Background Fifty percent of patients with uveal melanoma (UM) develop metastatic disease, surviving 6–12 months from metastatic diagnosis. Liver-directed therapies, immunotherapy, targeted therapy and chemotherapy have limited activity. Lymphocyte activation gene 3(LAG-3) is an immune checkpoint receptor associated with decreased T-cell effector function and tumor escape. Preclinical models have shown that dual inhibition of LAG-3 and PD-1 blockade generates synergistic anti-tumor activity.1 In uveal melanoma, CD8+ T cells express the checkpoint receptor LAG3 to a greater extent than PD1 or CTLA4.2 3 This recent discovery nominates LAG3 as a potential candidate for checkpoint inhibitor immunotherapy in UM.
Methods This is an open-label, single arm, single site investigator-initiated phase II study. Based on Simon two-stage minimax design, 13 patients will be enrolled in Stage 1. If at least one response is noted, the study will proceed to Stage 2 and enroll additional 14 patients. The null hypothesis will be rejected if 4 or more responses are observed among 27 patients. This design achieves 5% type I error and 80% power when the true ORR is 20%.Main eligibility criteria includes patients with biopsy proven metastatic uveal melanoma, previously untreated with PD-1, CTLA-4 and/or LAG-3 blocking antibodies and in good performance status.Enrolled patients will be treated in the outpatient setting. Nivolumab 480 mg will be mixed in the same bag with relatlimab 160 mg and administered intravenously over 60 minutes every 4 weeks until disease progression or intolerable toxicity for up to 24 months.The primary endpoint is best objective response rate (ORR). Secondary endpoints include disease control rate (DCR), progression-free survival (PFS), overall survival (OS), median duration of response (mDOR), and adverse events (AEs). Correlative studies will evaluate pre- and post-treatment characteristics of T cells in the tumor microenvironment and blood.
Ethics Approval The study was approved by the University of Miami Sylvester Cancer Center PRMC #20200847
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): p. 917–27.
Durante MA, Rodriguez DA, Kurtenbach S, et al. Single-cell analysis reveals new evolutionary complexity in uveal melanoma. Nat Commun2020;11(1):496. Published 2020 Jan 24. doi:10.1038/s41467-019-14256-1
Karlsson J, Nilsson LM, Mitra S, et al. Molecular profiling of driver events in metastatic uveal melanoma. Nat Commun2020;11(1):1894. Published 2020 Apr 20. doi:10.1038/s41467-020-15606-0
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