Opinion
Video
Treatment Strategies for Uncommon EGFR Mutations in NSCLC
Panelists discuss the intricacies of treating uncommon EGFR mutations, dissecting approved treatment options, considerations for specific mutations, and insights into the evolving drug landscape.
Transcript:
Charu Aggarwal, MD, MPH: Dr [Tarek] Mekhail, could you walk us through some of the currently approved treatment options for patients with uncommon EGFR mutations?
Tarek Mekhail, MD, MSc, FRCSI, FRCSEd: I want to go back to the classification of the mutations, and I think the Heymach classification is very nice for groups of patients, the types of mutations in different groups. But I don’t think it is quite relevant when you are addressing a particular patient. I think, as mentioned before, focusing on what type of mutation it is and what drugs are available for this kind of external mutation is the way to go. Grouping them is nice for a talk like today. One of the [considerations] of the different types of mutations is not only whether we have a drug or not, but the drugability of that type of mutation. What I’m trying to say is if you look at the whole mark of synthesizing mutation, talking about exon 19 and EGFR, that you have a great drug, and the reason you have a great drug, which is a third-generation drug, is the drugability of the mutation. The whole mark is decreased ATP [adenosine triphosphate] affinity for these types of mutations that favor drug binding.
If you’re looking at a mutation like exon 20 insertion, it does not have that decreased affinity to ATP, so the therapeutic end for any drug that we’re giving is not as high as the deletion 19 and the exon 21 L858R. One of the mechanisms of resistance we always talk about [is] T790M as a structural change that actually impedes the binding of the first and second generation, whether it’s afatinib, osimertinib, amivantamab, but also with the T790M that ATP affinity is restored. And when you look at the [patients with] exon 20 insertion, they don’t have that, and the therapeutic index for a drug like mobo [mobocertinib] is narrow. And mobo, as Dr Dietrich said, was put off the market based on a comparison in the front line compared with chemotherapy. But the reason I think it was pulled out is the toxicity profile. It was pulled out of a second-line indication where we actually have a vacancy.
Well, it’s filled nicely right now with amivantamab, but there are other TKIs [tyrosine kinase inhibitors] that are coming down the line. That’s why, perhaps, mobo was pulled out. Going back to your question, the drugs that are approved for uncommon mutations—again, if you want to group them in the way that the Heymach grouped them for the T790M, osimertinib is approved if you have not used osimertinib before, but for the major uncommon mutations or the PAK mutations like G719, L861Q, S768I, I think you have a couple of options.
The only approved drug really is afatinib based on the pulled analysis from LUX-Lung 3 [NCT00949650] and LUX-Lung 6 [NCT01121393]. But it doesn’t mean that it’s the only drug that we should use or can use, because perhaps it’s going to come up in the discussion, osimertinib has an activity in these patients based on anecdotal [evidence] as well as based on the UNICORN study [NCT05421936]. In my practice, sometimes I use afatinib, and actually, that’s most of the time based on the results from LUX 3 and LUX 6. But if a patient has a CNS [central nervous system] disease, what are you going to do? I mean, you’ve got to think outside the box, and perhaps osimertinib, because of the CNS availability, would be my choice in this drug. But I do not think there is any other drug that has official approval, correct me if I’m wrong, except afatinib for these PAK mutations. For the exon 20, that’s a different thing. I’m talking here about the exon 20 insertion where we have approval for a movement amount. And that’s currently the only approval for exon 20 insertion having had mobocertinib pulled out.
Charu Aggarwal, MD, MPH: What is your rationale? Do you look at the particular mutation when you’re making the decision in clinic? Are there patients whom you would favor one TKI over the other? Walk us through that. How do you think about this?
Tarek Mekhail, MD, MSc, FRCSI, FRCSEd: Again, you’re talking about the measure of common mutations. I think the data are reliant on pulled analysis with small numbers. The response rate varies from 60%, 70%, sometimes 100% with the S768I. If you look at the UNICORN study, you start diving into what mutations are included in every study. For example, the UNICORN study looked at osimertinib [and] did not have anybody with S768I. I don’t have any data except afatinib for these patients. So for these patients, I tend to use afatinib. For G719orN861Q, I use afatinib most of the time. We always say comutations are uncommon but comutations are quite common when you look at EGFR uncommon mutations. We see people with these uncommon mutations, where there are 1 or 2 mutations present at the same time.
For the exon 20 insertions, even the responses to exon 20 insertions that we saw with first-, second-, or third-generation TKIs, including osimertnib, might have been in patients with comutations, and the actual response happened because of the G719 that co-occurred with the exon 20 insertion. But in a pure exon 20 insertion, perhaps these patients are quite resistant to the first [or] second generation. As you know, there are data on high-dose osimertnib, double the dose on these patients with some responses, but that’s not something that I technically use, given the availability with any and the clinical trials that we have as well.
Charu Aggarwal, MD, MPH: Absolutely. I think afatinib is one very good option for us in clinic when it comes to some of the mutations, as you pointed out, which if we use the exon-based classification would fall on the exon 18 group, such as G719X, etc. We do know that afatinib is superior to chemotherapy. Evidence from the LUX-Lung 3 and LUX-Lung 6 trials will show us that, especially for patients with exon 19 deletion, there was an improvement in overall survival using afatinib. But when we look at the combined analyses of all the LUX trials, we can start to see a differentiation in terms of afatinib’s efficacy across different groups, which does support its use. And we have to remember that it’s actually one of the approved options for uncommon mutations.
There are website resources where you can go online and actually type in the mutation and pull out data as well as case studies on individual responses for those particular mutations. I think it’s important to remember that sometimes these mutations can actually be compound mutations, some of which are occurring in exon 18 and exon 20. There may be some differential sensitivity and efficacy, which we’ll move on to next.
But I think, needless to say, afatinib is one of the approved options and does offer itself as a meaningful option for our patients. When I think about EGFR mutations, I tend to think about them more so in a structure-based setting in the current era. I think of exon 20 insertion mutations separately when I think about uncommon mutations because I think exon 20 insertion mutations have really differentiated themselves in terms of both drug development and the number of available drugs.
We have amivantamab available, as was previously pointed out. Mobocertinib is no longer available, but several different drugs in clinical trial are being studied solely for the indication of exon 20 insertion mutations. But for uncommon mutations, for the other 3 structure-based mutations, I certainly think of afatinib first, thinking of slightly higher response rates.
Transcript edited for clarity.
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