Online first
Review paper
Published online: 2024-04-08
LAG-3 as a therapeutic target in melanoma
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DOI: 10.5603/ocp.99115
Abstract
The advent of immune checkpoint inhibitors (ICIs) marked a paradigm shift in melanoma therapy, particularly in advanced settings. Although anti-PD-1 and anti-CTLA-4 antibodies have already established their efficacy and safety profiles through extensive trials, the recognition of lymphocyte activation gene 3 (LAG-3, CD223) around three decades ago, introduced a promising alternative in improving the antitumor immune response. As a potent reactive checkpoint expressed in various populations of immune cells, including CD4+, CD8+, and regulatory T-cells, LAG-3 has attracted attention acrossmultiple tumor types, including melanoma. Preliminary findings and emerging phase III evidence already highlight the advantage of combining anti-PD-1 with anti-LAG-3 agents over anti-PD-1 monotherapy. This review investigates the current landscape of anti-LAG-3 therapies, encapsulating recent breakthroughs and pivotal trials, including the landmark RELATIVITY-047 study on the combination of nivolumab and relatlimab. In addition to comprehensively evaluating the latest findings, this analysis describes the ongoing phase I–III trials exploring novel agents, shedding light on the most promising data and perspectives. By synthesizing the latest advances in anti-LAG-3 treatment modalities, this article could serve as a timely and insightful resource for clinicians and researchers, navigating the evolving landscape of melanoma immunotherapy.
Keywords: melanomaimmune checkpoint inhibitorsimmunotherapyLAG-3relatlimabfianlimab
References
- Dimitriou F, Hauschild A, Mehnert JM, et al. Double Trouble: Immunotherapy Doublets in Melanoma-Approved and Novel Combinations to Optimize Treatment in Advanced Melanoma. Am Soc Clin Oncol Educ Book. 2022; 42: 1–22.
- Patel SP, Othus M, Chen Y, et al. Neoadjuvant-Adjuvant or Adjuvant-Only Pembrolizumab in Advanced Melanoma. N Engl J Med. 2023; 388(9): 813–823.
- Carlino MS, Larkin J, Long GV. Immune checkpoint inhibitors in melanoma. Lancet. 2021; 398(10304): 1002–1014.
- Jacob S, Micu M, Quandt Z, et al. 775 Phase Ib/II Study of XmAb23104 (PD1 X ICOS) and XmAb22841 (CTLA-4 X LAG3) combination in metastatic melanoma refractory to prior immune checkpoint Inhibitor therapy with and without CNS disease. J Immunother Cancer. 2023; 11(Suppl 1).
- Adashek J, Kato S, Pabla S, et al. LAG3 transcriptomic expression correlates with high levels of PD-1, PD-L1, PD-L2, and CTLA-4 checkpoints and with high tumor mutational burden across cancers. J Clin Oncol. 2022; 40(16_suppl): 2561–2561.
- Lipson E, Tawbi HH, Schadendorf D, et al. Relatlimab (RELA) plus nivolumab (NIVO) versus NIVO in first-line advanced melanoma: Primary phase III results from RELATIVITY-047 (CA224-047). J Clin Oncol. 2021; 39(15_suppl): 9503–9503.
- Seth R, Agarwala SS, Messersmith H, et al. Systemic Therapy for Melanoma: ASCO Guideline Update. J Clin Oncol. 2023; 41(30): 4794–4820.
- Woo SR, Turnis ME, Goldberg MV, et al. Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T-cell function to promote tumoral immune escape. Cancer Res. 2012; 72(4): 917–927.
- Anderson AC, Joller N, Kuchroo VK. Lag-3, Tim-3, and TIGIT: Co-inhibitory Receptors with Specialized Functions in Immune Regulation. Immunity. 2016; 44(5): 989–1004.
- Maeda TK, Sugiura D, Okazaki IM, et al. Atypical motifs in the cytoplasmic region of the inhibitory immune co-receptor LAG-3 inhibit T cell activation. J Biol Chem. 2019; 294(15): 6017–6026.
- Huard B, Tournier M, Hercend T, et al. Lymphocyte-activation gene 3/major histocompatibility complex class II interaction modulates the antigenic response of CD4+ T lymphocytes. Eur J Immunol. 1994; 24(12): 3216–3221.
