D Planchard1, Y Loriot2, F André3, A Gobert4, N Auger5, L Lacroix6, J C Soria7. 1. Department of Medical Oncology, Gustave Roussy, Villejuif david.planchard@gustaveroussy.fr. 2. Department of Medical Oncology, Gustave Roussy, Villejuif. 3. Department of Medical Oncology, Gustave Roussy, Villejuif INSERM U981, Gustave Roussy, University Paris XI, Villejuif, France. 4. Drug Development Department (DITEP), Gustave Roussy, and University Paris-Sud, Villejuif. 5. Department of Medical Biology and Pathology. 6. Translational Research Laboratory and BioBank, Gustave Roussy, Villejuif. 7. Drug Development Department (DITEP), Gustave Roussy, and University Paris-Sud, Villejuif INSERM U981, Gustave Roussy, University Paris XI, Villejuif, France.
Abstract
BACKGROUND: AZD9291 is an oral, irreversible, mutant-selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKI), which specifically targets both sensitizing and resistant T790M mutations. This compound has shown outstanding activity, in a phase I/II (AURA) trial. However, despite impressive tumor responses in T790M-positive patients, acquired resistance to this drug limits the benefit of this compound. Mutations at the EGFR C797 codon, located within the kinase-binding site, were very recently reported to be a potential mechanism of resistance to AZD9291 in T790M-positive patients. PATIENTS AND METHODS: To identify potential mechanisms of resistance to AZD9291, we report here on two patients with resistant biopsy specimens that had been treated with AZD9291. RESULTS: We identified in two distinct cases, HER2 and MET amplification by FISH and CGH as a potential mechanism of acquired resistance to third-generation EGFR-TKI. Interestingly, this event occurred with complete loss of the T790M mutation. In one case, we observed a different molecular status at two biopsy sites (the T790M mutation at the primary site and wild-type T790M at the metastatic site with different pathways of acquired resistance to AZD9291). CONCLUSION: Our observations suggest that T790M-positive and wild-type T790M clones may coexist at baseline. AZD9291 efficiently suppresses the growth of T790M-positive cells, but a population of wild-type T790M cells at baseline will mediate the development of resistance, here via a by-pass pathway activating either HER2 or MET.
BACKGROUND: AZD9291 is an oral, irreversible, mutant-selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKI), which specifically targets both sensitizing and resistant T790M mutations. This compound has shown outstanding activity, in a phase I/II (AURA) trial. However, despite impressive tumor responses in T790M-positive patients, acquired resistance to this drug limits the benefit of this compound. Mutations at the EGFR C797 codon, located within the kinase-binding site, were very recently reported to be a potential mechanism of resistance to AZD9291 in T790M-positive patients. PATIENTS AND METHODS: To identify potential mechanisms of resistance to AZD9291, we report here on two patients with resistant biopsy specimens that had been treated with AZD9291. RESULTS: We identified in two distinct cases, HER2 and MET amplification by FISH and CGH as a potential mechanism of acquired resistance to third-generation EGFR-TKI. Interestingly, this event occurred with complete loss of the T790M mutation. In one case, we observed a different molecular status at two biopsy sites (the T790M mutation at the primary site and wild-type T790M at the metastatic site with different pathways of acquired resistance to AZD9291). CONCLUSION: Our observations suggest that T790M-positive and wild-type T790M clones may coexist at baseline. AZD9291 efficiently suppresses the growth of T790M-positive cells, but a population of wild-type T790M cells at baseline will mediate the development of resistance, here via a by-pass pathway activating either HER2 or MET.
Authors: Osamu Tetsu; Matthew J Hangauer; Janyaporn Phuchareon; David W Eisele; Frank McCormick Journal: Chemotherapy Date: 2016-02-25 Impact factor: 2.544
Authors: Kian Kani; Carolina Garri; Katrin Tiemann; Paymaneh D Malihi; Vasu Punj; Anthony L Nguyen; Janet Lee; Lindsey D Hughes; Ruth M Alvarez; Damien M Wood; Ah Young Joo; Jonathan E Katz; David B Agus; Parag Mallick Journal: Mol Cancer Ther Date: 2017-05-31 Impact factor: 6.261