Metastatic Clear-cell Renal Cell Carcinoma With a Long-term Response to Sunitinib: A Distinct Phenotype Independently Associated With Low PD-L1 Expression.

Abstract

Long-term responders (LTRs) are defined by at least 18 months of response to sunitinib in metastatic clear-cell renal cell carcinoma (ccRCC). Well-described by clinical studies, the phenotype of these tumors has never been explored. In a retrospective and multicenter study, 90 ccRCCs of patients with metastatic disease were analyzed. Immunohistochemistry (carbonic anhydrase IX, vascular endothelial growth factor, c-MET, programmed death-ligand 1 [PD-L1], and PD-1) and VHL status were performed. Progression-free survival and overall survival were calculated from sunitinib introduction and from progression. LTRs and their corresponding tumors were compared with others using univariate and multivariate analysis. Twenty-eight patients were LTRs. They had a median progression-free survival of 28 months versus 4 months for other patients (P< .001). Similarly, LTRs had a median overall survival of 49 months versus 14 months (P< .001), even from progression (median, 21 vs. 7 months; P= .029). They were associated with a favorable or intermediate risk (International Metastatic Renal Cell Carcinoma Database Consortium model) (P= .007) and less liver metastasis (P= .036). They experienced more frequent complete or partial responses at the first radiologic evaluation (P=.035). The corresponding ccRCCs were associated with less nucleolar International Society for Urological Pathology grade 4 (P= .037) and hilar fat infiltration (P= .006). They were also associated with low PD-L1 expression (P= .02). Only the International Metastatic Renal Cell Carcinoma Database Consortium model and PD-L1 expression remained significant after multivariate analysis (P= .014 and P= .029, respectively). Primary tumor characteristics of LTRs were studied for the first time and demonstrated a different phenotype. Interestingly, they were characterized by low expression of PD-L1, suggesting a potentially lower impact of targeted immunotherapy in these patients.