Part 3: Review of Targeted Therapies for Lung Cancer with Actionable Mutations

Drs Langer, Lisberg, Bazhenova, and Nagasaka describe their use of targeted therapies in patients with the most common mutations and fusions. They share their experiences with these agents both in clinical trials and in clinical practice.

This roundtable discussion is sponsored by Daiichi-Sankyo.

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Corey Langer, MD:

I want to go into the actual mutations, very briefly because I realize this is a rapidly evolving field but we’ll start off with you Aaron, and we’ll strictly first on the mutations then we'll segway later to the fusions. How do you treat each of the general mutations?

EGFR

Aaron Lisberg, MD:

I'll start with EGFR, that’s where I was going to start anyway. It's the most common. So, I think the FLAURA data was very convincing. And certainly in EGFR patients with sensitizing mutations I'm using osimeritinib, one of the advances in the last year or so in the space is EGFR exon 20 insertions.

Aaron Lisberg, MD:

And we have afatinib and mobocertinib there. So those are both good options, there’s pros and cons to both approaches that we certainly can discuss more, but that’s generally how I’m approaching. And the EGFR approaches are certainly approved in the frontline setting. We have some trials evaluating the exon 20 insertion drugs in the frontline setting in combination with chemotherapy, but that's an evolving space as well.

Corey Langer, MD:

Outside of a clinical trial, what regimen would you typically use for exon 20?

Aaron Lisberg, MD:

I typically use platinum doublet, for the same reasons we talked about in terms of the EGFR sensitizing mutations, I typically do not include an immunotherapy component.

Corey Langer, MD:

Have any of you added chemo to osimertinib? Again, outside of a clinical trial, Lyudmila?

Lyudmila Bazhenova, MD:

Outside of the clinical trial? No, but I did have FLAURA open, and so we put all those patients on FLAURA too.

Corey Langer, MD:

Misako, any differences or anything else to add for EGFR?

Misako Nagasaka, MD:

Nope, not really.

BRAF

Corey Langer, MD:

Your practice matches Aaron and Lyudmila’s. So we'll start off with you then for BRAF.

Misako Nagasaka, MD:

So for BRAF I have done dabrafenib and trametinib, but it's not an easy combination for patients to take.It requires a lot of monitoring and nurse phone calls, and some of the patients I was treating didn’t even have a thermometer, so you start there. I think the toxicities of these drug combinations need to be improved as well as efficacy in the BRAF space. But I think the biology is probably much different from things like EGFR and ALK.

Corey Langer, MD:

Anything to add, Lyudmila or Aaron, for BRAF?

Lyudmila Bazhenova, MD:

Yeah. Just the one important thing is to be aware, what is that mutation, right? So far we haven’t specified it yet, but we are talking about BRAF V600E primarily. We don't know what to do with non-V600E mutations, and there are a couple of interesting clinical trials ongoing. But it is important to also know what BRAF mutation you have discovered.

MET

Corey Langer, MD:

Okay. Aaron, cMET.

Aaron Lisberg, MD:

Yeah. So obviously we have two drugs that have been approved there for a while: capmatinib and tepotinib. Data's pretty similar between the two, so it's a discussion with the patient. I'm typically using capmatinib just because I'm more familiar with the drug.

Corey Langer, MD:

HER2, exon 20, Lyudmila, I guess we’re going to cover that to a little extent when we go to ADCs, but if you can talk about that.

Lyudmila Bazhenova, MD:

Yeah. So, out of the mutations that we have discussed to this point, this is a mutation which does not yet have an FDA-approved therapy. So when you look at the HER2 you have to understand, is it a mutation? Is it amplification? Is it overexpression? Because they do mean different things. So HER2 exon 20 insertion happened at approximately 2% of the patients. They are targetable, and the best data we have is for T-Dxd, which is an antibody drug conjugate, which was used in second-line for patients with HER2 Exon 20 insertion and have an excellent response rate and responses appear to be durable. At this point, again, there are no approved agents. We have tried doing clinical trials with tyrosine kinase inhibitors, doing clinical trials with just a monoclonal antibody like Herceptin, and efficacy is just not there. So at this point it would be very important if we have access to a clinical trial to try to get  to HER2, or transfer them up trastuzumab deruxtecan for those patients if you can. But I cannot wait until the drug gets approved because I think it looks very promising.

