Most advanced (metastatic) non-small cell lung cancer (NSCLC) patients receiving first-line EGFR TKI treatment will respond well to the treatment for a period of time, but will eventually develop drug resistance.29
Common mechanisms of resistance to first-line EGFR TKI therapy include EGFR T790M mutation, HER2 amplification, MET amplification and small cell histologic transformation. Only EGFR T790M mutation is discussed here as it is the most common mechanism among all mechanisms of resistance.29
It has been shown that among those who developed resistance to first-line EGFR TKI therapies, 50-60% of them have EGFR T790M mutation.30
What is EGFR T790M mutation?
Targeted therapies often work well for a period of time, but then stop working. This means the cancer develops resistance to the treatment. T790M is a point mutation in the EGFR gene that is most frequently reported to associate with the resistance to first-line EGFR TKI treatment.29
A common example of this would be if a patient is positive for an EGFR mutation and taking a first-line EGFR TKI, the patient may initially respond very well to the drug, but after a while, about 8-16 months, the drug stops working.29 Doctors may order additional biopsies and mutation testing, and the repeat testing may show that the tumour now has developed a specific change in EGFR called T790M. In this situation, other treatment options may be considered.
Effect of EGFR T790M mutation
When tumours develop EGFR T790M mutations, it causes the targeted therapy a patient is taking stop working, and the disease starts to progress again. Studies have found that as many as 2 out of 3 cases (66%) of progression with first-line EGFR TKIs may be related to the EGFR T790M mutation.29
Patients with EGFR T790M mutation, nowadays have a treatment option known as third-generation EGFR TKI, e.g. osimertinib.31 However, patients have to get tested to identify the mutation and to know if they can benefit from the new treatment. Please see EGFR T790M Mutation Testing section for more information.
Patients who experience disease progression following EGFR TKI treatment and who have tumors that lack the T790M mutation may be treated with chemotherapy or immunotherapy.63
29. Yu HA, et al. Clin Cancer Res 2013;19:2240-2247.
30. Panagiotopoulos N, Lawrence D. J Respir Res 2015;1(1):5-6.
31. Pirker R. Curr Opin Oncol 2016;28(2):115-121.
63. NCCN Clinical Practice Guidelines in Oncology - Non-small Cell Lung Cancer. Version 3.2019. NSCL-19 & NSCL-28.