Wakelee Discusses Debate Surrounding Osimertinib in Frontline EGFR-Mutant Lung Cancer

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.

OncLive: Can you give an overview of your presentation on the rapidly changing landscape of frontline EGFR TKIs?

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.Wakelee: 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.

Are there any EGFR TKIs currently being looked at in the first-line setting?

Are there any combinations being studied?

What is the current standard for resistance mutation testing?

Aside from T790M, what other forms of resistance can patients develop?

If a patient progresses, but does not have a T790M mutation, what treatments are available to them?

Another important thing to mention is that in 2017, there was an extension of the approval for afatinib. Patients who have some of the less common activating mutations now have a label indication for afatinib. If we find some of these less common mutations that we know are activating mutations, then we can choose afatinib as well. The challenges now are not what we do first, because we have a lot of good choices, it's what we do second. Second is going to be osimertinib, if there is a T790M mutation in the first-line, but then what do you do after that? There are a lot of ongoing trials that are very encouraging. There are discussions around the idea that we could potentially add EGFR antibodies to the EGFR TKIs. There is a lot of work with VEGF antibodies, either adding VEGF antibodies such as bevacizumab to erlotinib, and then looking at it with some of the other combinations, or perhaps thinking about doing that in the resistance, so that is where a lot of the research is being done now.In first-line, we have 3 approved and then osimertinib is likely going to be approved. There are other drugs. There was a study with dacomitinib that was presented, but it's not clear that was going to be further developed in the United States. That was a head-to-head comparison with gefitinib and it was more potent, but also more toxic.Especially with the VEGFR drugs, the combination of erlotinib/bevacizumab has been looked at in a big phase II trial (NCT01562028). There are ongoing larger trials with ramucirumab (Cyramza) being looked at with erlotinib, and then with many of the EGFR antibodies there are combinations as well. There had been some work with the immune drugs, but there were a lot of toxicities seen, so a lot of those have been stalled or halted.Tissue testing is still the gold standard, and pretty much every patient who is diagnosed first-line should have tissue testing to look for mutations - EGFR, ALK, BRAF, and others where we have actionable drugs, like ROS1 and RET. For patients who develop resistance, the gold standard is to get a tissue test, but there is also a lot of new testing available with plasma testing. Many different companies have that available and that can be done either at the time of diagnosis if there is not sufficient tissue or at the time of progression. If you find it with plasma testing, you can avoid the tissue biopsy. If it's a negative test, you probably should still proceed to the tissue.There are a lot of different forms of resistance to EGFR TKIs, one of them is small cell transformation, and with that we are usually stuck with chemotherapy options. There are a lot of data showing MET overexpression becomes important, so there are trials looking at MET inhibitors in combination with EGFR drugs. It's not clear that we have hit a winner with that strategy, but the idea that MET overexpression comes up has been seen repeatedly. We know that with osimertinib resistance, there are other resistance mutations such as C797S. We are understanding the mechanisms, but taking that into the next step for treatment has been a little bit more challenging so far. We also see some of the bypass pathways, so you can get BRAF, KRAS, or ALK developing in the setting of EGFR as a resistance mechanism as well.If we don't find T790M, we look for trials, because there are some with combinations of EGFR TKI plus something else trying to get that response up, even though there isn't the T790M mutation. We also have chemotherapy. Most EGFR-mutant lung cancer is very sensitive to chemotherapy and so it's important that as we are talking with our patients, even from the beginning as we are excited that they have EGFR and we can start on that therapy, that we also start talking about chemotherapy, so when the time comes, the patient is prepared for it, and many of them do quite well.

If someone starts on a first- or second-generation drug, next line is going to be osimertinib or one of the other drugs that are being developed. There are a lot of other EGFR TKIs that are being developed, or chemotherapy. If we start with osimertinib first-line, we are starting to understand more what this resistance looks like. If you get C797S resistance mutation without the T790M, then perhaps some of the first- and second-generation drugs could work, whereas if you have both, that is not the case. The more we know, the more we understand that it's more complicated than we think it is.

Ramalingam S, Reungwetwattana T, Chewaskulyong B, et al. Osimertinib vs standard of care (SoC) EGFR-TKI as first-line therapy in patients (pts) with EGFRm advanced NSCLC: FLAURA. Presented at: 2017 ESMO Congress; Madrid, Spain; September 9-12, 2017. Abstract LBA2_PR.

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