ASCO 2020: Immunogenomic Characterization of Advanced Clear Cell Renal Cell Carcinoma Treated with PD-1 Blockade

(UroToday.com) Relative to other solid tumors that respond to immune checkpoint inhibitors (ICI), clear cell renal carcinoma has a modest tumor mutational burden and increased infiltration of CD8+ T cells is associated with worse prognosis in this disease. Biomarkers for response to ICI are needed to predict which patients will respond. David A. Braun, MD, Ph.D., and colleagues explored the genomic and immune determinants of response to PD-1 axis blockade in advanced clear cell renal carcinoma using samples from patients enrolled on three prospective trials of nivolumab: (1) phase 1 Checkmate 009, (2) phase 2 Checkmate 010, and (3) phase 3 CheckMate 025 with everolimus as a control arm. All patients in these studies had received prior anti-angiogenic tyrosine kinase inhibitors. These results have also been recently published in a manuscript.1


No differences were observed in somatic alteration burden as assessed by tumor mutational burden or overall copy number changes. Loss of function mutations in PBRM1 was significantly enriched across all patients treated with nivolumab and was significantly associated with overall survival.  
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Using immunofluorescence, the authors characterized the extent of CD8+ T cell infiltration in 219 tumors. Of the cohort, 5% of cases were classified as “T-cell excluded”, 22% were “T-cell deserts”, and 73% were “T-cell infiltrated”. Baseline T-cell infiltration was not associated with response to nivolumab or overall survival. 

The authors then looked for associations between T-cell infiltration status and genomic alterations. They discovered that PBRM1 mutation were enriched in tumors with a T-cell excluded or desert phenotype. 
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At the copy-number level, T-cell infiltrated tumor cells revealed numerous copy number alterations relative to T-cell desert or excluded tumors. Of these, the deletion of chromosome 9p21.3 was significantly associated with poorer response to nivolumab relative to patients diploid at this locus.
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These findings together suggest a model explaining why T-cell infiltrated clear cell renal carcinoma tumors do not respond better to immunotherapy despite theoretically being primed to respond due to the presence of cytotoxic T-cells. Specifically, they lack PBRM1 mutations, which are associated with a positive response, and have a genomic loss of chromosome 9p21.3, which is negatively associated with response to nivolumab. Further work is required to characterize the mechanisms whereby these genomic findings impact tumor response to ICI.   

Presented by: David A. Braun, MD, Ph.D., Instructor in Medicine and Physician, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA

Written by: Alok Tewari, MD, Ph.D., Medical Oncology Fellow at the Dana-Farber Cancer Institute, Boston, Massachusetts, at the 2020 American Society of Clinical Oncology Virtual Annual Meeting (#ASCO20), May 29th-May 31st, 2020

References: 
  1. Braun, D.A., Hou, Y., Bakouny, Z. et al. Interplay of somatic alterations and immune infiltration modulates response to PD-1 blockade in advanced clear cell renal cell carcinoma. Nat Med (2020). https://doi.org/10.1038/s41591-020-0839-y
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