Opinion
Video
NSCLC With Uncommon EGFR Mutations: First-Generation EGFR TKIs and Role of Immunotherapy
Author(s):
Shared insight on the use of first-generation EGFR tyrosine kinase inhibitors and the role of immunotherapy in treating patients with NSCLC with uncommon EGFR mutations.
Transcript:
Martin Dietrich, MD, PhD: Dr Sabari, I have questions for you about use of first-generation inhibitors. Do you still see any role for them? Erlotinib, gefitinib. And if you have these mutations that are not covered by an FDA label in the immunotherapy space, how do you see the role of immunotherapy in that context?
Joshua K. Sabari, MD: I’ve largely moved away from using the first- and second-generation EGFR TKIs [tyrosine kinase inhibitors]. There’s one instance in patients who have C797S, for example, post progression on a third-generation EGFR TKI who are not eligible for other trials, and may try utilizing a first-generation EGFR TKI in combination with a third generation. It really depends on the location of the alteration, whether it’s in cis or trans, which is quite complex, but I’ve seen 6-, 8-month durability there in some patients. But overall, [I have] really have moved away from using first- and second-generation EGFR TKIs.
To Dr Brahmer’s point, when you get these sort of uncommon mutations, and I think we really need to move away from exon but more structure of function, so when we see these pack mutations or P-loop alpha C-helix, the S768I, or the G719, as Dr Raez mentioned, I’m commonly using afatinib dose-reduced at 30 mg once a day. Interestingly, L861Q, which is known as an uncommon mutation as well, and exon 21 actually has pretty good activity with osimertinib, and it’s more like an activating mutation. This is nuanced, and here is where I commonly reach out to colleagues and friends. It’s important that the community understands that this is a complex space, and osimertinib may not always be the best treatment for every patient. Although it’s a great option for patients with exon 19 del and L85AR, some of the nuances are important.
Thinking about IO [immunotherapy] in this patient population, that’s a really difficult question. We’ve had many negative trials and maybe 1 or 2 sort of positive in this space. My own personal belief, and I’m curious to hear others’ [thoughts], is I really try to avoid IO until I’ve exhausted all targeted therapy options, both standard of care as well as on trial, in this population. I think…it’s critical that we study IO in this patient population because we are not curing patients with EGFR-mutant non–small cell lung cancer with targeted therapies. We need to do more for our patients.
Martin Dietrich, MD, PhD: Dr Sabari, allow me a follow-up question here. Close cousin to EGFR [is] HER2, immunotherapy—do you think it’s useful? Do you think it’s not excluded but biologically not fitting? How do you do this in your practice when you have a HER2 mutation?
Joshua K. Sabari, MD: It’s important that [a patient with an] EGFR exon 20 insertion mutation, or a patient with a HER2 exon 20 insertion mutation, these are…. These patients 50% of the time have a smoking history, and they do have potential neoantigens. So I don’t always shy away from immunotherapy in this population. There are many retrospective series showing mixed data. In a never-smoker, young patient who is fit, I usually try not to give immunotherapy. But in someone with a smoking history, I think the jury is still out here. I do have HER2 exon 20 patients on first-line chemotherapy and immunotherapy. You now have Enhertu, ado-trastuzumab emtansine, a HER2 ADC [antibody-drug conjugate] approved in the second-line setting. Many of my colleagues are even utilizing this off label in the front line. Curious with others; are people using immunotherapy in the EGFR and exon 20 insertion space? Let’s start with smokers.
Martin Dietrich, MD, PhD: Dr Brahmer, maybe you can go first.
Julie R. Brahmer, MD: One of my longest-surviving patients postchemotherapy-IO is someone with a HER2 mutation, and she wasn’t a smoker, so it’s makes it even more complicated there because we didn’t discover her abnormality until after she started therapy. Particularly in smokers, I favor considering chemotherapy and IO in the HER2 space or even the exon 20 space. And even for some of my patients who have MET exon 14 skipping mutation or even a BRAF V600E, if they’re smokers, I’m going to seriously consider immunotherapy in those patients.
Martin Dietrich, MD, PhD: Dr Raez, how do you approach immunotherapy?
Luis Raez, MD: There is a practical approach. There is the fact that if you don’t use immunotherapy with the chemotherapy, you will never use [it] in the future because you’re not going to give a senior [patient] pembrolizumab or nivolumab in second, third, or fifth line. That’s why until we get more information, I think we try to give the patients the benefit of the doubt and give the chemo-immunotherapy for exon 20. Of course, as Joshua was saying, we are very close to believe that hopefully we can give an ADC plus immune or IO or something else in the front line, and then we don’t have to go to this path anymore because the ADCs are becoming very popular.
Martin Dietrich, MD, PhD: Excellent. Very good summary.
Transcript is AI-generated and edited for clarity and readability.
