TERT Promoter Mutations Predict Benefit From Immunotherapy in Patients With Urothelial Cancer - Expert Commentary

A subset of patients with advanced urothelial cancer (aUC) achieves durable responses to immune checkpoint blockade (ICB), but the development of reliable biomarkers to identify these patients has proven challenging.

A recent study by de Kouchkovsky et al., published in the Journal for ImmunoTherapy of Cancer, examined clinical and genomic factors associated with progression-free (PFS) and overall (OS) survival in patients with aUC receiving ICB. The authors included 119 patients treated with ICB monotherapy for aUC at a single academic center from December 2014 to January 2020. Comprehensive genomic profiling was performed for 78/119 (65.6%) either by commercial assays (FoundationOne and StrataNGS) or an in-house assay (UCSF 500 Cancer Gene Panel Test). Fifty-eight patients received frontline ICB for metastatic disease, and 61 patients received ICB post-platinum.

The objective response rate (ORR) was 29%, and the median PFS was 2.6 months. On multivariable analysis, favorable baseline performance status (ECOG ≤1) was an independent predictor for OS (hazard ratio (HR) 0.46, 95% Confidence Intervals (CI) 0.23-0.90, p=0.03).
In the subgroup of patients who underwent genomic profiling, the most common genomic alterations involved the TERT promoter (61.0%), TP53 (51.9%), and RB1 (31.2%). Multivariable analysis showed that TERT promoter mutations were the only genomic predictor of longer PFS (HR 0.38, 95% CI 0.18-0.81, p=0.01) and OS (HR 0.32, 95% CI 0.10-0.93, p=0.04). Furthermore, combining TERT promoter mutation and performance status identified patients with a significantly longer median OS (21.2 vs. 7.5 months, p=0.03).

In the subgroup of patients with available TMB (n=62) and PD-L1 expression (n=21) status. TMB-high (≥10 mutations/Megabase) and PD-L1 positive (Combined Positive Score ≥10) patients were associated with longer PFS (15.0 vs. 3.1 months, p=0.005) and (not reached vs. 3.36 months, p=0.02), respectively. However, multivariable adjustment was not possible for these subgroup analyses due to the limited sample size.

This study highlights the role of TERT promoter mutations in predicting clinical benefits from immunotherapy in patients with aUC. Additional prospective studies are needed to determine the role of TERT promoter mutations as prognostic and predictive biomarkers.

Written by: Bishoy M. Faltas, MD, Director of Bladder Cancer Research, Englander Institute for Precision Medicine, Weill Cornell Medicine, New York City, New York

References:

  1. de Kouchkovsky I, Zhang L, Philip EJ, Wright F, Kim DM, Natesan D, et al. TERT promoter mutations and other prognostic factors in patients with advanced urothelial carcinoma treated with an immune checkpoint inhibitor. J Immunother Cancer. 2021;9(5):e002127. PMID: 33980590
  2. Allory Y, Beukers W, Sagrera A, Flández M, Marqués M, Márquez M, et al. Telomerase Reverse Transcriptase Promoter Mutations in Bladder Cancer: High Frequency Across Stages, Detection in Urine, and Lack of Association with Outcome. Eur Urol. 2014 Feb;65(2):360–6. PMID: 24018021


Read the Abstract
email news signup