Portal de investigación
Genomic Landscape of Primary Resistance to Osimertinib Among Hispanic Patients with EGFR-Mutant Non-Small Cell Lung Cancer (NSCLC): Results of an Observational Longitudinal Cohort Study
Fecha de publicación:
Fecha Ahead of Print:
Autores organización
Autores
- Chamorro D.F.
- Rodríguez J.
- Ruiz-Patiño A.
- Arrieta O.
- Moreno-Pérez D.A.
- Zatarain-Barrón Z.L.
- Ardila D.V.
- Viola L.
- Recondo G.
- Blaquier J.B.
- Martín C.
- Raez L.
- Samtani S.
- Ordóñez-Reyes C.
- Garcia-Robledo J.E.
- Corrales L.
- Sotelo C.
- Ricaurte L.
- Cuello M.
- Mejía S.
- Jaller E.
- Vargas C.
- Carranza H.
- Otero J.
- Archila P.
- Bermudez M.
- Gamez T.
- Russo A.
- Malapelle U.
- de Miguel Perez D.
- de Lima V.C.C.
- Freitas H.
- Saldahna E.
- Rolfo C.
- Rosell R.
Grupos de investigación
Resumen
Background: Epidermal growth factor receptor (EGFR) mutations (EGFRm) represent one of the most common genomic alterations identified among patients with non-small cell lung cancer (NSCLC). Several targeted agents for patients with EGFRm have been proven safe and effective, including the third-generation tyrosine kinase inhibitor (TKI) osimertinib. Nonetheless, some patients will present with or develop EGFR-TKI resistance mechanisms. Objective: We characterized the genomic landscape of primary resistance to osimertinib among Hispanic patients with EGFR-mutant NSCLC. Methods: An observational longitudinal cohort study was conducted with two groups of patients, those with intrinsic resistance (cohort A) and those with long-term survival (cohort B). All patients were treated and followed between January 2018 and May 2022. All patients were assessed for Programmed Cell Death Ligand 1 (PD-L1) expression and Bcl-2-like protein 11 (BIM)/AXL mRNA expression before starting TKI. After 8 weeks of treatment, a liquid biopsy was performed to determine the presence of circulating free DNA (cfDNA), and next-generation sequencing (NGS) was used to identify mutations at the time of progression. In both cohorts, overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) were evaluated. Results: We found a homogeneous distribution of EGFR-sensitizing mutations in both cohorts. For cohort A, exon 21 mutations were more common than exon 19 deletions (ex19dels) for cohort B (P = 0.0001). The reported ORR for osimertinib was 6.3% and 100% for cohorts A and B, respectively (P = 0.0001). PFS was significantly higher in cohort B (27.4 months vs. 3.1 months; P = 0.0001) and ex19del patients versus L858R (24.5 months, 95% confidence interval [CI] 18.2–NR), vs. 7.6 months, 95% CI 4.8–21.1; P = 0.001). OS was considerably lower for cohort A (20.1 months vs. 36.0 months; P = 0.0001) and was better for patients with ex19del, no brain metastasis, and low tumor mutation burden. At the time of progression, more mutations were found in cohort A, identifying off-target alterations more frequently, including TP53, RAS, and RB1. Conclusion: EGFR-independent alterations are common among patients with primary resistance to osimertinib and significantly impact PFS and OS. Our results suggest that among Hispanic patients, other variables associated with intrinsic resistance include the number of commutations, high levels AXL mRNA, and low levels of BIM mRNA, T790M de novo, EGFR p.L858R presence, and a high tumoral mutational burden. © 2023, The Author(s).
Datos de la publicación
- ISSN/ISSNe:
- 1776-2596, 1776-260X
- Tipo:
- Article
- Páginas:
- 425-440
- Enlace a otro recurso:
- www.scopus.com
Targeted Oncology Adis
Citas Recibidas en Web of Science: 4
Citas Recibidas en Scopus: 14
Documentos
- No hay documentos
Filiaciones
Keywords
- Aniline Compounds; Carcinoma, Non-Small-Cell Lung; Cell-Free Nucleic Acids; Cohort Studies; ErbB Receptors; Genomics; Hispanic or Latino; Humans; Longitudinal Studies; Lung Neoplasms; Mutation; Protein Kinase Inhibitors; AXL receptor tyrosine kinase; BIM protein; circulating free DNA; messenger RNA; osimertinib; programmed death 1 ligand 1; aniline derivative; cell free nucleic acid; EGFR protein, human; epidermal growth factor receptor; osimertinib; protein kinase inhibitor; adult; aged; Article; cancer growth; clinical article; clinical effectiveness; clinical feature; cohort analysis; drug effect; drug efficacy; drug response; EGFR gene; exon; female; follow up; gene; gene mutation; gene targeting; genetic association; genomics; high throughput sequencing; Hispanic; human; liquid biopsy; long term survival; longitudinal study; male; non small cell lung cancer; observational study; oncogene ras; overall survival; progression free survival; protein expression; RB1 gene; risk factor; s
Financiación
Proyectos asociados
Desarrollo de un modelo de Machine Learning para la prevención de infección de vías urinarias y enfermedad diarreica aguda en pacientes con trasplante renal
Investigador Principal: CARLOS ALBERTO PUENTES MORALES
PCI-2023-0010 . 2023
Citar la publicación
Chamorro DF,Cardona AF,Rodríguez J,Ruiz A,Arrieta O,Moreno DA,Rojas L,Zatarain ZL,Ardila DV,Viola L,Recondo G,Blaquier JB,Martín C,Raez L,Samtani S,Ordóñez C,Garcia JE,Corrales L,Sotelo C,Ricaurte L,Cuello M,Mejía S,Jaller E,Vargas C,Carranza H,Otero J,Archila P,Bermudez M,Gamez T,Russo A,Malapelle U,de Miguel D,de Lima VCC,Freitas H,Saldahna E,Rolfo C,Rosell R. Genomic Landscape of Primary Resistance to Osimertinib Among Hispanic Patients with EGFR-Mutant Non-Small Cell Lung Cancer (NSCLC): Results of an Observational Longitudinal Cohort Study. Target Oncol. 2023. 18. (3):p. 425-440. IF:4,400. (2).