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Title: Combination Osimertinib and Gefitinib in C797S and T790M EGFR-Mutated Non-Small Cell Lung Cancer.
Austin Authors: Arulananda, Surein;Do, Hongdo;Musafer, Ashan;Mitchell, Paul L R ;Dobrovic, Alexander ;John, Thomas 
Affiliation: School of Cancer Medicine, La Trobe University, Melbourne, Victoria, Australia
Translational Genomics and Epigenomics Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia
Department of Pathology, University of Melbourne, Parkville, Victoria, Australia
Cancer Immunobiology Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia
Department of Medical Oncology, Olivia Newton-John Cancer and Wellness Centre, Austin Health, Heidelberg, Victoria, Australia
Issue Date: Nov-2017 2017-08-24
Publication information: Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 2017-11; 12(11): 1728-1732
Abstract: Osimertinib, a third-generation EGFR tyrosine kinase inhibitor has demonstrated efficacy in tumors harboring the EGFR T790M resistance mutation. Inevitably, resistance to third-generation inhibitors results in disease progression, with the EGFR C797S mutation being one of several resistance pathways identified to date. On the basis of preclinical data, we report what is the first known case of a patient harboring the T790M and C797S mutations in trans treated with combination gefitinib and osimertinib. On development of progressive disease after multiple therapies, the patient's plasma was sequenced using the Oncomine Lung cfDNA Assay (Thermo Fisher Scientific, Waltham, MA). Subsequent monitoring of circulating tumor DNA in plasma was performed by droplet digital polymerase chain reaction. Sequencing showed that the T790M and C797S mutations were in trans. Within 2 weeks of commencement of combination therapy, rapid clinical improvement occurred. Accompanying this, a rapid decline in the C797S mutation subclone in plasma was detected. However, the levels of the EGFR exon 19 deletion driver mutation and the T790M resistance mutation in the circulating tumor DNA continued to rise and the patient died from progressive disease 6 weeks after commencement of combination therapy. There were no adverse events seen with the combination therapy. This is, to the best of our knowledge, the first reported case of combination EGFR tyrosine kinase inhibitor therapy tailored to the allelic conformation of T790M and C797S mutation that resulted in brief clinical improvement without toxicity.
DOI: 10.1016/j.jtho.2017.08.006
ORCID: 0000-0002-5636-6381
PubMed URL: 28843359
Type: Journal Article
Subjects: C797S mutation
EGFR mutation
Non–small cell lung cancer
Appears in Collections:Journal articles

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