Stephen Liu, MD, chief of hematology and oncology at Georgetown University, considers how to sequence zongertinib, sevabertinib, and trastuzumab deruxtecan in HER2-mutant non–small cell lung cancer. He explains how HER2 mutation location, pneumonitis risk, resistance patterns, and future trial eligibility may shape individualized treatment decisions, while emphasizing the need for more sequencing data.
Transcript:
Dr. Liu: Hi, my name is Dr. Stephen Liu. I’m the chief of hematology and oncology at Georgetown University.
Now that sevabertinib has joined zongertinib as an FDA-approved HER2-directed treatment option for patients with HER2-mutated NSCLC, how should clinicians interpret the available data and think about where each therapy may fit in practice?
Dr. Liu: All of a sudden, the frontline space for HER2-mutant lung cancer got a little crowded. We had the accelerated approval of zongertinib and now the accelerated approval of sevabertinib. Both TKIs, a little different in terms of their structure. Zongertinib probably a little more selective than sevabertinib, which is why you see a little more diarrhea with sevabertinib. But the resistance patterns will be a little different, and certainly on paper there are some mutations where sevabertinib could be more effective than zongertinib in terms of acquired resistance. But having two TKIs is certainly a bonus and something that’s welcome for our patients.
When trastuzumab deruxtecan becomes available based on DESTINY-Lung04, which I presume it will be, now we’ve got two TKIs and an ADC available. So how do you approach that problem? How do you make those recommendations? What we’ve learned over time is that zongertinib and sevabertinib both have activity in the non-tyrosine kinase domain HER2 mutations, but really it’s a lot less activity. So they can work, yes, but it’s nowhere near the efficacy that we see in the TKD mutations.
So for a non-TKD mutation, zongertinib and sevabertinib would not be my choice, and in that setting a drug like trastuzumab deruxtecan is something that I would favor. Whereas in the TKD setting, you know, based on primarily that ILD risk with T-DXd, my personal preference would be to start with TKI. We start with TKI. I think I’m very comfortable using T-DXd in the second-line setting over chemotherapy, absolutely.
My fear would be that if someone started T-DXd and developed pneumonitis, would that interfere with their ability to safely receive a TKI? Would that increase the risk of subsequent complications? I don’t know. But certainly it would compromise their ability to participate in clinical trials. And so that price is a little bit high. So until I learn a little bit more about how I can predict the pneumonitis, how we can better manage that, I’m a little concerned about. To me, that probably shifts that more as a second-line drug.
The big question in terms of sequencing really is the impact on resistance. And so what do our actions today do in terms of our consequences tomorrow? And if we start with TKI, is the resistance that we see from those drugs going to facilitate treatment with T-DXd? And vice versa, if we start with T-DXd, can we use TKIs afterwards? We’ve got a little bit of data, which I think is reassuring. But I do think that we need a lot more data in that space.
So as we learn more about resistance, we can craft optimal sequencing. And really, the ideal strategy shouldn’t be, which drug should we give for everybody? It’s, which drug should I give for this patient in front of me? There are probably unique characteristics, and there’s a lot of heterogeneity within HER2-mutant cancers that’ll help us choose the right patient for the right treatment for the patient in front of us.
