BACKGROUND: Previous studies in sarcoma found that a composite gene signature, including high expression of nucleotide excision repair (NER) genes (XPG and/or ERCC1) and low expression of homologous recombination repair (HR) genes (BRCA1), identifies a highly sensitive population of patients with significantly improved outcome to trabectedin. This exploratory phase II trial evaluated a customized trabectedin treatment according to this gene signature in patients with non-small cell lung cancer (NSCLC) after the failure of standard platinum-based treatment. METHODS: Patients were selected according to their mRNA expression (elevated XPG and/or ERCC1, with low BRCA1) using the following values as cutoff: XPG=0.99, ERCC1=3.47 and BRCA1=12.00. Trabectedin was administered as a 1.3mg/m(2) 3-hour intravenous infusion every 3 weeks (q3wk). The primary efficacy endpoint was the progression-free survival rate at 3 months. Objective response according to the Response Evaluation Criteria in Solid Tumors (RECIST) was a secondary efficacy endpoint. RESULTS: Two of 18 evaluable patients (11.1%; 95% CI, 1.38-34.7%) achieved progression-free survival rate at 3 months. The primary efficacy objective (at least 3 of 18 patients being progression-free at 3 months) was not met, and therefore the trial was early finalized. No objective responses per RECIST were achieved. Four patients had stable disease. Median PFS was 1.3 months, and median overall survival was 5.9 months. Trabectedin was usually well tolerated, with a safety profile similar to that described in patients with other tumor types. CONCLUSIONS: Customized treatment with trabectedin 1.3mg/m(2) 3-h q3wk according to composite gene signature (XPG and/or ERCC1 overexpression, and BRCA1 underexpression) was well tolerated, but had modest activity in NSCLC patients pretreated with platinum. Therefore, further clinical trials with trabectedin as single agent in this indication are not warranted.
BACKGROUND: Previous studies in sarcoma found that a composite gene signature, including high expression of nucleotide excision repair (NER) genes (XPG and/or ERCC1) and low expression of homologous recombination repair (HR) genes (BRCA1), identifies a highly sensitive population of patients with significantly improved outcome to trabectedin. This exploratory phase II trial evaluated a customized trabectedin treatment according to this gene signature in patients with non-small cell lung cancer (NSCLC) after the failure of standard platinum-based treatment. METHODS:Patients were selected according to their mRNA expression (elevated XPG and/or ERCC1, with low BRCA1) using the following values as cutoff: XPG=0.99, ERCC1=3.47 and BRCA1=12.00. Trabectedin was administered as a 1.3mg/m(2) 3-hour intravenous infusion every 3 weeks (q3wk). The primary efficacy endpoint was the progression-free survival rate at 3 months. Objective response according to the Response Evaluation Criteria in Solid Tumors (RECIST) was a secondary efficacy endpoint. RESULTS: Two of 18 evaluable patients (11.1%; 95% CI, 1.38-34.7%) achieved progression-free survival rate at 3 months. The primary efficacy objective (at least 3 of 18 patients being progression-free at 3 months) was not met, and therefore the trial was early finalized. No objective responses per RECIST were achieved. Four patients had stable disease. Median PFS was 1.3 months, and median overall survival was 5.9 months. Trabectedin was usually well tolerated, with a safety profile similar to that described in patients with other tumor types. CONCLUSIONS: Customized treatment with trabectedin 1.3mg/m(2) 3-h q3wk according to composite gene signature (XPG and/or ERCC1 overexpression, and BRCA1 underexpression) was well tolerated, but had modest activity in NSCLCpatients pretreated with platinum. Therefore, further clinical trials with trabectedin as single agent in this indication are not warranted.
Authors: David S Moura; Paloma Sanchez-Bustos; Antonio Fernandez-Serra; María Lopez-Alvarez; José L Mondaza-Hernandez; Elena Blanco-Alcaina; Angela Gavilan-Naranjo; Paula Martinez-Delgado; Serena Lacerenza; Paloma Santos-Fernandez; Irene Carrasco-Garcia; Samuel Hidalgo-Rios; Antonio Gutierrez; Rafael Ramos; Nadia Hindi; Miguel Taron; Jose Antonio Lopez-Guerrero; Javier Martin-Broto Journal: Cancers (Basel) Date: 2020-04-30 Impact factor: 6.639
Authors: Alessandra Merlini; Maria Laura Centomo; Giulio Ferrero; Giulia Chiabotto; Umberto Miglio; Enrico Berrino; Giorgia Giordano; Silvia Brusco; Alberto Pisacane; Elena Maldi; Ivana Sarotto; Federica Capozzi; Cristina Lano; Claudio Isella; Giovanni Crisafulli; Massimo Aglietta; Angelo Paolo Dei Tos; Marta Sbaraglia; Dario Sangiolo; Lorenzo D'Ambrosio; Alberto Bardelli; Ymera Pignochino; Giovanni Grignani Journal: Front Oncol Date: 2022-08-30 Impact factor: 5.738
Authors: David S Moura; Maria Peña-Chilet; Juan Antonio Cordero Varela; Ramiro Alvarez-Alegret; Carolina Agra-Pujol; Francisco Izquierdo; Rafael Ramos; Luis Ortega-Medina; Francisco Martin-Davila; Carolina Castilla-Ramirez; Carmen Nieves Hernandez-Leon; Cleofe Romagosa; Maria Angeles Vaz Salgado; Javier Lavernia; Silvia Bagué; Empar Mayodormo-Aranda; Luis Vicioso; Jose Emilio Hernández Barceló; Jordi Rubio-Casadevall; Ana de Juan; Maria Concepcion Fiaño-Valverde; Nadia Hindi; Maria Lopez-Alvarez; Serena Lacerenza; Joaquin Dopazo; Antonio Gutierrez; Rosa Alvarez; Claudia Valverde; Javier Martinez-Trufero; Javier Martín-Broto Journal: Mol Oncol Date: 2021-06-30 Impact factor: 6.603