Lag-3 expression and clinical outcomes in metastatic melanoma patients treated with combination anti-lag-3 + anti-PD-1-based immunotherapies

ABSTRACT

Lymphocyte-activation gene-3 (LAG-3), an immune checkpoint receptor, negatively regulates T-cell function and facilitates immune escape of tumors. Dual inhibition of LAG-3 and programmed cell death receptor-1 (PD-1) significantly improved progression-free survival (PFS) in metastatic melanoma patients compared to anti-PD-1 therapy alone. Investigating the utility of LAG-3 expression as a biomarker of response to anti-LAG-3 + anti-PD-1 immunotherapy is of great clinical relevance. This study sought to evaluate the association between baseline LAG-3 expression and clinical outcomes following anti-LAG-3 and anti-PD-1-based immunotherapy in metastatic melanoma. LAG-3 immunohistochemistry (clone D2G4O) was performed on pre-treatment formalin-fixed, paraffin-embedded metastatic melanoma specimens from 53 patients treated with combination anti-LAG-3 + anti-PD-1-based therapies. Eleven patients had received prior anti-PD-1-based treatment. Patients were categorized as responders (complete/partial response; n = 36) or non-responders (stable/progressive disease; n = 17) based on the Response Evaluation Criteria in Solid Tumours (RECIST). Tumor-infiltrating lymphocytes (TILs) were scored on hematoxylin and eosin-stained sections. LAG-3 expression was observed in 81% of patients, with staining in TILs and dendritic cells. Responders displayed significantly higher proportions of LAG-3+ cells compared to non-responders (P = .0210). LAG-3 expression positively correlated with TIL score (P < .01). There were no significant differences in LAG-3 expression between different sites of metastases (P > .05). Patients with ≥ 1% LAG-3+ cells in their tumors had significantly longer PFS compared to patients with < 1% LAG-3 expression (P = .0037). No significant difference was observed in overall survival between the two groups (P = .1417). Therefore, the assessment of LAG-3 expression via IHC warrants further evaluation to determine its role as a predictive marker of response and survival in metastatic melanoma.

KEYWORDS:

• LAG-3
• biomarker
• immune checkpoint inhibitors
• immunotherapy
• melanoma

Acknowledgments

Support from The Ainsworth Foundation, CLEARbridge Foundation, Melanoma March, the Cameron Family, Lady Mary Fairfax Charitable Trust, Deborah McMurtrie and John McMurtrie AM and The Ross Trust as well as from colleagues at Royal Prince Alfred Hospital and Melanoma Institute Australia are gratefully acknowledged.

Disclosure statement

G.V.L. is consultant advisor for Agenus, Amgen, Array Biopharma, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Evaxion, Hexal AG (Sandoz Company), Highlight Therapeutics S.L., Innovent Biologics USA, Merck Sharpe & Dohme, Novartis, OncoSec, PHMR Ltd, Pierre Fabre, Provectus, Qbiotics, Regeneron. R.A.S. has received fees for professional services from MetaOptima Technology Inc., F. Hoffmann-La Roche Ltd, Evaxion, Provectus Biopharmaceuticals Australia, Qbiotics, Novartis, Merck Sharp&Dohme, NeraCare, AMGEN Inc., Bristol Myers Squibb, Myriad Genetics, and GlaxoSmithKline. A.M.M. is on the advisory board of BMS, Merck (MSD), Novartis, Roche, Pierre Fabre and Qbiotics. I.P.d.S. has received travel support from BMS and MSD, and speaker fees from Roche, BMS, MSD and Novartis. All remaining authors declare no conflicts of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Data availability statement

The data that support the findings of this study are available from the corresponding author, G.V.L., upon reasonable request.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/2162402X.2023.2261248

Additional information

Funding

This work was supported by Melanoma Institute Australia, the New South Wales Department of Health, NSW Health Pathology, National Health and Medical Research Council of Australia (NHMRC) and Cancer Institute NSW. This research was funded by the Cancer Council NSW Program Grant (RG-15). T.N.G. is supported by a CINSW Early Career Fellowship (2020/ECF1244). G.V.L. and R.A.S. are supported by NHMRC Investigator Grants (GNT2007839 and GNT2018514). J.S.W. is supported by an NHMRC Fellowship (APP1174325). G.V.L. is supported by the Melanoma Foundation of the University of Sydney through the University of Sydney Medical Foundation. A.M.M. is supported by Nicholas and Helen Moore and Melanoma Institute Australia. E.C.P. was supported by the BB and A Miller Foundation’s Jani Haenke Melanoma Pathology Fellowship through Melanoma Institute Australia. I.P.d.S. is supported by a CINSW Early Career Fellowship. Project funding was supported by the Cancer Council NSW (RG19-15), Cancer Institute NSW (TPG2114) and Perpetual Philanthropic Services (2020HIG141).