Biomarkers for immunotherapy in bladder cancer: a moving target

Abstract

Treatment options for metastatic urothelial carcinoma (mUC) remained relative unchanged over the last 30 years with combination chemotherapy as the mainstay of treatment. Within the last year the landscape for mUC has seismically shifted following the approval of five therapies targeting the programmed cell death protein (PD-1)/programmed cell death ligand 1 (PD-L1) axis. Notably, the anti-PD-1 antibody pembrolizumab demonstrated improved OS relative to chemotherapy in a randomized phase III study for second line treatment of mUC; this level 1 evidence led to approval from the U.S. Food and Drug Administration (FDA). The PD-1 antibody nivolumab also demonstrated an overall survival benefit, in this case in comparison to historical controls. Similarly, antibodies targeting PD-L1 including atezolizumab, durvalumab, and avelumab have now received accelerated approval from the FDA as second line treatments for mUC, with durable response lasting more than 1 year in some patients. Some of these agents are approved in the first line setting as well - based on single-arm phase II studies atezolizumab and pembrolizumab received accelerated approval for first-line treatment of cisplatin ineligible patients. Despite these multiple approvals, the development of clinically useful biomarkers to determine the optimal treatment for patients remains somewhat elusive. In this review, we examine key clinical trial results with anti-PD1/PD-L1 antibodies and discuss progress towards developing novel biomarkers beyond PD-L1 expression.

Keywords: Atezolizumab; Avelumab; Biomarker; Bladder cancer; Durvalumab; Immune checkpoint inhibitor; Immunotherapy; Nanostring; Nivolumab; PD-1; Pd-L1; Pembrolizumab; Tumor mutation burden.

Fig. 1

Timeline of clinical studies of programmed cell death protein/programed death-ligand 1 inhibitors in urothelial carcinoma

Fig. 2

Tumor mutation burden as a biomarker for anti-PD-1/PD-L1 therapy. a Kaplan-Meier estimate of overall survival according to estimated mutational burden by quartiles in mUC patients treated with atezolizumab in IMVigor 210 – Cohort I. Range estimates next to each qauartile indicated number of mutations per megabase for each quartile. b Quantification of mutation burden across TCGA subtypes and PD-L1 immune cell IHC status and correlation with disease status. c and d Progression-free survival based on tertile of tumor mutation burden from Checkmate 026, a randomized study of nivolumab (c) compared to standard of care chemotherapy (d). A and B reprinted from The Lancet, Vol. 389, Balar et al. “Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicenter, phase 2 trial, p. 73, 2017 with permission from Elsevier [10]. C and D reproduced with permission from Carbone, D. et al. NEJM. 2017., [48]

Fig. 3

Advantages and disadvantages of potential biomarkers for immunotherapy

Fig. 4

Components of the tumor inflammatory signature as assessed by immune cell gene expression profiling. a Complex interplay of chemokines and cytokines classify the inflammatory state of the tumor microenvironment. Interferon-g (IFN-g) released by activated T cells and NK cells activates STAT1, IDO-1 (indolamine oxygenase I) and CMKLR1 in dendritic cells and macrophages (1). STAT-1 mediated signaling and additional pathways produce the chemokines CCL5 and CXCL9 (2). This recruits additional T cells into the tumor microenviroment through CXCR6. IFN-g stimulates the expression of HLA molecules and proteasome components including PSMB10 (3). Finally, IFN-g upregulates a number of immune checkpoint molecules including PD-L1, PD-L2, TIGIT, LAG-3, and B7-H3 on T cells (4). b Components of 18-gene immune signature under evaluation in prospective trials with pembrolizumab