Edward Arrowsmith, MD, MPH, EGFR Exon 20 Insertion + NSCLC, discusses how knowledge fits into pathways

Edward Arrowsmith, MD, MPH, Medical Director of Clinical Pathways for OneOncology, discussed treatment challenges in introducing EGFR Exon 20+ non-small cell lung cancer (NSCLC) and best practices in using clinical pathways.

Edward Arrowsmith, MD, MPH, a medical oncologist at the Chattanooga, Tennessee, oncology site, is the medical director of the Clinical Pathways for OneOncology. Discuss the challenges in treating EGFR Exon 20 insertion + non-small cell lung cancer (NSCLC), the benefits of next-generation sequencing (NGS), and the use of clinical pathways requires a team approach.

AJMC®: What are some clinical characteristics observed in individuals with EGFR mutations in non-small cell lung cancer?

arrows: The first thing I would say is that there are no satisfactory clinical characteristics. Any patient with non-small cell lung cancer has the potential to harbor an EGFR mutation. This is why anyone with advanced disease or with predisposing disease is eligible to try ADAURA with osimertinib1, we recommend EGFR testing and certainly for advanced disease and broad-spectrum next-generation sequencing. However, there are some things that increase the likelihood of having an EGFR mutation. Even bigger is that patients who have never smoked cigarettes or have been light smokers, usually defined as having less than 10 years of smoking, are more likely to have an EGFR mutation than those who have been heavy smokers their entire lives. Women are likely to be more likely than men to harbor an EGFR mutation, hence patients of Asian descent are also more likely to have an EGFR mutation than other races. There are also some clinical findings, so there is a distinct type of diffuse ground glass leakage into the lungs that is more often seen with EGFR mutations rather than the central solid tumors that we might see in squamous cell lung cancer or small cell lung cancer.

AJMC®: What are some unique aspects of the introduction of EGFR Exon 20 + NSCLC? What makes insertion of EGFR Exon 20 more difficult to treat than other EGFR mutations?

arrows: EGFR insertion mutations in which a base pair is inserted into a DNA strand is really, in my opinion, almost a disease separate from other EGFR mutations. Exon 20 and the more typical or classic deletion of Exon 19 or the L858R mutation of Exon 21 cause EGF kinase activation and increased activity of ATPs, but they do so in different ways. The traditional type of mutation causes a change in the shape of this binding moiety that turns the gene and protein on. Exon 20 mutations do this in a different way. It has been described by some that the anomaly of deletion 19 pulls this cleft, while insertions into exon 20 types of push open this cleft. When these Exon 20 mutations occur, a phosphate-binding loop or P-loop is pushed into this cleft and this prevents the ability of classic tyrosine kinase inhibitors such as osimertinib, gefitinib or erlotinib to enter and bind to the ATP site and prevent this disruption. These drugs bind to the protein in a non-covalent manner, and such binding with this shape difference is somewhat impossible with exon 20 insertion mutations. These drugs hardly work at all, and certainly do not work enough to be a viable therapeutic option for these patients.

AJMC®: That makes sense. When it comes to identifying EGFR mutations in non-small cell lung cancer, what are some considerations for genetic testing?

arrows: The main discovery that [causes] I recommend genetic or germline testing in patients with non-small cell lung cancer first, and finding the T790M mutation at initial presentation. This is a classic gefitinib or erlotinib-resistant mutation. When we have been using these drugs as our initial therapy, we often start patients and then find that T790M is there at the time of progression. It was a breakthrough in treatment resistance that patients can describe as similar to bacteria developing resistance to antibiotics. When you see this mutation at initial diagnosis – as they were not exposed to any factors that would allow this clone to develop – sometimes this is a familial T790M anomaly, and it is worth testing the patient’s germline and possibly family members for that. Then, it’s not just EGFR, the other place we often find lung cancer patients with germline mutations is when we do comprehensive genetic testing. We find other genes. We have had an interest in non-tumor clinical trials and have treated many people BRCA Mutations with lung cancer. BRCA isn’t in itself a risk factor for lung cancer in any way, but it’s a common enough mutation — and lung cancer is a common enough disease — that you get this crossover by chance. We found patients with lung cancer with Lynch syndrome and other genetic predispositions to cancer that were not considered by lung cancer, but only in comprehensive genomic testing. The other is that when you take a family history, you will sometimes find suspicious things. Often, the patient, [may not have something suspicious]but they have family members with colon cancer or breast and ovarian cancer where these syndromes are suspicious.

