Jon Zugazagoitia1, Ana Gómez-Rueda2, Eloisa Jantus-Lewintre3, Dolores Isla4, Carlos Camps5, Inmaculada Ramos6, Jose Manuel Trigo6, Reyes Bernabé7, Oscar Juan-Vidal8, Jose Miguel Sanchez-Torres9, Rosario García-Campelo10, Mariano Provencio11, Enriqueta Felip12, Javier de Castro13, Iris Faull14, Richard B Lanman15, Santiago Ponce-Aix16, Luis Paz-Ares17, Pilar Garrido18. 1. Medical Oncology Department, Hospital Universitario 12 de Octubre and i+12 Research Institute, Madrid, Spain; Lung Cancer Group, Clinical Research Program, Spanish National Cancer Research Center (CNIO), Madrid, Spain; CIBERONC, Spain; Department of Pathology, Yale School of Medicine, New Haven, CT, USA. 2. Medical Oncology Department, IRYCIS Hospital Universitario Ramón y Cajal, Universidad Alcalá, Madrid, Spain. 3. CIBERONC, Spain; Molecular Oncology Laboratory, Fundación para la Investigación del Hospital General Universitatio de Valencia, Biotechnology Department, Universitat Politècnica de València, Spain. 4. Medical Oncology Department, Hospital Universitario Lozano Blesa, Zaragoza, Spain. 5. CIBERONC, Spain; Medical Oncology Department, Hospital General Universitario de Valencia, Medicine Department, Universidad de Valencia, Spain. 6. Medical Oncology Department, Hospital Universitario Virgen de la Victoria, Málaga, Spain. 7. Medical Oncology Department, Hospital Universitario Vírgen del Rocío, Sevilla, Spain. 8. Medical Oncology Department. Hospital Universitari i Politècnic La Fe, Valencia, Spain. 9. Medical Oncology Department, Hospital Universitario La Princesa, Madrid, Spain. 10. Medical Oncology Department, Hospital Universitario Da Coruña, A Coruña, Spain. 11. Medical Oncology Department, Hospital Universitario Puerta de Hierro, Madrid, Spain. 12. Medical Oncology Department, Hospital Universitario Vall d'Hebron, Barcelona, Spain. 13. Medical Oncology Department. Hospital Universitario La Paz, Madrid, Spain. 14. Medical affairs, Guardant Health, Barcelona, Spain. 15. Medical affairs, Guardant Health, Redwood City, California. 16. Medical Oncology Department, Hospital Universitario 12 de Octubre and i+12 Research Institute, Madrid, Spain; Lung Cancer Group, Clinical Research Program, Spanish National Cancer Research Center (CNIO), Madrid, Spain. 17. Medical Oncology Department, Hospital Universitario 12 de Octubre and i+12 Research Institute, Madrid, Spain; Lung Cancer Group, Clinical Research Program, Spanish National Cancer Research Center (CNIO), Madrid, Spain; CIBERONC, Spain; Complutense University, Madrid, Spain. Electronic address: lpazares@seom.org. 18. CIBERONC, Spain; Medical Oncology Department, IRYCIS Hospital Universitario Ramón y Cajal, Universidad Alcalá, Madrid, Spain. Electronic address: pilargarridol@gmail.com.
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.
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 NSCLCpatients 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 EGFRT790M + 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 ALKG1202R mutation and received lorlatinib, and 1 had ROS1G2032R 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 NSCLCpatients 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.
Authors: Juan Moreno-Rubio; Santiago Ponce; Rosa Álvarez; María Eugenia Olmedo; Sandra Falagan; Xabier Mielgo; Fátima Navarro; Patricia Cruz; Luis Cabezón-Gutiérrez; Carlos Aguado; Gonzalo Colmenarejo; Marta Muñoz-Fernández de Leglaria; Ana Belén Enguita; María Cebollero; Amparo Benito; Isabel Alemany; Carolina Del Castillo; Ricardo Ramos; Ana Ramírez de Molina; Enrique Casado; Maria Sereno Journal: Cancer Biol Med Date: 2020-05-15 Impact factor: 4.248