Heterogeneity of Drug Resistance in EGFR-Mutant Non-Small Cell Lung Cancer

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The heterogeneity of resistance may make it difficult for drug developers to create combination therapies that prevent eventual resistance to osimertinib.
The heterogeneity of resistance may make it difficult for drug developers to create combination therapies that prevent eventual resistance to osimertinib.

Patient outcomes from treatment with osimertinib in non-small cell lung cancer (NSCLC) are influenced by the presence of drug-resistance mechanisms, but the appearance of such mechanisms is not easily predictable, according to authors of a study published in JAMA Oncology.1

“Although osimertinib is expected to move into the first-line setting for treatment of EGFR-mutant NSCLC, the challenge of detecting and targeting specific resistance mechanisms has relevance across a range of targetable genotypes where treatment of drug resistance is under active investigation,” the authors wrote.

Loss of T790M is associated with early resistance to osimertinib — but patients who develop resistance early are also likely have to have other resistance mechanisms working in other tumor subclones, said the study authors, and sometimes resistance appears late in the treatment course. New clinical trials that attempt to tease out patients who have T790M-positive resistance and acquired resistance to osimertinib “must consider which type of resistance is being targeted,” the investigators asserted.

To determine how to best detect which resistance mechanisms were commonly at play in NSCLC, the researchers looked across the databases of 4 cancer centers and selected patients with advanced NSCLC who received single-agent osimertinib and acquired resistance to prior EGFR tyrosine kinase inhibitors (TKIs) and were EGFR T790M-positive. They studied time to treatment discontinuation of osimertinib and conducted genomic analysis to identify the resistance mechanisms that were prevalent.

Of the 143 participants, 41 (approximately 29%) had next-generation sequencing done. Of these, 13 patients (32%) maintained EGFR T790M and 28 patients saw a loss of T790M. Mutations in EGFR C797S were observed in 9 (22%) patients. In some cases, plasma genotyping detected new resistance drivers that were not found through next-generation sequencing of the tumors themselves.

Although there are many known mechanisms of resistance described in the literature, the researchers of the current study determined there may be 2 types of T790M-positive resistance: acquired EGFR C797S mutations and loss of the T790M mutation. And, the variety of the resistance mechanisms seen in patients with loss of T790M, “including several acquired fusion genes, highlights the need for better strategies to prevent or delay the emergence of resistance.”

Editor's note: This article has been corrected to clarify that next-generation sequencing was used on tissue biopsy samples.


  1. Oxnard GR, Hu Y, Mileham KF, et al. Assessment of resistance mechanisms and clinical implications in patients with EGFR T790M-positive lung cancer and acquired resistance to osimertinib [published online August 2, 2018]. JAMA Oncology. doi: 10.1001/jamaoncol.2018.2969

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