Transcript:Mark Socinski, MD: Let’s talk a little bit about EGFR mutation-positive disease, realizing the vast majority of these will be the exon 19 and exon 21. We know that we have 3 approved agents: the 2 first-generation agents, erlotinib first and then gefitinib, and the second-generation agent, afatinib. Jared, walk us through what the key issues are and how do you decide what do you use and so on.

Jared Weiss, MD: I think you decide with low passion. All 3 agents are FDA-approved in the first-line and have legitimate arguments for them. In my mind, to simplify these, I think of them as taking on a spectrum of biologic-equivalent doses, with gefitinib having the lowest biologic-equivalent dose, erlotinib being in the middle, and afatinib having the highest biologic equivalent dose as well as irreversibility in HER2 activity. Clinically, we have only one real study comparing these 3 agents. At the median, the PFS was the same for the 2 agents at 11 months, but the hazard ratio did favor afatinib at about 0.7.

Mark Socinski, MD: There was a late difference in the tail of the PFS curve. And some see it as significant and some people see it as clinically underwhelming. Is that fair?

Jared Weiss, MD: I think that’s fair, and the real question, of course, is on quality of life and survival. That is what we really care about for our patients in the broadest sense.

Mark Socinski, MD: The other point about that trial though is it’s a funny trial from a statistical design point of view. I haven’t figured that out yet, but that’s a whole other issue. The one thing I think is helpful from that trial is the overall response rates, which were significantly favored, and they’re actually very different in exon 21. I forget the numbers, but it’s like 70% for afatinib versus 45% in the exon 21, which is pretty different in that setting. We tend to poo-poo response a lot, but if you shrink a tumor, patients feel better, and many of these patients are symptomatic. So, response is important in terms of the palliative aspect of treatment. It’s important to patients, too, because the first question they ask is, “Did my cancer shrink?”

Jared Weiss, MD: So, of course, quality of life is a balance between 2 factors: the response, particularly in symptomatic patients, but also toxicity. And so, the more potent agent did have more toxicity, particularly in terms of diarrhea and rash. When you try to compare erlotinib, it’s very hard to talk about PFS numbers because you’re doing cross-trial comparisons to do that. From a toxicity standpoint, I think they do make a spectrum with afatinib having the most rash and diarrhea, erlotinib being in between, and gefitinib having the least of those. The other question is, what will this mean for survival in an era where we have third-generation inhibitors? I think that’s completely unknown. The LUX-Lung 7 data we were just talking about for very happy reasons are completely immature for survival on either arm, and so we have to wait for more information.

Mark Socinski, MD: Alex, what’s your perspective on this first-line?

Alexander Drilon, MD: A couple of things strike me about the LUX-Lung 7 trial. Obviously, for the survival, while not mature, there wasn’t a significant difference from the last data cut that was presented. So, to me, my personal preference is to give a first-generation TKI because I don’t think that, in my mind, the marginal gains that we’re seeing in response and progression-free survival justify the toxicity for a drug that’s chronically dosed, which in some patients is 1 to 2 years. One other point to bring up is that there is a lot of buzz around using afatinib for exon 19 deletions before this because there was an analysis of the LUX-Lung 3 and LUX-Lung 6 trials, where it seemed like the exon 19 deletion patients did better. And so, now we’re seeing, as you mentioned, the flip side: why are the responses in L858R much more pronounced? The last point I want to make is if you have a motivated patient that’s really looking to improve their outcomes in the first-line setting, there are other things you can do that we’ll talk about shortly, like considering adding an antiangiogenic or if there’s a clinical trial of a third-generation TKI that might improve response.

Transcript Edited for Clarity