What APs Need to Know About the Management of EGFR-mutated Metastatic NSCLC

Beth Sandy:

Welcome to part two of our Roundtable discussion on the management of EGFR-mutated metastatic non-small cell lung cancer. My name is Beth Sandy and I'm back with my colleagues Whitney Lewis and Chaely Medley. Whitney and Chaely, thank you for joining me today, and we're going to talk about EGFR-mutated non-small cell lung cancer, the common mutations in the metastatic setting. And by common mutations, I mean the exon 19 deletion and the exon 21-point mutation, otherwise known as the L858R. So, this is going to make up the majority of EGFR mutations. And really, these were the first ones that we knew about that were actionable in lung cancer dating back 10 to 15 years ago.

So, it's been really exciting to see, over the years, different agents become approved. There are actually five EGFR TKIs that are approved now for the management, but typically the majority of us are using osimertinib in the frontline setting. And in the NCCN guidelines that is the preferred first-line agent, and that was based on the FLAURA trial, the first-line FLAURA trial, which looked at giving osimertinib at 80 mg once a day vs. either erlotinib or gefitinib, which were really the two other EGFR TKIs that primarily were in use at the time.

So, this was not an EGFR inhibitor vs. chemo. We already knew that EGFR inhibitors were better than chemotherapy in this population of patients with mutations. So, now it was a matter of looking at this third-generation EGFR TKI called osimertinib, and what we found that it was better and less toxic. So, in that trial, osimertinib was significantly better from a progression-free and overall survival advantage, even for patients who were on the erlotinib or gefitinib and could cross over and get osimertinib, there was still an overall survival advantage. Chaely or Whitney, do you want to briefly talk about the past and now with using osimertinib in the first line and how that's changed your practice?

Dr. Whitney Lewis:

I can go first. When I started about 10 years ago, we actually, I think, had osimertinib on clinical trials, so it was so exciting to see this get approved. And this was after patients had been on erlotinib for 9 to maybe 12 months, maybe a little bit longer if they were lucky. And we knew that they would start developing these T790M mutations, or at least a good chunk of them that would be the escape mechanism from these first-generation inhibitors. And then osimertinib came out and you're just really rooting for a patient when they progress to hopefully have that T790M mutation because you knew that the patient would tolerate osimertinib so much better than that earlier generation TKI.

So, I think when you look at the side effects from FLAURA, the percentages to me weren't actually that impressive. But when you look at the grade 3 differences and just clinical practice, how well these patients tolerate osimertinib, it's really beautiful in terms of rash, diarrhea, paronychia. Some of these things that when you're reading a trial is really easy to just blow off like, "Oh yeah, a little diarrhea, a little skin rash." But those are things that really matter to patients and really affects their quality of life and day-to-day.

So, then to have the osimertinib come out into the front line and not only be non-inferior but actually confer a pretty good survival benefit, I think was really exciting. So, that was certainly a landmark practice-changing trial for all of us as soon as that got published and approved. Chaely, what was your experience?

Chaely Medley:

So, my experience with the osimertinib has also been really great. I mean, when we get patients that have the EGFR mutation, we're celebrating in clinic because we anticipate that they're going to feel pretty well. We can give them a pill every day. They don't have to come to clinic nearly as much. And the counseling is, we are counseling them on the rash and the diarrhea, but we have lots of supportive care for these patients. And so being able to use osimertinib in the frontline setting has been very exciting for our patients.

Beth Sandy:

So, Chaely, that is a great lead-in because you said, "I'm so excited to give my patients a pill every day." And then voila, data has come out now in the FLAURA-2 trial. Because here in the U.S., if a pill worked good, why not add chemo? So, they looked at a clinical trial giving osimertinib daily, which was standard of care, vs. osimertinib plus pemetrexed and carboplatin chemotherapy. Where they would get the chemotherapy for 4 cycles along with osimertinib daily and then you had the choice of continuing the pemetrexed as a maintenance every 3 weeks but dropping out of carboplatin after 4 cycles.

So, in this study, we did find an improvement in progression-free survival of 25 months in favor of the chemotherapy and osimertinib arm vs. 16 months for the osimertinib-only arm. Now the obvious here is that you're adding chemotherapy, so you are back to, "Oh, it would've been nice to take a pill every day." And the pill works very well for many patients.

What I will say in this trial, and I'm interested to hear you guys' response to this is, I don't know that this is for everyone, adding chemotherapy to the osimertinib. The data is better. The progression-free survival data are better, sorry, the median duration of response is better. The duration of response was 24 months vs. 15 months for the osimertinib alone. However, there's obviously increased toxicity. There's GI toxicity such as nausea, constipation, diarrhea from the chemotherapy. There's lowering of blood counts associated with the chemotherapy.

What we saw in some of the subset analysis was that the patients who had brain metastases seemed to have derived a better benefit from adding chemotherapy. Seems odd because usually chemotherapy doesn't cross the blood-brain barrier well. We know that osimertinib does, but for some reason adding chemotherapy to that osimertinib, those patients did derive more of a benefit than the patients without brain metastases.

We also saw this benefit in the patients with the L858R mutation, where they typically don't do as well is the exon 19 deletion mutation. And so they seem to make up ground there and derive more benefit from adding chemotherapy. So, Whitney, is this something in your practice that you are offering to everyone? You're giving it to everyone. What has been the patient reaction to this?

