The Association Between PD‐L1 Expression and the Clinical Outcomes to Vascular Endothelial Growth Factor‐Targeted Therapy in Patients With Metastatic Clear Cell Renal Cell Carcinoma

Background. Vascular endothelial growth factor pathway (VEGF)‐tyrosine kinase inhibitors (TKIs) are used as the first‐line treatment for patients with metastatic clear cell renal cell carcinoma (mCCRCC). Recently, programmed death‐1 (PD‐1) and programmed death ligand‐1 (PD‐L1) blockade emerged as promising therapy for renal cell carcinoma. However, the expression pattern and prognostic implication of programmed death‐ligands (PD‐Ls) in mCCRCC patients receiving VEGF‐TKI remain unclear. Patients and Methods. PD‐L1 and PD‐L2 expression in tumor cells and the quantities of PD‐1+ tumor‐infiltrating lymphocytes were immunohistochemically evaluated in 91 mCCRCC patients treated with VEGF‐TKI, and their associations with VEGF‐TKI responsiveness and clinical outcome were analyzed. Results. PD‐L1 immunopositivity was observed in 17.6% and significantly associated with a high International Society of Urological Pathology grade (p = .031) and sarcomatoid features (p = .014). PD‐L2 immunopositivity was observed in 39.6% and was not associated with any of the assessed clinicopathological variables. PD‐L1‐positive cases showed poor VEGF‐TKI responsiveness (p = .012) compared with PD‐L1‐negative cases. In univariate survival analysis, PD‐L1 immunopositivity was significantly associated with shorter overall survival (OS) (p = .037) and progression‐free survival (PFS) (p = .043). Multivariate survival analysis revealed that PD‐L1 expression was independently associated with poor OS (p = .038) and PFS (p = .013) in addition to tumor necrosis (p = .006; p = .029, respectively) and Memorial Sloan Kettering Cancer Center score (p = .018; p = .032, respectively). PD‐L2 expression was neither associated with VEGF‐TKI responsiveness nor patients’ outcome. Conclusion. PD‐L1 expression was significantly related to lack of VEGF‐TKI responsiveness and independently associated with shorter survival in mCCRCC patients after VEGF‐TKI treatment. PD‐L1 may have a predictive and prognostic value for determining the value of VEGF‐TKI treatment in patients with mCCRCC. Implications for Practice: Vascular endothelial growth factor pathway (VEGF)‐tyrosine kinase inhibitors (TKIs) are essential for the treatment of metastatic renal cell carcinoma patients, but the treatment suffers from a lack of predictive markers. This study demonstrates that PD‐L1 expression is a predictor for unfavorable response to VEGF‐TKI and a prognostic indicator for poor overall survival and progression‐free survival