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Overcoming Resistance to EGFR Inhibitors in NSCLC

Insights From: Sai-Hong Ignatius Ou, MD, PhD, University of California, Irvine, School of Medicine
Published: Tuesday, Oct 23, 2018



Transcript: 

Sai-Hong Ignatius Ou, MD, PhD: As far as resistance to EGFR TKIs [tyrosine kinase inhibitors], there are essentially 3 generations of EGFR TKIs. The first-generation EGFR TKIs are erlotinib or gefitinib, and icotinib in China. The second-generation EGFR TKI is afatinib. Dacomitinib is another one that may be approved based on the ARCHER 1050 study. Right now, the only third-generation option is osimertinib.
There are 4 major resistance mechanisms to EGFR TKIs. No. 1 is the development of second-site mutations. With the first-generation EGFR TKIs we are looking at T790M mutations. With the third-generation EGFR TKI we are looking at the C797S mutation. Or, are there second site mutations in the EGFR gene? With second-generation resistance mechanisms we look at MET amplification. That has been demonstrated with first-generation or third-generation EGFR TKIs. Other resistance mechanisms—some of the small cell transformation—have also been reported in the literature from first-generation and third-generation EGFR TKI resistance.

The fourth mechanism of resistance to EGFR TKIs is the appearance of receptor tyrosine kinase fusions, or BRAF fusions. We published a paper recently in the Journal of Thoracic Oncology detailing about 31 patients who had receptor tyrosine kinase fusions or BRAF fusions. We have patient examples that demonstrate that combining osimertinib with alectinib in patients with ALK fusions had clinical benefit for about 4 to 6 months.

Recently, Memorial Sloan Kettering published 3 cases that looked at patients with ALK fusions and 1 patient with a RET fusion. In the 2 cases of ALK fusions, they were able to successfully treat the resistant mechanism with both EGFR TKI and ALK inhibitors.

Additionally, at this World Conference on Lung Cancer meeting, a mini abstract showed that the combination of osimertinib and BLU-667, which is a RET inhibitor, can also overcome resistance to osimertinib based on the emergence of RET fusions. The in vitro data, the patient example, is actually going to be appear in Cancer Discovery very soon. We also contributed 1 patient case to the study.

We also had a patient who was resistant to afatinib and cetuximab on the SWOG study. We were able to obtain BLU-667 and combine it with osimertinib, and it was approved for emergency use by the FDA. The patient had a dramatic response—about 78% reduction in the tumor measurements. This will be in the Cancer Discovery paper too.

In summary, there are 4 major resistance mechanisms. No. 1 is the development of acquired mutations in the EGFR gene. No. 2 is the MET amplification. No. 3 is small cell transformation. And No. 4 is receptor tyrosine kinase fusions such as ALK fusions, RET fusions, ROS1 fusions, FGFR fusions, and NTRK fusions. So those are the 4 major mechanisms of resistance to EGFR TKI therapy.

The prevalence of the resistance mechanisms is based on the generation of the EGFR TKI. If you have first-generation resistance, T790M is very common. If you have third-generation resistance, such as resistance to osimertinib, you may have the C797S mutation or MET amplification. You may also have receptor tyrosine kinase fusions. They may appear in the same frequency. And, of course, there are minor resistance mechanisms, but these are the 4 major resistance mechanisms, in my opinion.

Transcript Edited for Clarity 
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Transcript: 

Sai-Hong Ignatius Ou, MD, PhD: As far as resistance to EGFR TKIs [tyrosine kinase inhibitors], there are essentially 3 generations of EGFR TKIs. The first-generation EGFR TKIs are erlotinib or gefitinib, and icotinib in China. The second-generation EGFR TKI is afatinib. Dacomitinib is another one that may be approved based on the ARCHER 1050 study. Right now, the only third-generation option is osimertinib.
There are 4 major resistance mechanisms to EGFR TKIs. No. 1 is the development of second-site mutations. With the first-generation EGFR TKIs we are looking at T790M mutations. With the third-generation EGFR TKI we are looking at the C797S mutation. Or, are there second site mutations in the EGFR gene? With second-generation resistance mechanisms we look at MET amplification. That has been demonstrated with first-generation or third-generation EGFR TKIs. Other resistance mechanisms—some of the small cell transformation—have also been reported in the literature from first-generation and third-generation EGFR TKI resistance.

The fourth mechanism of resistance to EGFR TKIs is the appearance of receptor tyrosine kinase fusions, or BRAF fusions. We published a paper recently in the Journal of Thoracic Oncology detailing about 31 patients who had receptor tyrosine kinase fusions or BRAF fusions. We have patient examples that demonstrate that combining osimertinib with alectinib in patients with ALK fusions had clinical benefit for about 4 to 6 months.

Recently, Memorial Sloan Kettering published 3 cases that looked at patients with ALK fusions and 1 patient with a RET fusion. In the 2 cases of ALK fusions, they were able to successfully treat the resistant mechanism with both EGFR TKI and ALK inhibitors.

Additionally, at this World Conference on Lung Cancer meeting, a mini abstract showed that the combination of osimertinib and BLU-667, which is a RET inhibitor, can also overcome resistance to osimertinib based on the emergence of RET fusions. The in vitro data, the patient example, is actually going to be appear in Cancer Discovery very soon. We also contributed 1 patient case to the study.

We also had a patient who was resistant to afatinib and cetuximab on the SWOG study. We were able to obtain BLU-667 and combine it with osimertinib, and it was approved for emergency use by the FDA. The patient had a dramatic response—about 78% reduction in the tumor measurements. This will be in the Cancer Discovery paper too.

In summary, there are 4 major resistance mechanisms. No. 1 is the development of acquired mutations in the EGFR gene. No. 2 is the MET amplification. No. 3 is small cell transformation. And No. 4 is receptor tyrosine kinase fusions such as ALK fusions, RET fusions, ROS1 fusions, FGFR fusions, and NTRK fusions. So those are the 4 major mechanisms of resistance to EGFR TKI therapy.

The prevalence of the resistance mechanisms is based on the generation of the EGFR TKI. If you have first-generation resistance, T790M is very common. If you have third-generation resistance, such as resistance to osimertinib, you may have the C797S mutation or MET amplification. You may also have receptor tyrosine kinase fusions. They may appear in the same frequency. And, of course, there are minor resistance mechanisms, but these are the 4 major resistance mechanisms, in my opinion.

Transcript Edited for Clarity 
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