Correlation of PD-L1 Tumor Expression and Treatment Outcomes in Patients with Renal Cell Carcinoma Receiving Sunitinib or Pazopanib: Results from COMPARZ, a Randomized Controlled Trial

Purpose: The interaction of programmed death-1 ligand (PD-L1) with its receptor (PD-1) on T cells inactivates antitumor immune responses. PD-L1 expression has been associated with poor outcomes in renal cell carcinoma (RCC) but has not been investigated in advanced RCC patients receiving vascular endothelial growth factor (VEGF)-targeted therapy. Experimental Design: Formalin-fixed paraffin-embedded (specimens were collected at baseline from patients in the COMPARZ trial. Tumor cell PD-L1 expression by immunohistochemistry was evaluated using H-score (HS). Dual PD-L1/CD68 staining was used to differentiate PD-L1 tumor expression from tumor-associated macrophages. Intratumor CD8-positive T cells were quantified morphometrically. Associations between biomarkers and survival were investigated using the log-rank test. Results: HS data were available from 453 of 1110 patients. Sixty-four percent of patients had negative PD-L1 expression (HS=0). Patients with HS>55 (n=59, 13%) had significantly shorter overall survival (OS) than those with HS=55 in both pazopanib and sunitinib arms (median 15.1 vs 35.6 and 15.3 vs 27.8 months, respectively, P=0.03). In both arms, median OS was shortest in patients with HS>55 and intratumor CD8-positive T-cell counts >300 (9.6 and 11.9 months with pazopanib and sunitinib, respectively). Median OS in patients with HS=55 and CD8-positive T-cell counts =300 was 36.8 and 28.0 months with pazopanib and sunitinib, respectively. Progression-free survival results were similar to OS results. Conclusions: Increased tumor cell PD-L1, or PD-L1 plus tumor CD8-positive T-cell counts, were associated with shorter survival in metastatic RCC patients receiving VEGF-targeted agents. These findings may have implications for future design of randomized clinical trials in advanced RCC.