Osimertinib's Value in EGFR-Mutant NSCLC

Heather Wakelee, MD:FLAURA was a study for patients who had newly diagnosedEGFR-mutant lung cancer with either L858Ror deletion 19, and they were randomized to either get osimertinib at the standard 80 mg daily or to get standard dosing of gefitinib or erlotinib. So, it was osimertinib versus standard of care TKI—erlotinib and gefitinib mixed in there. Because the study was done in Asia, a lot of the patients were getting the gefitinib.

The study showed a clear progression-free survival benefit with the osimertinib. On average, patients were staying on close to 19 months versus—with the other tyrosine kinase inhibitors—under a year, but all within the realm that we would have expected. The only real challenge and interpretation is the fact that if you looked at patients getting erlotinib or gefitinib, many of them could later go on to get osimertinib if they developed T790M as a resistance.

If you started on osimertinib, you can’t really go back to get one of the other drugs later. I’m saying that hesitantly because there are some data that for some cases, you can get a C797S mutation, in which case going back to a first- or second-generation drug might work. That’s an area of research, but we wouldn’t consider that standard. So, after osimertinib, the standard is to go to chemotherapy. After erlotinib or gefitinib, maybe 60% of patients—or closer to half, really—can go on to get osimertinib before they have to go to chemotherapy.

So, if you look at that from that perspective, there certainly are some patients who would be fine getting erlotinib or gefitinib first and then going to osimertinib, same time period. The problem is, not everyone can, and so that’s where we are favoring starting on osimertinib. As for trying to understand what to do next, there are areas of a lot of investigation, and we’re still waiting for the definitive overall survival data from FLAURA. The trends are favoring starting with osimertinib, but until we have a definitive answer on that, there are a lot of people holding out and saying, “I can give gefitinib or erlotinib first. I know those drugs, and I then know what to go to next. If I start on osimertinib, I don’t feel as comfortable knowing what to go to next, and therefore, I’m going to start on erlotinib or gefitinib.” And so, those are the discussions that are ongoing that I hear about from patients coming to see me for another opinion, and as I talk to colleagues.

Patients with newly diagnosedEGFR-mutant non—small cell lung cancer—the vast majority are going to have either L858R or deletion 19. We think of them fairly similarly. There are some data that perhaps those with deletion 19 have slightly better outcomes than L858R, but it has not been shown definitively with any of the drugs in any of the more definitive analyses. And so, L858R versus deletion 19—I think of them relatively similarly; I’m going to treat them the same. And the data from FLAURA weren’t strikingly different between those groups.

We do have some other less commonEGFRmutations—L861Q and some others that do pop up once in a while—and we’re starting to understand how you best treat those. There is a label for afatinib for the less common mutations that are sensitive mutations. We don’t have that yet for osimertinib, but there are good data that are active in that setting then, too. So, those are things we’re trying to explore.

One of the unusualEGFRmutations is exon 20. So, those behave differently. They’re not as sensitive to the traditional EGFR tyrosine kinase inhibitor, so they’re newer drugs being developed that are showing promise. And so, I think we’re likely going to be in an era soon where we have exon 20 drugs, but we don’t yet. So, that one’s a little bit different.

When osimertinib and the other third-generation EGFR TKIs were first developed, it was in the setting of hitting T790M. We knew that with the first- and second-generation drugs—erlotinib, gefitinib, afatinib—that when they stopped working, 60% of the time it’s because of this newEGFRmutation, T790M. So, the third-generation drugs like osimertinib were designed specifically to hit T790M, in addition to the L858R deletion 19 to the sensitizing mutation. So, they get both.

So, when patients who were on erlotinib, gefitinib, and afatinib progressed, if they had T790M, osimertinib worked 70% of the time. And that was the AURA3 trial, which compared osimertinib in that setting to chemotherapy and showed a significant improvement in pretty much all the outcomes. So, that was the first indication for osimertinib, and it got us all thinking that that’s the drug to use with T790M.

However, osimertinib is just as, if not more, potent against L858R and deletion 19 than any of the first- and second-generation drugs. So, when we’re thinking about using osimertinib first-line, T790M is irrelevant. There is a small group of patients who have de novo T790M. I’ve got I think 2 patients in my practice. And osimertinib is a great choice for them first line, but for the rest of them, if they don’t have T790M—at least in measurable levels—osimertinib is still just as good of a choice. It just means that when the osimertinib stops working, you’re not looking for T790M, you’re looking for something else, and that something else is going to beT797S,METamplification, small-cell transformation, or there’s a long list of different things that can happen when osimertinib stops working.

Transcript edited for clarity.

December 2017

• A 73-year-old Caucasian man was seen in the emergency department for severe dyspnea and chest pain
• History: symptomatic COPD managed on fluticasone and vilanterol inhaler; 50-pack/year smoking history
• Imaging studies:
  • Chest X-Ray showed a large mass in the lung right upper lobe
  • CT of chest, abdomen, and pelvis revealed a 6.8-cm mass right-sided mass invading the chest wall, small left pleural effusion, and several small lytic lesions in the T4/5 vertebrae
• CT-guided transthoracic needle biopsy of the lung lesion showed grade 2 adenocarcinoma
• Molecular testing, NGS: EGFR exon 21 L858R mutation
• Staging: T3N0M1
• ECOG 1
• The patient was started on osimertinib 80 mg once daily