Next-generation sequencing using liquid biopsy in the care of patients with ALK-rearranged non-small cell lung cancer: a focus on lorlatinib

: Next-generation sequencing (NGS) has introduced new applications in the molecular profiling of lung cancer, expanding its use from the essential molecular diagnosis in advanced stages, to disease monitoring and the study of resistance mechanisms to targeted therapies and, most recently, to immunotherapy. Cell-free DNA (cfDNA) NGS is an easily accessible form of liquid biopsy, with the potential of sequencing tumor DNA shed from different metastasis and capturing tumor heterogeneity and tumor clonal evolution during treatment. Lorlatinib, is a novel third-generation ALK inhibitor, and current standard treatment for patients that experience disease progression with crizotinib and a second-generation ALK inhibitor or in the front line setting. Preclinical studies on predictive biomarkers of response and resistance to lorlatinib have been conducted, shedding a light on potential biological mechanisms of primary and acquired resistance to this compound. With the emerging role of cfDNA NGS, molecular profiling opens new opportunities to try to unravel potential key biomarkers to predict lorlatinib efficacy and to further learn about the molecular processes that lead to lorlatinib resistance in the clinical practice. Herein, we discuss the current landscape of ALK targeted therapies, including clinical and preclinical data supporting the use of lorlatinib, and the current evidence of the role of liquid biopsies and its potential contribution in improving the care of patients with ALK-rearranged NSCLC treated with lorlatinib. 14