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Emerging EGFR Inhibitors in NSCLC

Insights From: Sai-Hong Ignatius Ou, MD, PhD, University of California, Irvine, School of Medicine
Published: Tuesday, Oct 23, 2018



Transcript:

Sai-Hong Ignatius Ou, MD, PhD: Going forward, one of the unmet needs will be figuring out how to overcome osimertinib resistance. As far as I know, there is no fourth-generation EGFR TKI [tyrosine kinase inhibitor] in development. Most of the newer EGFR TKIs are third- generation, so they’re very similar to osimertinib.

As far as dacomitinib is concerned, it is generally considered to be a second-generation EGFR TKI. It is very similar in class as afatinib.

There is now published data on ARCHER 1050 that shows that dacomitinib has improved progression-free survival and overall survival over first-generation EGFR TKIs. However, the ARCHER 1050 study excluded patients with brain metastases. Also, there is up to a 60% dose reduction in older patients who are taking dacomitinib at the recommended dose of 45 mg once a day.

During the World Conference on Lung Cancer, Tony Mok, MD, presented on the dose reduction at 30 mg once a day. It seems like if you dose reduce to 30 mg, efficacy is preserved. It may actually be slightly better, numerically, in terms of progression-free survival and overall survival compared to starting at the 45-mg dose. But this is, of course, biased because this trial was not comparing 45 mg versus 30 mg. It was just a dose reduction trial—dose reductions in patients who were able to benefit on dacomitinib and dose reduce to 30 mg. So it’s a matter of the benefit and if they can continue at 30 mg.

The lesson that we learned is, as long as you can dose reduce, you don’t have to worry about dose reduction. If you can dose reduce to 30 mg, or even to 15 mg, as a long as the patient is getting benefit you don’t have to worry about losing the efficacy. It’s not a trial to compare 30 mg to 45 mg, but it’s a benefit. If you start with 45 mg and you dose reduce to 30 mg and the patient is benefitting but needs further dose reduction, it’s alright to dose reduce because they will continue with dacomitinib.

However, dacomitinib is still a second-generation EGFR TKI. It is not osimertinib. I have a feeling that in the future, when dacomitinib is approved as a frontline treatment option, it may actually be used in the second-line setting, post osimertinib failure. We have heard from the community that afatinib is being used post osimertinib. I think dacomitinib will be used post osimertinib.

As far as dacomitinib as a frontline treatment option is concerned, I think it’s going to be very challenging because of its adverse effect profile. Now that osimertinib is well established in the United States as a frontline treatment option, dacomitinib is probably going to be reserved as a second-line option, although this is not approved in the treatment paradigm.

Transcript Edited for Clarity 
 
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Transcript:

Sai-Hong Ignatius Ou, MD, PhD: Going forward, one of the unmet needs will be figuring out how to overcome osimertinib resistance. As far as I know, there is no fourth-generation EGFR TKI [tyrosine kinase inhibitor] in development. Most of the newer EGFR TKIs are third- generation, so they’re very similar to osimertinib.

As far as dacomitinib is concerned, it is generally considered to be a second-generation EGFR TKI. It is very similar in class as afatinib.

There is now published data on ARCHER 1050 that shows that dacomitinib has improved progression-free survival and overall survival over first-generation EGFR TKIs. However, the ARCHER 1050 study excluded patients with brain metastases. Also, there is up to a 60% dose reduction in older patients who are taking dacomitinib at the recommended dose of 45 mg once a day.

During the World Conference on Lung Cancer, Tony Mok, MD, presented on the dose reduction at 30 mg once a day. It seems like if you dose reduce to 30 mg, efficacy is preserved. It may actually be slightly better, numerically, in terms of progression-free survival and overall survival compared to starting at the 45-mg dose. But this is, of course, biased because this trial was not comparing 45 mg versus 30 mg. It was just a dose reduction trial—dose reductions in patients who were able to benefit on dacomitinib and dose reduce to 30 mg. So it’s a matter of the benefit and if they can continue at 30 mg.

The lesson that we learned is, as long as you can dose reduce, you don’t have to worry about dose reduction. If you can dose reduce to 30 mg, or even to 15 mg, as a long as the patient is getting benefit you don’t have to worry about losing the efficacy. It’s not a trial to compare 30 mg to 45 mg, but it’s a benefit. If you start with 45 mg and you dose reduce to 30 mg and the patient is benefitting but needs further dose reduction, it’s alright to dose reduce because they will continue with dacomitinib.

However, dacomitinib is still a second-generation EGFR TKI. It is not osimertinib. I have a feeling that in the future, when dacomitinib is approved as a frontline treatment option, it may actually be used in the second-line setting, post osimertinib failure. We have heard from the community that afatinib is being used post osimertinib. I think dacomitinib will be used post osimertinib.

As far as dacomitinib as a frontline treatment option is concerned, I think it’s going to be very challenging because of its adverse effect profile. Now that osimertinib is well established in the United States as a frontline treatment option, dacomitinib is probably going to be reserved as a second-line option, although this is not approved in the treatment paradigm.

Transcript Edited for Clarity 
 
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