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Uncommon EGFR Mutations in NSCLC: Real-World Selection and Use of Novel Agents
Author(s):
Benjamin Levy, MD, and Estelamari Rodriguez, MD, MPH, reflect on their experience managing real-world patients with uncommon EGFR mutations in non–small cell lung cancer.
Transcript:
Benjamin Levy, MD: Moving forward, how do you see these patients, Dr Rodriguez, in your practice? How do you approach these patients, really, in everyday practice?
Estelamari Rodriguez, MD, MPH: I think the No. 1 thing is to recognize [whether] they have something actionable because I think they have gone unnoticed. And if you look at when osimertinib came into use and [individuals] started moving away from afatinib—they also moved away from using it in the right patients, which are these patients with uncommon mutations. I think we see these patients and if you test everyone, you will find these patients. These are the mutations that sometimes get lost because they don’t come at the top of the report because they’re uncommon, and they don’t have a strong FDA approval. But this is why we discuss it in our molecular tumor boards—is there an option? [Are] there data? And I think with this large database, you’re correct. Afatinib has the longest, more robust data set to look at the effectiveness of treating these atypical mutations.I think I have used that database to see if this mutation could potentially respond to this agent. Because of these patients, we know in general, for biomarker-driven actionable mutations, really having a targeted therapy—patients will do best. So, I have seen it. It depends on where you practice. In our practice probably 15% to 20% of our patients have EGFR mutations, but these uncommon mutations are less. So I include the exon 20 insertions, which are about 6%. Then you have all the other ones uncommon that you mentioned, the L861Q, which is about 1%. So, these are not the patients you’re going to see every day. But if you do lung cancer only, which you and I do, we will see these patients, and you will have them in your practice. And you will see that they will get benefit from being treated with a targeted treatment instead of selecting chemotherapy and immunotherapy for them. I think I have learned that and recognize that these are not as uncommon. If you keep testing, you’ll find them.
Benjamin Levy, MD: Absolutely.
Estelamari Rodriguez, MD, MPH: How do we approach treating these patients? Right now, I will, if I find an uncommon mutation, and I know that afatinib also does a great job of penetrating the CNS [central nervous system], the brain—I will treat these patients up front, with an uncommon EGFR mutation. I think that you will give them the benefit of seeing if there’s a response to a targeted option up front. If I found mutations later after the patients have had chemotherapy, I switched them to afatinib as an option. And the experience has been that it’s a different drug. I think that if we are not using afatinib as much, you don’t get as good as you used to be at managing rash and diarrhea, which are some of the main adverse effects of this drug. But we, for a long time, did a great job of managing that on patients who were on erlotinib and afatinib. And I think it’s all about patient education, having the team be very proactive about managing rash and diarrhea. And we’re able to have patients [who] have stayed on these drugs for a long time if you can dose-reduce and manage appropriately. I think right now, if I find these mutations early, I will treat the patients up front. In the second line, I will either find clinical trials, although many clinical trials exclude them. That’s a problem. But they will get chemotherapy second line. I would ask you, Dr Levy, [whether] the use of immunotherapy on some of these atypical mutations is controversial because the series doesn’t really show great responses. And it depends on which one you’re looking at. But if you include an EGFR, exon 20 insertions, we know the responses to immunotherapy, they are not great. And those patients now have their own drugs that we can offer them. But for the other uncommon mutations, have you used immunotherapy with chemo[therapy]?
Benjamin Levy, MD: [T]his is a tough question. I have some exon 20s for sure [who] are former smokers that have a high PD-L1, which I’ll use it. We learned obviously from ASCO [the American Society of Clinical Oncology Annual Meeting] in KEYNOTE-789 [NCT03515837], post targeted therapy for EGFR-mutant lung cancer, the addition of immunotherapy to chemo[therapy] doesn’t do anything. That said, there are some subtypes of EGFR mutations if you integrate other things. Like PD-L1 in heavy smoking history, then I will. I will use it. Will I use it alone? No. But I will use it with chemo[therapy]. I think the lesson here is, for EGFR mutations, immunotherapy is not a good choice. We have too many good drugs and too many drugs that are coming down the pike that are important. I think for patients, you really must pump the brakes and tell them, “Look”—because they want immunotherapy. You must tell them that immunotherapy may not be the best for them.
Estelamari Rodriguez, MD, MPH: Thank you. Now, in terms of afatinib, I was mentioning my experience, but what are some of the adverse events that you have seen, and what kind of strategies have you learned to put into place so patients can tolerate treatment well?
Benjamin Levy, MD: My strategies are predicated on a wealth of experience. And the thing I say about any drug that you give, anyone, is the juice worth the squeeze?
Because drugs have toxicity and they have efficacy. And in some drugs, the balance is a little bit off. In some drugs, there’s no question at all. I think the nice thing about my use of afatinib is we’ve learned very well how to mitigate some of the toxicities. The toxicities are your common toxicities: rash, diarrhea, and paronychia. But I think you can get patients through this quite well. One of the things we do have is that we have a low threshold to go down to 30 mg. We actually know that 30 mg is probably as good as 40 mg. Some data [were] presented by Balazs Halmos [MD] many, many years ago showing that’s the case. But I think being proactive with rash, being proactive with diarrhea, educating patients on this, educating them to talk to us about them, and also understanding the algorithm of how [to] do this—certainly, clindamycin gels and hydrocortisone creams can be used for rash, but I have a low threshold to go to doxycycline sometimes. And the diarrhea is Imodium [loperamide] and educating. And then the paronychia; everyone’s got their special sauce for paronychia. Every institution has its own creative ways to treat it. I’ve been partnering with my podiatrist for paronychia that exists on the toes, and I’ve had a really good experience with these types of things. And there’s a special sauce. We use tea tree oil. I’ve heard, “Put vinegar and water.” I mean, it’s interesting to see how this is done. But you gain experience with this drug and you’re able to really mitigate these strategies. And I do think for our uncommon mutations, afatinib is the right choice for most patients. I’m not just saying that because we’re here to talk about afatinib. This is my clinical experience. And the juice is worth the squeeze.
Transcript edited for clarity.
