City of Hope’s Afkhami Discusses NSCLC With EGFR Exon 20 Insertion-Positive Mutations

Michelle Afkhami, MD, is associate professor and division chief, Molecular Pathology and Therapy Biomarkers, medical director, Clinical Molecular Diagnostics and Cytogenetics Laboratories, Department of Pathology, City of Hope, Duarte, California. Here, she joins The American Journal of Managed Care® (AJMC®) for a discussion on EGFR exon 20 insertion positive mutations in non-small cell lung cancer, how to identify these mutations, and the importance of tumor boards.

AJMC®: What is EGFR exon 20 insertion positive non-small cell lung cancer?

Afkhami: So, let's talk about EGFR and EGFR-resistant mutation, as well as EGFR inhibitor-resistant activating mutation in lung cancer. Epidermal growth factor receptor—which is EGFR—is one the most common alterations found in non-small lung cancer. It's reported to be between 30% to 40% for all EGFR in non-small cell lung cancer, and detection of this alteration has significant clinical value in diagnosis, prognosis, and treatment of lung cancer.

With EGFR, the most common activating mutations occur in exon 18, 19, and 21. Exon 20, for the longest time, has been famous for being the resistant mutation. However, some of the most sensitive mutation of EGFR also located in that exon. So, the most common exon is 21, and that includes about 40% to 50% of all EGFR mutated non-small cell lung cancer. It depends on how advanced—what stage—the lung cancer is. The rate of the development of this EGFR exon 20 resistant mutation is different for the point mutation of this exon 20 mutation. Usually, after treatment, it's between 10% to 15%.

AJMC®: And what are some of the demographic characteristics of individuals who develop the EGFR exon 20 mutation in non-small cell lung cancer?

Afkhami: The demographic characteristics of the individuals that develop the EGFR exon 20 mutation are similar to demographics of those who develop an EGFR mutation in general; these are nonsmokers. We’ve known for a long time now that EGFR mutations are most common in nonsmokers, versus the KRAS mutation, which is more common in smokers. So, subsequent to the event, when you do the EGFR TKI [tyrosine kinase inhibitor] therapy, you get the EGFR exon 20 in a nonsmoker more than a smoker.

AJMC®: Any gender differences?

Afkhami: For EGFR exon 20, it’s more common to that females will have these mutations than male non-small cell cancer patients.

AJMC®: And how are exon 20 insertion positive mutations identified in non-small cell lung cancer? And are there any barriers to diagnosing them?

Afkhami: The diagnostic method for detection and identifying an exon 20 insertion mutation are very important. As you know, historically—before the age of [next generation sequencing] we did Sanger sequencing, which is the sensitivity of the Sanger as lower than NGS. So, you needed at least 30% tumors to confidently detect any mutation at 10% to 15% allele frequency. Recently, with the availability of next generation sequencing, detection of these resistant mutations has become very important as well. Because you have to have good tumor cellularity, robust DNA extraction method—and then your next generation sequencing analysis should set up a very specific bioinformatic rules and criteria to detect this lower allele frequency mutation. Then, so when you start treating these EGFR-mutated cancer cells, a subset of these cells develop the resistant mutation in exon 20. So, for example, if your tumor cellularity for the lung cancer in general is 20% to 30%, this can happen in only 5% to 10% of your tumor cells. And then your assay should have the capability to call out if you have 5% to 10% tumor cellularity for this subset of the cell. So, that's one of the challenges—that not so many assays, especially the expanded assays, they have the capability to report any of these alterations with less than 20% tumor cellularity.

AJMC®: Can you discuss the heterogeneity of EGFR exon 20 insertion mutations?

Afkhami: Remember the EGFR exon 20 mutations are very heterogeneous. They can be point mutation or they can be insertion. So, the point mutation, as we know, the TK790M is one of the most common mutations for this exon 20, which is, as I said, it's about 10% to 15% of the lung cancer [development]. The other point mutation, the C797S, G724S, or L792H, they happen in a lower rate. The insertion in the exon 20 which causes the frame shift and also TKI resistant, can happen in less than 1% of all the EGFR mutation.

AJMC®: What is a molecular tumor board? Describe the role of the molecular tumor board in treating EGFR exon 20 mutations.

Afkhami: With the expansion of these assays and then with all that's known other than EGFR, TK inhibitors we have for the other targetable lung cancer mutations, we have to have this larger panel. So, some of this genes are put in the panel as a diagnostic, some of them are prognostic, some of them are therapeutic. Where EGFR is one of those gene that has all 3 criteria. So molecular tumor board is very important to connect the pathologist, the clinician, and the radiologist, and discuss this wide spectrum or range of mutation that we see especially. This is inevitable….emergence of EGFR resistant mutations after this TKI, which sometimes is not only other than this exon 20 mutation of EGFR, you see the non-EGFR mutation in post-target therapy—and these are amplification of MET, FGFR, FGF, CDK6, BRAF. And each one—like MET amplification, again—now we know as you curate with this TK inhibitors, it can develop, and it has its own targeted therapy. So, it's so important to have the tumor board, to connect the team, and to come to a consensus for the treatment of the patient. This is becoming personalized medicine, curated individually for each patient. We discuss this at the genomic tumor board. We, personally at my center, I set up a daily genomic tumor board, so we can everyday discuss even the negative cases. Because, as I said, the subset of these cases have a very low allele frequency, and it's very important to look at it manually at the point of your sequence and identify this low level for any EGFR-treated cancer case.

AJMC®: Finally, can you offer any closing thoughts on disease management considerations for non-small cell lung cancer exon 20 insertions?

Afkhami: So, as a conclusion of our discussion, my recommendation to other colleagues is to be mindful of your tumor cellularity and know exactly the criteria for the NGS assay. Choose the specific test that fits your patients’ needs. If you have a resection with a high tumor cellularity, you might have more option to send that to any lab you desire. However, if you have a small core biopsy with a small tumor cellularity really you have to choose your assay carefully. Also, there are other non-invasive ways of detecting all these GFR mutations and also the exon 20 resistant mutation, which is liquid biopsy. But again, as much as we love liquid biopsy because it's non-invasive, you have to be mindful of negative results. Because that subset of cell might not be in your circulating tumor cell or cell free DNA, you might not detect due to these low tumors that you have. So, these are the most important point for the detection of the EGFR resistant mutations.