Mark A. Socinski, MD: One of the more exciting trials in the past year or so is the FLAURA trial, testing the third-generation osimertinib. Summarize those results and tell us, is that now the first-line standard?

Leora Horn, MD, MSc, FRCPC: So it is the first-line standard, and that trial, again, was a randomized phase III trial, looking at osimertinib compared…with erlotinib or gefitinib, in patients who are EGFR-mutant—positive, and again, looking at the common mutations, [exon 19 deletion] and L858R. And the study demonstrated a clear progression-free survival benefit for our patients getting osimertinib compared with the first-generation TKIs [tyrosine kinase inhibitors]. And importantly, there was also a benefit in the CNS [central nervous system], because we know that osimertinib is a drug that does penetrate the CNS better than either gefitinib or erlotinib. We haven’t seen the OS [overall survival] data, and so whereas before we might get a first-generation TKI, or afatinib, first-line therapy and on progression hope for T790M and give osimertinib. Second-line therapy has now become chemotherapy for those patients who are getting osimertinib. But osimertinib has become the preferred frontline regimen and is listed in NCCN [National Comprehensive Cancer Network] guidelines.

Mark A. Socinski, MD: Everyone agree?

Heather A. Wakelee, MD: Yes, but I think there’s still room to talk about the erlotinib/bevacizumab data. And I was very intrigued by the data that came out of Japan that looked at chemo [chemotherapy] plus gefitinib. And I think we’re still not quite sure what to make of that because we learned for so many years, don’t give chemo [chemotherapy] and EGFR TKIs together coming way back to the initial trials. We didn’t even know about the EGFR mutations and we just gave everybody plus EGFR TKI and didn’t see any benefits from that.

The Japanese did a trial that was chemo [chemotherapy] plus gefitinib, or gefitinib followed by chemo [chemotherapy]. And they looked at the first progression-free survival [PFS]. And then they looked at the progression-free survival, which was I thought the right way to do it, because you didn’t want to say, well you give everything together and you have this PFS, or if you give sequentially then how do you look at all that together?

And in the end the study showed that whether you gave everything together or you gave it sequentially, the progression-free survival was about the same, and it was pretty good. But what was really interesting was that the group that everything at the beginning actually had a longer survival.

So we only have 1 study showing that now, but it was definitely intriguing. And when asked, how is that possible, the presenter really didn’t have a great answer, but did talk about the fact that maybe if you’re suppressing more of the potentially resistant clones early, even though they eventually come up, having that more time with less disease burden, maybe let it less, I mean it was, it didn’t really come across as a clear answer. I don’t think we know, and it was a rough question to ask. What can we do to explore that further? And so maybe there’s the opportunity to do some sort of first-generation drug plus chemo [chemotherapy] and then go to third generation. Or maybe there’s some opportunity to do anti-VEGF plus first or second generation. But, of course, the anti-VEGF plus third generation plus osimertinib trials are ongoing. So I’m not, I usually give osimertinib in first-line therapy, but I don’t think it’s as simple, “Oh, everybody should get it,” because then we are faced with what next and what after chemo [chemotherapy].

Mark A. Socinski, MD: Right, we’ve seen over the year’s trial paradigms done in Japanese populations that can’t necessarily be replicated in other populations. Does that concern you about that?

Heather A. Wakelee, MD: Not particularly. But my patient population is mostly Asian, right? And so what I’ve seen of the Japanese data is often reflective in my own patient population. So in the setting of EGFR, I don’t think it’s as much ethnic differences; with TKIs there isn’t as much. With chemo [chemotherapy] there certainly can be with toxicity. I’m not changing my practice yet, I’m not giving chemo [chemotherapy] plus TKI, but I think it’s worth further exploration. And I think that as we learn more about osimertinib resistance, as we learn, you know, keep having these questions about what’s next, I think that we need to be mindful that there might be other options for some patients. I think that’s where that comes from. I mean we have, thinking about when osimertinib was approved in my patient population, and then they get their chemo [chemotherapy], we’re having a lot now of the what’s next? And of course there are lots of trials that we’re all doing. But I think I’m always cautious about saying everything should be the same for all people, right? So not every EGFR patient necessarily.

Mark A. Socinski, MD: Yeah, sure, I had a patient recently that was an exon—I can’t remember if it’s 19, I think it’s 19—and I started on osimertinib. He had a cardiac history. And when you start getting phone calls from the cardiologist about the QTC interval. So I actually treated him with erlotinib and he’s having a great response. I’m very grateful that he’s responding.

Heather A. Wakelee, MD: Great. And osimertinib toxicity is relatively low, but we do have to be mindful that cardiac toxicity; I’ve had at least one patient I can think of where QTC prolongation we had to stop and he’s doing very well now on afatinib. It’s rare, but just like any drug, there can be toxicities that are just specific to that.

Mark A. Socinski, MD: John?

John V. Heymach, MD, PhD: Yeah. So I agree with Heather that there’s a lot of paradigms and questions we need to start asking now. I personally do think that osimertinib data supports using that as the backbone for all these questions. I think the chemotherapy question is an important one, and there’s a randomized study of chemo [chemotherapy] with osimertinib that we’ll eagerly await. I think the VEGF study is an important one, and there’s an osimertinib plus bevacizumab, and an osimertinib plus ramucirumab study. I think those are great questions.

Transcript Edited for Clarity