Phase I/II study of the LAG-3 inhibitor ieramilimab (LAG525) ± anti-PD-1 spartalizumab (PDR001) in patients with advanced malignancies PMID: 35217575

ADC Targets in Oncology

2026-04-10

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

J Immunother Cancer. 2022 Feb;10(2):e003776. doi: 10.1136/jitc-2021-003776.

Patrick Schöffski ^# ¹ , Daniel S W Tan ^# ² ³ , Miguel Martín ⁴ , María Ochoa-de-Olza ⁵ , John Sarantopoulos ⁶ , Richard D Carvajal ⁷ , Chrisann Kyi ⁸ , Taito Esaki ⁹ , Amy Prawira ¹⁰ , Wallace Akerley ¹¹ , Filippo De Braud ¹² , Rina Hui ¹³ , Tian Zhang ¹⁴ , Ross A Soo ¹⁵ , Michela Maur ¹⁶ , Andrew Weickhardt ¹⁷ , Jürgen Krauss ¹⁸ , Barbara Deschler-Baier ¹⁹ , Allen Lau ²⁰ , Tanay S Samant ²⁰ , Tyler Longmire ²⁰ , Niladri Roy Chowdhury ²⁰ , Catherine A Sabatos-Peyton ²⁰ , Nidhi Patel ²⁰ , Radha Ramesh ²⁰ , Tiancen Hu ²⁰ , Ana Carion ²⁰ , Daniel Gusenleitner ²⁰ , Padmaja Yerramilli-Rao ²⁰ , Vasileios Askoxylakis ²⁰ , Eunice L Kwak ²⁰ , David S Hong ²¹

Affiliations

1. Department of General Medical Oncology, Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium.
2. National Cancer Centre Singapore, Singapore.
3. Duke-NUS Medical School, Singapore.
4. Hospital General Universitario Gregorio Maranon, Madrid, Spain.
5. Vall d'Hebron University Hospital, Barcelona, Spain.
6. Institute for Drug Development, Mays Cancer Center at University of Texas Health San Antonio MD Anderson Cancer Center, San Antonio, Texas, USA.
7. Columbia University Irving Medical Center, New York, New York, USA.
8. Memorial Sloan Kettering Cancer Center, New York, New York, USA.
9. National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan.
10. Princess Margaret Hospital Cancer Centre, Toronto, Ontario, Canada.
11. Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA.
12. Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy.
13. Westmead Hospital and The University of Sydney, Sydney, New South Wales, Australia.
14. University of Texas Southwestern Medical Center, Dallas, Texas, USA.
15. National University Cancer Institute, Singapore.
16. Oncologia Medica, AOU Policlinico di Modena, Modena, Emilia-Romagna, Italy.
17. Austin Health, Heidelberg, Victoria, Australia.
18. National Center for Tumor Diseases, Heidelberg, Germany.
19. Universitätsklinikum Würzburg, Wurzburg, Germany.
20. Novartis Institutes for BioMedical Research Inc, Cambridge, Massachusetts, USA.
21. The University of Texas MD Anderson Cancer Center, Houston, Texas, USA [email protected].
# Contributed equally.

Abstract

Background: 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.

Methods: 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).

Results: 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.

Conclusions: 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.

Trial registration number: NCT02460224.

Keywords

combination; drug therapy; immunotherapy.