The impact of PBRM1 mutations on overall survival in greater than 2,100 patients treated with immune checkpoint blockade (ICB).

Abstract

666 Background: PBRM1 is the second most commonly mutated gene in clear cell renal cell carcinoma (ccRCC). We have previously shown favorable outcomes in PBRM1-mutated ccRCC tumors treated with vascular endothelial growth factor (VEGF) inhibitors. Recent data suggested PBRM1 mutations may sensitize ccRCC and non RCC malignancies to ICB therapy. We queried the impact of PBRM1 loss on overall survival (OS) across 2,152 patients treated with ICB. Methods: PBRM1 mutations were assessed in metastatic ccRCC patients who received first line (n = 82) or second line (n = 61) ICB or ICB/VEGF combinations. Additionally, 41 cohorts of non-RCC malignancies treated with ICB and combination (n = 2,009) were analyzed. Mutations were assessed by next generation targeted sequencing using archival tissue. Association of mutation status and overall survival (OS) was tested by multivariate Cox regression analysis (MVA) and adjusted for tumor mutation burden (TMB), copy number alterations (CNA), loss of function(LOF) mutations (non RCC cohort) and IMDC risk (for ccRCC patients). Results: PBRM1 mutations were not associated with improved OS in ICB the entire ccRCC cohort (HR 1.37; CI 0.79-2.4; p = 0.265), the first line (p = 0.624) or second line setting (p = 0.39) or as combination with VEGF inhibitors (p = 0.2). Several RCC subgroups were investigated (see Table at bottom). In the non-RCC cohorts (n = 2,009) PBRM1 mutations were not significantly associated with OS on univariate analysis (HR = 0.73, p = 0.22 for LOF and HR = 0.84,p = 0.34 for non LOF), and remained insignificant after adjusting for TMB, total CNA, and drug class (CTLA4, PD-1/PDL-1 and combinations) (HR = 1.07, p = 0.78 for LOF and HR = 1.08,p = 0.67 for non LOF). Conclusions: Neither in ccRCC nor in the pan-cancer cohort did PBRM1 mutations appear to be associated with improved overall survival with ICB therapy.[Table: see text]

Characterization of tumor mutation burden, PD-L1 and DNA repair genes to assess relationship to immune checkpoint inhibitors response in metastatic renal cell carcinoma

“…10 However, in a larger cohort of patients with mRCC, PBRM1 loss was not associated with improved OS (HR 1.37; 95% CI 0.79 to 2.4, p=0.265). 36 Similarly, our results found that PBRM1 mutation did not predict immunotherapy responses.…”

PBRM1 loss defines a nonimmunogenic tumor phenotype associated with checkpoint inhibitor resistance in renal carcinoma

“…PBRM1 loss was previously linked to better ICB response in ccRCC 20,21 . Several additional studies failed to find an association between functional PBRM1 loss and clinical benefit from immunotherapy 5,22,23 . In our study, further analysis of patients from the IMmotion150 trial treated with anti-PD-L1 or plus bevacizumab revealed a decreased response rate in tumors with PBRM1 mutations (Fig.…”

“…Recently, PBRM1 mutations were reported to be associated with clinical benefit from anti-PD-1 therapy in ccRCC patients who received prior antiangiogenic therapy 20,21 . However, other contemporary studies failed to indicate PBRM1 mutations were a positive predictive biomarker for response to ICB 5,22,23 . It was reported that Pbrm1-deficient murine B16F10 melanomas were more immunogenic and more responsive to immunotherapy 24 .…”

Altered regulation of DPF3, a member of the SWI/SNF complexes, underlies the 14q24 renal cancer susceptibility locus

“…Together, these results suggest that the allele-specific effect of rs4903064 could be partially mediated through STAT3 activation, comparable to the effect of select PBRM1 somatic mutations. 15 DPF3 effect on T-cell-mediated cytotoxic and immunotherapy response Previous studies have suggested that mutations within the SWI/SNF complexes, particularly in PBRM1, could contribute to response to immune checkpoint inhibitor therapy in RCC affected individuals, 77,78 but other studies could not find this association; [79][80][81] confirmation studies are needed. 82 Ex vivo data suggest that PBRM1 mutations are associated with enhanced sensitization to killing by T cells, 83 an effect most likely mediated through mSWI/ SNF complex regulation of chromatin accessibility for INF-g target genes.…”