Defining Osimertinib's Value in Treating EGFR+ NSCLC

Mark Socinski, MD:As I had mentioned previously, osimertinib has very good brain penetration. In the initial AURA studies, there were clearly durable responses in the brain and control of disease in the brain. In the FLAURA trial, there was an analysis of progression-free survival in patients with brain metastases and those without brain metastases. The benefit seemed to be identical in both. So, it suggests that osimertinib does have good activity in the brain. As I mentioned previously, I think that we need to educate our radiation oncology colleagues and our neurosurgeons to make sure that we don’t have this knee-jerk reflex by using radiation first. These EGFR TKIs that have good CNS penetration do have activity that’s quite substantial and can control brain metastases. It’s not that you’re going to never use radiation, but at least you can delay radiotherapy and delay the side effects of radiotherapy to a time when they’re in the later stages of their disease.

The initial role of osimertinib was in the treatment ofT790M-positive disease. Patients would typically get erlotinib, gefitinib, or afatinib. The average patient would go about a year and then they would have disease progression. Roughly 60% of those patients would be found to haveT790M. Osimertinib is a very good drugfor T790M, and we would use it as a second-line EGFR TKI after the first or second generation. The problem with that is, what do you do with the 40% who areT790Mnegative?

It’s important to emphasize that based on the FLAURA data, osimertinib has been shown to be a better drug. I want to give the best drug to all the patients who can benefit from it rather than save it for the 60% of patients who developT790M. I do think the FLAURA data are compelling. This is a better drug for exon 19, exon 21, andT790M. We knowT790Mis the major mechanism of acquired resistance from the first- or second-generation drugs. If you use your better drug up front, which is the FLAURA strategy, you get better outcomes, better progression-free survival, greater durability of responses, clinically significant overall survival benefit, and less toxicity. That’s why I think osimertinib is your first-line choice.

As I mentioned, the toxicity profile in the FLAURA trial favored osimertinib versus the first- or second-generation drugs. Osimertinib has the advantage of being a very good mutation-specific drug, a very goodT790Mdrug, and spares the wild-typeEGFRthat’s in our gut, that’s in our skin. You see less gut and skin toxicity.

My personal experience has actually been quite favorable relative to what we’ve been doing with the first- and second-generation drugs, which have more skin and GI toxicity, as well as more liver toxicity. In general, the patients who I have on osimertinib now have some grade 1 toxicities but not the grade 2 and 3 skin toxicities we saw with the first- and second-generation drugs with GI toxicity. So, I think it’s a more active drug. It just happens that because it spares wild-typeEGFR, it’s less toxic. I think it’s a win-win situation.

There are a few situations where you need to think about using it in patients with prolonged QTc interval, patients with a history of interstitial pneumonitis, or patients with borderline cardiac function. I wouldn’t say those are an absolute contraindication to osimertinib. They should be thought about as relative contraindications. Sometimes patients are on other drugs that may affect their QTc. You can switch those drugs and use osimertinib safely. So, I think that there are very few patients in this setting, but there a few things that you have to think twice about. It’s not that I wouldn’t use it in those situations, it’s just that you have to be a bit more careful in those patients.

Transcript edited for clarity.

December 2017

• A 66-year-old Asian woman presents to her PCP complaining of visual disturbances, nausea, fatigue, and sporadic headaches
• History: HTN, managed on candesartan; hyperlipidemia managed on simvastatin; no smoking history
• PE: BP, 148/70; LLL auscultation reveals decreased breath sounds
• CBC: WNL
• Imaging studies:
  • MRI of the head demonstrated a right parietal mass at the gray—white junction with vasogenic edema
  • CT of chest, abdomen, and pelvis revealed a 3.4-cm mass in the left lower lobe, and several small liver nodules
• CT-guided transthoracic needle biopsy of the lung lesion showed grade 2 adenocarcinoma, acinar
• Molecular testing: EGFR exon 19 deletion
• Staging: T2aN0M1c
• ECOG 1
• The patient was started on osimertinib 80 mg once daily