Optimizing Therapy at Progression of EGFR-Mutant NSCLC

Heather Wakelee, MD:Our patient is a 73-year-old man with some emphysema, otherwise relatively healthy, with metastaticEGFR-mutant lung cancer with an L858R mutation and bone metastases.

So, he was started on osimertinib. At the time of progression, the decision about whether or not to rebiopsy isn’t as straightforward as someone who’s on erlotinib, gefitinib, or afatinib. For those—for patients on a first- or second-generation drug—we definitely look. We get a liquid biopsy. If that’s negative, we’ll get a tissue biopsy, looking for T790M. And we look hard, because the T790M in that setting lets us know whether or not we can go with osimertinib.

In this particular case, he’s already on first-line osimertinib. We’re not expecting to ever find T790M. So, at the time of resistance, he’s either going to have a C797S mutation or aMETamplification, a new mutation, small-cell transformation, or maybe we can’t figure it out. And so, it’s a little bit less useful. We often still are looking to try to help guide, mostly for trials, though. I think it’s not going to practically change his treatment, because the standard is really then to move on to chemotherapy. So, we’ll talk about the biopsy. We might do it more from a research perspective or for a particular trial, but we’re going to go ahead and transition him to chemotherapy at that point.

Once he has been on chemotherapy for a while and that’s no longer working, we have to think about what’s next. I will often go back to an EGFR drug. Again, looking at trials—there are a lot of interesting combination trials right now going on, some with EGFR antibodies in addition to the TKIs and others with different mechanisms. So, we’ll be thinking toward that. But if I don’t have that choice, I’ll sometimes just go back to an EGFR TKI. And then we have to start thinking about when to bring in a checkpoint inhibitor or not, and that will depend a little bit on PD-L1.

We now have these questions about, well, what about after osimertinib? We have chemotherapy. We don’t have a lot yet, but there are exciting trials looking at GFR antibodies in addition to the EGFR TKIs, a lot of other mechanisms, and MET inhibitors being looked at in combination with EGFR TKIs. Kind of going back to first- or second-generation drugs, if you’ve been on the third-generation drug and you get T790, these are little hints that we’ll be thinking about.

And we are also trying to figure out, how do we get checkpoint inhibitors to work in patients withEGFRmutations? So far, it has not been very encouraging, although there are some who are benefiting. We are trying to figure out, how do we increase those numbers? Where else are we going to be able to offer more options? And then there are some fourth-generation EGFR TKIs being developed that might be working after osimertinib. So, those are the areas that are very exciting and where there’s a lot happening.

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