Dr. Whitney Lewis:

That's a great question. I think, to Chaely's earlier point about going from just an easy pill once a day to then coming in and feeling sick, when you think about an EGFR population, a lot of these patients are young. They're still working. This isn't the average, I'm retired, I'm-70-years-old type of patient. This is much younger. So, I think it is absolutely a new standard of care. I think the data looks really great. So, we're certainly having that discussion with all of our patients, but I would say it hasn't necessarily been adopted as a one-size-fits-all. I think the patients that have baseline brain metastases, that's really who we would encourage to use this as an option. To your point, the PFS was 25 vs. 14 months. So, a huge difference for those patients because once you start progressing in the brain, it's like you can only radiate it once.

So, that's a really big thing, but we're not necessarily giving it to everyone, maybe a young patient that really wants to be very aggressive. But when I think about this trial, they also, what I thought was interesting was reported on PFS-2. Meaning what's the time at second progression? So, patients that got just the osimertinib, then they could cross over to get all three of those. And the PFS-2 was pretty similar. I'd love to see some survival benefit before we really pushed hard to give this to all of our patients because I think there is a real quality of life issue here, to your point. Chaely, have you started adopting this in your practice for all of your patients?

Chaely Medley:

Not really, because I agree in that it has to be very patient-specific. The patients that are going to get this are going to be somebody who wants to be aggressive and is already pretty robust. Adding chemo to the osimertinib does take the wind out of your sails in terms of not having to be at clinic as often and managing some of the additional side effects with nausea, worsening fatigue, additional GI upset, things like that.

And so I agree, I think it needs to be somebody who wants to be really aggressive. Again, maybe they already have brain mets, they're very young, and have an ECOG of 0. These are not going to be patients who are older and really are going to be interested in piling on all of these side effects. But I do think that the data looks encouraging and promising and good for certain populations. But in my practice, I'm still using osimertinib monotherapy in frontline.

Beth Sandy:

Yeah, I think, for me, we feel compelled to say the data to all the patients, “But here's the trade-off and is this something that you want to add and potentially experience this toxicity?” I think the other thing that people think about is, "Okay. If I did all of this in the front line, what am I then going to do in the second line once they progress?" But we're going to talk about that in the third round of this series, which is exciting.

So, anyway, let's move on and talk about new data. And this is a trial called the MARIPOSA-1 trial. And this is looking at, again, frontline management of metastatic EGFR mutation-positive patients. And this is using amivantamab, which was the drug we spoke about earlier in the exon 20 insertion EGFR space, now in the common EGFR mutation space, in combination with a new EGFR TKI, so an oral called lazertinib. So, you could combine this amivantamab and lazertinib vs. osimertinib in the frontline setting, which is standard of care. So, this was a non-chemotherapy clinical trial.

So, what we saw in the MARIPOSA-1 trial with amivantamab and lazertinib was an improvement in medium progression-free survival of around 23 months vs. 16 months for the osimertinib-only arm. So again, are we going to be willing here to consider adding toxicity? This was a more toxic regimen for the amivantamab-lazertinib arm in terms of things like infusion-related reactions, which we talked about earlier. But just to remind everyone, the amivantamab is administered with long infusions in the first two treatments, which are day 1 and day 2, back-to-back, and then it slowly gets better, and you can space them out as you go on.

The lazertinib also combined with amivantamab has increased rash, significantly increased rash than what we would see with osimertinib alone. Now, the one toxicity that was actually more in the osimertinib arm in this trial was diarrhea. So, you have your trade-offs here, but if this is something that did have some better data in the front line. The median duration of response was also longer: 25 months vs. 16 months. So Whitney or Chaely, is this something that you guys are looking to consider? And what are your thoughts about this now vs. using osimertinib plus chemotherapy? Because this would be a chemotherapy-free regimen.

Chaely Medley:

I think combining the ami-laz, to your point about the worsening of the side effects significantly with something like rash, that can be, as we discussed prior, is something that's so bothersome for patients and can be really difficult to get a hold of. And so, when we're talking about combining two of these drugs that carry a lot of the same side effects, I think it can be really complicated because we want to be able to manage the side effects so that patients can keep going and experience the benefits of staying on the drug for X amount of time.

I do think that the combination of the ami-laz would be preferable to osi-chemo because patients are not having a lot of the compounded chemo side effects of significant fatigue, nausea, vomiting, appetite changes, all of the things that we see with chemo that patients really are just not looking forward to and are wanting to avoid and that we get excited about when we see that we have something that we can action with the TKI.

Beth Sandy:

You make a great point, actually. If you look cross-trial the data's similar for the chemo-osi and the ami-laz. So, it's like you're saying chemo or a bispecific and a TKI. I don't want to say pick your poison, but that's why they always say it.

Chaely Medley:

I mean you do counsel the patients that way though. What are your goals? What matters most to you? Would you rather have nausea and vomiting maybe fairly significantly for 12 weeks or are you okay with maybe having this unsightly rash that's really bothersome that you might be taking medication twice a day, every day indefinitely for? So I don't know when you say it like that, it sounds bad either way. But these drugs are real. They do have real side effects, and our job is to counsel them and help them to be able to make informed decisions about what's going to work best for them personally.

Dr. Whitney Lewis:

Yes. And I think that's a very similar conversation to what we have with our patients in clinic. And also setting the expectation that it would be our dream that you would never have to change therapies, but there will likely come a point in the future, and again, hopefully, in a couple of years from now where we do have to switch gears. So, it's also almost at least right now, like, "Well, what do you want first? Because you're probably going to wind up getting both," which I think is... We'll talk a little bit more about that later, but that's also a great way to start introducing patients into that mindset of thinking about some of those side effects that maybe they haven't yet.

Beth Sandy:

Great. Great discussion, guys. Thank you so much. This brings us to the end of this part of the discussion. Whitney and Chaely, thank you for taking time to talk with me today. For more information and to view other discussions on EGFR-mutated metastatic non-small cell lung cancer, please visit JADPRO online at JADPRO.com.