Download EGFR resistance, primary or secondary

EGFR-TKI resistance, primary or secondary
上皮生長因子接受器酪胺酸激脢抑制劑的抗藥性，原發或繼發
105/4/21 邱昭華醫師
Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) can
provide remarkable benefit to advanced non-small cell lung cancer patients with
EGFR gene mutations; however, disease relapse develops eventually, with an average
of 10 months. Emergence of EGFR T790M mutation is the major resistance
mechanism and accounts for about half of the cases. Several T790M-directed “third
generation” EGFR-TKI are developing. Osimertinib (AZD9291) is the leading
compound and has gotten the FDA approval based on its phase 1 and 2 study results
in 2015. Traditionally, tumor rebiopsy is warranted to obtain information for drug
resistance but it is risky and not every patient has lesions to be biopsied. Recently,
using highly sensitive methods, it is demonstrated that tumors’ genetic alterations can
be detected in peripheral blood through the analysis of circulating cell-free DNA.
Other resistance mechanisms include MET amplification, small cell transformation,
epithelial-mesenchymal transition, and so on. In addition to the secondary resistance,
primary resistance also occurs, such as high de novo T790M mutation, PTEN loss,
KRAS mutation and BIM polymorphism. Recently, we identified MLH1 V384D
would contribute to a worse EGFR-TKI response in patients with EGFR L858R
mutation. Besides, EGFR mutations are not created equal. Classical mutations (exon
19 deletions and L858R mutation) are sensitive to EGFR-TKI, but uncommon
mutations (G719X, S768I and L861Q) are less sensitive, and exon 20 insertions are
not sensitive. In vitro data and some retrospective clinical studies suggested that
second generation EGFR-TKI might provide a better response to tumors with
uncommon mutations. Lately, a preclinical study implied that a higher dose of
EGF816, a third generation EGFR-TKI, may be the solution for patients with EGFR
exon 20 insertions. Further studies are needed for “precision medicine”, even in
patients with who have known targets, such as EGFR mutations.