Marzia Del Re1, Iacopo Petrini2, Francesca Mazzoni3, Simona Valleggi2, Giulia Gianfilippo1, Daniele Pozzessere4, Antonio Chella2, Stefania Crucitta1, Eleonora Rofi1, Giuliana Restante1, Mario Miccoli5, Marina Chiara Garassino6, Romano Danesi7. 1. Unit of Clinical Pharmacology and Pharmacogenetics, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy. 2. Unit of Pneumology, Azienda Ospedaliero-Universitaria Pisana and Department of Translational Research and New Technologies in Medicine, University of Pisa, Pisa, Italy. 3. Unit of Medical Oncology, Department of Oncology, University Hospital of Firenze, Firenze, Italy. 4. Unit of Medical Oncology, Department of Oncology, Hospital of Prato, Prato, Italy. 5. Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy. 6. Thoraco-pulmonary Medical Oncology Unit, Medical Oncology and Hematology Department, National Tumor Institute, IRCCS, Milan, Italy. 7. Unit of Clinical Pharmacology and Pharmacogenetics, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy. Electronic address: romano.danesi@unipi.it.
Abstract
BACKGROUND: Insights into the mechanism of resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) could provide important information for further patient management, including the choice of second-line treatment. The EGFR T790M mutation is the most common mechanism of resistance to first- and second-generation EGFR TKIs. Owing to its biologic relevance in the response of non-small-cell lung cancer (NSCLC) to the selective pressure of treatment, the present study investigated whether the occurrence of T790M at progression differed among patients receiving gefitinib, erlotinib, or afatinib. PATIENTS AND METHODS: The present retrospective study included patients with NSCLC with an EGFR activating mutation, who had received gefitinib, erlotinib, or afatinib as first-line treatment. Plasma samples for the analysis of cell-free DNA were taken at disease progression and analyzed using a digital droplet polymerase chain reaction EGFR mutation assay. RESULTS: A total of 83 patients were enrolled; 42 had received gefitinib or erlotinib and 41afatinib. The patient characteristics were comparable across the 2 groups. The median time to progression (TTP) was 14.4 months for the gefitinib and erlotinib group and 10.2 months for the afatinib group (P = .09). Of the 83 patients, 47 (56.6%) were positive for the T790M in plasma. A greater incidence of T790M was observed in patients with progression during gefitinib or erlotinib therapy compared with patients treated with afatinib (33 [79%] vs. 14 [34%], respectively; odds ratio, 7.1; 95% confidence interval, 2.7-18.5; P = .0001). CONCLUSIONS: Although gefitinib, erlotinib, and afatinib showed a comparable TTP in patients receiving first-line therapy, the incidence of T790M differed among them, as demonstrated by the present study, which could have implications for the choice of second-line treatment.
BACKGROUND: Insights into the mechanism of resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) could provide important information for further patient management, including the choice of second-line treatment. The EGFRT790M mutation is the most common mechanism of resistance to first- and second-generation EGFR TKIs. Owing to its biologic relevance in the response of non-small-cell lung cancer (NSCLC) to the selective pressure of treatment, the present study investigated whether the occurrence of T790M at progression differed among patients receiving gefitinib, erlotinib, or afatinib. PATIENTS AND METHODS: The present retrospective study included patients with NSCLC with an EGFR activating mutation, who had received gefitinib, erlotinib, or afatinib as first-line treatment. Plasma samples for the analysis of cell-free DNA were taken at disease progression and analyzed using a digital droplet polymerase chain reaction EGFR mutation assay. RESULTS: A total of 83 patients were enrolled; 42 had received gefitinib or erlotinib and 41afatinib. The patient characteristics were comparable across the 2 groups. The median time to progression (TTP) was 14.4 months for the gefitinib and erlotinib group and 10.2 months for the afatinib group (P = .09). Of the 83 patients, 47 (56.6%) were positive for the T790M in plasma. A greater incidence of T790M was observed in patients with progression during gefitinib or erlotinib therapy compared with patients treated with afatinib (33 [79%] vs. 14 [34%], respectively; odds ratio, 7.1; 95% confidence interval, 2.7-18.5; P = .0001). CONCLUSIONS: Although gefitinib, erlotinib, and afatinib showed a comparable TTP in patients receiving first-line therapy, the incidence of T790M differed among them, as demonstrated by the present study, which could have implications for the choice of second-line treatment.
Authors: Marzia Del Re; Federico Cucchiara; Iacopo Petrini; Stefano Fogli; Antonio Passaro; Stefania Crucitta; Ilaria Attili; Filippo De Marinis; Antonio Chella; Romano Danesi Journal: ESMO Open Date: 2020-08