Evaluation of tumor microenvironment and biomarkers of immune checkpoint inhibitor (ICI) response in metastatic renal cell carcinoma (mRCC).
Zhu, J; Pabla, S; Labriola, M; Gupta, RT; McCall, S; George, DJ; Dressman, D; Glenn, ST; Nesline, M; George, S; Morrison, C; Zhang, T
Published in: Journal of Clinical Oncology
63 Background: ICIs are now standard of care for mRCC; however, there are few biomarkers to predict ICI response. Recent data from atezolizumab/bevacizumab trials in mRCC suggest tumors with high T/PD-L1+ are more likely to respond to ICI. Here, we use this T gene panel as well as other markers of inflammation in the tumor microenvironment to correlate with ICI responses. Methods: This multicenter study evaluated 69 pts with mRCC treated with ICIs. FFPE tumor samples were evaluated by RNA sequencing to measure transcript levels of genes related T status. T status was defined as the mRNA expression of 17 genes (CD8, CD27, IFNG, GZMA, GZMB, PRF1, EOMES, CXCL9, CXCL10, CXCL11, CD274, CTLA4, FOXP3, TIGIT, IDO1, PSMB9, TAP1), with T separated at the median. PD-L1 positivity was defined as ≥1% TPS based on Dako 22C3 IHC assay, and TMB high as > 10 mutations per megabase. Inflamed tumors were defined as CD8 expression in the top 75th percentile compared to a large reference population of multiple tumor types. Best responses to ICI was determined by an expert radiologist using RECIST 1.1 criteria. Inflamed tumor status, T gene expression, PD-L1 positive, and TMB were associated with disease control (DC, defined as CR, PR, or stable disease). DC comparisons were tested using a chi-squared test with Yates’s continuity correction. Results: DC was 63% (5/8) amongst PD-L1 positive pts and 52% (31/60) in PD-L1 negative patients (p = 0.84). Only 2 pts were TMB high. The majority of mRCC tumors (97%, 67/69) were TMB low. 6-month DC in TMB high tumors was 50% (1/2) and 49.3% (33/67) in TMB low tumors (p = 1.0). 36 pts were classified as T and 33 patients were classified as T. 6-month DC was 61% (22/36) in the T cohort and 36% (12/33) in the T cohort (p = 0.069). 6-month DC was 64% of inflamed tumors (16/25) vs 41% of non-inflamed tumors (18/44) (p = 0.111). Conclusions: TMB high and PD-L1 expression do not reliably predict for DC in pts with mRCC. Utilizing a gene signature score may better predict ICI response.
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