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HER2 Overexpression in NSCLC: From Testing to Treatment

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Released: August 26, 2026

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The landscape of HER2-positive NSCLC has evolved to encompass HER2 mutations, HER2 gene amplification, and HER2 protein overexpression—distinct alterations that require different clinical management approaches. In this commentary, experts discuss the nuances of biomarker testing for HER2-mutated and HER2-overexpressing NSCLC and share how they currently approach treatment selection and sequencing.

Benjamin Levy
Benjamin Levy, MD, FASCO
Helena Yu
Helena Yu, MD
HER2 Overexpression NSCLC

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Key Takeaways
  • HER2 IHC 3+ overexpression is distinct from HER2 mutation and amplification and identifies an actionable treatment opportunity using trastuzumab deruxtecan in patients with advanced NSCLC.
  • HER2 IHC testing requires an adequate biopsy specimen and coordinated planning among oncologists, pulmonologists, interventional teams, and pathologists to obtain sufficient tissue for both genomic profiling and IHC.
  • For patients with active brain metastases, multidisciplinary consultation with radiation oncology is essential to guide the use of HER2-directed systemic therapy, radiation, and close CNS monitoring based on lesion size, location, and symptoms.

Making HER2 Overexpression Actionable in NSCLC
Helena Yu, MD
For many years, our understanding of HER2 in non-small-cell lung cancer (NSCLC) centered primarily on genomic alterations. That landscape has changed. HER2 overexpression now represents an actionable biomarker in its own right, creating another treatment opportunity for patients who may otherwise have relatively limited options after progression on standard therapy. For me, the practical message is straightforward: we will not find HER2 overexpression if we do not look for it. As treatment options expand, we need to ensure that our testing workflows evolve alongside them.

HER2-Positive NSCLC Is Not 1 Entity
Helena Yu, MD
One of the first distinctions I make when discussing HER2-positive NSCLC is that “HER2-positive” can mean several different things. We may be referring to a HER2 mutation, HER2 gene amplification, or HER2 protein overexpression. These biomarkers are related biologically, but they are not interchangeable in terms of how to manage them. HER2 overexpression is assessed by immunohistochemistry (IHC). Strong, complete membrane staining in greater than 10% of tumor cells constitutes IHC 3+ disease. Of importance, HER2 overexpression can also coexist with other oncogenic drivers, unlike HER2 exon 20 mutations, which are typically mutually exclusive.

That distinction has direct therapeutic implications. In patients with HER2 IHC 3+ solid tumors who have received prior systemic therapy and do not have satisfactory alternative treatment options, T-DXd provides an approved treatment option. The DESTINY-Lung01 and DESTINY-PanTumor02 data support meaningful activity in HER2-overexpressing disease, with the greatest benefit observed among tumors with IHC 3+ expression. However, responses in previously treated HER2-overexpressing (IHC 3+) NSCLC appear less durable than those in HER2-mutant disease, with an overall response rate (ORR) of 53% and median duration of response of 6.9 months in DESTINY-Lung01 compared with an ORR of 50% and median duration of response of 12.6 months in DESTINY-Lung02.

HER2 Alterations: When and How to Test
Benjamin Levy, MD
Testing is critical. For all of my treatment-naive patients, I try to get tissue genotyping that includes both DNA and RNA concurrently with liquid biopsy. There are data to support that the addition of liquid biopsy to tissue biopsy with initial testing is more likely to capture alterations of interest compared to just doing tissue alone. For the past year or so, I have also started testing for HER2 overexpression via IHC during this initial testing in the frontline, treatment-naive setting. Another option is to test for HER2 overexpression at the time of resistance, but I prefer to have all the information upfront for the relevant IHC results, including PD-L1, MET, and HER2.

There are sometimes cases where HER2 IHC was not tested upfront. This could be that the patient got their first line of therapy 3 or 4 years ago, before testing for HER2 overexpression was clinically relevant, or sometimes there is not enough tissue sample, and we have to prioritize PD-L1 status for frontline therapy. In these cases, it is important that we still do a tissue sample at progression for IHC testing. This is very important because we have a drug now, T-DXd, that is approved for the IHC 3+ patient population, so we need to know who is eligible for what before making treatment decisions at progression.

This is also where collaboration with pulmonologists becomes essential. Tissue acquisition is no longer simply about establishing that a patient has lung cancer. We need enough high-quality tissue to support increasingly complex biomarker testing. That requires communication before the procedure about which lesion to biopsy, how much tissue is needed, and how the specimen will be allocated. For pulmonologists, obtaining adequate tissue can directly influence the number of treatment options available later. For oncologists, we need to communicate those needs clearly and resist assuming that a negative or incomplete molecular report tells us everything we need to know.

Helena Yu, MD
Absolutely. You will not find it if you do not look for it. We are following a similar testing sequence where we try to test everyone with next-generation sequencing upfront with tumor tissue and liquid biopsy. We can sometimes run into tissue allocation issues, so sometimes we do not get HER2 or MET IHC on everyone upfront, but certainly at progression if we are unable to do so with the first sample. It is not reflexive at my institution yet, but I am hoping that it soon will be because I think having that information upfront really allows us to be more seamless about subsequent treatment options.

Treatment Sequencing in NSCLC With Activating HER2 (ERBB2) Mutations
Benjamin Levy, MD
As of August 2026, it is hard to argue against using zongertinib as a frontline option for patients with unresectable or metastatic nonsquamous NSCLC harboring HER2 TKD–activating mutations. Its frontline approval was based on the phase Ia/Ib Beamion LUNG-01 trial, which demonstrated an ORR of 76%, with 64% of responders maintaining a response for ≥6 months. We know this drug also yields responses in the brain and is well tolerated. I look forward to seeing the results from the phase III DESTINY-Lung04 (NCT05048797) trial evaluating first-line T-DXd vs standard-of-care therapy in patients with HER2 exon 19 or 20–mutated, unresectable locally advanced or metastatic nonsquamous NSCLC.

