Evaluation of tumor microenvironment and biomarkers of immune checkpoint inhibitor response in metastatic renal cell carcinoma

• DOI: 10.1136/jitc-2022-005249
• Publication Date: 2022-10-17T15:13:00Z
• Authors: Landon C Brown; Jason Zhu; Kunal Desai; Emily Kinsey; Chester Kao; Yong Hee Lee; Sarabjot Pabla; Matthew K Labriola; Jennifer Tran; Konstantin H Dragnev; Laura J Tafe; Farshid Dayyani; Rajan T Gupta; Shannon McCall; Daniel J George; Sean T Glenn; Mary K Nesline; Saby George; Matthew Zibelman; Carl Morrison; Moshe C Ornstein; Tian Zhang
• Keywords: Immune checkpoint

Background Immunotherapy combinations including ipilimumab and nivolumab are now the standard of care for untreated metastatic renal cell carcinoma (mRCC). Biomarkers response lacking to predict patients who will have a favorable or unfavorable immunotherapy. This study aimed use OmniSeq transcriptome-based platform develop biomarkers Methods Two cohorts were retrospectively collected. These included an investigational cohort with mRCC treated immune checkpoint inhibitor therapy from five institutions, subsequent validation combination two institutions (Duke Cancer Institute Cleveland Clinic Taussig Center). Tissue-based RNA sequencing was performed using Immune Report Card on banked specimens identify gene signatures checkpoints associated differential clinical outcomes. A 5-gene expression panel developed based subsequently evaluated in cohort. Clinical outcomes progression-free survival (PFS) overall (OS) extracted by retrospective chart review. Objective rate (ORR) assessed Response Evaluation Criteria Solid Tumors (RECIST) V.1.1. Results The initial investigation identified 86 received (80%, 69/86), ipilimumab/nivolumab (14%, 12/86), pembrolizumab (6%, 5/86). score created top genes found responders versus non-responders (FOXP3, CCR4, KLRK1, ITK, TIGIT). ORR high (GE ) 29% (14/48), compared low 3% (1/38, χ 2 p=0.001). comprised 62 ipilimumab/nivolumab. There no difference between GE terms (44% vs 38.5%), PFS (HR 1.5, 95% CI 0.58 3.89), OS 0.96, 0.51 1.83). Similarly, differences ORR, observed when stratified tumor mutational burden (high=top 20%), PD-L1 (programmed death-ligand 1) immunohistochemistry expression, CTLA-4 (cytotoxic T-lymphocytes-associated protein 4) expression. International Metastatic RCC Database Consortium (IMDC) risk prognostic but not PFS. Conclusion that improved predominantly monotherapy population predictive radiographic response, PFS, among nivolumab.