Heather Wakelee, MD
There are currently 3 drugs approved by the FDA for the first-line treatment of patients with EGFR
-mutant lung cancer. The FDA is now weighing the frontline approval of the third-generation EGFR inhibitor osimertinib (Tagrisso), which is already approved in the second-line setting for patients who progress due to a T790M mutation.
In the phase III FLAURA study, osimertinib demonstrated a significant improvement in progression-free survival (PFS) over erlotinib (Tarceva) and gefitinib (Iressa), 2 of the current standard first-line therapies. Now, explains Heather Wakelee, MD, there is debate regarding which of these agents to use first.
Some physicians believe patients should be given erlotinib, gefitinib, or afatanib (Gilotrif) first, and then receive osimertinib once they progress. Others, however, believe osimertinib should be given first so that patients do not need to switch from one therapy to another.
"The idea is most likely if you can start on osimertinib, you're going to get the full benefit of time on that drug, versus if you switch from 1 to the other. There will be patients who aren't able to do that, so it's better to potentially start with osimertinib," said Wakelee, who gave a presentation on the rapidly changing landscape of frontline EGFR tyrosine kinase inhibitors (TKIs) during the 5th Annual Miami Lung Cancer Conference.
Treatment strategies following progression on these available EGFR TKIs are currently being investigated. In an interview with OncLive
, Wakelee, professor of medicine, division of oncology, Stanford University, discussed the ongoing debate in this area and potential combination strategies.
OncLive: Can you give an overview of your presentation on the rapidly changing landscape of frontline EGFR TKIs?
: I'm talking about EGFR therapy in the first-line setting for patients with EGFR
-mutant lung cancer. I see a lot of those patients where I am in northern California.
We currently have 3 FDA approved drugs in the first-line setting, and there is a fourth that is under consideration in that setting. It's standard of care to check for EGFR
mutations in patients who are newly diagnosed with advanced stage lung cancer, especially adenocarcinoma. If we find one of the activating mutations, especially the 2 most common, deletion 19 or L858R, then we can choose from erlotinib, gefitinib, or afatinib. They are all approved and they have incredibly high response rates and reasonable PFS. It has been difficult to distinguish between them in the past. More recently, we have had a frontline trial that looked at the third-generation drug osimertinib (Tagrisso), which has been approved to be given to patients after they have had one of those other 3, if the resistance mechanism is T790M. But the debate surrounds osimertinib, which also works incredibly well against the common activating mutations, such as deletion 17 and L858R.
There was a head-to-head trial of osimertinib versus gefitinib or erlotinib, and it showed that with all the drugs, response rates were incredibly high, in the 80% range. However, there was a difference in PFS. With osimertinib, there was a much longer PFS than with erlotinib or gefitinib. There was no clear overall survival benefit with osimertinib, but there is a trend in its favor. There is considerable debate now about which one we should choose.
Some people are arguing if you can go on erlotinib, gefitinib, or afatinib, and then at time of progression go to osimertinib, and that amount of time is this long, versus if you start on osimertinib and that amount of time is this long, why do we really need to start with osimertinib? The argument, of course, is if you are taking erlotinib, gefitinib, or afatinib, and it stops working, it doesn't always stop working because of T790M. About 60% of the time it does, but that means about 40% of the time it's something else. In which case, switching to osimertinib isn't necessarily going to work. You're also going to have patients who can't make that transition for a variety of different reasons of progression. The idea is most likely if you can start on osimertinib, you're going to get the full benefit of time on that drug, versus if you switch from 1 to the other. There will be patients who aren't able to do that, so it's better to potentially start with osimertinib. That was what the FLAURA trial demonstrated. We don't yet have that FDA approval. It's likely going to come soon, but in the short term, we still have to decide which patients we can start with osimertinib, and which ones we will be waiting on that for later.