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

Dr. Whitney Lewis:

Welcome to part three of our roundtable discussion on EGFR-mutated metastatic non-small cell lung cancer. My name is Whitney Lewis, and I'm back with my colleagues Chaely Medley and Beth Sandy. Chaely and Beth, thank you so much for joining me today. In our previous discussions, we talked about what's new with EGFR exon 20, as well as more classical EGFR mutations and some of the toxicities that we see with these agents and how we're choosing our regimens. Now, I'd like to get us into what we don't want to always have to talk to our patients about, which is what to do after first-line therapy for these patients with EGFR-mutated lung cancers.

So I wanted to spend a little bit of time just talking about what are some of these resistance mechanisms to frontline osimertinib. And so we have a graph here. It looks really busy, but essentially it just breaks it down into there's a pretty good chunk of patients where we don't really know why they're progressing. There may be a small cell lung cancer histologic transformation that we can see. Additional acquired EGFR mutations may pop up. Acquired amplifications, for example, MET amplification is a very common escape pathway for osimertinib.

Patients can also develop new oncogene fusions. I've seen some patients that develop an ALK fusion, FGFR fusion. So, we've seen some really interesting targets pop up as patients retain their EGFR mutation. So we know it's the same cancer and they haven't developed a new primary as well as some other mutations. So I'd really like to spend a little bit of time talking about what do you guys do in clinic when you start to have patients that are progressing on their therapies. Beth, do you want to give us a little bit of a head start into what we should be doing?

Beth Sandy:

Yes. Well, we know there's two ways to look for mutations, and one is by doing a biopsy and testing the tumor, and the other would be a liquid biopsy or blood test. So I think the easiest thing to do right away is to send off the blood test. We will typically do that even when they're having just what we call smoldering progression, just a little bit of progression, and we'll send off that blood test and see if they're still having that EGFR mutation. Did they lose the mutation? Did they develop a new resistance? And just see what that looks like even if we aren't necessarily considering stopping their frontline therapy.

But I think when they're truly progressing, new sites of metastases or significant growth, it's important to do a tissue biopsy. And the main reason for that is this idea that EGFR-mutated lung cancer can transform to small cell lung cancer, and you will not find that on a liquid biopsy. You need the histology from a biopsy of a tumor tissue. So we really do press for that. And I'll tell you, it appears in the literature right now that the small cell transformation is 10% or less, but I feel like it's going to be more than that in the future because I feel like a lot of that data, we weren't always biopsying new sites of disease.

And in my clinical practice now that we are re-biopsying really everybody that we can, when they progress, I feel like we're finding it more and more and more commonly, and it just becomes so aggressive. You treat it just like you're going to treat a patient who has small cell and start them on small cell chemotherapy. And unfortunately, prognostically, it's not good either because it follows the same prognosis as small cell lung cancer. So I would really recommend that tissue biopsy in addition to the liquid biopsy. Chaely, what have you guys been doing?

Chaely Medley:

That's similar to my practice as well. I mean, we are sending serum DNA testing if we can, on the patient when they're in the clinic because that's the quickest thing that we can do. It tends to result quicker, certainly, than when we're sending actual tissue biopsies and we're not waiting to get the patient in for a procedure to get the biopsy. And then sometimes patients have bone mets, maybe they have new bone mets or they don't have an easily biopsiable site. So, if we can send the CRM test first thing, then that's priority. And then again, trying to get in there so that we can get an actual tissue biopsy.

We do know that when these patients have small cell transformation, as you're saying, they tend to be sicker, they're going to have increased risk of brain metastases. And so identifying that is really paramount in making sure that we're treating them properly and not just assuming, "Okay, this was progression. Okay, moving on now to the next guideline of treatment." If we're being really thorough, we need to get the biopsy.