The more challenging question is what I do after frontline therapy. We do not have much data on sequencing T-DXd after zongertinib, whereas we do have data on sequencing zongertinib post T-DXd. Nevertheless, I think it is not an unreasonable strategy to move towards an antibody–drug conjugate like T-DXd that also targets HER2 20 insertions following progression on zongertinib. Chemotherapy is another option. One thing I would not do following progression on zongertinib is start an alternative TKI like sevabertinib. I get many questions about whether you can sequence these 2 TKIs from the community, and at this time, I would probably not do that.

Helena Yu, MD
My approach is quite similar. Zongertinib is first. It is an active oral agent, well tolerated, and has good CNS penetration. I tend to use T-DXd following progression on frontline zongertinib as well. Although there are currently not much data on this sequence, if there is not full cross-resistance between T-DXd followed by zongertinib, you would assume that the converse is true as well. This is an important gap in information that we, as a community, need to answer in the coming years.

If somebody has active progressive brain metastasis, does that change your choice of HER2-directed therapy?
Benjamin Levy, MD
In this scenario, I would have a consultation with a radiation oncologist and have that conversation with the patient as well. I have been encouraged by the CNS responses I have seen with zongertinib—47% intracranial response. Now, this may not be as meaningful or durable as some of the other genotype-directed therapies by cross-trial comparison and my own anecdotal experience, but a response rate of greater than 40% is still certainly clinically meaningful. Again, it highlights and underscores the importance of your discussion with the radiation oncologist.

The only other thing I would like to add is that I have seen a number of patients with HER2 mutations, and I have been encouraged with the intracranial responses I have seen with T-DXd as well. In my clinical experience, I have seen real, meaningful, durable responses in the brain. Whether you are using zongertinib or whether you are using T-DXd in a patient with active brain metastases, you have to work closely with the radiation oncologist. My radiation oncologist will always ask, Do you have anything that can cross the blood–brain barrier here? So, there is an education piece; I have to educate them on the intracranial activity the same way they have to educate me on what type of radiation they are going to use. It is a discussion that helps to inform and make these decisions in real time.

Helena Yu, MD
I think having that discussion upfront with the radiation oncologist is always helpful. Is the lesion in an area of the brain that is really important for a certain function where, if this grows a millimeter, are we going to lead to symptoms for our patient? In those cases, they are especially helpful in guiding us. Sometimes we have done radiation upfront to try to eradicate that site and prevent any neurologic morbidity. But I feel like I have the same comfort level as you, Dr Levy. For a lot of our first-line systemic therapies, even chemotherapy plus immunotherapy, for many people, if they are asymptomatic and their lesions are small, doing a short interval brain scan in 6-8 weeks is not dangerous for the vast majority of patients and allows us to save radiation for salvage later. I do try to do that if at all possible.

HER2 IHC 3+ Can Open an Important Treatment Door
Benjamin Levy, MD
It is really important to get this information upfront if you can. If a patient with no genomic alterations but HER2 IHC 3+ progresses on chemotherapy or chemoimmunotherapy, this is where I would leverage T-DXd. This is not a large subset of patients, but when you do find it, it is important as a second-line option.

Helena Yu, MD
I do feel like it is a good thing when I find HER2 IHC 3+ after chemoimmunotherapy because, for our patients who do not have actionable gene alterations, we have pretty limited options right now. Although conventional chemotherapy such as docetaxel remains an option after progression on platinum-based therapy, its modest response rates and limited progression-free survival make it less attractive when an effective HER2-directed therapy is available. This is why I think it is very important to advocate for HER2 IHC testing in our workflow. If we do not test for it upfront, we might not have that information when we need it.

I am also excited to see results from ongoing trials that will better define the role of HER2 overexpression in the NSCLC treatment landscape and evaluate HER2-directed therapy in earlier lines of treatment. For example, DESTINY-Lung06 (NCT06899126) is evaluating T-DXd plus pembrolizumab as first-line treatment for patients with unresectable, locally advanced, or metastatic HER2-overexpressing (IHC 1+, 2+, or 3+) nonsquamous NSCLC and PD-L1 tumor proportion score <50%. For now, however, these studies do not change the standard first-line treatment approach, making it especially important that we identify HER2 IHC 3+ disease so that we can leverage this option when it becomes appropriate later in the treatment course.

Looking Ahead
Helena Yu, MD
HER2 overexpression adds another layer to precision medicine in NSCLC. We are also studying HER2-directed strategies earlier in the disease course, including trials evaluating T-DXd-based approaches across broader levels of HER2 expression.

There is still much to learn about optimal sequencing, resistance, and how expression may evolve. But we already have an actionable message for today's practice: comprehensive NSCLC biomarker assessment increasingly requires us to think beyond genomic alterations alone. For patients whose tumors are HER2 IHC 3+, identifying that expression may reveal a meaningful therapeutic option. Making that happen requires adequate tissue, thoughtful pathology workflows, and close multidisciplinary communication.

Your Thoughts
How has HER2 IHC testing been incorporated into your NSCLC workflow? Do you routinely obtain HER2 expression results by IHC at diagnosis, or do you reserve this testing for patients with disease progression? Join the conversation by answering our poll and leaving a comment.

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When do you typically test for HER2 overexpression by IHC in patients with advanced NSCLC?

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