EGFR+ Non-Small Cell Lung Cancer: Frontline Options

Mark Socinski, MD:Currently, we have 2 first-generation EGFR TKIs, erlotinib and gefitinib; we have 1 second-generation agent, afatinib; and we have 1 third-generation agent, osimertinib. These are all EGFR TKIs. The difference is that the first-generation agents are reversible inhibitors, and they do inhibit wild-typeEGFR. The second-generation agents are irreversible inhibitors. And the third-generation agents are active against the native mutations, or the common mutations, and againstT790M.T790Mis the major acquired resistance mechanism from first- and second-generation agents.

Until recently, we would typically use a first- or second-generation agent. The average patient would have control over the disease for about a year and then they would progress. We would rebiopsy them, or plasma test them, to try to findT790M. You foundT790Min about 60% of the patients, and you used a third-generation drug, osimertinib.

We recently had data from the FLAURA trial in which osimertinib, the third-generation agent, was compared in a phase III trial against the 2 first-generation drugs, gefitinib and erlotinib. It was a positive trial in favor of osimertinib. The progression-free survival hazard ratio was in the range of 0.47 or 0.46, so slightly more than a 50% risk reduction in progression of disease. The response rates were about the same at 76%, 80%. But the duration of response with osimertinib was significantly better than it was with the first-generation drugs. An initial early look at survival—although it wasn’t statistically significant—was, in my opinion, clinically significant in favor of osimertinib.

You have response durability; progression-free survival benefit; a clinically important survival benefit, although not statistically significant; and less toxicities. Less rash and less liver function abnormalities. So, it tastes great and is less filling. It’s a better drug. It’s changed my practice, where formerly I would use a first- or second-generation drug. I think the FLAURA data are compelling such that I have switched my first-line treatment to osimertinib in patients with either exon 19 or exon 21EGFRmutations.

The optimal management of brain metastases in patients with lung cancer, particularly with an oncogenic driver, should be in the context of a multidisciplinary team. We rely heavily on our neurosurgeons and on our radiation oncologists. There’s an expanding role for stereotactic radiotherapy, or gamma 9 therapies. There also continues to be a role for whole-brain radiotherapy, although we certainly use that as a last-ditch effort in patients like this.

We also know that this is a population that can respond to oral therapy. A drug like osimertinib very effectively gets into the brain, and the brain can respond just as well as the rest of the body. I think the teaching point for the multidisciplinary radiation oncology neurosurgical team is that it shouldn’t be a knee-jerk reflex to use radiation. If her symptoms got better on dexamethasone, then I would give this patient osimertinib and follow the brain and try to save radiotherapy as the next option for when these TKIs fail.

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