HER2-Mutant NSCLC: Frontline Treatment Options and CNS Activity

Drs. Joshua Sabari, Alfredo Addeo, Julia Rotow, and Helena Yu examine emerging frontline treatment options for HER2-mutant non-small cell lung cancer (NSCLC), focusing on zongertinib, sevabertinib, and trastuzumab deruxtecan (T-DXd). They discuss findings from Beamion-LUNG 1 and other early-phase studies demonstrating response rates exceeding 70% in treatment-naive patients, while comparing efficacy, tolerability, and treatment sequencing considerations. The panel also examines the importance of intracranial activity, highlighting encouraging CNS responses with zongertinib and existing evidence supporting T-DXd in patients with brain metastases. They emphasize how differences in toxicity, prior HER2-directed treatment, and CNS involvement may influence treatment selection as additional randomized trial data emerge.

Transcript:

Dr. Sabari:  So let’s dive into the data, right? We have three drugs now, two TKIs: zongertinib, which is a HER2-selective agent. We also have sevabertinib, a HER2 and EGFR exon 20 inhibitor. And we also have trastuzumab deruxtecan, a HER2-directed ADC.

Interestingly, if you look back a year or two ago, we didn’t really have any of these agents in the frontline setting. So this space, HER2 exon 20, has really changed dramatically.

So let’s jump into the data. Julia, maybe I’ll start with you on Beamion-LUNG 1. Talk to me about the data for zongertinib in the frontline setting, and then maybe I’ll get from both of you how that compares and contrasts with sevabertinib and trastuzumab deruxtecan.

Dr. Rotow: Yeah. So we’ve had data now for three different agents in the frontline setting for HER2. We’ve had the data that recently emerged for HER2 ADCs with trastuzumab deruxtecan, and we have the frontline TKI data for zongertinib and sevabertinib here in the Phase 1, but robust, cohorts.

The Beamion-LUNG 1 trial was a multicohort study of zongertinib, which evaluated the TKI both in previously treated patients and also upfront in TKI-naive and frontline treatment-naive patients and looked at outcomes. And I think my takeaway here is that these drugs are very active and they’re well tolerated.

So my real top-line takeaway from this is that we saw objective response rates over 70% if you give these to patients who have not had prior HER2-directed therapies, and a PFS of about 14 months, just over 14 months. So again, seeing durability of effect as well, which is nice in clinical practice.

There are randomized studies ongoing, of course, comparing this to chemoimmunotherapy in the frontline setting. So it’s the Beamion-LUNG 2 trial, and we’re waiting on those results. I think they’re very much anticipated.

Dr. Sabari: Yeah. So zongertinib really, to me, is the standard FDA-approved agent in the frontline setting. Based on the data, it appears to be best in class.

But Alfredo, we also have sevabertinib, right? A HER2 and EGFR exon 20 inhibitor. I know it’s not yet approved in Switzerland, but compare and contrast these agents. How do you think about using one versus the other in your clinical practice?

Dr. Addeo: Good point. I think, of course, we’re going to cross-compare as usual. Even if we shouldn’t be doing it, we’re going to end up doing that because we don’t have an alternative.

And the study was quite similar to the study that was discussed before, so a multicohort study, and overall it showed similar results in terms of efficacy.

If the patient was treatment-naive, of course, the response rate was over 70%. If the patient had been exposed to trastuzumab deruxtecan, because at some point we’re also going to talk about sequencing, the activity is lower. It’s about 35%.

The main difference, perhaps, is not the activity but more the toxicity. So the impression is, because there is also anti-EGFR activity, that diarrhea seems to be slightly higher than what we see with zongertinib. Again, we’re cross-comparing here, but it’s the only thing we can do.

So of course, if we had access to the drug, I would certainly use it with no hesitation. But if I have to choose, I would like to discuss with the patient the pros and cons, including the toxicity profile.

And of course, we’re going to talk about the intracranial activity and whether the patient has already been exposed to another drug like trastuzumab deruxtecan, for instance.

Dr. Sabari: So actually, let’s talk about that, the intracranial activity of the therapies that we have. And Helena, we’ll come to you in a moment on trastuzumab deruxtecan.

How do you differentiate in a patient with CNS metastases if you’re thinking about zongertinib versus sevabertinib? And maybe we’ll hear about trastuzumab deruxtecan as well. What are the data for zongertinib in the CNS, Alfredo, versus sevabertinib?

Dr. Addeo: This is the point. I think if we think about the biological rationale, I would be very surprised if the two drugs don’t have intracranial activity. They’re small molecules, and they seem to have consistent activity, so I think both drugs should have intracranial activity.

Now, of course, we have some data, but we don’t have a dedicated study to assess intracranial activity. It is not the only situation where we don’t have this. Most of the patients perhaps had their brain metastases treated, so it’s difficult to assess.

There seems to be a slight difference in terms of the data. For one drug, we have intracranial activity proven and shown, if I’m not mistaken, zongertinib, where we have it. And for the other, I assume there is activity, but we don’t have a lot of evidence.

So if I have to be guided purely by the data I have, and I have a patient in front of me with brain metastases, if I only have sevabertinib, I will use it. But if I can choose between the two, perhaps I will go with a drug that has proven intracranial activity already.

Dr. Sabari: Yeah. So zongertinib, we’ve shown in two cohorts now in untreated patients some CNS activity in the 40% to 50% range. For sevabertinib, we haven’t really seen robust data for active, untreated CNS metastases.

But Helena, what about trastuzumab deruxtecan? That’s an ADC that’s been around for quite a bit, commonly used in practice in the community, both in breast cancer and other cancers.

How does that fit into this space? It was a drug I was mostly using in the second-line setting. How do you compare and contrast the data in the frontline? We have the world expert here, Julia, but I’ll go to you on this, Helena.

Dr. Yu: Sure. I think the one thing to say out loud first is that this population, patients with HER2-positive lung cancers, has a very high incidence of brain metastases, right?

So I think we bring this up because it’s highly clinically relevant. And really understanding which of these drugs has the best brain penetration is going to impact or influence our choice. And so obviously, I agree. I think having that data is really crucial.

I think with T-DXd, we have some of that data. We know from breast cancer they’ve had some specific studies looking at CNS penetration and activity in breast cancer. And then we also have some data from DESTINY as well.

So I see that despite being an ADC and a larger, bulkier molecule, I do think that there is brain penetration there as well.

So I would put zongertinib and T-DXd as drugs where, if somebody has small asymptomatic brain metastases, I would consider starting systemic therapy and doing a short-interval scan. It’s not a targeted therapy where I would say, “Oh, I have to treat this with radiation first.”

Dr. Sabari: Completely agree. I feel very confident and comfortable watching small asymptomatic brain metastases, no vasogenic edema, and they’re not on steroids. I completely agree. I think that fits in that EGFR paradigm.