Characterization of tumor mutational burden (TMB), PD-L1, and DNA repair genes to assess correlation with immune checkpoint inhibitors (ICIs) response in metastatic renal cell carcinoma (mRCC).

Abstract

589 Background: ICIs have revolutionized treatment for mRCC; however there are limited predictive biomarkers for response to ICIs. PD-L1 status is still controversial demonstrating little predictive utility in mRCC. TMB is predictive for response to ICIs in melanoma and non-small cell lung cancer (NSCLC), but has not been validated in mRCC. Here, we assess the correlations between TMB and PD-L1 status with outcomes to ICI treatment in mRCC. Methods: 34 patients (pts) with mRCC who had previously received ICI therapy at Duke Cancer Institute were identified. Tumor samples were retrospectively evaluated using a Personal Genome Diagnostics Assay for somatic variants across > 500 genes, as well as TMB and microsatellite status. Tumor samples were also analyzed with the Dako 28-8 PD-L1 IHC assay. Deidentified clinical information was extracted from the medical record and tumor response was evaluated based on RECIST criteria. Results: Pts were grouped by overall response following ICI therapy into either progressive disease (“PD”, n = 18) or disease control group (“DC”, n = 16), defined as either stable disease, partial response, or complete response. Pts displayed a TMB range from 0.36 to 12.24 mutations/Mb with a mean score of 2.83 muts/Mb, with no significant difference between the PD and DC groups (mean 3.01 muts/Mb vs. 2.63 muts/Mb, p > 0.05). 9 of 32 evaluable samples were PD-L1 positive, with 4 in the PD group and 5 in the DC group. Notably, the DC group displayed a significant enrichment of mutations in genes affiliated with DNA repair (including BRCA1, BRCA2, FANCA, FANCB, FANCG, FANCM, MSH3, MSH6, RAD50, RAD51C, RAD51D, RAD54B, RECQL4, and SLX4; p = 0.0444). Conclusions: Overall, in this mRCC cohort, neither TMB nor PD-L1 correlated with patient outcomes or with ICI response. Furthermore, high TMB was not significantly associated with PD-L1 expression within the samples. The higher frequency of mutations in DNA repair genes in the DC group suggests potential use as a predictive signature for ICI response, warranting future prospective studies.

https://cdrjournal.com/article/view/3531

“…Special attention should be given to mRCC because no positive correlation between tumor mutational burden and ICI response was observed in this tumor type. In a small cohort of 34 patients, Labriola et al [36] showed that neither tumor mutational burden nor PD-L1 expression was correlated with patient outcomes or with ICI response [36] . Interestingly, Turajlic et al [37] showed that ccRCC tumors harbour the highest rate of insertion-deletion (indels) DNA alterations, leading to one of the highest neoantigenicity potential.…”

“…In a small cohort of 34 patients, Labriola et al . [ 36 ] showed that neither tumor mutational burden nor PD-L1 expression was correlated with patient outcomes or with ICI response [ 36 ] . Interestingly, Turajlic et al .…”

Tumour mutational burden as a biomarker for immunotherapy: Current data and emerging concepts

“…This may be related to the higher quality of antigens in these tumor types, resulting from viral antigens (in MCC), a high number of indel mutations (in RCC), and complex chromosomal rearrangements (in mesothelioma). TMB also has poor predictive value within some tumor types such as gliomas and renal cell cancers (25). Concerning clear cell renal cancer, Swanton's group showed that TMB is not a biomarker of efficacy of ICI therapy.…”