24P - Chromosome 3p-related gene alterations (GA) as biomarkers for immunocombinations in metastatic renal cell carcinoma (mRCC): a hypothesis-generating analysis

Background

Identifying biomarkers for mRCC is an unmet need in actual immunotherapy (IO) era. Available data regarding chromosome 3p-related genes (i.e., VHL, PBRM1, SETD2) as potential predictors for therapy response is conflicting. We describe the correlation of these GA with clinical outcomes in mRCC pts treated with IO/IO or IO/tyrosine kinase inhibitor (TKI).

Methods

We performed a single-center retrospective analysis on mRCC pts treated with first line IO/IO or IO/TKI. A multi-gene panel was used, allowing the amplification of 841 amplicons (54.93kb, 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

30 mRCC pts undergoing IO/IO and IO/TKI were included. Of these, 18 had tumor tissue adequate for molecular analysis: 77.8% male, 22.2% female. Histology was 100% clear cell. IMDC risk was 50% intermediate, 33.4% good, 16.6% poor. First line therapy was 89% IO/TKI, 11% IO/IO. 83.3% pts (n=15) carried GA, among which 61.1% had a known pathogenic mutation (PAT). Most common GA included VHL in 44% (n=8; 7 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 pts had lower median progression free (mPFS) and overall survival (mOS) than non-SETD2 mutated pts. Higher mPFS and mOS were shown with VHL or PBRM1 GA, especially in PBRM1+VHL mutated pts (Table). Of note, all PBRM1+VHL mutated pts underwent IO/TKI. Table: 24P

Conclusions

Our data shows a possible negative predictive role of SETD2 GA for IO-based therapy in RCC. Concomitant VHL and PBRM1 GA could act as a predictor for IO/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.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.