Dr. Whitney Lewis:

Yes, and I would say we're very similar. We're often, as Beth said, checking as it starts to look like patients are having some growth, and go ahead and try to check that liquid biopsy earlier and try to have those results back in clinic for the next checkup. So, then we could maybe start talking about, "Okay. You truly have real progression now." And it's time to start talking about, "Is there a clinical trial that would make sense for you based on what we're seeing here?" Or, "Have we identified a fusion that we could try to target with dual TKIs?" Or if there's, like Beth said, more rapid progression, then we want to get a tissue biopsy, especially for patients that have that TP53 and RB co-mutations. Those patients also seem to be almost predestined to transition to small cell lung cancer at some point.

So, I also think clinical trials play a really big role in this space right now too, because we don't necessarily know what's best for a lot of these patients once they start to progress on the first-line therapy. And we're very excited to talk about some things that aren't necessarily approved yet, but hopefully, will be in the near future that you at home may have even seen on clinical trial in your institution. And so what's new and upcoming, I think, in all solid tumors is the concept of these antibody-drug conjugates. So, you have a monoclonal antibody and then a little linker and then that toxic payload of chemotherapy. So, ideally, and theoretically, these drugs are a lot less toxic in terms of myelosuppression and just a little bit more targeted when we're thinking about how to treat these cancer cells.

And so there's a couple of upcoming drugs, patritumab deruxtecan, which we expect to get FDA approval in the somewhat near future in the next couple of quarters. And may also see datapotamab deruxtecan approved, either just broadly for salvage non-small cell lung cancer, or also for patients with EGFR mutations. And so what's unique about patritumab is it's really a first-in-class novel antibody and it binds to HER3 extracellularly. So, this was studied in a pretty heavily pre-treated population post-osimertinib and post-platinum–based chemotherapy, but there actually wasn't a limit on the number of lines of previous therapy.

So the fact that it still had about a 30% response rate blows one's mind. If you think about second line, docetaxel is 12-ish percent. So despite a heavily pre-treated population, still had a pretty good benefit in terms of response rate, a decent duration of response of about six months, about six-month progression-free survival as well. And what I thought was really important, especially for this population, is that it also had a good intracranial response rate of about 33%. So once these patients start progressing in the brain, there's really only so much that we can do. Were either of you able to participate in this clinical trial or have you guys seen anything in your sites that you're getting excited about seeing in terms of what to do for these patients once they progress?

Beth Sandy:

Yeah, we actually enrolled a fair amount of patients on this trial at our institution, and I'm excited to use this drug. I mean, it is generally well tolerated. It still has the deruxtecan, which is chemotherapy. It does have that chemotherapy payload, so there was a 66% nausea rate reported in this trial. Though the majority with grade 1 and grade 2, but you will still have some of that. The neutropenia, thrombocytopenia rates again around that 35% to 45% range. So you do see some of that typical chemotherapy-like side effects, even though it is targeted to HER3. And I want to remind HER3 is overexpressed in 85% to 100% of non-small cell lung cancer, EGFR-specific patients.

So, this will be a nice treatment option for our patients with EGFR mutation-positive disease post-progression on these frontline therapies. So I'm excited to use it. I always remind people the HER3 doesn't have a tyrosine kinase domain. Not that we want to get into the thick of HER3 or the HER family receptors but that was that weird niche with the HER3 is that they don't have ligand binding or a tyrosine kinase domain.

So this will have to be an IV drug to hit this target. But it is something certainly druggable in EGFR mutation-positive non-small cell lung cancer and something I'm looking forward to giving. And I saw the overall survival in this was almost a year in this trial. I think it was 11.9 months. And that's, again, like you said, Whitney, that's really good considering a lot of these patients were second, third, fourth line for treatment, still able to live another year as a median overall survival. So, Chaely, did you have any experience with this drug?

Chaely Medley:

I don't have experience with it, but from what you guys are saying, it does sound really exciting, especially for these patients that are so heavily pretreated and multiple lines of therapy. And obviously, we know that these patients, the more therapy they have and the longer that they've had these cancers, the sicker they are. And so really, we're looking for treatments where they are going to have decent tolerance, where they want to keep going, and that they have good response.

In my practice, after progression on frontline therapy, we've added chemo to frontline therapy and just kept going with our frontline therapy with the addition of chemo. And then also just if that's not in the patient's values, then we're looking for clinical trials elsewhere if we don't have anything to offer them at our facility.

