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

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.

Conflict of interest statement

Competing interests: PS reports honoraria and consulting/advisory roles for Deciphera, Blueprint Medicines, and Boehringer Ingelheim; consulting/advisory roles for Ellipses Pharma, Transgene, Exelixis, Medscape, Guided Clarity, Ysios Capital, Adaptimmune, Intellisphere, and Advanced Medicine; research funding for CoBioRes NV, Eisai, GI Therapeutics, Novartis, and PharmaMar; and travel expenses for Boehringer Ingelheim, MSD, and Ipsen. DSWT reports honoraria and consulting/advisory roles for Merck, Pfizer, Novartis, Boehringer Ingelheim, Roche, and Takeda; consulting/advisory roles for Bayer, AstraZeneca, Eli Lilly, and GlaxoSmithKline; and research funding for Novartis, AstraZeneca, GlaxoSmithKline, Bayer, Pfizer, and Amgen. MigM reports honoraria and consulting/advisory roles for Roche/Genentech, Eli Lilly, Pfizer, Novartis, and Pierre-Fabre; consulting/advisory roles for AstraZeneca, Taiho Pharmaceuticals, and PharmaMar; research funding for Novartis, Roche/Genentech, and Puma; speaker’s bureau for Eli Lilly/ImClone, Roche/Genentech, and Pierre-Fabre; and other relationship with Roche/Genentech. MOdO reports honoraria for MSD. JS reports consulting/advisory roles for Astellas Pharma, AstraZeneca/MedImmune, Bayer, Eisai, Roche/Genentech, Pfizer, Immunocore, Seagen, Novartis, Sun Pharma, EMD Serono, Amgen, Bristol-Myer Squib, Flugent Therapeutics, Exelixis, Merck, Takeda, and Array BioPharma. RDC reports consulting/advisory roles and research funding for Merck, Aura Biosciences, Castle Biosciences, Immunocore, PureTech, Sorrento Therapeutics, Chimeron Bio, Regenix, InxMed, Pierre Fabre, TriSalus Life Sciences, Iovance Biotherapeutics, Oncosec, Regeneron, Genzyme, Amgen, Astellas Pharma, AstraZeneca, Bristol-Myer Squib/Medarex, Corvus Pharmaceuticals, Ideya, Mirati Therapeutics, Novartis, Pfizer, Plexxikon, and Roche/Genentech; research funding for Bayer, Bellicum Pharmaceuticals, Eli Lilly, Immunocore, Incyte, Macrogenics, Merck, Mirati Therapeutics, Array BioPharma, IDEAYA Biosciences, and Regeneron; and speaker’s bureau for Bristol-Myer Squib/Medarex.CK reports research funding for Bristol-Myers Squibb, Merus, and Gritstone Oncology. TE reports research funding for Novartis, Astellas Pharma, Sumitomo Group, Eli Lilly, Amgen, Quintiles, Daiichi Sankyo, Bayer, Eisai, IQVIA, MSD, Ono Pharmaceutical, Parexel, Nihonkayaku, and Taiho Pharmaceuticals. AP is an employee of, and reports honoraria for, Novotech; and reports research funding for Roche/Genentech, Bristol-Myers Squibb, Hutchison MediPharma, Merck, Bayer, Macrogenics, Pfizer, Akeso Biopharma, BeiGene, CStone Pharmaceuticals, Five Prime Therapeutics, CBT Pharmaceuticals, Arcus Biosciences, Corvus Pharmaceuticals, Eli Lilly, Henlius, QBiotics, Virogin, GlaxoSmithKline, Theradex, ENB Therapeutics, InxMed, Seattle Genetics, Janssen, Starpharma, and QBiotics. FDB reports honoraria and consulting/advisory roles for Roche, Pfizer, Bristol-Myers Squibb, Merk, MSD, Servier, and Sanofi; consulting/advisory roles for Incyte, Teofarma, EMD Serono, Nerviano Medical Sciences, Sanofi, and Novartis; and research funding for Novartis, Roche, Merck Serono, Pfizer, Servier, Philogen, Loxo Oncology, Tesaro, Nerviano Medical Sciences, and Kymab. RH reports honoraria and consulting/advisory roles for AstraZenca, Bristol-Myers Squibb, Eisai, Eli Lilly, Merck, MSD, Novartis, Oncosec, Pfizer, Roche and Seagen; research funding from AstraZeneca, Eli