DL): 25 mg, 75 mg, 250 mg, 350 mg, or 750 mg. The primary endpoint was safety and tolerability; other endpoints included assessments of PK, pharmacodynamics, and preliminary efficacy per RECIST v1.1.
Results
22 pts (median age, 63 y) were enrolled, 55% were male and 82% had ECOG PS 1. Lead cancer types were lung (n=4), endometrial, breast, gastric, melanoma, and ovarian cancer (n=2 each). All pts received prior systemic therapy (64% ≥ 3 lines) and 82% had prior immunotherapy. No DLT was observed and MTD was not reached. Most common treatment-emergent adverse events (TEAEs) were fatigue (36%) and cough (27%); 1 drug-related grade 3 lymphopenia occurred at 75 mg and 1 pt in the 350-mg DL had a drug-unrelated stroke leading to discontinuation. One drug-unrelated fatal TEAE of failure to thrive occurred at 250-mg DL. INCAGN02385 trough plasma concentrations increased across cycles in all DLs, and maximum concentration and area under the serum concentration-time curve were dose-proportional across DLs. Doses ≥250 mg led to trough LAG-3 receptor occupancy of ≥90% in peripheral blood and increased markers for CD4+ T-cell proliferation. Overall disease control rate (DCR) was 27%.
Conclusions
INCAGN02385 monotherapy was generally well tolerated and exhibited linear PK. The 350 mg Q2W dose is selected for further investigation in phase 1b/2 studies in combinations with other immunotherapies (NCT04370704, NCT05287113).
Clinical trial identification
NCT03538028.
Editorial acknowledgement
Writing assistance was provided by Cory Pfeiffenberger, PhD (ICON, Blue Bell, PA, USA), and was funded by Incyte Corporation.
Legal entity responsible for the study
Incyte Corporation.
Funding
Incyte Corporation.
Disclosure
J.D. Powderly: Financial Interests, Personal, Consulting: Boxer Capital; Financial Interests, Personal, Invited Speaker, Consulting: Aavocyte; Financial Interests, Personal, Invited Speaker, Founder and Owner: Carolina BioOncology Institute, PLLC, BioCytics Inc.; Financial Interests, Personal, Ownership Interest, Founder and Owner: BioCytics Inc.; Financial Interests, Personal, Ownership Interest, Founder and Owner of phase 1 cancer research clinic.: Carolina BioOncology Institute, PLLC; Financial Interests, Personal, Founder and Owner, developing intellectual property for cellular therapies: BioCytics Inc; Financial Interests, Personal and Institutional, Invited Speaker: Bristol Myers Squibb, Cullinan, Genentech/Roche, AstraZeneca/MedImmune, EMD Serono, Macrogenics, InCyte, Top Alliance BioSciience, Seattle Genetics, AbbVie, FLX Bio, Alkermes, Arcus BioSciences, Tempest Therapeutics, Calico Life Sciences, Apros, Jounce Therapeutics, Atreca, Sequenom, Repertoire Immune Medicines, Molecular Templates, I-MAB Pharma, NexCure, Xilio Therapeutics, Immune-Onc, Trethera, Zenshine Pharma, Adagene, BJ BioScience, Fate Therapeutics, Conjupro BioTherapeutics; Financial Interests, Institutional, Funding: Precision for Medicine, MT Group, Stemcell Technologies, Replimmune, Merck, Xilis; Financial Interests, Personal And Institutional, Funding: Pioma; Financial Interests, Personal and Institutional, Invited Speaker, Also funding for contract laboratory services: Nuvation; As Founder and Owner of BioCytics Inc. developing immune cellular therapy.: BioCytics Inc.. O. Hamid: Financial Interests, Personal, Invited Speaker: BMS, Novartis, Pfizer, Sanofi / Regeneron; Financial Interests, Personal, Advisory Board: Aduro, Akeso, Amgen, Beigene, BMS, Roche Genentech, GSK, Immunocore, Idera, Incyte, Janssen, Merck, Nextcure, Novartis, Pfizer, Sanofi / Regeneron, SEAGEN, Tempus, Zelluna, Bioatla, Alkermes, Instil Bio, Iovance; Financial Interests, Institutional, Invited Speaker: Arcus, Aduro, Akeso, Amgen, Bioatla, BMS, CytomX, Exelixis, Roche Genentech, GSK, Immunocore, Idera, Incyte, Iovance, Merck, Moderna, Merck Serono, Nextcure, Novartis, Pfizer, Sanofi / Regeneron, SEAGEN, Torque, Zelluna, Rubius. M.E. Gutierrez: Financial Interests, Institutional, Funding: Incyte. A.S. Balmanoukian: Financial Interests, Institutional, Funding: Incyte. J. Janik: Financial Interests, Personal, Full or part-time Employment: Incyte. P. Hoyle: Financial Interests, Personal, Full or part-time Employment: Incyte. Z. Dong: Financial Interests, Personal, Full or part-time Employment: Incyte. W. Wei: Financial Interests, Personal, Full or part-time Employment: Incyte. X. Chen: Financial Interests, Personal, Full or part-time Employment: Incyte. N. Bourayou: Financial Interests, Personal, Full or part-time Employment: Incyte. L. Horn: Financial Interests, Institutional, Funding: Incyte.