EGFR-independent mechanisms of acquired resistance to AZD9291 in EGFR T790M-positive NSCLC patients.
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.


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).


CONCLUSIONS
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.
Department of Medical Oncology, Gustave Roussy, Villejuif david.planchard@gustaveroussy.fr.
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D
Planchard
Department of Medical Oncology, Gustave Roussy, Villejuif.
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Loriot
Department of Medical Oncology, Gustave Roussy, Villejuif INSERM U981, Gustave Roussy, University Paris XI, Villejuif, France.
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André
Drug Development Department (DITEP), Gustave Roussy, and University Paris-Sud, Villejuif.
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Gobert
Department of Medical Biology and Pathology.
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N
Auger
Translational Research Laboratory and BioBank, Gustave Roussy, Villejuif.
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Lacroix
Drug Development Department (DITEP), Gustave Roussy, and University Paris-Sud, Villejuif INSERM U981, Gustave Roussy, University Paris XI, Villejuif, France.
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Soria
D000178:Acrylamides / Q000627:therapeutic use*; D000814:Aniline Compounds / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics*; D005260:Female; D005784:Gene Amplification; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009367:Neoplasm Staging; D011379:Prognosis; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D007211:Indoles; D011743:Pyrimidines
D000178:Acrylamides; D000814:Aniline Compounds; D066246:ErbB Receptors; D019859:Proto-Oncogene Proteins c-met; D018719:Erb-b2 Receptor Tyrosine Kinases; C000596361:osimertinib; D007211:Indoles; D011743:Pyrimidines; C512478:EGFR protein, human; C508053:ERBB2 protein, human; C491743:MET protein, human
AZD9291; EGFR; HER2; MET; NSCLC; T790M