- Maruhashi T, Okazaki IM, Sugiura D, et al. LAG-3 inhibits the activation of CD4 T cells that recognize stable pMHCII through its conformation-dependent recognition of pMHCII. Nat Immunol. 2018; 19(12): 1415–1426.
- Guy C, Mitrea DM, Chou PC, et al. LAG3 associates with TCR-CD3 complexes and suppresses signaling by driving co-receptor-Lck dissociation. Nat Immunol. 2022; 23(5): 757–767.
- Chocarro L, Blanco E, Zuazo M, et al. Understanding LAG-3 Signaling. Int J Mol Sci. 2021; 22(10).
- Cocks MM, Mills AM. The Immune Checkpoint Inhibitor LAG-3 and Its Ligand GAL-3 in Vulvar Squamous Neoplasia. Int J Gynecol Pathol. 2022; 41(2): 113–121.
- Shi AP, Tang XY, Xiong YL, et al. Immune Checkpoint LAG3 and Its Ligand FGL1 in Cancer. Front Immunol. 2021; 12: 785091.
- Wang J, Sanmamed MF, Datar I, et al. Fibrinogen-like Protein 1 Is a Major Immune Inhibitory Ligand of LAG-3. Cell. 2019; 176(1-2): 334–347.e12.
- Mao X, Ou MT, Karuppagounder SS, et al. Pathological α-synuclein transmission initiated by binding lymphocyte-activation gene 3. Science. 2016; 353(6307).
- Xu F, Liu J, Liu Di, et al. LSECtin expressed on melanoma cells promotes tumor progression by inhibiting antitumor T-cell responses. Cancer Res. 2014; 74(13): 3418–3428.
- Matsuzaki J, Gnjatic S, Mhawech-Fauceglia P, et al. Tumor-infiltrating NY-ESO-1-specific CD8+ T cells are negatively regulated by LAG-3 and PD-1 in human ovarian cancer. Proc Natl Acad Sci U S A. 2010; 107(17): 7875–7880.
- Chen F, Sherwood T, Costa ADe, et al. Immunohistochemistry analyses of LAG-3 expression across different tumor types and co-expression with PD-1. J Clin Oncol. 2020; 38(15_suppl): e15086–e15086.
- Kreidieh FY, Tawbi HA. The introduction of LAG-3 checkpoint blockade in melanoma: immunotherapy landscape beyond PD-1 and CTLA-4 inhibition. Ther Adv Med Oncol. 2023; 15: 17588359231186027.
- Hemon P, Jean-Louis F, Ramgolam K, et al. MHC class II engagement by its ligand LAG-3 (CD223) contributes to melanoma resistance to apoptosis. J Immunol. 2011; 186(9): 5173–5183.
- Machiraju D, Wiecken M, Lang N, et al. Soluble immune checkpoints and T-cell subsets in blood as biomarkers for resistance to immunotherapy in melanoma patients. Oncoimmunology. 2021; 10(1): 1926762.
- Fröhlich A, Sirokay J, Fietz S, et al. Molecular, clinicopathological, and immune correlates of LAG3 promoter DNA methylation in melanoma. EBioMedicine. 2020; 59: 102962.
- Souri Z, Wierenga APA, Kroes WGM, et al. LAG3 and Its Ligands Show Increased Expression in High-Risk Uveal Melanoma. Cancers (Basel). 2021; 13(17).
- Tawbi HA, Schadendorf D, Lipson EJ, et al. RELATIVITY-047 Investigators. Relatlimab and Nivolumab versus Nivolumab in Untreated Advanced Melanoma. N Engl J Med. 2022; 386(1): 24–34.
- Ibrahim R, Saleh K, Chahine C, et al. LAG-3 Inhibitors: Novel Immune Checkpoint Inhibitors Changing the Landscape of Immunotherapy. Biomedicines. 2023; 11(7).
- Mallardo D, Woodford R, Menzies AM, et al. The role of diabetes in metastatic melanoma patients treated with nivolumab plus relatlimab. J Transl Med. 2023; 21(1): 753.
