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Burden of EGFR Exon 20 Mutation in NSCLC

Insights From: John Heymach, MD, PhD, MD Anderson Cancer Center
Published: Wednesday, Apr 25, 2018



Transcript: 

John Heymach, MD, PhD: EGFR-mutant lung cancer, as a whole, is about 10% to 15% of lung cancer in North America. But in other areas it’s much more common. In Asia, for example, it’s more like 30% to 40% of lung adenocarcinoma. Out of EGFR-mutant lung cancer, exon 20 mutations are about 10% to 15% of that group, as a whole. We think of EGFR-mutant lung cancer in a few different groups. We think of the classical mutations. The 2 most common classical ones are L858R and the exon 19 deletion. Those are the ones that respond to our first- and third-generation inhibitors. Then we think of the atypical mutations. The atypical mutations, about half, include exon 20. Atypical mutations also include some exon 18 mutations, as well. So, if you put all of that together, exon 20 EGFR-mutant lung cancer is about 1% to 2% in North America and 2 or 3 times that in Asia. It occurs with some frequency, but it’s relatively rare compared with classical EGFR mutations.

As you know, for classical EGFR mutations—the L858Rs and the exon 19 deletions—they respond extremely well to first-generation inhibitor drugs like gefitinib and erlotinib, second-generation inhibitors like afatinib, and to third-generation inhibitors as well. This is where exon 20-mutant EGFR disease is really different from the others. If you take all of the studies that are out there—there are not a lot of large studies—the response rate to exon 20 mutations, to standard first-generation drugs, is about 3% to 8%. This percentage really consists of responses to one particular mutation, called 763FQEA, and a second mutation, S768I. But if you take those 2 mutations out of the equation, exon 20 mutations basically do not respond to any of the standard drugs that are available.

Exon 20-mutant non–small cell lung cancer, overall, appears to carry a little bit of a worse prognosis than regular EGFR-mutant lung cancer. There are some studies out there that say that they have a higher prevalence of brain metastases and are associated with a slightly more aggressive form of the disease. Now, that said, the studies are very small. It’s harder to separate whether this is because the disease is actually more aggressive or just because we don’t have any good standard therapies for it. If you look at the response to standard drugs, our standard inhibitors, the normal progression-free survival for classical EGFR mutations would be 12 or 13 months or so. For exon 20 mutations, it’s only about 2 months. So, these patients really do not get a lot of benefit from first- and second-generation drugs, unfortunately. This really highlights the pressing need for better drugs. Now, these patients can respond to chemotherapy. They can respond to immunotherapy, like other types of lung cancer. So, it’s not that they don’t have any options at all, but so far, we don’t have any targeted therapies that are approved for patients with exon 20 mutations.

Transcript Edited for Clarity 
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Transcript: 

John Heymach, MD, PhD: EGFR-mutant lung cancer, as a whole, is about 10% to 15% of lung cancer in North America. But in other areas it’s much more common. In Asia, for example, it’s more like 30% to 40% of lung adenocarcinoma. Out of EGFR-mutant lung cancer, exon 20 mutations are about 10% to 15% of that group, as a whole. We think of EGFR-mutant lung cancer in a few different groups. We think of the classical mutations. The 2 most common classical ones are L858R and the exon 19 deletion. Those are the ones that respond to our first- and third-generation inhibitors. Then we think of the atypical mutations. The atypical mutations, about half, include exon 20. Atypical mutations also include some exon 18 mutations, as well. So, if you put all of that together, exon 20 EGFR-mutant lung cancer is about 1% to 2% in North America and 2 or 3 times that in Asia. It occurs with some frequency, but it’s relatively rare compared with classical EGFR mutations.

As you know, for classical EGFR mutations—the L858Rs and the exon 19 deletions—they respond extremely well to first-generation inhibitor drugs like gefitinib and erlotinib, second-generation inhibitors like afatinib, and to third-generation inhibitors as well. This is where exon 20-mutant EGFR disease is really different from the others. If you take all of the studies that are out there—there are not a lot of large studies—the response rate to exon 20 mutations, to standard first-generation drugs, is about 3% to 8%. This percentage really consists of responses to one particular mutation, called 763FQEA, and a second mutation, S768I. But if you take those 2 mutations out of the equation, exon 20 mutations basically do not respond to any of the standard drugs that are available.

Exon 20-mutant non–small cell lung cancer, overall, appears to carry a little bit of a worse prognosis than regular EGFR-mutant lung cancer. There are some studies out there that say that they have a higher prevalence of brain metastases and are associated with a slightly more aggressive form of the disease. Now, that said, the studies are very small. It’s harder to separate whether this is because the disease is actually more aggressive or just because we don’t have any good standard therapies for it. If you look at the response to standard drugs, our standard inhibitors, the normal progression-free survival for classical EGFR mutations would be 12 or 13 months or so. For exon 20 mutations, it’s only about 2 months. So, these patients really do not get a lot of benefit from first- and second-generation drugs, unfortunately. This really highlights the pressing need for better drugs. Now, these patients can respond to chemotherapy. They can respond to immunotherapy, like other types of lung cancer. So, it’s not that they don’t have any options at all, but so far, we don’t have any targeted therapies that are approved for patients with exon 20 mutations.

Transcript Edited for Clarity 
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