Lilly, MSD, Roche, Seagen, OncoSec, and Novartis; and travel expenses from Novartis. TZ reports immediate family connections to Capio BioSciences and Archimmume Therapeutics; these relatives also own stock at these companies and at Nanarobotics. TZ reports honoraria for Exelixis, Roche/Genentech, MJH Life Sciences, and Pacific Genuity; consulting/advisory roles for Janssen, Roche/Genentech, Sanofi, Exelixis, AstraZeneca, Pfizer, Bristol-Myers Squibb, Foundation Medicine, Pharmacyclics, Amgen, Merck, Seattle Genetics, Dendreon, and Calithera Biosciences; speaker’s Bureau for Exelixis, Roche/Genentech, Genomic Health, and Sanofi/Aventis; research funding for Astellas Pharma, Janssen, Acerta Pharma, Pfizer, Merrimack, Stem CentRx, Novartis, OmniSeq, Personal Genome Diagnostics, Regeneron, Merck, and Mirati Therapeutics; patents, royalties and other intellectual property for circulating tumor cell novel capture by c-MET technology and prochelators as Targeted Prodrugs for Prostate Cancer; and travel expenses for Acerta Pharma, Genomic Health, and AstraZeneca. RAS reports honoraria and consulting/advisory roles for AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Novartis, Pfizer, Roche/Genentech, Takeda, Yuhan, Amgen, Bayer, and Merck; consulting/advisory roles for Taiho Pharmaceutical, Yuhan, Takeda, Amgen, and Merck; and research funding for AstraZeneca and Boehringer Ingelheim. AW reports honoraria for Eisai and Merck; consulting/advisory roles for Merck and Bristol-Myers Squibb; speaker’s bureau for Astellas Pharma and Merck; and travel expenses for Astellas Pharma, Ipsen, and Merck. JK is employed by, and reports receiving leadership fees, patents, royalties or other intellectual property for, Heidelberg ImmunoTherapeutics; and reports research funding for Vaccibody. AL, TS, VA, and EK are employees of Novartis. DG is an employee of Novartis and Mercy BioAnalytics. TS has a spouse who is employed by Teva Pharmaceuticals. NRC is an employee of, and owns stock in, Novartis. CASP was an employee of Novartis and owns stock in, holds patents, royalties, or other intellectual property in Novartis, and is also employed by, and has stock options in, Larkspur Biosciences. RR is an employee of, and holds stock in, Novartis and Takeda. TH is an employee of ViiV Healthcare, owns stock in ViiV Healthcare and Novartis, and holds patents, royalties, or other intellectual property in Novartis. PYR is an employee of, and holds stock in, Novartis. DSH owns stock in MolecularMatch, Presagia, and OncoResponse; reports consulting/advisory roles and research funding for Bayer, Guidepoint Global, Alpha Insights, Axiom Biotechnologies, Merrimack, Medscape, Numab, Pfizer, Seattle Genetics, Takeda, Trieza Therapeutics, WebMD, Infinity Pharmaceuticals, Amgen, Adaptimmune, Boxer Capital, ECOR1, Tavistock, Baxter, COG, Genentech, Group H, Janssen, Acuta, HCW Precision, Infinity, Prime Oncology, and ST Cube; research funding for Daiichi Sankyo, AbbVie, Kite Pharma, MedImmune, Molecular Templates, NCI-CTEP Fate Therapeutics, Novartis, Turning Point Therapeutics, Verstatem, Kyowa, Loxo Oncology, Merck, Eisai, Genmab, Ignyta, Mirati Therapeutics, miRNA, Mologen, Takeda, AstraZeneca, Navier, VM Oncology, Erasca, Inc, Eli Lilly, Bristol-Myers Squibb, EMD Serono, GlaxoSmithKline, Millenium, and Adlai Nortye; and travel expenses for Genmab, SITC, Bayer Schering Pharma, miRNA, Loxo Oncology, Amgen, AstraZeneca, Celgene, Eli Lilly, Genentech, GlaxoSmithKline, Janssen, Pfizer, Philips, and Takeda. MicM, WA, BDB, TL, NP, and AC report no conflicts of interest.

© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.

Figures

Figure 1

Preclinical characterization of ieramilimab. (A) Overall structure of ieramilimab antigen-binding fragment binding to LAG-3. Shown are (i) the heavy and light chains of ieramilimab in surface and LAG-3 domain 1 (D1) in ribbons, (ii) the N-terminus (N), the names of the β stands, and the C-terminus of D1 that leads to domain 2 (D2) of LAG-3, (iii) the BC and DE loops of LAG-3 that comprise the epitope of ieramilimab, in which the RGD motif critical for binding MHC-II is shown as spheres, and (iv) the unique ‘extra loop’ of LAG-3, which is far away from the ieramilimab epitope. (B) Detailed view of ieramilimab epitope residues on LAG-3 (shown as sticks and labeled). (C) Ieramilimab blocks the binding of FGL-1 to LAG-3. (D) In three out of eight healthy human donors assayed, ieramilimab enhances IFN-γ secretion in Tfh/B cell co-cultures stimulated with SEB, relative to hIgG4 isotype control. FGL-1, fibrinogen-like protein 1; hIgG4, human immunoglobulin G4; IFN, interferon; LAG-3, lymphocyte-activation gene 3; MHC-II, major histocompatibility complex class II; RGD, arginylglycylaspartic acid; SEB, Staphylococcal enterotoxin B; Tfh, T follicular helper.

Figure 2

AEs per CTCAE V.4.03, suspected to be treatment related, with an overall incidence of at least 2% for both the single-agent ieramilimab arm and the spartalizumab combination arm. AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CTCAE, Common Terminology Criteria for Adverse Events.

Figure 3

Pharmacokinetics and best percentage change in tumors. (A) Median concentration–time profiles for Q2W dosing regimens for SA ieramilimab. (B) Median concentration–time profiles for Q2W dosing regimens for ieramilimab in combination with spartalizumab. (C) Waterfall plot for best percentage change of predefined target lesions from baseline in sum of longest diameters based on local radiology review of RECIST V.1.1 for patients treated with ieramilimab +spartalizumab *Indicates the bars where best percentage change from baseline has been cut at 100%. CR, complete response; PD, progressive disease; PR, partial response; Q2W, every 2 weeks; Q4W, every 4 weeks; RECIST, Response Evaluation Criteria In Solid Tumors; SA, single agent; SD, stable disease.

Figure 4

Duration of exposure and response plots. (A) Duration of exposure in patients receiving single-agent ieramilimab with best overall response of SD or NCRNPD, (B) Duration of exposure in patients receiving combination ieramilimab +spartalizumab with best overall response of CR, PR or SD, (C) Duration of response in patients receiving combination ieramilimab +spartalizumab with a best overall response of CR and PR. CR, complete response; NCRNPD, non-complete response/non-progressive disease (the presence of any non-target lesions or abnormal nodal lesions); PD, progressive disease; PR, partial response; SD, stable disease; UNK, unknown.

Figure 5

Effect of combination treatment (ieramilimab +spartalizumab) on immune-related markers. (A) IHC and RNA sequencing data at baseline (n=75), (B) IHC and RNA sequencing fold change data (n=28), (C) IFN-γ expression by BOR at baseline (n=91).: BOR, best overall response; CR, complete response; CRC, colorectal cancer; HNSC, head-neck squamous cell carcinoma; IFN, interferon-γ; IHC, immunohistochemistry; NCRNPD, non-complete response/non-progressive disease (the presence of any non-target lesions or abnormal nodal lesions); PD, progressive disease; PR, partial response; SD, stable disease; UNK, unknown.