Benjamin P. Levy, MD: Let’s talk about some practical considerations related to the brain activity, and this was discussed with immunotherapy as well. A patient walks in—EGFR-mutated, exon 19, has some centimeter brain metastases, or even a 1-cm brain metastasis. Are you comfortable sparing them approaches with radiation and just giving them osimertinib?

Suresh S. Ramalingam, MD: I think for small brain metastases, 1 cm may be a little bit beyond my comfort zone. But if they are a few millimeter lesions, I’m comfortable starting them on an osimertinib regimen and then watching their brain closely.

Hossein Borghaei, DO, MS: What would you use on symptomatic brain metastases as opposed to a centimeter? Clearly over 1 cm, a centimeter and a half, we all feel nervous about not doing it. But should we use symptoms as that, if they’re asymptomatic, and they have something up to 1 cm?

Naiyer A. Rizvi, MD: I think it’s case by case.

Hossein Borghaei, DO, MS: It’s very case by case.

Suresh S. Ramalingam, MD: It’s not often that you see a 3-mm brain lesion being symptomatic. So, it is a case by case. But what the studies show is there is activity in the brain, and particularly we’re going to talk about ALK, where that’s, again, a major clinical challenge. If you look at EGFR patients, nearly 40% to 45% of them at some point during their course will develop brain metastases. So, it’s good to have a drug that has brain activity.

Benjamin P. Levy, MD: And I think we saw this in AURA3 in the EGFR/TKI-refractory setting where osimertinib responses in the brain were north of 50% to 60%. So, this is a very potent drug that can elicit intracranial responses.

Naiyer A. Rizvi, MD: That’s a pretty significant activity to the CNS.

Benjamin P. Levy, MD: Is there a specific patient, Suresh, who is not an osimertinib candidate, like an uncommon mutation? These weren’t allowed in the trial, and we haven’t expanded approval for afatinib in that setting. What would you do in that setting?

Suresh S. Ramalingam, MD: So, the FLAURA studies specifically look at exon 19 and exon 21 mutations, which are probably 85% of all EGFR mutations we see. At ECOG-ACRIN, we’re soon allowed a study specifically looking at insertion exon 20-mutation patients with osimertinib. And that study will use a higher dose of osimertinib; it’s a phase II study. So, these kinds of efforts to look at less common mutations are ongoing in the incidence of exon 20. There are also some other exciting drugs in development, which are in clinical trials. So, what we’re talking about specifically in exon 19 and 21, the trials have been done and show clear superiority.

Naiyer A. Rizvi, MD: What if you had a different sensitizing mutation other than the traditional ones? Would you use osimertinib up front?

Suresh S. Ramalingam, MD: I would say it’s as good as any of the other drugs at this point. I would certainly feel comfortable using it, but…

Hossein Borghaei, DO, MS: I think as long as I have an activating mutation, I’ll feel comfortable using osimertinib.

Benjamin P. Levy, MD: Difficult question. I guess we’re trying to figure this out, but I guess now that osimertinib is being pushed to the frontline setting, which I think it should, I’ve started using it on my patients in the frontline setting, but what to do afterward? You’ve had some data from your phase I AURA trial looking at CTDNA (circulating tumor DNA) analysis, looking at putative mechanisms of action, mechanisms of resistance. We’ve had some data at World Lung looking at C797S. We’ve had some data also looking at the retention of T790M versus those that don’t retain T790M and how they do with osimertinib. How do we go about doing this? What’s the message to the clinician right now? Is it just chemotherapy and call it a day?

Suresh S. Ramalingam, MD: We’re beginning to understand some of the mechanisms of resistance when you use frontline osimertinib. And what is already becoming clear is the resistance mechanisms are not the same when you use osimertinib in the second-line setting versus when you use it in the first-line setting. The C797S mutations that we see as the resistance mechanism in the frontline setting do not have a coexisting T790 mutation. So, that may be a patient you may actually be able to treat with erlotinib or gefitinib at that point. We’re still learning about it in the prevalence of these; the systems mechanisms are yet to be defined.

But what I would say is, this is a new era when erlotinib and gefitinib, where used in the frontline setting initially, we did not know anything about the mechanisms of resistance. And as we learned them, we brought in new drugs to treat. Now we will anticipate that this is going to happen in the frontline osimertinib scenario. There are already combination approaches that people are beginning to look at combining osimertinib with agents that could potentially block known escape pathways. So, I think those kinds of approaches will help us provide these answers. Until then, in a standard-of-care clinical setting where we don’t have a clinical trial, if a patient progresses on osimertinib, then we will put them on platinum doublet chemotherapy.

Thomas E. Stinchcombe, MD: I would do the same thing. But immunotherapy wouldn’t be my choice at osimertinib progression, and I sometimes get that question from people.

Roy S. Herbst, MD, PhD: I think we have to be a little bit selective. There are other choices, too. We have sometimes been using a combination of an EGFR antibody with a small molecule. So, it’s still clinical trial related but based on data with cetuximab, afatinib in the past; we’ve seen some activity there in the non-T790M. But in C797S, sometimes going back to a first-generation drug will work as well. So, that’s being tried. But this is an area of greatest need right now because these patients have done well now for really long periods of time. And to say chemotherapy is what we have for you, that doesn’t go over very well. One lesson that I’ve learned over the years is don’t forget the chemotherapy, and you have to push it because it does have some activity.

Benjamin P. Levy, MD: It works.

Roy S. Herbst, MD, PhD: Yes. We are going to need to find other molecular therapies. And immunotherapy might work someday. What about an EGFR vaccine? There aren’t many mutations in that tumor. Can we wake up the EGFR? Can we treat with an EGFR inhibitor first and sequence in some way? Is that something that’s a possibility?

Naiyer A. Rizvi, MD: Probably not. The mutations themselves are not particularly immunogenic, but I think there are certainly some efforts around EGFR, c-MET combination antibodies, which are looking interesting. So, I think some sort of combination with an antibody approach may be of interest.

Roy S. Herbst, MD, PhD: What about these data where CD73 is upregulated in EGFR-mutant patients? Have you seen some of that?

Naiyer A. Rizvi, MD: Right. So, I think the adenosine pathway has been suggested as a possible target, particularly for EGFR-mutant lung cancers, but it’s seen more broadly, and there are trials that are being conducted now.

Transcript Edited for Clarity