- Chocarro L, Blanco E, Arasanz H, et al. Clinical landscape of LAG-3-targeted therapy. Immunooncol Technol. 2022; 14: 100079.
- Sordo-Bahamonde C, Lorenzo-Herrero S, González-Rodríguez AP, et al. LAG-3 Blockade with Relatlimab (BMS-986016) Restores Anti-Leukemic Responses in Chronic Lymphocytic Leukemia. Cancers (Basel). 2021; 13(9).
- Long G, Hodi F, Lipson E, et al. Relatlimab and nivolumab versus nivolumab in previously untreated metastatic or unresectable melanoma: Overall survival and response rates from RELATIVITY-047 (CA224-047). J Clin Oncol. 2022; 40(36_suppl): 360385–360385.
- Tawbi H, Hodi F, Lipson E, et al. Nivolumab (NIVO) plus relatlimab (RELA) vs NIVO in previously untreated metastatic or unresectable melanoma: 2-year results from RELATIVITY-047. J Clin Oncol. 2023; 41(16_suppl): 9502–9502.
- Quarto LG, Rodrigues TS, Nuriev R, et al. Abstract 14926: Case of Severe Myocarditis Associated With Nivolumab-Relatlimab. Circulation. 2023; 148(Suppl_1).
- Lipson EJ, Dolfi S, Tang H, et al. LBA51 Unraveling relatlimab (RELA)-specific biology using biomarker analyses in patients with advanced melanoma treated with nivolumab (NIVO)+RELA or NIVO alone in RELATIVITY-047. Ann Oncol. 2023; 34: S1290–S1291.
- Long GV, Hodi FS, Lipson EJ, et al. Nivolumab plus relatlimab vs nivolumab in previously untreated metastatic or unresectable melanoma: 2-year subgroup analyses from RELATIVITY-047. ESMO Congress 2023.
- Long GV, Hodi FS, Lipson EJ, et al. 1103P Nivolumab (NIVO) plus relatlimab (RELA) vs NIVO in previously untreated metastatic or unresectable melanoma: 2-year subgroup analyses from RELATIVITY-047. Ann Oncol. 2023; 34: S664–S665.
- NCT05704647. Phase II Study of Nivolumab in Combination With Relatlimab in Patients With Active Melanoma Brain Metastases. ClinicalTrials.gov; 2023 [December 2023]. https://classic.clinicaltrials.gov/show/NCT05704647.
- Phillips S, Burton E, Kreidieh F, et al. Phase II study of nivolumab (nivo) in combination with relatlimab (rela) in patients (pts) with active melanoma brain metastases (MBM). J Clin Oncol. 2023; 41(16_suppl): TPS9605–TPS9605.
- NCT05704933. Pilot Study of Nivolumab w/Ipilimumab or Relatlimab in Surgically Resectable Melanoma Brain Metastases. ClinicalTrials.gov; 2023 [December 2023]. https://classic.clinicaltrials.gov/show/NCT05704933.
- Schadendorf D, Tawbi H, Lipson EJ, et al. Health-related quality of life with nivolumab plus relatlimab versus nivolumab monotherapy in patients with previously untreated unresectable or metastatic melanoma: RELATIVITY-047 trial. Eur J Cancer. 2023; 187: 164–173.
- Nie RC, Wang Y, Yuan SQ, et al. LAG3-PD1 or CTLA4-PD1 inhibition in advanced melanoma: Indirect cross comparisons of the CheckMate-067 and relativity-047 trials. J Clin Oncol. 2022; 40(16_suppl): e21511–e21511.
- Schadendorf D, Tawbi H, Lipson E, et al. Efficacy and safety of first-line (1L) nivolumab plus relatlimab (NIVO + RELA) versus NIVO plus ipilimumab (NIVO + IPI) in advanced melanoma: An indirect treatment comparison (ITC) using patient-level data (PLD). J Clin Oncol. 2023; 41(16_suppl): 9552–9552.
- Boutros A, Tanda ET, Croce E, et al. Activity and safety of first-line treatments for advanced melanoma: A network meta-analysis. Eur J Cancer. 2023; 188: 64–79.
