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Approved checkpoint inhibitors in bladder cancer: which drug should be used when?

ABSTRACT: The treatment of advanced metastatic urothelial carcinoma has recently evolved with the approval of five checkpoint inhibitors. In the second-line setting, in patients who have progressed on cisplatin-based chemotherapy, pembrolizumab, atezolizumab, durvalumab, nivolumab and avelumab are United States Food and Drug Administration (FDA) approved. In cisplatin-ineligible patients, atezolizumab and pembrolizumab are the FDA-approved checkpoint inhibitors. Here we describe the updated clinical efficacy of these checkpoint inhibitors in the treatment of advanced urothelial carcinoma and then suggest how they can be sequenced in the context of available chemotherapeutic options. For cisplatin-eligible patients, platinum-based chemotherapy remains the standard first-line treatment. For patients progressing on platinum-based therapy, phase III trials have been performed comparing pembrolizumab and atezolizumab separately with standard chemotherapy, and results favor the use of pembrolizumab.

SUBMITTER: Ghatalia P

PROVIDER: S-EPMC6066800 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Approved checkpoint inhibitors in bladder cancer: which drug should be used when?

Ghatalia Pooja P Zibelman Matthew M Geynisman Daniel M DM Plimack Elizabeth E

Therapeutic advances in medical oncology 20180730

The treatment of advanced metastatic urothelial carcinoma has recently evolved with the approval of five checkpoint inhibitors. In the second-line setting, in patients who have progressed on cisplatin-based chemotherapy, pembrolizumab, atezolizumab, durvalumab, nivolumab and avelumab are United States Food and Drug Administration (FDA) approved. In cisplatin-ineligible patients, atezolizumab and pembrolizumab are the FDA-approved checkpoint inhibitors. Here we describe the updated clinical effic ...[more]

PMID: 30083254

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Project description:Background: Bladder urothelial cancer (BLCA) treatment using immune checkpoint inhibitors (IMCIs) can result in long-lasting clinical benefits. However, only a fraction of patients respond to such treatment. In this study, we aimed to identify the relationships between immune cell infiltration levels (ICILs) and IMCIs and identify markers for ICILs. Methods: ICILs were estimated based on single-sample gene set enrichment analysis. The response rates of different ICILs to IMCIs were calculated by combining the ICILs of molecular subtypes in BLCA with the response rates of different molecular subtypes of IMvigor 210 trials to a programmed cell death ligand-1 inhibitor. Weighted gene co-expression network analysis was used to identify modules of interest with ICILs. Functional enrichment analysis was performed to functionally annotate the modules. Screening of key genes and unsupervised clustering were used to identify candidate biomarkers. Tumor IMmune Estimation Resource was used to validate the relationships between the biomarkers and ICILs. Finally, we verified the expression of key genes in molecular subtypes of different response rates for IMCIs. Findings: The basal squamous subtype and luminal infiltrated subtype, which showed low response rates for IMCIs, had the highest levels of immune infiltration. The neuronal subtypes, which showed the highest response rates to IMCIs, had low ICILs. The modules of interest and key genes were determined based on topological overlap measurement, clustering results, and inclusion criteria. Modules highly correlated with ICILs were mainly enriched in immune responses and epithelial-mesenchymal transition. After screening the key genes in the modules, five candidate biomarkers (CD48, SEPT1, ACAP1, PPP1R16B, and IL16) were selected by unsupervised clustering. The key genes were inversely associated with tumor purity and were mostly expressed in the basal squamous subtype and luminal infiltrated subtypes. Interpretation: Patients with high ICILs may benefit the least from treatment with IMCIs. Five key genes could predict ICILs in BLCA, and their high expression suggested that the response rate to IMCIs may decrease.

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Approved checkpoint inhibitors in bladder cancer: which drug should be used when?

Publications

Approved checkpoint inhibitors in bladder cancer: which drug should be used when?

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