Phase I/II study of the LAG-3 inhibitor ieramilimab (LAG525) ± anti-PD-1 spartalizumab (PDR001) in patients with advanced malignancies

BackgroundLymphocyte-activation gene 3 (LAG-3) is an inhibitory immunoreceptor that negatively regulates T-cell activation. This paper presents preclinical characterization of the LAG-3 inhibitor, ieramilimab (LAG525), and phase I data for the treatment of patients with advanced/metastatic solid tum...

Full description

Saved in:

Bibliographic Details
Published in:	Journal for immunotherapy of cancer Vol. 10; no. 2; p. e003776
Main Authors:	Schöffski, Patrick, Tan, Daniel S W, Martín, Miguel, Ochoa-de-Olza, María, Sarantopoulos, John, Carvajal, Richard D, Kyi, Chrisann, Esaki, Taito, Prawira, Amy, Akerley, Wallace, De Braud, Filippo, Hui, Rina, Zhang, Tian, Soo, Ross A, Maur, Michela, Weickhardt, Andrew, Krauss, Jürgen, Deschler-Baier, Barbara, Lau, Allen, Samant, Tanay S, Longmire, Tyler, Chowdhury, Niladri Roy, Sabatos-Peyton, Catherine A, Patel, Nidhi, Ramesh, Radha, Hu, Tiancen, Carion, Ana, Gusenleitner, Daniel, Yerramilli-Rao, Padmaja, Askoxylakis, Vasileios, Kwak, Eunice L, Hong, David S
Format:	Journal Article
Language:	English
Published:	England BMJ Publishing Group Ltd 01-02-2022 BMJ Publishing Group LTD BMJ Publishing Group
Series:	Original research
Subjects:	Adult Aged Aged, 80 and over Antibodies Antibodies, Monoclonal, Humanized - pharmacology Antibodies, Monoclonal, Humanized - therapeutic use Biomarkers Biopsy Cancer Clinical/Translational Cancer Immunotherapy combination Cytokines Drug dosages drug therapy Gene expression Humans Immune Checkpoint Inhibitors - pharmacology Immune Checkpoint Inhibitors - therapeutic use Immunoglobulins Immunotherapy Immunotherapy - methods Ligands Metastasis Middle Aged Neoplasms - drug therapy Patients Pharmacodynamics Proteins Signal transduction Tumors Young Adult drug therapy immunotherapy combination
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	BackgroundLymphocyte-activation gene 3 (LAG-3) is an inhibitory immunoreceptor that negatively regulates T-cell activation. This paper presents preclinical characterization of the LAG-3 inhibitor, ieramilimab (LAG525), and phase I data for the treatment of patients with advanced/metastatic solid tumors with ieramilimab ±the anti-programmed cell death-1 antibody, spartalizumab.MethodsEligible patients had advanced/metastatic solid tumors and progressed after, or were unsuitable for, standard-of-care therapy, including checkpoint inhibitors in some cases. Patients received ieramilimab ±spartalizumab across various dose-escalation schedules. The primary objective was to assess the maximum tolerated dose (MTD) or recommended phase II dose (RP2D).ResultsIn total, 255 patients were allocated to single-agent ieramilimab (n=134) and combination (n=121) treatment arms. The majority (98%) had received prior antineoplastic therapy (median, 3). Four patients experienced dose-limiting toxicities in each treatment arm across various dosing cohorts. No MTD was reached. The RP2D on a 3-week schedule was declared as 400 mg ieramilimab plus 300 mg spartalizumab and, on a 4-week schedule (once every 4 weeks; Q4W), as 800 mg ieramilimab plus 400 mg spartalizumab; tumor target (LAG-3) suppression with 600 mg ieramilimab Q4W was predicted to be similar to the Q4W, RP2D schedule. Treatment-related adverse events (TRAEs) occurred in 75 (56%) and 84 (69%) patients in the single-agent and combination arms, respectively. Most common TRAEs were fatigue, gastrointestinal, and skin disorders, and were of mild severity; seven patients experienced at least one treatment-related serious adverse event in the single-agent (5%) and combination group (5.8%). Antitumor activity was observed in the combination arm, with 3 (2%) complete responses and 10 (8%) partial responses in a mixed population of tumor types. In the combination arm, eight patients (6.6%) experienced stable disease for 6 months or longer versus six patients (4.5%) in the single-agent arm. Responding patients trended towards having higher levels of immune gene expression, including CD8 and LAG3, in tumor tissue at baseline.ConclusionsIeramilimab was well tolerated as monotherapy and in combination with spartalizumab. The toxicity profile of ieramilimab in combination with spartalizumab was comparable to that of spartalizumab alone. Modest antitumor activity was seen with combination treatment.Trial registration numberNCT02460224.
Bibliography:	Original research ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2051-1426 2051-1426
DOI:	10.1136/jitc-2021-003776