- NCT03743766. Nivolumab, BMS-936558 in Combination With Relatlimab, BMS-986016 in Patients With Metastatic Melanoma Naïve to Prior Immunotherapy in the Metastatic Setting. ClinicalTrials.gov; 2019 [December 2023]. https://classic.clinicaltrials.gov/show/NCT03743766.
- Rohatgi A, Massa R, Gooding W, et al. A phase II study of anti-PD1 monoclonal antibody (Nivolumab) administered in combination with anti-LAG3 monoclonal antibody (Relatlimab) in patients with metastatic melanoma naive to prior immunotherapy in the metastatic setting. J Clin Oncol. 2020; 38(15_suppl): TPS10085–TPS10085.
- Karapetyan L, Karunamurthy A, Cillo A, et al. Phase II study of nivolumab (nivo) with relatlimab (rela) in patients (pts) with first-line advanced melanoma: Early on-treatment major pathologic response on biopsy. J Clin Oncol. 2022; 40(16_suppl): 9514–9514.
- Ascierto PA, Lipson EJ, Dummer R, et al. Nivolumab and Relatlimab in Patients With Advanced Melanoma That Had Progressed on Anti-Programmed Death-1/Programmed Death Ligand 1 Therapy: Results From the Phase I/IIa RELATIVITY-020 Trial. J Clin Oncol. 2023; 41(15): 2724–2735.
- NCT03978611. A Study to Assess Safety of Relatlimab With Ipilimumab in Participants With Advanced Melanoma Who Progressed on Anti-Programmed Cell Death Protein 1 (Anti-PD-1) Treatment. ClinicalTrials.gov; 2021 [January 2024]. https://classic.clinicaltrials.gov/show/NCT03978611.
- NCT05629546. Memory-Like Natural Killer Cells With Nivolumab and Relatlimab in Advanced or Metastatic Melanoma After Progression on Checkpoint Inhibitors. ClinicalTrials.gov; 2024 [January 2024]. https://classic.clinicaltrials.gov/show/NCT05629546.
- NCT02519322. Neoadjuvant and Adjuvant Checkpoint Blockade. ClinicalTrials.gov; 2016 [December 2023]. https://classic.clinicaltrials.gov/show/NCT02519322.
- Amaria RN, Postow M, Burton EM, et al. Neoadjuvant relatlimab and nivolumab in resectable melanoma. Nature. 2022; 611(7934): 155–160.
- Amaria RN, Reddy SM, Tawbi HA, et al. Neoadjuvant immune checkpoint blockade in high-risk resectable melanoma. Nat Med. 2018; 24(11): 1649–1654.
- NCT05418972. A Phase 2 Clinical Trial of Neoadjuvant Relatlimab and Nivolumab in High Risk, Clinical Stage II Cutaneous Melanoma. ClinicalTrials.gov; 2023 [December 2023]. https://classic.clinicaltrials.gov/show/NCT05418972.
- Rutkowski P, Jagodzińska-Mucha P. What role can LAG-3-blocking antibodies play in melanoma therapy? Expert Opin Biol Ther. 2023; 23(12): 1155–1158.
- Panella T, Thomas S, McKean M, et al. A phase 3 trial comparing fianlimab (anti–LAG-3) plus cemiplimab (anti–PD-1) to pembrolizumab in patients with completely resected high-risk melanoma. J Clin Oncol. 2023; 41(16_suppl): TPS9598–TPS9598.
- Sauer N, Szlasa W, Jonderko L, et al. LAG-3 as a Potent Target for Novel Anticancer Therapies of a Wide Range of Tumors. Int J Mol Sci. 2022; 23(17).
- NCT03005782. Study of REGN3767 (Anti-LAG-3) With or Without REGN2810 (Anti-PD1) in Advanced Cancers. ClinicalTrials.gov; 2016 [December 2023]. https://classic.clinicaltrials.gov/show/NCT03005782.
- Hamid O, Lewis K, Weise A, et al. Significant durable response with fianlimab (anti-LAG-3) and cemiplimab (anti-PD-1) in advanced melanoma: Post adjuvant PD-1 analysis. J Clin Oncol. 2023; 41(16_suppl): 9501–9501.
