Immunotherapy Trumps TKI in Clear Cell RCC With Altered DDR Genes

San Francisco, California—Patients with metastatic clear cell renal cell carcinoma (RCC) and a loss of function in DNA damage repair (DDR) genes had better survival outcomes when treated with immunotherapy versus tyrosine kinase inhibitor (TKI) therapy, according to study results presented at the 2019 ASCO Genitourinary Cancers Symposium.

“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 [immune-oncology] therapies as shown in colon cancer,” explained lead investigator Yasser Ged, MBBS, MRCP, Memorial Sloan Kettering Cancer Center, New York, and colleagues, who added that the significance for standard immunotherapy and TKI treatments in patients with metastatic, clear cell RCC is not currently known.

Using the genomic data and treatment outcomes of 225 patients with metastatic, clear cell RCC from 2 large cohorts, Dr Ged and colleagues conducted a retrospective study comparing the use of pure immunotherapy (cohort 1, n = 107) with first-line TKI therapy (cohort 2, n = 118). Patients had their tumor and germline DNA tested using a panel that analyzed >400 genes of interest, including 34 DDR machinery genes.

Patients were classified as having altered DDR genes if there was a presence of truncating mutations, deletions, and functionally validated missense mutations; tumor mutational burden (TMB) was inferred for all patients. Dr Ged and colleagues used nonparametric tests to determine the relationship between DDR status, TMB, and treatment outcomes.

Of the 225 patients in the study, 37 (16%) had alterations in their DDR genes. However, only 23 (5%) patients had DDR germline alterations. ATM and CHEK2 were the most frequently altered genes (n = 8 for both genes).

Notably, a higher TMB correlated with altered DDR genes (Fisher’s exact test, P = .03). In addition, altered DDR status correlated significantly with longer overall survival (OS) in cohort 1 (hazard ratio [HR], 0.29; logrank P = .04) but not in cohort 2 (HR, 0.74; logrank P = .44).

“We found no interaction between objective response and DDR status in either cohort,” Dr Ged and colleagues said.

“Loss of function in DDR genes was associated with superior OS in IO [immunotherapy]-treated but not in TKI-treated RCC pts [patients]. Possible underlying mechanisms beyond increase in TMB observed here deserve further study,” they concluded.—Hina Khaliq

Ged Y, Chaim J, Knezevic A, et al. 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). Presented at: the 2019 Genitourinary Cancers Symposium; February 14-16, 2019; San Francisco, CA. Abstract 551.