Development of a Blood Test for Selection of Lung Cancer Patients Who Could Benefit From

Development of a blood test for selection of lung cancer patients who could benefit from immunotherapy.

Van der Linden M1, VermaelenK2, DemedtsI3, SurmontV2, Claes K4, Menten B4, Van Dorpe J5.

1Department of Medical and Forensic Pathology, Ghent University, Ghent, Belgium.

2Department of Pulmonary Medicine, Ghent University Hospital, Ghent, Belgium.

3Department of Pulmonary Medicine, AZ Delta Roeselare Menen, Roeselare, Belgium.

4Center for Medical Genetics Ghent, Ghent University Hospital, Ghent, Belgium.

5Department of Pathology, Ghent University Hospital, Ghent, Belgium.

Introduction

Lung cancer is the third most common and deadly cancer in Belgium, with an annual incidence of more than 8,000 cases. Compounds targeting immune checkpoint pathways such as PD1/PD-L1 are showing remarkable clinical benefit in non-small cell lung cancer, albeit in a subset of patients. Currently, enrichment of responders is achieved by selection based on PD-L1 immunohistochemical expression. However, evidence accumulates that mutational load, as a source of neo-antigens that are potentially recognizable by the immune system, correlates with response to PD1-blockade irrespectively of PDL1 expression in the tumor bed. However, assessment of mutational load requires tissue sampling, which is often a stumbling block in patients with advanced disease.

Objectives

To explore whether non-invasive assessment of mutational load in lung cancer by analysis of cell-free DNAin plasma can stratify responders to immune checkpoint blockade in lung cancer.

Method

Optimization experiments will be carried out to establish the extent of the genome or exome that has to be sequenced and to determine the sequencing depth that is necessary to make the test sensitive enough to be predictive. Our current estimation amounts to 10% of the exome (3Mb or about 2,000 genes, with focus on oncogenes, tumor suppressor genes and DNA repair enzymes) with a sequencing depth of x1,000 (3,000Mb to be sequenced).

A discovery cohort (preclinical phase) will be used for determination of cut-off points for non-synonymous mutation burden and for the frequency of C-to-A transversions that can predict response to immunotherapy.

Several clinical studies involving immune checkpoint blockade in lung cancer are conducted at Ghent University Hospital and other hospitals in Belgium. Blood samples from patients selected for immunotherapy will be prospectively collected before initiation of the treatment. A validation cohort (clinical phase) will be used to validate our blood test as a predictive biomerker for response to immune checkpoint blockade.

Impact

Anti-PD-1 therapy is expensive with an estimate cost of€100,000 to €150,000 per patient per year. As lung cancer is a prevalent malignancy, there is a real pressure to develop more reliable strategies aimed at identifying patients who will derive benefit. Analysis of circulating tumor DNA could provide a patient-friendly way to extract theragnostic information in the setting of immune checkpoint blockade.