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

Web

Nov. 25, 2019

SCIENTIFIC

JAMA Oncol. 2019;5(11):1631-1633. doi:10.1001/jamaoncol.2019.3158  https://jamanetwork.com/journals/jamaoncology/article-abstract/2749253

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 trial1 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.This study was conducted under a secondary use protocol, approved by the Dana-FarberCancer Institute.Written informed consentwas obtained from participants. This post hoc analysis included 382 of 803 patients who were consented for genomic studies and passed quality control. 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) in PBRM1 were manually reviewed using the Integrative Genomics Viewer. Results: PBRM1 mutations were identified in 55 of 189 nivolumab-treated (29%) and of 45 of 193 everolimus-treated (23%) patients. Among nivolumab-treated patients, 15 of 38 responding (39%) and 16 of 74 nonresponding (22%) patients had truncating PBRM1 mutations (odds ratio [OR], 2.34; 95% CI, 1.05-; P = .04). PBRM1 mutations were also associatedwith clinical benefit (18/52 with clinical benefit, 14/71 with no clinical benefit; OR, 2.14; 95% CI, 1.00-;P = .0497).PBRM1 mutation was associated with increased PFS (HR, 0.67; 95% CI, 0.47-0.96; P = .03) and OS (HR, 0.65; 95% CI, 0.44-0.96; P = .03) (Figure). Among patients treated with everolimus, 1 of 5 responding (20%) and 10 of 56 nonresponding (17.9%)patients had truncating PBRM1 mutations (OR, 1.15; 95% CI, 0.04-; P = .64). There was no evidence of an association between PBRM1 mutation and PFS (HR, 0.83; 95% CI, 0.58-1.2; P = .32) or OS (HR, 0.81; 95% CI, 0.56-1.18; P = .27) in patients treated with everolimus.

Conclusions

This validated association between PBRM1 alterations and ICI response in a large randomized study represents a further step toward the development of genomic predictors for immunotherapies in advanced RCC.