Abstract
Anti-programmed cell death (PD)-1/PD-ligand 1 (L1) therapies have significantly improved the outcomes for non-small cell lung cancer (NSCLC) patients in recent years. These therapies work by reactivating the immune system and enabling it to target cancer cells once more. There is a general agreement that expression of PD-L1 on tumour cells predicts the therapeutic response to PD-1/PD-L1 inhibitors in NSCLC. Hence, immunohistochemical staining of tumour tissue biopsies from NSCLC patients with PD-L1 antibodies is the current standard used to aid selection of patients for treatment with anti-PD-1 as first line therapy. However, issues of small tissue samples, tissue heterogeneity, the emergence of new metastatic sites, and dynamic changes in the expression of PD-L1 may influence PD-L1 status during disease evolution. Re-biopsy would expose patients to the risk of complications and tardy results. Analysis of PD-L1 expression on circulating tumour cells (CTCs) may provide an accessible and non-invasive means to select patients for anti-PD-1 therapies. Additionally, CTCs could potentially provide a useful biomarker in their own right. Several published studies have assessed PD-L1 expression on CTCs from NSCLC patients. Overall, analysis of PD-L1 on CTCs is feasible and could be detected prior to and after frontline therapy. However, there is no evidence on whether PD-L1 expression on CTCs could predict the response to anti-PD-1/PD-L1 treatment. This review examines the challenges that need to be addressed to demonstrate the clinical validity of PD-L1 analysis in CTCs as a biomarker capable of predicting the response to immune checkpoint blockade.
Highlights
Lung cancer incidence rates have increased substantially since the start of the 20th century, with non-small cell lung cancer (NSCLC) accounting for approximately 85% of reported cases [1].Survival for advanced NSCLC has improved dramatically with the advent of molecular targeted therapies such as erlotinib and crizotinib for the treatment of patients whose tumours harbour specific sensitising mutations in the epidermal growth factor receptor (EGFR) and translocations in the anaplastic lymphoma kinase (ALK) [2,3]
The studies reviewed here demonstrated that programmed cell death (PD)-ligand 1 (L1) expression could be assessed on circulating tumour cells (CTCs) and that their presence is associated with worse survival outcomes, in the absence of immune checkpoint blockade inhibition
Two studies to date have evaluated the predictive value of programmed cell death ligand-1 (PD-L1) expression on CTCs, with major constraining limitations
Summary
Lung cancer incidence rates have increased substantially since the start of the 20th century, with non-small cell lung cancer (NSCLC) accounting for approximately 85% of reported cases [1]. CheckMate 057 found a predictive association of PD-L1 expression with clinical benefit from nivolumab treatment PD-L1 in patients with advanced non-squamous NSCLC after failure of platinum-based chemotherapy [13]. There was a significantly longer PFS and OS benefit with pembrolizumab compared with standard platinum-based chemotherapy in the KEYNOTE-O24 trial that enrolled only NSCLC patients with ≥50% PD-L1 tumour proportion score [14]. The FDA expanded the indication of pembrolizumab to be included in frontline treatment of NSCLC patients with a PD-L1 expression level ≥1% that do not harbor ALK or EGFR mutations, who are unqualified for surgery or conclusive chemoradiation based on findings from. Positive CTCs to inform risk stratification, and explore its utility as a predictive biomarker for selecting patients for immunotherapy
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