Afatinib in Patients With Uncommon EGFR Mutations

Sarah Goldberg, MD:This patient has a point mutation in exon 18 actually, theG719mutation. And again, this mutation, although uncommon, does result in sensitivity to afatinib. That’s the drug that specifically has been studied in this uncommon mutation as well as other uncommon point mutations.

There was a recent retrospective analysis of several large randomized and actually nonrandomized trials. So, there were several trials of afatinib that then, at the time, included these uncommonEGFRmutations. Whereas other trials did not include these uncommon mutations but several afatinib trials did include them. So, the authors of this retrospective study were able to go back to those prospective trials and retrospectively look at the data from the uncommon mutation. And they found that 32 patients had these uncommon mutations, and they were able to see how they did with afatinib.

And impressively, they found that the outcomes were very similar to patients who have the common mutation, who have what we’re used to seeing—the exon 19 deletions and the L858R point mutations. But with these uncommon mutations, such as with the one this patient has, the data looked very similar. So, the response rate was in the high 70s, the progression-free survival was around 10 months, and overall survival was around 19 months. So, again, the data looked very similar with these uncommon mutations as with the common mutations, which I think fully support the use of afatinib with these uncommon mutations.

What we don’t know is, what about the other EGFR inhibitors? Those have not been nearly as well studied with these uncommon mutations because these mutations were not included in those trials. So, we really just don’t know about their effectiveness with these mutations. Most other trials really just included the common mutation. So, potentially they could work. We just really don’t know as much about them.

I think that afatinib is a very good option for this patient, and we now have good data showing that it does sensitize the tumor to afatinib. Again, we just know a lot less about the other drugs with this and other uncommon mutations. Potentially, they could work. Potentially, osimertinib could be effective as well. Again, it’s just because the trials excluded those mutations, we just don’t know as much. So, I think afatinib is a very reasonable option for this patient.

There are some uncommonEGFRmutations that make the tumor not sensitive to EGFR inhibitors, and that includes afatinib or really any of the other first- or second-generation EGFR inhibitors. And those mutations include the de novoT790Mmutation.T790Mis typically something that arises after treatment with EGFR inhibitors. But occasionally, we can see it at baseline at diagnosis. So, that would be one situation where we’ve seen, in this retrospective study I was describing earlier, those patients don’t typically benefit from afatinib treatment.

Also, theEGFRexon 20 insertion mutations. Those tumors also tend to not respond very well to afatinib. Or in the instance where they do respond, the duration of response or the progression-free survival is fairly short. We also learned that from the retrospective analysis of the afatinib trials.

So, those are the 2 instances—the de novoT790Mand the exon 20 insertion mutations in EGFR. Although those areEGFRmutations, those don’t tend to respond well to afatinib, and so I would not use the drug in those patients.

Transcript edited for clarity.

• A female patient, Chinese descent, aged 66, is referred from primary care with persistent cough, sputum with blood, shortness of breath and chest pain
• History
  • Never smoked
  • Recurrent bronchitis over past 5 years
  • Has never been screened for lung cancer (by radiography or low-dose CT [LDCT])
  • Hypertension controlled on HCTZ; no diabetes, renal impairment
  • Family history
    • Grew up in China, moved to US at age 29; married for 30 years
    • Grew up in family with heavy smokers
    • Husband is current smoker
• LDCT reveals multiple tumors in left lung with pleural metastases
• Biopsy reveals non-small cell lung cancer
• Molecular analysis:
  • EGFRmutation: G719X
  • Negative forALKrearrangement
  • Wild-typeKRAS
• The patient was started on afatinib, 40 mg once daily
• After one month on therapy, she reported having rather severe diarrhea (5 times/day)
• Treatment was discontinued, then re-started treatment at 30 mg/day