- Mehmi I, Lewis K, Weise A, et al. A phase 1 study of fianlimab (anti-LAG-3) in combination with cemiplimab (anti-PD-1) in patients with advanced melanoma: Poor-prognosis subgroup analysis. J Clin Oncol. 2023; 41(16_suppl): 9548–9548.
- NCT05608291. A Trial to See if the Combination of Fianlimab With Cemiplimab Works Better Than Pembrolizumab for Preventing or Delaying Melanoma From Coming Back After it Has Been Removed With Surgery. ClinicalTrials.gov; [December 2023]. https://classic.clinicaltrials.gov/ct2/show/NCT05608291.
- NCT05352672. Clinical Study of Fianlimab in Combination With Cemiplimab in Adolescent and Adult Patients With Previously Untreated Unresectable Locally Advanced or Metastatic Melanoma. ClinicalTrials.gov; 2022 [December 2023]. https://classic.clinicaltrials.gov/show/NCT05352672.
- Al-Batran SE, Mueller DW, Rafiyan MR, et al. A soluble LAG-3 protein (eftilagimod alpha) and an anti-PD-L1 antibody (avelumab) tested in a phase I trial: a new combination in immuno-oncology. ESMO Open. 2023; 8(5): 101623.
- Atkinson V, Khattak A, Haydon A, et al. Eftilagimod alpha, a soluble lymphocyte activation gene-3 (LAG-3) protein plus pembrolizumab in patients with metastatic melanoma. J Immunother Cancer. 2020; 8(2).
- Eastgate M, Atkinson V, Khattak M, et al. Pushing the accelerator and releasing the brake: A phase I dose escalation study evaluating a LAG-3 fusion protein (eftilagimod alpha), together with pembrolizumab in unresectable or metastatic melanoma. J Clin Oncol. 2018; 36(15_suppl): e15099–e15099.
- NCT02676869. Phase 1 Study of IMP321 (Eftilagimod Alpha) Adjuvant to Anti-PD-1 Therapy in Unresectable or Metastatic Melanoma. ClinicalTrials.gov; 2016 [December 2023]. https://classic.clinicaltrials.gov/show/NCT02676869.
- NCT03625323. Combination Study With Soluble LAG-3 Fusion Protein Eftilagimod Alpha (IMP321) and Pembrolizumab in Patients With Previously Untreated Unresectable or Metastatic NSCLC, or Recurrent PD-X Refractory NSCLC or With Recurrent or Metastatic HNSCC. ClinicalTrials.gov; 2019 [December 2023]. https://classic.clinicaltrials.gov/show/NCT03625323.
- NCT05695898. XmAb23104 (PD1 X ICOS) and XmAb22841 (CTLA-4 X LAG3) in Treating Melanoma Prior Immune Checkpoint Inhibitor Therapy. ClinicalTrials.gov; 2023 [December 2023]. https://classic.clinicaltrials.gov/show/NCT05695898.
- NCT03849469. A Study of XmAb®22841 Monotherapy & in Combination w/ Pembrolizumab in Subjects w/ Selected Advanced Solid Tumors. ClinicalTrials.gov; 2019 [December 2023]. https://classic.clinicaltrials.gov/show/NCT03849469.
- NCT04140500. Dose Escalation Study of a PD1-LAG3 Bispecific Antibody in Patients With Advanced and/or Metastatic Solid Tumors. ClinicalTrials.gov; 2019. https://classic.clinicaltrials.gov/ct2/show/NCT04140500.
- NCT04370704. Study of Combination Therapy With INCMGA00012 (Anti-PD-1), INCAGN02385 (Anti-LAG-3), and INCAGN02390 (Anti-TIM-3) in Participants With Select Advanced Malignancies. ClinicalTrials.gov; 2020 [December 2023]. https://classic.clinicaltrials.gov/show/NCT04370704.
- Hamid O, Gutierrez M, Mehmi I, et al. A phase 1/2 study of retifanlimab (INCMGA00012, Anti–PD-1), INCAGN02385 (Anti–LAG-3), and INCAGN02390 (Anti–TIM-3) combination therapy in patients (Pts) with advanced solid tumors. J Clin Oncol. 2023; 41(16_suppl): 2599–2599.
