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Treatment Options for Patients with Uncommon EGFR Mutations in NSCLC
Author(s):
Focused discussion on uncommon EGFR mutations in non–small cell lung cancer and concurrent treatment options in this setting.
Transcript:
Benjamin Levy, MD: Dr Rodriguez, what are the currently approved treatment options for patients with uncommon EGFR mutations in non–small cell lung cancer?
Estelamari Rodriguez, MD, MPH: So, what’s great is we are really seeing an explosion of options. I think the importance of doing NGS [next-generation sequencing]—because one thing we lose when we do single-gene analysis—is sometimes you don’t get the complexity of these changes within all these exons in EGFR. One thing that I tell myself is that we call these uncommon, atypical mutations, but they’re not that uncommon. If you look at a pie chart of all the EGFR mutations, the classical mutations—they combined, [exon 19 deletion], L858R, comprised about 67% to 70%. But everything else is uncommon, atypical, [and] compound mutations. So, it’s a big chunk of patients [who] I think have these changes that are being left untreated. Now, we do have data. Afatinib is really the one drug that has FDA approval for atypical mutations because they did the work of including those patients in their LUX-Lung trials. So, we saw data, and they have done a great job of collecting case reports of patients [whom] we wouldn’t expect them to respond to afatinib where they did. So, they have a large registry that you can access. It’s called uncommon EGFR mutations, and you can see this mutation because there are so many, how patients have responded to their drug. So, I think we have at least one FDA-approved agent that you can go to for atypical mutations. I was involved in also an international series looking at the use of osimertinib in some of these uncommon mutations. And although that was a retrospective review, not a formalized clinical trial, there is a signal of activity in uncommon mutations also with osimertinib. So, it is something that we need to discuss with patients. And I think as we get more knowledge about the structure of each of these uncommon mutations and this drug will be better, I think we’ll be able to decide what’s the next plan for these patients. But again, these mutations are not as uncommon as you may think. We are seeing them in the reports. And they sometimes go to the bottom unnoticed because they don’t have an attached treatment option. But afatinib is an option that should be included. If you find an atypical mutation, they did have data that [were] reviewed by the FDA where they have activity. And they saw activity. You can probably, Dr Levy, really describe to us what efficacy outcomes they saw in these trials supporting the use of afatinib as a second-generation TKI in these patients with uncommon EGFR mutations.
Benjamin Levy, MD: First, kudos to you for looking at osimertinib in these uncommon mutations. The thing is we can talk about osimertinib and all the ways that it works, and it’s a beautiful drug, but I will tell you, based on the data that I’ll share with you, that I am more inclined to use afatinib for my uncommon mutations. I’ve been an early adopter, or at least stuck with afatinib even when osimertinib came around. That’s not to say that osimertinib doesn’t have activity. I think your group has shown this in an international effort. And you still must think about it. But the data perhaps that sort of support this [involves] this pooled analysis from the LUX-Lung 2, 3, and 6 trials [NCT00525148, NCT00949650, NCT01121393]. These were trials exploring afatinib in all EGFR mutations. LUX-Lung 2 was a phase 2 trial. LUX-Lung 3 and 6 were phase 3 trials, comparing afatinib to chemotherapy, which led to the approval of afatinib for all EGFR mutations. And the importance of these studies is that they did include uncommon mutations, and perhaps because of that, we have the most data with afatinib in uncommon mutations. When they looked at the data in the pooled analysis, I think, they separated the groups into 3 cohorts. The first were the most common uncommon mutations, these point mutations and duplications, andexon 18 and 21. They looked at de novo T790M mutations, and they looked at exon 20 insertions. And the takeaway from this is essentially when you looked at the most common uncommon EGFR mutations, they found a very high objective response rate that was north of 60% based on survival times that approach 2 years. So because of that, I think the data would suggest that afatinib is a little bit better by cross-trial comparisons in osimertinib. Again, [this is] an apples-to-oranges comparison here. But I would say, because we always do this, we say we don’t want to do it, but we do. I have really leaned on afatinib for my uncommon mutations. That’s not to say that there’s not some efficacy with osimertinib. And it’s always a decision. We must balance out efficacy and toxicity. But again, [these are] the data that I think [are] so important.
Transcript edited for clarity.
