Drs. Joshua Sabari, Alfredo Addeo, Julia Rotow, and Helena Yu examine evolving treatment sequencing strategies for HER2-mutant non-small cell lung cancer (NSCLC), focusing on zongertinib, sevabertinib, and trastuzumab deruxtecan (T-DXd). They examine the rationale for using HER2-directed TKIs in the frontline setting, followed by T-DXd, while considering how mutation subtype, prior treatment, and patient preferences may influence therapy selection. The panel also explores the uncertain role of immunotherapy in HER2-mutant NSCLC, particularly among patients with different smoking histories and PD-L1 expression levels. They emphasize the continued role of chemotherapy in later treatment lines and the need for additional evidence to establish optimal sequencing and better understand resistance mechanisms.

Transcript:

Dr. Sabari:  So, thinking about the landscape, we just heard about zongertinib, FDA-approved in the frontline setting with an accelerated approval. We have the Beamion-LUNG 2 study ongoing, which you mentioned. That’s the randomized Phase 3. We also have a label for sevabertinib approved in the frontline, and there’s a SOHO-02 ongoing Phase 3 study.

We just talked about DESTINY-Lung04 with trastuzumab deruxtecan. Alfredo, you brought up this idea of sequencing, right? So how are you sequencing these agents? Is there no longer a role for chemotherapy and immunotherapy in patients with HER2-mutant non-small cell lung cancer? Let’s imagine that in Switzerland all these were approved. How would you sequence these agents? And I apologize if you’re getting in trouble with the regulators here.

Dr. Addeo: No. Hopefully they will not watch it. Now, jokes aside, I think the more the better. So if we have all the drugs, it’d be even better. I think the obvious thing is, of course, patient discussion. I’ve had many patients who are not happy to have IV treatment. I don’t know whether it’s something in Switzerland, but they’re more likely to go for oral than for IV.

Dr. Sabari: Yeah, that’s the same thing I see in my practice. Patients prefer that.

Dr. Addeo: Irrespective of the other stuff, the first thing is the route of treatment. Is it IV? So oral plays a major role because they think they can get on with their lives easier. That’s the first thing. The second thing is always going to be driven by the data. Going back to trastuzumab deruxtecan and the data we’ve seen so far, it seems that all the TKIs we have are more effective when the patient hasn’t received T-DXd yet. The overall response rate was higher if the patient hadn’t received T-DXd.

So that would perhaps be the first option to use. I would, of course, consider trastuzumab deruxtecan. Now, going back to chemo-IO, I’ve got to be honest with you, I’m not a great fan of immunotherapy in HER2-mutated lung cancer, particularly because they quite often are never smokers, and I don’t necessarily believe that immunotherapy in never smokers makes an impact.

So I’m more about chemotherapy, which will be part of it at some point. If I have to pick the right sequence, that would be more a TKI, then trastuzumab deruxtecan, and perhaps some chemotherapy.

Of course, if you have a trial, a trial would be perfect. Perhaps there’s going to be a role for mutations, and the type of mutation they have might play a role. Where there’s a TKI-specific mutation in the kinase domain, that would push me toward a TKI. Where there’s not a mutation in the kinase domain, that would push me more, perhaps, to even discuss trastuzumab deruxtecan first line. That would be an option.

Dr. Sabari: Yeah, I think you hit a nerve with the role for IO in the frontline setting. I think in academia we’re all on the same page that maybe there’s not a significant role for PD-1 or PD-L1 inhibitors in the frontline setting. But we know in the community, chemo-IO is still very commonly used in this setting.

Helena, is there any rationale for that? We know that 30% to 40% of patients with HER2 mutations are smokers. What would you think about the role of IO in this setting?

Dr. Yu: I think it’s unknown. I see HER2 and probably BRAF mutations as a little bit more bimodal, right? Where there is definitely a subset of patients that are similar to our EGFR and ALK patients, younger, never smokers. And then there is another subset that has a higher smoking history or more significant smoking history.

So I don’t have data for this, but it would be nice to layer on smoking signatures to see where things fall. Because I do think there is a subset of patients with HER2-positive lung cancer that might benefit, although the majority probably do not. So I think more to come there.

Dr. Sabari: I agree with you. I think in a younger patient, never smoker, I would tend to think about using a TKI in the frontline setting. But remember, there are ongoing studies in the frontline comparing to chemo-IO. Based on the data we have so far, it looks very promising. Julia, PD-L1 expression, does that factor into how you think about frontline treatment in this patient population? Or like EGFR, do you go with the driver mutation and use the TKI upfront?

Dr. Rotow: Yeah, and I agree. I think the control arm of DESTINY-Lung04 was interesting for its outcomes. The PFS in the eight-month range and response rate in the 40% range were very similar to the kinds of response rates we see in the broader lung cancer population with chemoimmunotherapy.

And that, to me, didn’t run entirely along with our concerns about IO and HER2, because I share those concerns where this seems to be often a nonsmoking-associated patient population where we worry about the efficacy of immunotherapy.

So I agree, never give immunotherapy monotherapy in these patients. And I’m not typically using PD-L1 to heavily make my choices. I think the HER2-directed treatments and chemotherapy are very much our first and second go-to strategies for these patients.

In DESTINY-Lung04, we could see it’s consistent with a lot of the HER2 population. Most were PD-L1 low, so the majority were actually PD-L1 negative, and then the next subset was PD-L1 low. Very few were PD-L1 high, and the majority also had no history of tobacco use. And despite that, we still saw that PFS in the eight-month range.

So I have to say, in my own clinical practice, I’ve often included immunotherapy with chemotherapy, not first line, not second line, but when I eventually give chemotherapy, I’ll often add immunotherapy on top of it just in case of benefit. And with the outcomes of DESTINY-Lung04, though it wasn’t the primary focus and it does not truly answer the question, it does make me feel good about maybe including that at some point in my patient’s course just in case.

Dr. Sabari: Yeah, that’s my practice as well. Use a TKI upfront, zongertinib, for example, then trastuzumab deruxtecan, and it’s great to see that you have activity post-TKI, a different mechanism there. And I agree with you. I think in the later line, maybe third line, I would use outside of a trial chemotherapy or chemo-IO. Curious if your practice pattern is different, Helena, there.

Dr. Yu: No, I think that we have to also say, from Beamion and SOHO, we have the data of T-DXd first, then TKI. We assume that the converse is true, right? That TKI then T-DXd will have similar activity. But I do think we need to generate those data and better understand mechanisms of resistance. Yeah, I would say that I sort of follow that phenotype, and I think for people who are never smokers, Asian, younger, I’m not opposed to giving immunotherapy, but I don’t always.

Dr. Sabari: Yeah. Alfredo, your practice?

Dr. Addeo: Yeah, same. And I would say that for the vast majority, just chemotherapy. There’d be a few cases where I’d have the discussion, and as I didn’t have anything else to offer, we’d say, “Okay, fine, I’ll add the immunotherapy,” without, to be honest, being particularly confident about the added value.