Montelukast as a novel therapeutic approach in metastatic uveal melanoma harboring a CYSLTR2 mutation: a translational case report.

[BACKGROUND] Uveal melanoma (UM), the most common primary intraocular malignancy in adults, has limited systemic treatment options in the metastatic setting. Recent insights into cysteinyl leukotriene receptors (CysLTRs)-particularly CYSLTR2 mutations (prevalence 2%-4%)-suggest new therapeutic approaches for patients who progress despite standard therapies.

[CASE] We report the case of a 59-year-old male with metastatic UM harboring a CYSLTR2 mutation. The patient experienced progression after multiple systemic treatments, including immune checkpoint inhibitors (ipilimumab/nivolumab, pembrolizumab), chemotherapy (dacarbazine, gemcitabine/treosulfan), and local radiotherapy. Lacking human leukocyte antigen-A∗02:01, he was ineligible for tebentafusp. In November 2022, next-generation sequencing identified a CYSLTR2 mutation. Based on molecular tumor board recommendation, off-label treatment with montelukast, a selective CysLT1 receptor antagonist, was initiated in March 2024. At that time, the patient had widespread metastases. Montelukast led to sustained disease stabilization for >12 months, with excellent tolerability and no reported adverse events. The observed effect may be explained by inhibition of CYSLTR1 and modulation of CYSLTR2 signaling in the mutated receptor context.

[CONCLUSION] This is the first published case suggesting a potential role for leukotriene receptor antagonists in CYSLTR2-mutant UM. These findings support further preclinical and clinical investigation of montelukast as a repurposed therapy in this challenging disease entity.