- Shi Y, Luo S, Zhou H, et al. Phase I study of LBL-007, a novel anti-human lymphocyte activation gene 3 (LAG-3) antibody in patients with advanced solid tumors. J Clin Oncol. 2021; 39(15_suppl): 2523–2523.
- NCT04640545. A Study to Assess LBL-007 in Combination With Toripalimab and Axitinib Tablets Subjects With Advanced Melanoma. ClinicalTrials.gov; 2020 [December 2023]. https://classic.clinicaltrials.gov/show/NCT04640545.
- Bai X, Li M, Chen Yu, et al. Updated safety and efficacy results from the phase I study of either LBL-007 (an anti-LAG-3 antibody) in combination with toripalimab (an anti-PD-1 antibody) or LBL-007 in combination with toripalimab and axitinib in patients with advanced melanoma. J Clin Oncol. 2023; 41(16_suppl): 9541–9541.
- NCT05577182. Study of INCA32459 a LAG-3 and PD-1 Bispecific Antibody in Participants With Select Advanced Malignancies. ClinicalTrials.gov; 2022 [December 2023]. https://classic.clinicaltrials.gov/show/NCT05577182.
- Zhou C, He Y, Ren S, et al. Phase Ia/Ib dose-escalation study of IBI110 (anti-LAG-3 mAb) as a single agent and in combination with sintilimab (anti-PD-1 mAb) in patients (pts) with advanced solid tumors. J Clin Oncol. 2021; 39(15_suppl): 2589–2589.
- Xu N, Mao C, Qian J, et al. IBI110 (anti-LAG-3 mAb) as a single agent or in combination with sintilimab (anti-PD-1 mAb) in patients with advanced solid tumors: Updated results from the phase Ia/Ib dose-escalation study. J Clin Oncol. 2022; 40(16_suppl): 2650–2650.
- NCT04085185. A Study Evaluating the Safety, Tolerability, and Initial Efficacy of IBI110 in Subjects With Advanced Malignant Tumors. ClinicalTrials.gov; 2019 [December 2023]. https://classic.clinicaltrials.gov/show/NCT04085185.
- NCT03780725. This Study Tests How BI 754111 is Distributed in Patients With Advanced Non-small Cell Lung Cancer or Patients With Head and Neck Cancer Who Are Treated With BI 754091. ClinicalTrials.gov; 2019 [December 2023]. https://classic.clinicaltrials.gov/show/NCT03780725.
- NCT03433898. This Study Aims to Find a Safe and Effective Dose of BI 754091. The Study Also Aims to Find Safe and Effective Doses of BI 754091 and BI 754111 in Combination. This Study is Done in Asian Patients With Different Types of Cancer. ClinicalTrials.gov; 2018 [December 2023]. https://classic.clinicaltrials.gov/show/NCT03433898.
- NCT03156114. This Study Tests the New Medicine BI 754111 Alone or in Combination With Another New Substance BI 754091 in Patients With Advanced Cancer. The Study Tests Different Doses to Find the Best Dose for Continuous Treatment. ClinicalTrials.gov; 2017 [December 2023]. https://classic.clinicaltrials.gov/show/NCT03156114.
- Johnson M, Patel M, Cherry M, et al. Safety of BI 754111, an anti-LAG-3 monoclonal antibody (mAb), in combination with BI 754091, an anti-PD-1 mAb, in patients with advanced solid tumors. J Clin Oncol. 2020; 38(15_suppl): 3063–3063.
- NCT03697304. Platform Trial Evaluating Safety and Efficacy of BI 754091 Anti- PD-1 Based Combination Therapies in PD-(L)1 naïve and PD- (L)1 Pretreated Patient Populations With Advanced/Metastatic Solid Tumours. ClinicalTrials.gov; 2019 [December 2023]. https://classic.clinicaltrials.gov/show/NCT03697304.
- Yamamoto N, Hafez N, Tolcher A, et al. A phase Ia/Ib, dose-escalation/expansion study of BI 907828 in combination with BI 754091 (ezabenlimab) and BI 754111 in patients (pts) with advanced solid tumors. J Clin Oncol. 2022; 40(16_suppl): 3095–3095.