Clinical Validation of PBRM1 Alterations as a Marker of Immune Checkpoint Inhibitor Response in Renal Cell Carcinoma

Abstract

Nivolumab, an immune checkpoint inhibitor (ICI) targeting the programmed death-1 (PD-1) pathway, is approved for metastatic clear cell renal cell carcinoma (ccRCC). 1 Loss-of-function (truncating) mutations in PBRM1, a PBAF-complex gene commonly mutated in ccRCC, were previously associated with clinical benefit from anti-PD-1 therapy in a smaller study, 2 Herein, this association was examined in an independent cohort from a randomized clinical trial 1 to determine whether PBRM1 alterations are a marker of response to ICI treatment.Methods | Archival tumor tissue (collected before antiangiogenic therapy) was obtained from patients enrolled in a randomized, phase 3 trial that demonstrated improved overall survival (OS) with nivolumab vs everolimus in patients with ccRCC who received prior antiangiogenic therapy. 1 This study was conducted under a secondary use protocol, approved by the Dana-Farber Cancer Institute. Written informed consent was obtained from participants. This post hoc analysis included 382 of 803 patients who were consented for genomic studies and passed quality control. 2 This cohort was not significantly different from the other 421 patients in response or progressionfree survival (PFS). Putative truncating mutations (frameshift insertion/deletion, nonsense, splice-site) 2 in PBRM1 were manually reviewed using the Integrative Genomics Viewer. 3

Molecular correlates and therapeutic targets in T cell-inflamed versus non-T cell-inflamed tumors across cancer types

“…In lung adenocarcinoma, the gene most significantly mutated was KEAP1, recently associated with resistance to PD1 blockade in lung cancer (Rizvi). Alternatively, we identified mutations that are differentially present in T cell-inflamed tumors, such as PBRM1 in ccRCC, consistent previous reports (Miao et al 2018;Braun et al 2019). In metastatic melanoma, DCTN1 was found to be associated with the presence of T cell-inflammation while ITGAX (alias CD11c), is more frequently mutated in non-T cell-inflamed tumors.…”

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

“…In one study, biallelic PBRM1 loss demonstrated improved OS (p=0.0074) and progression-free survival (p=0.029) compared with those without PBRM1 loss. 35 In the Checkmate 025 trial, PBRM1 loss was associated with clinical benefit to nivolumab, although the presence of PBRM1 loss alone was not sufficient for responses. 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).…”

Prognostic and Predictive Value of PBRM1 in Clear Cell Renal Cell Carcinoma

“…The results showed a significant correlation between PRBM1 status and response to anti-PD1 therapy, with a significant benefit both in PFS and OS in those patients harboring PBRM1 mutations (HR 0.67, 95% CI, 0.47-0.96; p = 0.03, and HR 0.65, 95% CI, 0.44-0.96; p = 0.03 respectively) compared to those with PBRM1 wild type tumors. There was no evidence of an association between PBRM1 status and clinical outcomes in the everolimus cohort [58].…”

“…There are studies that suggest the correlation of certain mutations with treatment outcomes [53][54][55]. According to some retrospective studies and preclinical data it seems that the mutational status of PBRM1 could have a predictive role [48,[56][57][58]…”

“…More recently, a post hoc analysis of the CHECKMATE025 trial which compared nivolumab and sunitinib in ccRCC patients previously treated with antiangiogenics, analyzed the correlation between PBRM1 status and outcomes (PFS and OS) across-treatment in 382 of the 803 patients included in the trial [58]. The results showed a significant correlation between PRBM1 status and response to anti-PD1 therapy, with a significant benefit both in PFS and OS in those patients harboring PBRM1 mutations (HR 0.67, 95% CI, 0.47-0.96; p = 0.03, and HR 0.65, 95% CI, 0.44-0.96; p = 0.03 respectively) compared to those with PBRM1 wild type tumors.…”