Immune landscape of patients with metastatic non-clear cell renal cell carcinoma (nccRCC) treated with atezolizumab plus bevacizumab.
Authors: Saliby Renee Maria , El Zarif Talal , Bakouny Ziad , Xie Wanling , Flippot Ronan , Denize Thomas , Shah Valisha , Kane Harry , Madsen Katrine , Harshman Lauren C , Vaishampayan Ulka N. , McDermott David F. , Lee Gwo-Shu Mary , Xu Wenxin , Van Allen Eliezer Mendel , McGregor Bradley Alexander , Signoretti Sabina , Choueiri Toni K. , McKay Rana R. , Braun David A. 
Published: June 2023

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Background: The treatment of metastatic nccRCC remains an area of unmet clinical need. A multicenter phase II trial of atezolizumab/bevacizumab in patients with advanced nccRCC or any RCC type with ≥ 20% sarcomatoid differentiation (NCT02724878) demonstrated clinical activity of these agents, with objective response rates of 50% in patients with sarcomatoid clear-cell RCC (sccRCC) and 26% in patients with nccRCC. We aim to understand the intratumoral and circulating factors that impact immunotherapy response in this population. Methods: We collected blood samples prior to therapy and on-treatment (following 2 cycles of therapy) and quantified levels of plasma soluble factors (cytokines and growth factors) using a fluorescent bead array platform. We used high dimensional flow cytometry on peripheral blood mononuclear cells to analyze the composition and phenotype of peripheral immune cells. Immunohistochemistry and immunofluorescence were performed on available formalin-fixed, paraffin-embedded tumor tissue samples (archival or on-study biopsy) collected prior to the start of therapy. We assessed relationships between biomarkers and outcomes using pairwise Wilcoxon rank-sum test and log-rank tests, and univariate Cox regression models. Results: We collected blood samples from 60 patients with paired tumor samples from 38 patients. Baseline circulating inflammatory cytokines MIP-1b, IL-1, MCP-1, IL-6, and IL-13 were highly correlated with one another, forming an “inflammatory module” that was increased in IMDC-poor risk patients and associated with worse progression-free survival (PFS) (p = 0.028). At baseline, elevated circulating VEGF-A was associated with a lack of response (p=0.03) and worse PFS (p=0.021). Whereas a larger increase in on-treatment levels of circulating VEGF-A was associated with clinical benefit as defined by Braun et al. (Nat Med. 2020) (p=0.01) and improved overall survival (p=0.006). Among peripheral immune cell populations, an on-treatment decrease in circulating PD-L1+ T cells was associated with improved outcomes: reductions in CD4+ PD-L1+ (HR:0.62[0.49-0.91], p=0.016) and CD8+ PD-L1+ T cells (HR:0.59[0.39-0.87], p=0.009) correlated with improved PFS. Within the tumor, a higher percentage of terminally exhausted (PD-1+, TIM-3+ and/or LAG-3+) CD8+ T cells at baseline was associated with worse PFS (p=0.028). Conclusions: Among patients with advanced nccRCC or sccRCC, a baseline high systemic inflammatory state and high circulating VEGF-A are associated with worse outcomes after treatment with atezolizumab and bevacizumab. High levels of intratumor terminally exhausted CD8+ T cells were associated with worse PFS. These results highlight the importance of an integrative approach to explore biomarkers of response in advanced variant histology RCC which may inform future therapeutic approaches.