Chromosome 3p gene alterations as biomarkers for immunocombinations in metastatic renal cell carcinoma: A hypothesis-generating analysis

Background: Identifying biomarkers for metastatic renal cell carcinoma (mRCC) is an unmet need in actual immunotherapy era. Available data regarding chromosome 3p genes (i.e., VHL, PBRM1, SETD2) mutations as potential predictors for therapy response is conflicting. We describe the impact of these mutations on clinical outcomes in mRCC patients treated with immune checkpoint inhibitor (ICI)-doublet or ICI/tyrosine kinase inhibitor (TKI) combinations. Methods: We performed a single-center retrospective analysis on mRCC patients treated with first line ICI/ICI or ICI/TKI. A multi-gene panel was used, allowing the amplification of 841 amplicons (54.93 kb, human reference sequence hg19/GRCh37) in the coding sequences of the following genes: ATM, BAP1, KDM5C, MET, MTOR, NF2, PBRM1, PIK3CA, PTEN, SETD2, SMARCB1, TP53, TSC1, TSC2, VHL. Results: 18 patients undergoing ICI/ICI and ICI/TKI who had tumor tissue adequate for molecular analysis were included. Histology was 100% clear cell. IMDC risk was 50% intermediate, 33.4% good, 16.6% poor. First line therapy was 89% ICI/TKI, 11% ICI/ICI. 83.3% pts (n = 15) carried genomic alterations (GA). Most common GA included VHL in 44% (n = 8; 7 pathogenic - PAT and 1 variant of unknown significance - VUS), PBRM1 in 44% (n = 8; 5 PAT and 3 VUS) and SETD2 in 33% (n = 6; 4 PAT and 2 VUS). With the limit of a small sample that did not allow proper statistical analyses, SETD2-mutated patients had lower median progression free (mPFS) and overall survival (mOS) than non-SETD2 mutated patients. Higher mPFS and mOS were shown with VHL or PBRM1 GA, especially in PBRM1 +VHL mutated pts. Conclusions: Our data shows a possible negative predictive role of SETD2 GA for ICI-based therapy in RCC. Concomitant VHL and PBRM1 GA could act as a predictor for ICI/TKI efficacy. Our hypothesis-generating analysis highlights the need of an integrated evaluation of these genes as promising biomarkers in RCC. Further larger studies are required.