Immune Biomarkers Predictive for Disease-Free Survival with Adjuvant Sunitinib in High-Risk Locoregional Renal Cell Carcinoma: From Randomized Phase III S-TRAC Study

Abstract

Adjuvant sunitinib therapy compared with placebo prolonged disease-free survival (DFS) in patients with locoregional high-risk renal cell carcinoma (RCC) in the S-TRAC trial (ClinicalTrials.gov number NCT00375674). A prospectively designed exploratory analysis of tissue biomarkers was conducted to identify predictors of treatment benefit. Tissue blocks were used for immunohistochemistry (IHC) staining of programmed cell death ligand 1 (PD-L1), CD4, CD8, and CD68. DFS was compared between < versus ≥ median IHC parameter using the Kaplan-Meier method. For biomarkers with predictive potential, receiver operating characteristics curves were generated. Baseline characteristics were similar in patients with ( = 191) and without ( = 419) IHC analysis. Among patients with IHC, longer DFS was observed in patients with tumor CD8 T-cell density ≥ versus < median [median (95% CI), not reached (6.83-not reached) versus 3.47 years (1.73-not reached); hazard ratio (HR) 0.40 (95% CI, 0.20-0.81); = 0.009] treated with sunitinib ( = 101), but not with placebo ( = 90). The sensitivity and specificity for CD8 T-cell density in predicting DFS were 0.604 and 0.658, respectively. Shorter DFS was observed in placebo-treated patients with PD-L1 versus PD-L1 tumors (HR 1.75; = 0.103). Among all patients with PD-L1 tumors, DFS was numerically longer with sunitinib versus placebo (HR 0.58; = 0.175). Greater CD8 T-cell density in tumor tissue was associated with longer DFS with sunitinib but not placebo, suggesting predictive treatment effect utility. Further independent cohort validation studies are warranted. The prognostic value of PD-L1 expression in primary tumors from patients with high-risk nonmetastatic RCC should also be further explored. .

Validation of the 16-Gene Recurrence Score in Patients with Locoregional, High-Risk Renal Cell Carcinoma from a Phase III Trial of Adjuvant Sunitinib

“…The immune response group and one of vascular normalization genes reached nominal statistical significance although no adjustment for multiple comparison was made. These findings appear to be consistent with sunitinib having both antiangiogenic and possibly immunomodulatory effects (20,21) but would warrant further research. The current study has limitations.…”

Rapid progression of recurrent disease in a patient with renal cell carcinoma with vaginal metastasis

“…6,7 However, George et al reported that increased abundance of CD8-positive T cells in tumor tissue was associated with increased disease-free survival of patients with sunitinib adjuvant therapy. 8 MTT increased the infiltration of CD4-positive and CD8-positive T lymphocytes. However, immune cell reactions were evident as tumor grade/biological malignancy progressed, possibly because of the increased antigenicity of the tumor cells.…”

Checkpoint molecule PD-1-assisted CD8⁺ T lymphocyte count in tumor microenvironment predicts overall survival of patients with metastatic renal cell carcinoma treated with tyrosine kinase inhibitors

“…However, the prognostic value of PD-L1 expression in high-risk locoregional RCC had no significance. 18 A meta-analysis indicates that a higher level of PD-L1 expression is a negative prognostic factor in RCC. 19 …”