Presentation Authors: Renzo DiNatale*, Chung-Han Lee, Diego Chowell, Vladimir Makarov, Almedina Redzematovic, Samuel Murray, Maria Carlo, Martin Voss, Jonathan Coleman, Paul Russo, Robert Motzer, Timothy Chan, Ari Hakimi, New York, NY
Introduction: Immune-checkpoint blockade (ICB) has shown efficacy across multiple malignancies, including clear cell Renal Cell Carcinoma (ccRCC). Biomarkers such as tumor mutation burden (TMB), neoantigen load and zygosity at the HLA class-I loci have been shown to be predictors of response in non-kidney neoplasms. However, they remain unvalidated in ccRCC. We aim to investigate the genomic biomarkers associated with ICB response in this setting.
Methods: Whole exome sequencing (WES) was performed on 27 pretreatment tumor derived DNA samples from patients treated at our institution. Additionally, data from 75 treated patients was obtained from publicly available WES datasets. Somatic mutations, TMB, neoantigen load, and HLA zygosity were called and analyzed with respect to objective response rate (ORR), progression free survival (PFS), and overall survival (OS) estimates. Continuous covariates were categorized into high and low groups using the median cut-off value for each parameter. All the data was processed using our previously-validated pipeline and commonly-used computational tools. Survival estimates were computed using the Kaplan-Meier method. A pre-rejection alpha level of 0.05 was set in advance of the analyses.
Results: We analyzed a total of 108 samples, 32 from patients treated with ipi/nivo and 76 with nivolumab only. No individual factor showed a significant association across both treatments. Some of the previously-reported biomarkers were found to be of prognostic significance in the ipi/nivo group, however, the findings could not be validated in the nivolumab cohort. When accounting for germline HLA-zygosity and TMB as a single predictor, we found that patients who were fully heterozygous at their HLA class-I loci and had tumors with high TMB, had a better PFS than homozygous patients (Cox, p=0.048, HR:1.72, 95%CI 1.00-2.76). This suggests that multiple factors are responsible for the likelihood of response to ICB therapy in ccRCC.
Conclusions: The predictors of response to combination immunotherapy may not be generalizable to the single-agent setting. No single factor could reliably predict response to therapy in metastatic ccRCC, multiple factors must be taken into account in order to understand ICB response.
Source of Funding: Clinical trial was funded by Bristol-Myers SquibbResearchers from the urology department received support through the NIH/NCI Cancer Center Support Grant P30 CA008748.