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K.S. Lam

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    MA 15 - Lung Cancer Biology II (ID 670)

    • Event: WCLC 2017
    • Type: Mini Oral
    • Track: Biology/Pathology
    • Presentations: 1
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      MA 15.08 - Safety and Efficacy of Osimertinib in Treating an EGFR-Mutant Lung Cancer Patient with a Germline EGFR T790M Mutation (ID 9712)

      15:45 - 17:30  |  Author(s): K.S. Lam

      • Abstract
      • Presentation
      • Slides

      Limited and conflicting data are available for the safety and clinical efficacy of EGFR TKIs, especially third-generation TKI osimertinib, in the rare (<0.1%) subset of NSCLC patients carrying a germline EGFR T790M mutation. We here report a patient with concurrent somatic EGFR L858R and germline EGFR T790M mutations detected by liquid biopsy and tumor genomic profiling assay.

      A 67-year-old male, life-long never smoker was initially found to have bilateral, small lung nodules incidentally on a CT scan during the workup for a kidney stone. His family history suggests a hereditary predisposition to lung cancer given there were three other individuals (including two never smokers) across three generations with a history of lung cancer. The patient underwent annual surveillance chest CT scans over a two-year period before a biopsy-proven stage IA lung adenocarcinoma was found, which was treated with stereotactic body radiation. Unfortunately, this patient developed local tumor recurrence in the lung and wide spread bony metastases in less than one year. To determine the effect of EGFR TKIs on normal blood cells, we established a permanent Epstein-Barr Virus (EBV)-transformed lymphoblastoid cell line from the patient’s peripheral blood mononuclear cells (PBMCs) and determined the in vitro cytotoxicity of the cell line to first, second, and third generation EGFR TKIs. Serial tumor genomic profiling of plasma ctDNA by the Guardant360 assay was obtained each time clinical treatment was changed for this patient.

      We found neither EGFR nor AKT expression in the PBMCs and the EBV-transformed lymphoblastoid cell line established from this patient. The EBV-transformed lymphoblastoid cells were resistant to all first, second and third generation EGFR TKIs tested. This patient achieved rapid clinical response to osimertinib after progression on radiation, chemotherapy, and afatinib. Serial genotyping of plasma ctDNA showed the alteration of EGFR L858R level correlated with tumor response while the mutant allelic frequency of EGFR T790M remained at ~50%. A heterozygous EGFR T790M germline mutation was confirmed by genetic testing.

      To our knowledge, this is the first combined in vitro and clinical data supporting the safety and efficacy of osimertinib in patients with the germline EGFR T790M mutation. Further mechanistic studies are needed to understand the tumorigenesis and clinical management for lung cancer patients and carriers with a germline EGFR T790M mutation.

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