Abstract 1312: Identifying the genomic correlates of clinical benefit (CB) from immunotherapies (IO) and vascular endothelial growth factor-tyrosine kinase inhibitors (VEGF-TKI) in metastatic renal cell carcinoma (mRCC)
Authors: Dizman Nazli , Byron Sara , Lyou Yung , Bergerot Paulo Gustavo , Hsu JoAnn , Sam Andre-Philippe , Trieu Denise Phan , Trent Jeffrey , Pal Sumanta Kumar 
Published: September 2020

Background: Along with the expanding treatment landscape of mRCC, a substantial need for ways to predict individual patients' (pts) benefit from different therapies has emerged. Recent studies highlight the clinical significance of tumor-specific genomic alterations, revealing a prognostic and/or predictive role of PBRM1 mutations with IO in mRCC (Miao et al Nature 2018). Employing a large institutional database, we aimed to identify genomic correlates of CB from IO and VEGF-TKIs in mRCC. Methods: Consecutive pts who underwent genomic profiling (GP) as part of routine clinical care at the City of Hope Comprehensive Cancer Center were retrospectively identified. GP included the GEM ExTra assay, a clinical tumor-normal whole exome sequencing and tumor whole transcriptome sequencing test performed at Ashion Analytics (Phoenix, AZ), a CAP-accredited, CLIA-certified laboratory. The clinical database included detailed information regarding demographics, treatment, response and survival outcomes. Pts who had complete response (CR), partial response (PR) or stable disease (SD) for &gt;6 months were considered as having CB. Progressive disease (PD) as best response was considered no clinical benefit (NCB). Genomic findings were compared between pts with CB and NCB in the IO and VEGF-TKI cohorts. Results: Among the 58 (45:13 M:F) pts, 17 received sequencing treatment involving both a VEGF-TKI and IO, resulting in 32 pts in the IO cohort and 43 pts in the VEGF-TKI cohort. The most commonly used IO and VEGF-TKIs were nivolumab (59%) and sunitinib (40%). CB rate and median progression free survival were 59.4% (CR: 3.1%, PR: 18.8%, SD: 37.5%) and 15.6 months (95%CI NR-NR) in the IO cohort, and 86% and 14.2 months (95%CI 9.0 - 18.5) in the VEGF-TKI cohort. The most frequently detected alterations in the overall cohort were in VHL (64%), PBRM1 (38%), SETD2 (24%), KDM5C (17%) and TERT (12%). Interestingly, TERT promoter mutations and PBRM1 mutations were found to be mutually exclusive. In both IO and VEGF-TKI cohorts, tumor mutational burden did not differ between CB and NCB pts. No single genes were significantly associated with CB from VEGF-TKIs. While PBRM1 loss of function (LOF) was more common in IO pts with CB, and SETD2, KDM5C, TP53 alteration were more common in IO pts with NCB, there was no statistical significance observed (p values &gt; 0.05). TERT promoter mutations were associated with NCB in the IO cohort (p=0.038). TERT promoter mutant tumors did not have CB with IO. Conclusion: Our analysis found that TERT promoter mutations are enriched in pts with NCB from IO and were mutually exclusive with PBRM1 LOF which had previously been shown to be an indicator of IO sensitivity. These results suggest that TERT promoter mutations may be a negative predictor of IO outcomes, which warrants future investigations with a larger sample size.

Citation Format: Nazli Dizman, Sara Byron, Yung Lyou, Paulo Gustavo Bergerot, JoAnn Hsu, Andre-Philippe Sam, Denise Phan Trieu, Jeffrey Trent, Sumanta Kumar Pal. Identifying the genomic correlates of clinical benefit (CB) from immunotherapies (IO) and vascular endothelial growth factor-tyrosine kinase inhibitors (VEGF-TKI) in metastatic renal cell carcinoma (mRCC) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1312.