Clinical utility of plasma-based digital next-generation sequencing in oncogene-driven non-small-cell lung cancer patients with tyrosine kinase inhibitor resistance. (August 2019)

• Record Type: Journal Article
• Authors: Zugazagoitia, Jon; Gómez-Rueda, Ana; Jantus-Lewintre, Eloisa; Isla, Dolores; Camps, Carlos; Ramos, Inmaculada; Trigo, Jose Manuel; Bernabé, Reyes; Juan-Vidal, Oscar; Sanchez-Torres, Jose Miguel; García-Campelo, Rosario; Provencio, Mariano; Felip, Enriqueta; de Castro, Javier; Faull, Iris; Lanman, Richard B.; Ponce-Aix, Santiago; Paz-Ares, Luis; Garrido, Pilar
• Is Part Of: Lung cancer. Volume 134(2019)
• Page Start: 72
• Page End: 78
• Publication Date: 2019-08
• Subjects: Oncogene-driven NSCLC -- TKI resistance -- Osimertinib -- ctDNA -- Digital next-generation sequencing; Lungs -- Cancer -- Periodicals; Lung Neoplasms -- Abstracts; Lung Neoplasms -- Periodicals; Poumons -- Cancer -- Périodiques; Lungs -- Cancer; Periodicals; Electronic journals; Electronic journals; 616.99424
• DOI: 10.1016/j.lungcan.2019.05.032
• Languages: English
• ISSNs: 0169-5002

Abstract

Highlights: Multicenter prospective study including 53 EGFR / ALK / ROS1- TKI-resistant patients. Thirty-four patients (64%) had evidence of tumor-DNA shed for resistance assessment. Actionable resistance alterations were detected in 45% of the patients. Target-independent alterations were more frequent in osimertinib-resistant patients. Eleven patients (20%) received molecularly-informed therapies based on plasma NGS. Abstract: Objectives: Resistance to tyrosine-kinase inhibitors (TKIs) is a clinical challenge in patients with oncogene-driven non-small-cell lung cancers (NSCLC). We have analyzed the utility of next-generation sequencing (NGS) of cell-free circulating tumor DNA (ctDNA) to impact the clinical care of patients with TKI resistance. Materials and methods: We conducted a multi-institutional prospective study including consecutive EGFR, ALK, or ROS1 -altered NSCLC patients with TKI resistance from 12 Spanish institutions. Post-progression ctDNA NGS was performed by Guardant Health (Guardant360 assay). Results: We included 53 patients separated in 3 cohorts: 31 EGFR -mutant NSCLCs with first/second-generation TKI resistance (cohort 1), 15 EGFR T790M + NSCLCs with osimertinib resistance (cohort 2), and 7 ALK/ROS1 -rearranged NSCLCs with crizotinib and/or next-generation TKI resistance (cohort 3). Besides Guardant360, 22 patients from cohort 1 (71%) underwent post-progression tumor biopsies and/or alternative plasma-based genotyping. In the entire study population, 34 patients (64%) had reliable evidence of tumor-DNA shed for resistance assessment, and 24 patients (45%) had actionable alterations. Target-independent pathogenic alterations were frequently detected, particularly at osimertinib resistance. Eleven patients (20%) received subsequent molecular-guided therapies indicated by plasma NGS alone (n = 9, 17%), or plasma NGS and tissue sequencing (n = 2, 4%), deriving the expected clinical benefit. Of these, 9 had EGFR T790 M mutation and received osimertinib, 1 had ALK G1202R mutation and received lorlatinib, and 1 had ROS1 G2032R mutation and received cabozantinib. Two additional cases from cohort 1 (6%) had undetectable EGFR T790 M by Guardant360 but were T790M + by tissue and BEAMing digital PCR respectively, and also received osimertinib. Conclusion: NGS of ctDNA detects actionable alterations in a large proportion of oncogene-driven NSCLC patients with TKI resistance, and can be used to guide subsequent treatments as a complement or alternative to tissue or PCR-based plasma genotyping in the real-world clinical setting.