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Afatinib Therapy for Uncommon EGFR Alterations in NSCLC

Panelists: Benjamin P. Levy, MD, Johns Hopkins Sidney Kimmel Cancer Center; Lyudmila A. Bazhenova, MD, University of California San Diego; Alexander Drilon, MD, Memorial Sloan Kettering Cancer Center; Zofia Piotrowska, MD, Massachusetts General Hospital Cancer Center; Jonathan W. Riess, MD, MS, UC Davis Comprehensive Cancer Center
Published: Thursday, Aug 16, 2018



Transcript: 

Benjamin P. Levy, MD: We talked about osimertinib being approved in the frontline setting, but we have these uncommon mutations. We’re not really sure what to do with these. I think it’s important to really look at the EGFR mutation that you’ve identified, and the tissue. Lyudmila, do you want to talk to us about the data on afatinib and the potential management of uncommon EGFR mutations?

Lyudmila A. Bazhenova, MD: Uncommon mutations have been described in about 12% of patients with EGFR mutations. There are 3 mutations that we see the most of. There is G719X, which is on codon 18. There is L861Q, which is on codon 21. And there is S761, which is on codon 18.

The only drug that we currently have approved for those uncommon mutations is afatinib. There’s plenty of preclinical data and some early clinical data that demonstrate that in order to inhibit those uncommon mutations, older first-generation drugs need to have a pretty high IC50. The IC50 for afatinib, in cell cultures, is less than 100. The IC50 of both gefitinib and erlotinib is between 100 and 800. Osimertinib is intermediate, and it seems to have a better efficacy in preclinical settings for the L861Q mutation. There is some efficacy in the preclinical setting for other mutations.

We have some clinical data looking at the response rates of erlotinib and gefitinib, and they appear to be approximately 25% to 30%. Afatinib gives us a response rate of 60% to 70%. There was an interesting poster at the ASCO Annual Meeting that looked at the efficacy of osimertinib in patients with uncommon mutations. This was a small number of patients—like 5, 6, 7 per group—but it showed that patients with the L861Q mutation had a 70% response to osimertinib. Patients with the G719X mutation had a 50% response rate. S761-mutant patients had a 30% response to osimertinib, which is very consistent with the preclinical data. I think this gives some confidence for afatinib. But in the future, once the data is more generated, maybe osimertinib could be an option there?

Zofia Piotrowska, MD: The other uncommon mutation, that is in a little bit of a different category, is the exon 20 insertion of EGFR. That is an important subset to really identify when you send off EGFR testing. The exon 20 insertions have been shown to be refractory to first- and second-generation EGFR inhibitors. And right now, in the standard-of-care setting, for those patients, I think chemotherapy is the first-line therapy. But there are many clinical trials. At the ASCO Annual Meeting, there were some exciting data with some new drugs—TAK-788, poziotinib. There are more that are coming down the pipeline for exon 20–insertion patients, and that’s another population in which referral for clinical trials can sometimes be very appropriate.

Benjamin P. Levy, MD: That’s a very good point. I think we need to remember that not all EGFR mutations are the same. We have uncommon mutations, and we have exon 20 mutations that are historically TKI-refractory. Standard of care would be chemotherapy. But as you mentioned, we’ve seen a lot of emerging data. There is poziotinib, which shows selective activity in these patients. Hopefully, it will be ready for prime time soon.

Zofia Piotrowska, MD: Or testing osimertinib in that setting through our Cooperative Oncology groups.

Benjamin P. Levy, MD: So, there is a lot of movement here. This is very exciting, but a distinction needs to be made up front.

Transcript Edited for Clarity 

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Transcript: 

Benjamin P. Levy, MD: We talked about osimertinib being approved in the frontline setting, but we have these uncommon mutations. We’re not really sure what to do with these. I think it’s important to really look at the EGFR mutation that you’ve identified, and the tissue. Lyudmila, do you want to talk to us about the data on afatinib and the potential management of uncommon EGFR mutations?

Lyudmila A. Bazhenova, MD: Uncommon mutations have been described in about 12% of patients with EGFR mutations. There are 3 mutations that we see the most of. There is G719X, which is on codon 18. There is L861Q, which is on codon 21. And there is S761, which is on codon 18.

The only drug that we currently have approved for those uncommon mutations is afatinib. There’s plenty of preclinical data and some early clinical data that demonstrate that in order to inhibit those uncommon mutations, older first-generation drugs need to have a pretty high IC50. The IC50 for afatinib, in cell cultures, is less than 100. The IC50 of both gefitinib and erlotinib is between 100 and 800. Osimertinib is intermediate, and it seems to have a better efficacy in preclinical settings for the L861Q mutation. There is some efficacy in the preclinical setting for other mutations.

We have some clinical data looking at the response rates of erlotinib and gefitinib, and they appear to be approximately 25% to 30%. Afatinib gives us a response rate of 60% to 70%. There was an interesting poster at the ASCO Annual Meeting that looked at the efficacy of osimertinib in patients with uncommon mutations. This was a small number of patients—like 5, 6, 7 per group—but it showed that patients with the L861Q mutation had a 70% response to osimertinib. Patients with the G719X mutation had a 50% response rate. S761-mutant patients had a 30% response to osimertinib, which is very consistent with the preclinical data. I think this gives some confidence for afatinib. But in the future, once the data is more generated, maybe osimertinib could be an option there?

Zofia Piotrowska, MD: The other uncommon mutation, that is in a little bit of a different category, is the exon 20 insertion of EGFR. That is an important subset to really identify when you send off EGFR testing. The exon 20 insertions have been shown to be refractory to first- and second-generation EGFR inhibitors. And right now, in the standard-of-care setting, for those patients, I think chemotherapy is the first-line therapy. But there are many clinical trials. At the ASCO Annual Meeting, there were some exciting data with some new drugs—TAK-788, poziotinib. There are more that are coming down the pipeline for exon 20–insertion patients, and that’s another population in which referral for clinical trials can sometimes be very appropriate.

Benjamin P. Levy, MD: That’s a very good point. I think we need to remember that not all EGFR mutations are the same. We have uncommon mutations, and we have exon 20 mutations that are historically TKI-refractory. Standard of care would be chemotherapy. But as you mentioned, we’ve seen a lot of emerging data. There is poziotinib, which shows selective activity in these patients. Hopefully, it will be ready for prime time soon.

Zofia Piotrowska, MD: Or testing osimertinib in that setting through our Cooperative Oncology groups.

Benjamin P. Levy, MD: So, there is a lot of movement here. This is very exciting, but a distinction needs to be made up front.

Transcript Edited for Clarity 
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