Update on Metastatic Squamous Non-Small Cell Lung Cancer - Episode 11

EGFR-Targeted Therapy for Squamous NCSLC

Transcript:Mark A. Socinski, MD: I want to transition to getting back to EGFR. We talked about targeting EGFRs in the first-line setting. Ed, I want to get back to you. Is there a rationale for targeting EGFR with a TKI? We’ve discussed male smokers with squamous cell disease, erlotinib versus placebo, and the doubling of the median from 2.5 months to 5 months in the second-, third-line setting, suggesting that it’s an active agent, at least for OS. I don’t ever anticipate seeing responses, but if you can slow progression, maybe that’s enough.

Edward S. Kim, MD: Yes, and I think it’s, again, how we talked about that earlier, what we consider what’s an active versus not an active agent. Placebo is a pretty inactive agent, although it has done OK in some arms, which kind of just tells you, from a humility standpoint, that we as scientists, researchers, and clinicians don’t have it all figured out.

I think when you’re dealing with an unselected population—we’re talking about a pathway here that exists on how many cells are in your body, and there’s a good percentage of them, more than 90%—it makes rational sense to target that receptor. But, again, being so omnipresent, it really dilutes out. Then, getting into the clinic where we’re all clinicians, one therapy versus another, or cytotoxic chemotherapy versus an EGFR drug, again, I think in an unselected population, gets diluted out.

And so, have I always believed that these oral EGFR TKIs, as well as the IV ones before, had activity in patients with lung cancer, specifically squamous disease? Yes. Have we seen that with the IV drugs? Not so much as single agents at all, but in combinations, only modestly. And as pills, I think we still have that data. It still exists. But we now know that not all these drugs are created equal either, and I think we see that in squamous as well as nonsquamous with mutations. They’re starting to cull each other out, as well, a little bit.

Mark A. Socinski, MD: Based on the BR.21 trial, we had the erlotinib indication initially for second-, third-line therapy, and then maintenance therapy. Then, all of a sudden, I think we all got the “Dear Doctor” letter in June saying that those were being erased, if you will. And based on the IUNO trial, who here knew that that trial was ongoing?

Edward S. Kim, MD: I knew.

Mark A. Socinski, MD: They told you?

Edward S. Kim, MD: Yes. I knew from the companies.

Tracey L. Evans, MD: I think I knew it, but the connection when they took away the approval, there was no connection that that was the reason why.

Edward S. Kim, MD: It went for years.

Tracey L. Evans, MD: Right, because this is a maintenance trial.

Mark A. Socinski, MD: Well, it is a trial of either erlotinib as maintenance therapy or erlotinib as second-line therapy. And in the second-line patients, distinctions of the SATURN trial, where only 11% of the placebo patients got erlotinib, here, I think it was 77%. So, it’s like “erlotinib now,” or “erlotinib later.”

Tracey L. Evans, MD: And this is the perfect design for a maintenance trial. It’s the way the immediate versus delayed docetaxel study had initially been done. If you want to ask the question about what’s important—that you get the drug right away at the end of your induction, or that you get it eventually—this is the way you want to design the trial, and this is how this trial was designed. In fact, there was no difference in the overall survival, so it didn’t matter. But that doesn’t necessarily mean that there’s not a survival benefit to the drug. The SATURN study was positive for overall survival when the drug was given as maintenance, and the BR.21 trial was positive for overall survival when it was given second line, third line. Granted, there was not a dramatic benefit, but there was a benefit nonetheless.

Mark A. Socinski, MD: I understand the rationale of taking away in the maintenance indication. I don’t understand the rationale of taking away a second line, third line, but that’s not where I want to go. We can argue about whether or not second-, third-line erlotinib has a role. But it seems like many people could agree with the following statement: it is not an inactive control arm. I want Ed’s perspective on LUX-Lung 8, which was in second-line squamous before the immunotherapy, or afatinib, a second-generation TKI, versus erlotinib. Thoughts?

Edward S. Kim, MD: You always hope that as you get more generations, and newer generations, that they are going to be better with at least not worse toxicities, etc. This was a head-to-head study. For years, when we were in the gefitinib and erlotinib era, and we were trying to be convinced that we should use erlotinib, we asked, “Where’s the head-to-head? Where’s the head-to-head?” We never got that and we didn’t need to because, obviously, gefitinib was taken away from us. So, we didn’t have any choice. Now, we have head-to-head trials, and one of the head-to-heads is LUX-Lung 8.

And, although modest, there still was a month better survival than with erlotinib. I think in a second-line squamous patient population, that’s meaningful enough. Again, you can’t compare this to immunotherapies or other things that are now taking the landscape. But when looking in the realm of oral TKIs against treating with docetaxel in a second-line setting, I would pick afatinib or previously, erlotinib, to do that. So, I think the data are meaningful. I think the toxicities weren’t something that scares you away. But, again, it’s about management. With erlotinib, nobody knew how to manage 150 mg of erlotinib. People started using 100 mg and 75 mg. The same thing happened with afatinib. People got a 50-mg dose that was tested early on, and that was way too high. And 40 mg doses can be tough in some folks, but we have people at 30 mg or 20 mg, and they do just fine. I’d much rather have them on it than on a cytotoxic.

Mark A. Socinski, MD: Yes. So, has LUX-Lung 8 impacted your practices?

David M. Jackman, MD: When I first saw the data, I thought the win for afatinib, from this trial, was going to be outside the squamous setting. I thought finding the toxicities for afatinib and erlotinib were fairly similar. I thought it was going to be a win for afatinib in EGFR-mutated patients because of that toxicity comparison. We’ve never been huge believers of the use of these agents in squamous cell patients, again, not because we don’t believe there’s activity. I think the real question, at least in my practice, is not, “Is this better than placebo?” or in this case, “Is it better than erlotinib?” Instead, it is, “Is it better than the other options we have now, currently?” In almost all cases, I just feel like the efficacy benefit is there.

Edward S. Kim, MD: I would agree with that now. But if this data were revealed 3 years ago, before the I-O tsunami, would you rather give afatinib, gemcitabine, or docetaxel?

Mark A. Socinski, MD: It has really been relegated almost to third, fourth, fifth line.

Edward S. Kim, MD: Fourth-line for us, honestly.

Mark A. Socinski, MD: Yes. In the percentage of patients that make it to the fourth line with squamous disease, you can count them on a hand.

Edward S. Kim, MD: But to me, and just as David talked about, it was also symbolic that it’s a different drug. I think we started seeing some hints in mutant populations with deletion 19 data and others. Not everybody was on board with that, and maybe now everyone is on board with that. But there may be a difference between these generation inhibitors and how they affect not only the general unselected population, but also the selected population.

Tracey L. Evans, MD: On the other hand, we always thought, in the wild-type population, that biologic effective dose was more important. Erlotinib had a benefit in BR.21, but gefitinib didn’t. We always thought that was because erlotinib was at its maximum tolerated dose and gefitinib wasn’t. I’m not quite sure how that applies to the mutation population where they don’t seem as dependent on dose, although it does give me some angst that they’re not all the same.

Transcript Edited for Clarity