Alterations in DNA damage repair (DDR) genes and outcomes to systemic therapy in 225 immune-oncology (IO) versus tyrosine kinase inhibitor (TKI) treated metastatic clear cell renal cell carcinoma (mccRCC) patients (pts).

Abstract

551 Background: Loss of function alterations in DDR genes including core components of mismatch repair and homologous recombination deficiency pathways are associated with tumorigenesis and may determine benefit from IO therapies as shown in colon cancer. The significance for standard IO and TKI treatments in mccRCC is unknown. Methods: Genomic data and treatment outcomes were retrospectively collected for two large cohorts of mccRCC: pts treated with pure IO therapy (cohort 1); and pts receiving first-line TKI (cohort 2). Tumor and germline DNA was subject to targeted panel testing across >400 genes of interest, including 34 DDR machinery genes. Presence of truncating mutations, deletions and functionally validated missense mutations identified individual patient as ‘DDR altered’ (DDRa). Tumor mutational burden (TMB) was inferred for all pts. Non-parametric tests were applied to determine association between DDR status, TMB and treatment outcomes. Results: 225 pts were included (cohort 1=107, cohort 2=118), 37 (16%) were DDRa. Most commonly altered genes were ATM (n=8, 4%) and CHEK2 (n=8, 4%). DDR germline alterations were seen in 12 pts (5%). Median TMB was 4.1 per megabase (range: 0-21.7), and higher TMB (≥ median) was associated with being DDRa (Fisher’s exact, p=0.03). DDRa status correlated significantly with longer overall survival (OS) in the IO cohort (HR 0.29, logrank p=0.04) but not in the TKI cohort (HR 0.74, logrank p=0.44). We found no interaction between objective response and DDR status in either cohort. Conclusions: Loss of function in DDR genes was associated with superior OS in IO-treated but not in TKI-treated RCC pts. Possible underlying mechanisms beyond increase in TMB observed here deserve further study. [Table: see text]