Extensive plasma proteomic profiling revealed receptor activator of nuclear factor kappa-Β ligand (RANKL) as emerging biomarker of nivolumab clinical benefit in patients with metastatic renal cell carcinoma

BACKGROUND: The advent of immune checkpoint inhibitors (ICIs) have led to a paradigm change in the management of metastatic renal cell carcinoma (mRCC), nevertheless, the benefit of treatment is confined to a limited proportion of patients. Therefore, the identification of predictive biomarkers for response to ICIs represents an unmet clinical need. Here, we performed a large-scale plasma proteomic profile of patients with mRCC, treated with nivolumab, to identify soluble molecules potentially associated with clinical benefit. METHODS: We analyzed the levels of 507 soluble molecules in the pretreatment plasma of 16 patients with mRCC (discovery set) who received nivolumab therapy as a single agent. The ELISA assay was performed to confirm the protein level of candidate biomarkers associated to clinical benefit in 15 patients with mRCC (validation set). Survival curves of complete cohort were estimated by the Kaplan-Meier method and compared with the log-rank test. RESULTS: Out of 507 screened molecules, 135 factors were selected as expressed above background and 12 of them were significantly overexpressed in patients who did not benefit from treatment (non-responders (NR)) compared with responders (R) group. After multiplicity adjustment, receptor activator of nuclear factor kappa-Β ligand (RANKL) was the only molecule that retained the statistical significance (false discovery rate: 0.023). RANKL overexpression in NR patients was confirmed both in discovery (median NR: 528 pg/mL vs median R: 288 pg/mL, p=0.011) and validation set (median NR: 440 pg/mL vs median R: 253 pg/mL, p<0.001). Considering the complete cohort of patients (discovery+validation set), significantly higher RANKL levels were found in patients who primarily progressed from treatment compared with those who had a partial response (p=0.003) or stable disease (p=0.006). Moreover, patients with low RANKL levels had significant improvements in progression-free survival (median 14.0 months vs 3.4 months, p=0.004) and overall survival (median not reached vs 30.1 months, p=0.003). CONCLUSIONS: Our exploratory study suggests RANKL as a novel independent biomarker of response and survival in patients with mRCC treated with nivolumab.