Corey Langer, MD:

So you would use it frontline or second-line, Lyudmila, and we'll go around the board?

Lyudmila Bazhenova, MD:

Right now I'm using it in second-line, but I'm opening a first-line trial. So as soon as the trial is open, I will be using it in first-line.

Aaron Lisberg, MD:

Yeah, I actually, exactly the same. I'm also opening a frontline trial, and that's where I'll be evaluating, but yeah, that's how I'm approaching it right now.

Corey Langer, MD:

Misako, same question: frontline, second-line, agnostic?

Misako Nagasaka, MD:

Currently second-line, but yes, I'm also opening DESTINY Lung04, so we'll see. Interestingly, the study is comparing it with carbo, the 189 regimen. So that'll be really interesting to see.

KRAS G12C

Corey Langer, MD:

And finally, of course, KRAS G12C, how can I forget? Aaron, we’ll go to you first and then around the board.

Aaron Lisberg, MD:

Sure. So definitely second-line approach there with sotorasib, you know, additional data came out at ASCO with adagrasib, not approved yet. Data looks similar but I am using sotorasib in the second-line setting for my patients with KRAS G12C.

Corey Langer, MD:

And response rates are in the 30%, 35% range?

Corey Langer, MD:

PFS of what is it, about 6, 7 months.

Aaron Lisberg, MD:

Yeah.

Corey Langer, MD:

Not terribly overwhelming, but at least somewhat active.

ALK

Corey Langer, MD:

Anything to add about mutations before we segway to fusions? Nope. I guess we've covered it all there.

Corey Langer, MD:

So, Aaron, you were chomping at the bit: ALK -- how do you deal with it, and what do you do when the first-line treatment fails?

Aaron Lisberg, MD:

Yeah, I mean, I think we have a lot of options there. I haven’t had an new patient, most of my patients have been historical, but my go-to has been alectinib.  The data with some of the newer agents looks good. Lorlatinib is what I usually use in the resistance setting, but it does have that unique neurotoxicity, which can become troublesome. And so that's why I haven't moved that into the front line of my practice.

Lyudmila Bazhenova, MD:

I think lorlatinib updated their data on AACR, and the PFS curves look stunning. So I, at this point, still using alectinib. But the more I look at the data, the more I'm opening up to an idea of using lorlatinib, and the main concern that we always have with lorlatinib is the CNS toxicity. And I think as I experience more of lorlatinib for my second-line patients, I think I'm getting more comfortable with the CNS toxicity and I am seeing it less than what is reported in the clinical trial. Maybe I’m just lucky the same way you were lucky with BRAF patients who are doing very well. But I think the jury is still out on what is the best ALK drug. We know what's the wrong ALK drug for everybody, and the wrong ALK drug would be crizotinib, because we have every single second-generation TKI has overcome the crizotinib in efficacy.

Corey Langer, MD:

Of course, crizotinib is not really an ALK drug. It started out as a MET inhibitor and just serendipitously seemed to have activity in ALK. So, Misako, tell us what we're going to be doing down the pike.

Misako Nagasaka, MD:

For ALK?

Corey Langer, MD:

Yes.

Misako Nagasaka, MD:

I did have exposure to lorlatinib on a clinical trial and also on the expanded access program. So, perhaps my comfort level of using lorlatinib is different than, maybe, the community oncologist. I do agree that it's not for everyone. I would not use it on a patient who lives alone or if the patient has a job that requires quick thinking.

Misako Nagasaka, MD:

But not everyone develops CNS toxicities as well and the 3-year follow-up data of lorlatinib looks fantastic. It looks much better compared to the alectinib and brigatinib data. So I worry about the missed opportunities for these patients, potentially. So I think all of us would probably consider making a switch if and when we get the median progression-free survival as a concrete number, like if we're told it's 60 months versus 25, 24 months, you're probably going to choose lorlatinib. But until we get that median, I think it's going to be difficult. But I have a feeling that the median's going to take at least a couple more, if not several years to get there. And I just worry about the patients that may not have toxicities from lorlatinib may benefit from long-term use of lorlatinib if we're not giving them a chance to challenge on it. We might be missing an opportunity.

