RT Journal Article
SR Electronic
T1 Correlates of clinical benefit from immunotherapy and targeted therapy in metastatic renal cell carcinoma: comprehensive genomic and transcriptomic analysis
JF Journal for ImmunoTherapy of Cancer
JO J Immunother Cancer
FD BMJ Publishing Group Ltd
SP e000953
DO 10.1136/jitc-2020-000953
VO 8
IS 2
A1 Nazli Dizman
A1 Yung Lyou
A1 Nicholas Salgia
A1 Paulo Gustavo Bergerot
A1 JoAnn Hsu
A1 Daniel Enriquez
A1 Tyler Izatt
A1 Jeffrey M Trent
A1 Sara Byron
A1 Sumanta Pal
YR 2020
UL http://jitc.bmj.com/content/8/2/e000953.abstract
AB Background The clinical significance of tumor-specific genomic alterations in metastatic renal cell carcinoma (mRCC) is emerging, with several studies suggesting an association between PBRM1 mutations and response with immunotherapy (IO). We sought to determine genomic predictors of differential response to vascular endothelial growth factor–tyrosine kinase inhibitors (VEGF-TKIs) and IO.Methods Consecutive patients who underwent genomic profiling were identified; patients receiving either VEGF-TKIs or IO were included. Clinical tumor-normal whole exome sequencing and tumor whole transcriptome sequencing test were performed using a Clinical Laboratory Improvement Amendments (CLIA)-certified assay (Ashion Analytics; Phoenix, Arizona, USA). Genomic findings were compared between patients with clinical benefit (CB; complete/partial response or stable disease for >6 months) and no clinical benefit (NCB) in VEGF-TKI-treated patient cohort and IO-treated patient cohort.Results 91 patients received genomic profiling and 58 patients received VEGF-TKI and/or IO therapy. 17 received sequenced treatment involving both VEGF-TKI and IO, resulting in 32 patients in the IO cohort and 43 patients in the VEGF-TKI cohort. The most commonly used IO and VEGF-TKIs were nivolumab (66%) and sunitinib (40%). The most frequently detected alterations in the overall cohort were in VHL (64%), PBRM1 (38%), SETD2 (24%), KDM5C (17%) and TERT (12%). TERT promoter mutations were associated with NCB in the IO cohort (p=0.038); transcriptomic analysis revealed multiple differentially regulated pathways downstream of TERT. TERT promoter mutations and PBRM1 mutations were found to be mutually exclusive. While PBRM1 mutations were more prevalent in patients with CB with IO and VEGF-TKIs, no statistically significant association was found.Conclusions Our analysis found that TERT promoter mutations may be a negative predictor of outcome with IO and are mutually exclusive with PBRM1 loss-of-function mutations.