Drs. Joshua Sabari, Alfredo Addeo, Julia Rotow, and Helena Yu highlight emerging resistance mechanisms to HER2-directed therapies in non-small cell lung cancer (NSCLC), including acquired HER2 mutations following treatment with targeted TKIs and antibody-drug conjugates. They emphasize the importance of tissue rebiopsy and comprehensive molecular testing at progression to identify resistance mechanisms that liquid biopsy alone may miss. The panel also explores future treatment strategies, including combining HER2-directed TKIs with chemotherapy or ADCs, while discussing how these approaches could improve treatment durability and CNS outcomes. They conclude with practical recommendations for managing treatment-related toxicities, including interstitial lung disease, diarrhea, and liver enzyme elevations, and highlight the importance of upfront molecular testing to guide therapy selection.
Transcript:
Dr. Sabari: So, really interesting discussion so far. I want to bring up resistance mechanisms, which you talked about, Helena, and how important they’ve been in how we think about later lines. You talked about the SAFFRON data just recently with MET.
For patients with HER2 mutations who are treated with HER2 TKIs or even HER2 ADCs, what are you doing at progression? What are the common resistance mechanisms to the HER2 TKIs? And then how does that affect how you think about sequencing these agents? Or is it not yet prime time?
Dr. Yu: I think we’re still learning. The earliest data are just coming out. I think mechanisms of resistance to ADCs are particularly challenging, right? Because you can have mechanisms of resistance to the antibody and to the payload. And so that needs to be further fleshed out.
For the TKIs, we’re seeing second-site HER2 mutations. But I think the challenge there is that some of those second-site mutations, say that we get on zongertinib, might be sensitive to sevabertinib, right? So I think we still have to sort that out, but happy to hear what other people’s impressions are.
Dr. Sabari: Julia?
Dr. Rotow: Yeah, I agree. We’ve seen some data beginning to emerge looking at HER2 TKI resistance, and there does seem to be, though not dominant, potential for acquired HER2 resistance mutations, as you would expect, right? You’re binding at the kinase domain. You expect that mutations could block that binding.
Now, there hasn’t been any one that’s emerged as a dominant mechanism. There is a little bit of difference between the two drugs in which mutations emerge because of zongertinib and sevabertinib, just because they do bind differently, which makes sense.
I think right now we don’t know what to do with that in clinical practice. I think routinely we don’t expect to be sequencing TKIs as a standard practice. So, for example, having given zongertinib, I’m not going to give sevabertinib next as my routine.
We may find, if we are identifying any reasonably dominant acquired resistance that is differentially active between the two drugs, there might be a small population of patients where a sequencing strategy could become useful in clinical practice. And I expect as we have more and more people being treated with these agents, we’re going to get a much more robust understanding of the true resistance profile.
Dr. Addeo: Yeah. I just want to add that I think it’s essential we keep doing biopsies also to learn. I don’t know whether you have ever seen this before, but we also do biopsies for other oncogene alterations. And because we want to look at resistance mechanisms, I’ve ended up finding small cell lung cancer. I have no idea about the HER2 experience, but I’ve had some in other oncogenes, not just EGFR and ALK, which is something I wasn’t expecting.
So the reason why I’m bringing this up is that when we say liquid biopsy is fine, if we can, we should also go for tissue, which will provide a lot of information that we would miss if we just go for the liquid biopsy. And so we need to learn as much as possible.
Dr. Sabari: Yeah, Alfredo, this is a great point that liquid biopsy can miss a lot of resistance mechanisms, including histologic transformation. Helena, you’ve done a lot of work looking at small cell and squamous transformation in EGFR. I think that’s not really been clearly defined yet in the HER2 space.
But it is interesting that in two presentations at the World Conference on Lung Cancer just a few months ago, we didn’t see any dominant resistance mechanism emerge for either zongertinib or sevabertinib. So I think we really need to learn more, and I agree with you, rebiopsying patients, getting tissue, and doing tissue NGS is important.
Julia, what’s your rebiopsy rate in practice? You’re in academic practice. Is it 100%, 50%? And I know in the community, when I talk to community oncologists, it’s very hard to biopsy patients again. It delays care. So how are you integrating that into your practice?
Dr. Rotow: Yeah, this is relevant across many of our patient populations with lung cancer, so EGFR, HER2, and potentially others. Really anywhere I think that I may be seeing acquired resistance that may lend itself to selection of next-line therapies in a more personalized, biomarker-directed fashion. So in HER2, I think at least the preclinical and some early emerging clinical data suggest that these resistance alterations potentially could be actionable.
I do expect to be rebiopsying these patients. I have a fairly high rebiopsy rate. We’re an academic practice. We’re often very motivated to try to understand this resistance, and of course, we want to offer our patients every possible effective line of treatment. So we do tend to run very high in our rebiopsy rates, which I’m happy about.
And I hope that’s going to increase as more and more folks throughout the community are also able to see that we can potentially treat effectively for this acquired resistance. I think more to come, but I would encourage it.
Dr. Sabari: Yeah. I want to end in a little theoretical manner. Where do you think we’re going? So looking to the future, in the last two years, we saw the rapid approval of both zongertinib and sevabertinib in the frontline setting. We just discussed trastuzumab deruxtecan as well, for me mainly being used in the second-line setting. Where do you see us, Helena, in the next two to three years? How do we improve upon the successes of the current HER2-directed therapies?