ROS1

Corey Langer, MD:

ROS1, Aaron?

Aaron Lisberg, MD:

Yeah. So that's an area where I really haven't had a patient recently. Obviously, crizotinib is historical there, but I think there's been emerging data with ceritinib  and entrectinib. So I don't know where I would go, honestly, with my initial choice. I'd be interested to hear what others would do in that setting.

Lyudmila Bazhenova, MD:

I tend to favor entrectinib over crizotinib, just because at least this drug has more data on CNS coverage and CNS protection, and because those patients do live longer. I think natural history of the disease is that eventually they will have a CNS metastasis, even if they didn't have it at the beginning. And I think also, in my personal experience, the toxicity of entrectinib is a little bit better than toxicity of crizotinib, mainly as it pertains to lower-extremity edema, which is very difficult to handle. And I think the nausea, in my opinion, is a little bit worse with crizotinib. Again, my personal bias is to use entrectinib for my ROS1 patients.

Misako Nagasaka, MD:
So  I've always had ROS1 clinical trials, so I try to put them on the clinical trials that I have. Outside of clinical trials, I would probably favor entrectinib over crizotinib or ceritinib.

Corey Langer, MD:

My institution, crizotinib still probably favored, although certainly it's the patient presents with brain metastasis, or that's a worry that they'll preferentially get entrectinib again, we're at the level of anecdote. But I’ve encountered more toxicity with entrectinib, so still using crizotinib, the response rates for both are phenomenal - in the 70% or so range. The original PFS, I think, reported by Alice Shaw was on the order of 19 months. I truly think it's a bit of a toss-up.

RET

Corey Langer, MD:

Aaron go back to you, RET.

Aaron Lisberg, MD:

Yeah. So in that setting, we have two approved drugs: selpercatinib and pralsetinib. I'm typically using selpercatinib, again, the data looks pretty similar between the two. I think it's more of an experience thing, familiarity and first to market, but that is what I'm using and I've had good experience with the drug.

Lyudmila Bazhenova, MD:
Ah, same as Aaron. I was involved with selpercatinib trial and kind of stuck with the drug once it got approved. I have talked to many physicians who have pralsetinib clinical trial open when it was developed, and they are using pralsetinib primarily over selpercatinib. It's just a matter of what experience you have. And I don't think it matters which drug you use as long as you use it.

Corey Langer, MD:

They look almost interchangeable. Again, it was the first approved and I've typically been using selpercatinib. Here's an example of a designer drug that far exceeds the dirty kinase inhibitors in the same setting. When you go back to vandetanib, cabozantinib, other drugs that have been used, the gulf and response rate and progression-free survival between the established agents and the prior agents is, it looks like the Grand Canyon.

NTRK

Corey Langer, MD:

Finally, NTRK. Misako, I am waiting for my first N-TRK fusion-positive patient. Have you seen any?

Misako Nagasaka, MD:

Clinical trial, so, I put her on that study. So I have not actually used larotrectinib or entrectinib for a TRK patient. But, it is quite rare.

Lyudmila Bazhenova, MD:

I haven’t seen a lung cancer patient which is N-TRK-positive.

Aaron Lisberg, MD:

Nope. Haven’t seen one yet.

Corey Langer, MD:
Before we finish up with ADCs, anything else in the targetable area, conventional targets?

Lyudmila Bazhenova, MD:

We can talk about emergence of the NRG fusion as a target.  I don’t know, Misako if you know more about it, It's an emerging fusion, it's an NRG fusion. They're very, very, very rare in lung cancer, even much more rare than N-TRK fusions. And there are some drugs which use HER3 as pathway, which has activity. And there was a presentation at ASCO seribantumab with a response rate in the order of about 30%, 40%. PFS is not yet known, so something to watch out for.