Effects of SMARCA-4 and LAG-3 expression on nivolumab response in metastatic renal cell cancer patients

Currently, for the management of metastatic renal cell cancer (RCC), the majority of treatment regimens include immunotherapy agents. At present, studies are ongoing in order to determine a biomarker that can indicate which patients may benefit from immunotherapy in metastatic RCC treatment. However, a biomarker has not yet been found and applied in clinical practice. The SMARCA-4 gene is part of the SWI/SNF chromatin remodeling gene, and there are some rare SMARCA-4-related cancer types for which small studies have indicated a positive response to immunotherapy. LAG-3 (Lymphocyte activation gene 3) is a newly discovered immune checkpoint inhibitor. Numerous studies are being conducted in order to discover its relevance in immunotherapy response and new LAG-3 based treatment agents. In our study, we aim to investigate the relation between nivolumab (anti-PD1) response and SMARCA-4 and LAG-3 expression in metastatic RCC patients. Tumor tissue samples of 72 metastatic RCC patients who received nivolumab treatment were immunohistochemically stained with SMARCA-4 and LAG-3. Nivolumab-related overall survival of the aberrant SMARCA-4 expression group was 41.1 months (95% CI 6.4-75.8), significantly higher than the normal SMARCA-4 expression group, which was 13.8 months (95% CI 0.0-28.2) (p=0.015). Nivolumab-related progression-free survival was 8.7 months (95% CI 1.2-16.3) in the aberrant SMARCA-4 expression group and 4.3 months (95% CI 2.9-5.7) in the normal SMARCA-4 expression group (p=0.01). It was not possible to describe statistically meaningful survival differences based on LAG-3 expression. In univariate analysis, normal SMARCA-4 expression was associated with a hazard ratio of 2.08 (95% CI 1.1-3.8) (p=0.018) for overall survival; however, in multivariate analysis, normal SMARCA-4 expression could not be identified as an independent risk factor. In conclusion, our study found that patients with tumors exhibiting aberrant SMARCA-4 expression had better clinical responses to nivolumab treatment; however, we did not find evidence to support its independent prognostic importance. Therefore, further studies are needed to investigate the potential relationship between SMARCA-4 and LAG-3 expression and their association with response to nivolumab.