The relationship between blood biomarkers, tumor immunity, and benefit from immune checkpoint inhibitors (ICIs) is not well understood. The JAVELIN Bladder 100 trial (NCT02603432) demonstrated that avelumab 1L maintenance prolongs overall survival (OS) in pts with aUC that has not progressed with 1L chemotherapy. Blood biomarkers associated with tumor immune gene signatures in this trial may provide mechanistic insight into the development of antitumor immunity and indicate patient subpopulations that could benefit from ICIs. We used EpiSwitch analysis of PB to identify structural-functional epigenetic changes in genomic architecture, designated chromatin conformation signatures (CCSs).
PB from 496 pts in the JAVELIN Bladder 100 trial underwent EpiSwitch analysis by PCR assay of 3D genomic templates prepared from fixed intact nuclei. Tumor immune activity was scored using a gene expression signature (JAVELIN Renal 101 Immune [JR101I]). CCS association with tumor JR101I scores was determined via univariate and multivariate analyses of a training set of 80 specimens.
We identified 25 CCSs from the training set. One CCS was proximal to POU2F2, a transcription factor instrumental in B cell development. Patients whose PB lacked the POU2F2 CCS had elevated tumor JR101I scores, corresponding to increased gene expression associated with tertiary lymphoid structures (TLSs). The POU2F2 CCS may therefore influence key steps in TLS formation. In patients with a median tumor mutation burden (TMB) of ≤ 7.66 non-synonymous SNVs per Mb, the avelumab+BSC vs BSC hazard ratios in the CCS-absent subpopulation was 0.56 (95% CI, 0.32–0.96; p=0.037; n=83); and in the CCS-present population was 1.2 (95% CI, 0.83–1.75; P=0.34; n=158). CCSs affecting the ability to form TLSs may influence response to avelumab at low TMB.
PB CCSs may be associated with TLS, tumor JR101I scores, and the degree of OS benefit. These findings support further analysis of CCSs to assess potential clinical utility.