Dr. Yu: Yeah, I would say just to start with where we are now, I agree with you, Josh. I would do zongertinib or a HER2 TKI first, followed by T-DXd, and then really move chemotherapy to the third-line setting. So that’s my treatment paradigm.
I hope that we see improvements. This is the first generation of HER2 TKIs. I know that there are several new ones in development, so we’ll see if they have better systemic efficacy, better CNS penetration. Interesting to think about combinations. Can an ADC and a TKI be combined, or will that lead to too much toxicity? But those would be where my mind went next.
Dr. Sabari: Yeah, interesting. The rate of ILD for TKIs is quite low, sub 1%. We heard for trastuzumab deruxtecan about 20%. But I always think about that too. Can we combine these? Definitely not FDA-approved, and I wouldn’t recommend doing that in clinical practice right now. But I think it’s an exciting question. Right. Alfredo?
Dr. Addeo: The question is whether it should be an ADC or just chemotherapy.
Dr. Yu: Chemo. Like FLAURA2, right?
Dr. Addeo: Exactly. That’s maybe doing a little bit as we’ve done with FLAURA2. Just adding old-fashioned platinum-based chemotherapy.
Dr. Sabari: Right. Improve on the CNS response, improve on the durability, maybe reduce resistance mechanisms and persister clones. Julia, your thoughts here?
Dr. Rotow: Yeah, I completely agree. I think in HER2 now we have multiple tools available to us. I think we can take some lessons that we’ve learned from EGFR lung cancer and hopefully speed up our improvement in outcomes for patients with HER2-mutant lung cancer. And there, I think cytotoxic therapy plus TKI in the frontline setting is very interesting. There’s biological rationale that TKIs and ADCs may have synergistic effects as well.
Of course, in EGFR, we do chemo, but we don’t have an equivalent ADC. We know that now we have something more effective. So I share your interest in understanding, in research settings, whether we can do these types of combinations upfront with acceptable quality of life, acceptable toxicity, but also hopefully improved outcomes for our patients.
Dr. Sabari: Great discussion. To end, any tricks of the trade, things you’ve taken away in the HER2 space with any of these agents? Something, if you were talking to an oncologist in the community, to give them some experience or hope. I’ll start with you, Julia, with trastuzumab deruxtecan. Any nuances that you’ve seen in your practice?
Dr. Rotow: I think it’s a drug where you want to pay attention to toxicity management, right? And you have to remember this is an ADC. There’s a set of toxic components, so be very aggressive with antiemetic management and very aggressive with supportive care. I counsel my patients carefully about these things. I teach and monitor for ILD.
And I think with those measures, patients can be treated successfully for quite some time. We’ve been using this for years in practice with good success for our patients and good clinical benefit. But it is a drug that requires appropriate monitoring and management. So I think that’s a useful tool that we have in our armamentarium now with multiple effective classes of drugs.
Dr. Sabari: Yeah. Alfredo, you get sevabertinib.
Dr. Addeo: Yeah. Any of the TKIs, to be honest. What we need as a message is to get access to the drugs as soon as possible. There are lots of patients out there who need to be treated. We only have limited access at the moment, given the efficacy of the drugs. And I don’t think those drugs are difficult to manage, to be honest, and they are very effective. So the only point now is to get access to them.
Dr. Sabari: Yeah, completely agree. I think for sevabertinib, using prophylactic antidiarrheals upfront can be very helpful.
Dr. Addeo: And it’s something we’re quite familiar with.
Dr. Sabari: Yeah, for sure.
Dr. Yu: And I would just say that compared to drug development in EGFR or ALK, I think we got these initial approvals and very quickly moved them to the first-line setting. So I do think that we had this feeling that we could start chemotherapy and find out about HER2 later.
But I think testing upfront, right? Now that we have these first-line oral HER2 TKIs, knowing that someone’s HER2-positive upfront really becomes critical because we know that there’s significant drop-off between lines of therapy, and we really want those people to get a HER2 TKI upfront.
Dr. Sabari: Yeah. And I’m thinking of a recent case in my clinic, a young woman who was very symptomatic when she came in. We didn’t have NGS back yet. I’m not at one of the premier academic centers, right? It doesn’t come with the patient. So we started chemotherapy. We started carboplatin and pemetrexed, and we did not use pembrolizumab, like Alfredo mentioned.
And once I got the results back that she had a HER2 exon 20 YVMA mutation, I very quickly transitioned her to zongertinib. And there are clear NCCN guidelines that if you identify a driver, you can transition a patient to the correct appropriate therapy. So I think this is an important thing to think about.
My own experience with zongertinib, I think you do need to monitor the LFTs closely. So every two weeks for the first 12 weeks because you do see a slight bump in the AST and ALT. It’s manageable, but I think it should be looked at very closely.
And then overall, it’s a very well-tolerated medicine in practice. So with that, I want to thank you guys for joining us. It’s been an exciting ESMO 2026. A lot happening in the targeted therapy space.
I guess the one takeaway is that if you don’t test your patients, if you don’t do broad-panel tissue-based NGS, so plasma is insufficient in 2026, your patients can’t benefit from all these amazing advances in the targeted therapy space. So thank you for joining us.
