Background: Adjuvant therapy with sunitinib (SU) compared with placebo (PBO) prolonged disease-free survival (DFS) in patients (pts) with loco-regional high-risk renal cell carcinoma (HR=0.76, 95% CI: 0.59-0.98; P=0.03; median[m] DFS, 6.8 vs 5.6 years). Here, we report the results of a retrospective exploratory molecular biomarker analysis using nephrectomy biospecimens from the S-TRAC trial.

Materials and Methods: Formalin-fixed paraffin-embedded tumor tissue blocks from patients who provided informed consent were used for immunohistochemistry (IHC) staining of PD-L1, CD4, CD8, and CD68. Biomarker quantification was done by automated image analysis of the regions of interest (ROI). The analysis algorithm utilized an immunoscore approach applied to ROI, reflecting assessment of both the center and invasive margin of tumors (for PD-L1 and CD8 staining). DFS was compared between biomarker stratum by < median vs ≥ median values of a particular IHC parameter using Kaplan-Meier (K-M) analysis. Receiver Operating Characteristics (ROC) curves were generated to further assess the potential clinical utility of biomarkers for which significant (P < 0.05) results were obtained in K-M analysis.

Results: In total, 191/615 (101, SU and 90, PBO) pts in the intent-to-treat population were included for IHC analysis. Baseline characteristics were similar in the subpopulations with and without IHC data. Shorter DFS was observed in the PBO group for pts with PD-L1+ vs PD-L1- tumors, although not statistically significant (HR=1.75; 95% CI: 0.89-3.46; P=0.103). In pts with PD-L1+ tumors, DFS was numerically longer for SU vs PBO (mDFS=6.17 vs 2.67 years) (HR=0.58; 95% CI: 0.26-1.29; P=0.175). In the SU group, pts with CD8+ T-cell density ≥ median (cutoff=269.5 CD8+ cells/mm2) had longer DFS (mDFS=not reached [NR]; 95% CI: 6.83-NR) than pts with CD8+ T-cell density < median (mDFS=3.47 years; 95% CI: 1.73-NR), and the difference was statistically significant (HR=0.40, 95% CI: 0.20-0.81; P=0.009), while CD8+ T-cell density showed no significant difference in DFS for PBO pts (HR=0.80, 95% CI: 0.42-1.50; P=0.484). The sensitivity and specificity for CD8+ T-cell density in predicting DFS were 0.604 and 0.658, respectively, and the optimal cutoff was 222.22 cells/mm2 with an area under ROC curve of 0.622.

Conclusions: Increased density of CD8+ T-cells in tumor tissue was associated with longer DFS in SU-randomized pts but not PBO, suggesting this may be predictive of treatment effect. Further validation in an independent cohort is warranted. The prognostic value of PD-L1 expression in primary tumors from patients with high-risk non-metastatic RCC should be further explored.

Citation Format: Daniel J. George, Jean-Francois Martini, Yen-Hwa Chang, Michael Staehler, Jan Breza, Jean-Jacques Patard, Robert J. Motzer, Ahmed Magheli, Bernard Escudier, Giacomo Carteni, Paola Gerletti, Sherry Li, Michelle Casey, Brigitte Laguerre, Hardev S. Pandha, Allan J. Pantuck, Anup Patel, Maria Lechuga, Alain Ravaud. Phase 3 trial of adjuvant sunitinib in patients with high-risk renal cell carcinoma: exploratory molecular analysis of tumor biomarkers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1771. doi:10.1158/1538-7445.AM2017-1771