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 of progression with first-line EGFR TKIs may be related to the EGFR T790M mutation.29
Fortunately, with medical advances, patients with EGFR T790M mutation-positive nowadays have a new 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.
29. Yu HA, Arcila ME, Rekhtman N, et al. Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin Cancer Res. 2013;19:2240-2247.
30. Panagiotopoulos N, LawrenceD. 3rd Generation EGFR TKIs – A Major Breakthrough for NSCLC Treatment. Journal of Respiratory Research 2015;1(1):5-6.
31 Pirker R. Third-generation epidermal growth factor receptor tyrosine kinase inhibitors in advanced nonsmall cell lung cancer. Curr Opin Oncol. 2016;28(2):115-121.
The only way to know if patients have EGFR T790M mutation is to get tested. This helps identify the mutation and to know if patients can benefit from a treatment option known as third-generation EGFR TKI therapy.32
How to get tested
Testing for the EGFR T790M mutation is now possible using similar methods as those for EGFR mutation testing at the time of primary diagnosis. See EGFR Mutation Testing section for more information.
In general, a fresh sample and test at progression is needed to get accurate results. However, biological samples other than tumour tissue can be used, such as circulating tumour DNA (ctDNA) taken from plasma samples.33
Results of the testing may be available in 1 to 3 weeks’ time25. Usually, ctDNA testing is likely to be quicker to obtain than a tissue biopsy sample.34 However, the EGFR mutation detection rate (sensitivity) is lower for ctDNA compared with tumour samples.35 Doctors are now incorporating both ctDNA and tissue tests into practice to identify more patients with the EGFR T790M mutation.36
25. New lung cancer treatment possibilities through molecular tumor testing. freetobreathe.org, USA 2016. Available at: http://www.freetobreathe.org/images/uploads/MTTBrochure-2017update.pdf. Accessed 9 Feb 2017.
32. Wang SH, et al_Third-generation inhibitors targeting EGFR T790M mutation in advanced non-small cell lung cancer. J Hematol Oncol. 2016;9:34.
33. Diaz LA Jr, Bardelli A. Liquid biopsies: genotyping circulating tumor DNA. J Clin Oncol. 2014;32:579-586.
34. EGFR mutation test turnaround time. AstraZeneca. Available at: http://www.egfr-mutation.com/how-to-test/tat.html. Accessed 9 Feb 2017.
35. Douillard J-Y, Ostoros G, Cobo M et al. Gefitinib treatment in EGFR mutated Caucasian NSCLC: circulating-free tumor DNA as a surrogate for determination of EGFR status. J Thorac Oncol. 2014;9:1345–1353.
36. Karlovich C, et al. Assessment of EGFR mutation status in matched plasma and tumor tissue of NSCLCP atients from a phase I study of Rociletinib (CO-1686). Clin Cancer Res. 2016;22(10);2386–95.
Previously, treatment options were limited for patients with advanced (metastatic) non-small cell lung cancer (NSCLC) who developed resistance to first-line EGFR TKI treatment and are EGFR T790M mutation-positive.37
Thanks to the medical advances, a third-generation EGFR TKI (tyrosine kinase inhibitor) designed to target the EGFR T790M mutation is nowadays available, providing EGFR T790M mutation-positive lung cancer patients with another treatment option and a hope to live longer.38
About first- second- and third-generation EGFR TKIs
The first-generation EGFR-TKIs (epidermal growth factor receptor tyrosine kinase inhibitors) refer to drugs including gefitinib and erlotinib.39 They are effective as first-line treatment of advanced non-small cell lung cancer (NSCLC) harboring activating EGFR mutations.
The second-generation EGFR-TKI, e.g. afatinib, irreversibly bind to the tyrosine kinase of EGFR and other ErbB-family members.39 Afatinib is also effective as first-line treatment of advanced NSCLC harboring activating EGFR mutations.39
Third-generation EGFR-TKI, such as osimertinib, inhibit both EGFR activating and resistance mutations, while sparing wild-type EGFR.39 In medical studies, ostimertinib demonstrated promising response rates against tumors with EGFR T790M mutation.38
37. Soria JC, Wu YL, Nakagawa K, et al. Gefitinib plus chemotherapy versus placebo plus chemotherapy in EGFR-mutation-positive non-small-cell lung cancer after progression on first-line gefitinib (IMPRESS): a phase 3 randomised trial. Lancet Oncol. 2015;16:990-998.
38. Mok TS, et al. Osimertinib or Platinum-Pemetrexed in EGFR T790M-Positive Lung Cancer. N Engl J Med. 2017;376(7):629-640.
39. Liao BC, et al. Second and third-generation epidermal growth factor receptor tyrosine kinase inhibitors in advanced nonsmall cell lung cancer. Curr Opin Oncol. 2015;27(2):94-101.
For patients whose disease have progressed after first-line EGFR TKI treatment, it is important to talk with your doctor about secondary mutation and if EGFR T790N mutation testing is recommended for you. If your doctor recommends another treatment option, it is important to discuss the treatment risks and benefits, as well as the expected outcome.
Sample questions to ask your doctor
- Why does my disease get worse and the target therapy stop working?
- Do I have a secondary mutation and need another testing?
- What type of tests do you recommend if I need another testing?
- What should be done if my tumour is EGFR T790M mutation-positive?
- What should be done if my tumour is EGFR T790M mutation-negative?
- If third-generation EGFR TKI treatment is recommended, what are the benefits and risks/side effects of this treatment?
- How can I get help to manage any side effects?
- When can I start my treatment, and how long will it last?