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Title: Phase I/II study of the LAG-3 inhibitor ieramilimab (LAG525) ± anti-PD-1 spartalizumab (PDR001) in patients with advanced malignancies.
Austin 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
Affiliation: Vall d'Hebron University Hospital, Barcelona, Spain
Department of General Medical Oncology, Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium..
Westmead Hospital and The University of Sydney, Sydney, New South Wales, Australia
Austin Health, Heidelberg, Victoria, Australia
University of Texas Southwestern Medical Center, Dallas, Texas, USA
National Cancer Centre Singapore, Singapore
Duke-NUS Medical School, Singapore..
Institute for Drug Development, Mays Cancer Center at University of Texas Health San Antonio MD Anderson Cancer Center, San Antonio, Texas, USA
Columbia University Irving Medical Center, New York, New York, USA
Memorial Sloan Kettering Cancer Center, New York, New York, USA
Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA
Novartis Institutes for BioMedical Research Inc, Cambridge, Massachusetts, USA
Hospital General Universitario Gregorio Maranon, Madrid, Spain
National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan..
Princess Margaret Hospital Cancer Centre, Toronto, Ontario, Canada..
Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy..
National University Cancer Institute, Singapore..
Oncologia Medica, AOU Policlinico di Modena, Modena, Emilia-Romagna, Italy..
National Center for Tumor Diseases, Heidelberg, Germany..
Universitätsklinikum Würzburg, Wurzburg, Germany..
The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
Issue Date: Feb-2022
Publication information: Journal for immunotherapy of cancer 2022-02; 10(2)
Abstract: Lymphocyte-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. Eligible 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). In 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. Ieramilimab 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. NCT02460224.
DOI: 10.1136/jitc-2021-003776
Journal: Journal for immunotherapy of cancer
PubMed URL: 35217575
Type: Journal Article
Subjects: combination
drug therapy
Appears in Collections:Journal articles

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