Immune Checkpoint Inhibitors in Urothelial Carcinoma: Recommendations for Practical Approaches to PD-L1 and Other Potential Predictive Biomarker Testing

Abstract

Immuno-oncology (IO) agents (anti–programmed cell death 1 (PD-1) and anti–programmed cell death-ligand 1 (PD-L1)) are approved as first- and second-line treatments for metastatic UC. PD-L1 expression levels in UC tumors help clinicians determine which patients are more likely to respond to IO therapies. Assays for approved IO agents use different antibodies, immunohistochemical protocols, cutoffs (defining “high” vs. “low” PD-L1 expression), and scoring algorithms. The robust control of pre-analytical and analytical standards is needed to obtain high-quality PD-L1 results. To better understand the status and perspectives of biomarker-guided patient selection for anti–PD-1 and anti–PD-L1 agents in UC, three workshops were held from December 2018 to December 2019 in Italy, Malaysia, and Spain. The primary goal was to develop recommendations for best practice approaches to PD-L1 testing in UC. Recommendations pertaining to the interpretation and reporting of the results of PD-L1 assays from experienced pathologists and oncologists from around the globe are included. A test request form for pathology laboratories was developed as a critical first step for oncologists/urologists to encourage communication between clinicians and pathologists, ensuring fast and high-quality test results. In this era of personalized medicine, we briefly discuss novel biomarkers being evaluated for IO agents in UC.

Molecular Classification of Bladder Urothelial Carcinoma Using NanoString-Based Gene Expression Analysis

“…In contrast, patients with MIBC typically receive neoadjuvant chemotherapy (NAC) followed by radical cystectomy [9]. The locally advanced and metastatic disease typically requires biomarker-guided immune checkpoint inhibitors (ICI), targeted therapies, or other novel drugs conjugates [10][11][12][13][14][15][16][17][18][19].…”

Prognostic and Predictive Factors in Advanced Urothelial Carcinoma Treated with Immune Checkpoint Inhibitors: A Review of the Current Evidence

“…Furthermore, because the TMB and/or the PD-L1 expression did not precisely identify patients who were more likely to derive benefit from immunotherapy [ 34 , 35 ], the assessment of tumour-related or immune-related gene signatures was actively investigated.…”

Advances and Controversies With Checkpoint Inhibitors in Bladder Cancer

“…One such therapy of immune checkpoint inhibition, primarily those targeting programmed cell death-1 protein (PD-1) or its ligand (PD-L1), has become widely studied in oncology, including bladder cancer. 13 Based on durable responses and favorable overall survival (OS) in clinical trials, antibodies inhibiting PD-1 (pembrolizumab, nivolumab) and PD-L1 (atezolizumab, avelumab, and durvalumab) are used for a number of clinical indications. While all 5 of those agents were initially approved by the US Food and Drug Administration (FDA) as second-line therapy for patients who have progressed during or after platinum-based therapy (see Table 1 ), and have not received prior immunotherapy, the approval for durvalumab was recently voluntarily withdrawn given inability to meet primary endpoints for the confirmatory DANUBE trial, 14 with atezolizumab soon following voluntary withdrawal in March 2021 given failure to meet primary endpoint for the IMvigor211.…”