AJMC®: So what are the differences between the NGS test and the PCR test?

arrows: PCR [polymerase chain reaction] The test is usually a test for one or two genes, and what we recommend and [National Comprehensive Cancer Network] Recommended for lung cancer in particular, for most patients with incurable metastatic disease, it is a comprehensive next-generation sequencing of multiple genes involving 300 or more genes. These tests all the genes we know about today in non-small cell lung cancer that can be targeted, but they also look for other mutations that could be targets for a clinical trial — or targets for drugs in development. Just in the past couple of years, things like EGFR Exon 20 mutations or other abnormalities, KRAS-G12C is another good example of this, where we find targets all the time. Comprehensive genomic testing allows you to go back and treat these patients appropriately, rather than having to retest and retest in a piecemeal fashion. What we always say is that the cost of this comprehensive exam is less than the cost of admission. It’s not about the cost of a PET scan, and we think it’s worth it to find the best treatment for patients with metastatic cancer.

AJMC®: That’s a good point. How can clinical pathways for rare forms of diseases that may have limited treatment options, such as EGFR Exon 20 insertion-positive non-small cell lung cancer, be tapped?

arrows: We believe that one of the primary functions of Pathways is how to ensure that busy clinicians are using the best treatment for rare diseases. Perhaps the biggest change over the past 10 years or so in cancer care has been the division of common diseases such as lung cancer into a large number of rare diseases, such as the exon 20 insertion mutations of the epidermal growth factor receptor in non-small cell lung cancer. At OneOncology, we have what we like to think of as a kind of dynamic pathway program, where we both choose what we think are our optimal treatments for patients and put that into a PDF, but then we also use data analytics and point-of-care programs to help clinicians remember these rare mutations or Rare diseases for which there may be particularly useful treatments for these patients.

The other thing I would add is that we believe that analyzing next-generation sequencing reports should be a team effort. Although I have been trained to look at the bone marrow during my hematology fellowship, I always find the hematologist also looking at the bone marrow slices and explaining things for me. Likewise, I always have people who are more trained than I am in molecular biology, genetics, and cell biology help me interpret next generation sequencing reports or the raw data from those reports so that we can make the best decisions for our patients. We have molecular oncology panels across OneOncology where we have both working oncology panels where we analyze prospectively, the reports we get, and then also educational molecular oncology panels where we either look at new treatments or new understanding of those molecular reports and how to best use that information to treat our patients on optimally.

AJMC®: This takes advantage of everyone’s experience. How do you approach incorporating new treatments for rare diseases like this into clinical pathways of care?

arrows: I would say the way we look at pathways is to be comprehensive, to include all abnormalities, including things like insertion mutations in Exon 20. We look at things like Exon 20 insertions where they are currently approved and we try to anticipate where we would expect treatments which may be approved or become standard in the future. Before the approval of two drugs in the past year or so for Exon 20 mutations, these were patients we were looking to identify for clinical trials and then move on to our pathways as standard of care when the data was mature and pointing in that direction. Another thing we do is try to have educational programs as new drugs come out to educate our doctors about these new treatments, their side effects, their optimal use, and how they might be different, for example, exon 20 versus exon 19 or 21 mutations, whether those The drugs use first-line and those for Exon 20 are generally second-line therapy.

AJMC®: In conclusion, could you provide any closing thoughts on disease management considerations for non-small cell lung cancer, [00:15:00] An Exon 20 listing that you find noteworthy to share with colleagues?

arrows: The thing that I would say is most important in managing these rare diseases repeats what I said earlier, which is, try to have a system to help you find these patients, so you don’t overlook them in your NGS report. We are all very busy these days. You don’t want to have your system [that lets you] Look at a document on your computer the moment you enter a patient’s room and think that over the course of your career, you won’t miss this kind of precise molecular discovery. Build what works for you in your practice, a way to catch all these patients and mark their schemes so that you treat them optimally, the best treatment for the best patient at the best time. I think using pathways to help guide your treatment also helps with that. In this dynamic world where we seem to have one or two FDA approvals every week, relying on the Pathways Team to help guide your treatment is a great way to go.


Wu YL, Tsuboi M, He J et al. for the ADAURA investigators. Osimertinib in EGFR-mutated non-small cell lung cancer. In Angel J Med. 2020; 383 (18): 1711–1723. doi: 10.1056/NEJMoa2027071

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