Dr. Whitney Lewis:

Thank you so much, Chaely. That piggybacks perfectly into the last trial that I wanted to talk about, which is not FDA-approved as of yet, but this is the MARIPOSA-2 trial. So similar to what Beth talked about in our last segment, but post-progression on osimertinib. So, we're looking at patients with these classical sensitizing EGFR mutations who've progressed on osimertinib, and patients were randomized into three different arms of chemotherapy, which would be the standard of care, amivantamab plus chemotherapy, or amivantamab plus lazertinib plus chemotherapy. And so they were really trying to look at the progression-free survival but then had a lot of good, interesting secondary endpoints for this as well.

And so you can see that we did have a better median progression-free survival compared to chemotherapy with both of the study arms. Response rates were also better than compared to chemotherapy at about 36% compared to 64-ish. We also had better durations of response. And again, with that intracranial progression-free survival, where I thought these regimens were really surprising, especially with just the amivantamab and chemotherapy had a very similar intracranial progression-free survival compared to the amivantamab-lazertinib chemotherapy.

So you don't normally think of these big chunky antibodies as having great intracranial penetration, but it does seem like it's doing something in that space. So I'm very excited to see if and when this gets approved, how it gets adapted into practice because there are a lot of side effects. And we've talked about a lot of these already, but a lot of things to consider and it's a big mindset shift for these patients as well. Beth or Chaely, have you got any experience with using some of these regimens for the EGFR progressors?

Chaely Medley:

Not necessarily with EGFR progressors, but I guess just to speak on some of the side effects, it sounds like such a heavy regimen to do ami-laz and chemo. We've talked in the other discussions about the EGFR dual drugs doubling down on those side effects and then you're adding the side effects of chemo. It sounds so burdensome, but this is something that if patients are responding and they have good intracranial response, it's encouraging, I think, for patients.

Beth Sandy:

I think with MARIPOSA-2, one of the main toxicities that was problematic is the rates of DVT. So in the arm that carried lazertinib, there was a 22% rate of DVT. So that is actually likely not to be approved once this gets approved because of that high rate of DVT. I think a lot of people are going to hesitate to use that four-drug regimen based on that, and they may need to look at studies going forward with that four-drug regimen, maybe tweaking doses or something to figure out why that was such a high rate. I think that once we see that get approved, they may actually recommend therapeutic anticoagulation for those patients, is my understanding.

Now, the ami-chemo though, that is realistic as a second-line therapy, but so much of this is going to depend on what your sequence was in the first line. So if you listen to our earlier presentation, we talked about all the different things that we can use in the frontline setting, including regimens that contain chemotherapy, or amivantamab, or both. So if you've already used them, this may not be where you go, but if you haven't, this may be a nice second-line option. So much of this may depend on sequencing. Whitney, what was your feeling about the DVTs in this trial, and where you would go with this clinically?

Dr. Whitney Lewis:

I think it makes us all really a little bit anxious. And even in some of the other amivantamab combination arms, I think with PALOMA-3, they even started giving prophylactic anticoagulation. So, it just adds a whole other layer of complexity to managing these patients and to your patient counseling as well, to say, "Oh, you've got cancer." And, "Oh, here's all of the side effects from the treatment." And, "Oh, here's how to manage that. Also, here's a blood thinner." And a lot of these patients are young and active. So I think there's just a lot of conversations that we'll continue to have and evolve and what do these toxicities look like in a real-world population as well?

So, I think there’s a lot to be discussed, but one thing I do love about this population is they're usually very motivated and they want to be treated. So I don't really have any concerns about implementing some of these, but I do think it's going to take a very careful balance of toxicity and talking to patients about being really proactive and really communicative.

And I think that brings us to the end of our EGFR-mutated metastatic non-small cell lung cancer Roundtable Series. Chaely and Beth, thank you so much for sharing your expertise with me and the viewers. For more information and to view our other discussions on EGFR-mutated metastatic non-small cell lung cancer, please visit JADPRO online at JADPRO.com.