EGFR-Mutant NSCLC: Selecting Patients for Osimertinib

Heather Wakelee, MD:All of the EGFR TKIs have some risk of rash. The third-generation drugs like osimertinib have less rash, which has been a good thing, but there are still other toxicities that we need to be watching for—GI toxicity, particularly a risk for diarrhea, other things that are watched for. But, in general, the osimertinib has been relatively well tolerated.

Some of the unique side effects that we have to think about with the third-generation drugs are some more cardiac toxicities. They’re very rare, but we do think about QTc prolongation and a low risk of cardiomyopathy. So, for my patients who I am starting on osimertinib, I do get an EKG at baseline, then I get another one 2 to 3 weeks after starting, and then spread that out not too often afterward.

The patients who have QTc issues get them relatively early, but it can happen, and it’s not something they’re going to know about unless you look. So, I do strongly encourage people to be mindful of that QTc risk, to be mindful of the medications that can interact to cause it, and to check.

There’s also a very low risk of cardiomyopathy, so we do check an echo at baseline and then intermittently, sometime within the first 3 months. If that one’s still fine, I tend not to check so often afterward, but for label, we would continue looking at those, as well.

So, those are the main things to be thinking about that are different. Otherwise, there’s less diarrhea, there’s less rash, and there’s less of the common toxicities we think about with the first- and second-generation drugs. In general, my patients have tended to tell me they tolerated it better, but we do have to look for those cardiac issues. And from that, the patients I wouldn’t start on osimertinib where I would absolutely think about a different line of therapy, such as erlotinib or afatinib, would be those who have underlying cardiac issues, especially any QTc issues or any underlying cardiomyopathies.

The other thing we’re seeing with osimertinib that we don’t see with the other EGFR drugs is that there can be some myelosuppression, so we will see patients with low white blood cells, especially some borderline neutropenia and, occasionally, thrombocytopenia—and so another thing just to be mindful of. I haven’t had to stop drugs for any patients, but we have had to lower for a couple of them, and it’s not something we’re used to thinking about with the EGFR TKIs, so just something to be mindful of.

When making a decision about first-line EGFR TKI therapy, we’re tending to favor osimertinib over the other drugs at this time because of the FLAURA data, because of the increased CNS penetration, at least based on lowered risk of developing brain metastases that was demonstrated in FLAURA. So, that’s the choice.

Osimertinib’s toxicities in general are a little bit lower. There is some cardiac risk and some myelosuppression risk. And so, for patients who have reasons why I’m worried about that, I will tend to go with either erlotinib, afatinib, or gefitinib—also if there are issues with reimbursement. That has been the major reason why we continue to stick with some of the other drugs, because it’s not yet FDA approved; it’s not always being covered. And, therefore, I feel very comfortable for a patient who doesn’t have easy access to it starting on a first- or second-generation drug and continuing that, getting maximum benefit from it, and then switching over to osimertinib if they’ve developed T790M as a resistance mechanism.

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