Purpose: irRECIST were designed to capture atypical responses seen with immunotherapy. We hypothesized that, in patients with metastatic clear cell Renal Cell Carcinoma (mccRCC), candidate biomarkers for nivolumab response would show improved association with clinical endpoints capturing atypical responders (irRECIST) compared to standard clinical endpoints (RECISTv1.1). Experimental Design: Endpoints based on RECISTv1·1 (ORR/PFS) or irRECIST (irORR/irPFS) were compared in patients enrolled in the CheckMate-010 trial. Pretreatment tumors were analyzed by PD-L1 and PD-L2 immunohistochemistry, and by multiplex-immunofluorescence for CD8, PD-1, TIM-3 and LAG-3. T-cell activation signatures were assessed by RNAseq. Results: Median irPFS was significantly longer than median PFS. irORR was not significantly different from ORR but irPD rate was significantly lower than PD rate. Tumor cell (TC) PD-L1 expression was not associated with PFS or ORR but patients with TC PD-L1 ≥ 1% had longer median irPFS and higher irORR. High percentage of CD8+ tumor infiltrating cells (TIC) that are PD-1+TIM-3-LAG-3- (% CD8+PD-1+TIM-3-LAG-3- TIC) correlated with high levels of T-cell activation and was associated with longer median irPFS and higher irORR. Notably, combination of TC PD-L1 expression with % CD8+PD-1+TIM-3-LAG-3- TIC identified 3 groups of patients for which irPFS and irORR were significantly different. Conclusions: Atypical responders to nivolumab were identified in the CheckMate-010 trial. We observed improved association of candidate biomarkers for nivolumab response with endpoints defined by irRECIST compared to RECISTv1.1. TC PD-L1 expression in combination with PD-1 expression on CD8+ TIC may predict outcome on nivolumab in mccRCC.
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