Patti: [00:00:00] HER2-positive represents one of the most consequential advances in thoracic oncology in recent years. Yet, this lung cancer remains one of the least understood by patients and clinicians alike. Hello and welcome. I'm your host, Patti Tripathi.
I have no disclosure or conflict of interest to report. Please welcome Dr. Christine Lovly, MD and PhD, who is the division chief of thoracic medical oncology at City of Hope Cancer Center in Duarte. Dr. Lovly is an internationally respected expert of lung cancer and a physician scientist whose research has helped advance targeted lung cancer treatments and other options for patients worldwide.
Welcome, doctor.
Christine: Thank you so much for having me today
Patti: And please explain what distinguishes HER2 positive non-small cell lung cancer.
Christine: Yeah, and I think this is a really important to segue to say, what [00:01:00] is HER2?
And we could spend a lot of time on this, but I'm gonna say right off the bat, this is really confusing, because we can use HER2 as a biomarker in lung cancer as both a DNA biomarker, HER2 mutations, and as a protein biomarker, HER2 positive, and they tag to different drugs. What we are largely gonna talk about today is HER2 mutant lung cancer, which is where there is a mutation in the DNA that confers sensitivity to targeted therapies in lung cancer.
But I wanna immediately say this is confusing because there's multiple ways we can actually test for HER2, both at the DNA level and the protein level, and they tag to different drugs. HER2 mutations occur in 5% or less of non-small cell lung cancer, but are very important to detect because they help direct us to specific targeted therapy options for our patients.
Patti: Okay. Joining us from Houston is Nicole Field, and she is going to shed some insight from a patient perspective. Nicole, you were experiencing a worsening [00:02:00] cough and fatigue that you initially ignored, and walk us through how you ended up getting gene testing.
Nicole: I finally decided to go to my primary care physician who did an X-ray for me, and then saw that there was something there, a mass, and we did a CT.
So when the CT came back, he referred me to MD Anderson, and at that point, we scheduled my bronchoscopy where they initially did the testing. It took a little bit of time for it to come back, but they did take the tissue they needed to do the testing right off the bat.
Patti: W- what I found very significant when you were telling me about this was that your tumor was about, you know- not golf ball, but baseball-sized Nine stitches But you didn't have many, many symptoms at all.
Nicole: I had a bit of an intermittent cough that had become a little bit worse. I did [00:03:00] have some symptoms, but I was, because it wasn't consistent I kind of blew it off, which was a mistake. I should have addressed it- Mm-hmm ... earlier. And I did notice that I had some slight tightness in my chest and I was feeling a little bit of fatigue, but I was attributing that to potentially my age, you know, with other hormonal fluctuations going on.
Patti: Yeah. You, you're 46, I think, last year.
Nicole: It is 48 now, but when,
Patti: yes,
Nicole: these things were beginning, I was 46, and then diagnosed at 47.
Patti: Dr. Lovly, immunotherapy didn't go so well for Nicole Field after chemotherapy and radiation, she said, for six weeks. Please explain HER2 biology in lung cancer for our listeners and viewers specifically the difference between HER2 mutations, [00:04:00] amplifications, and overexpression, and why these distinctions actually matter when selecting the right therapy.
Christine: Yeah. These are really important questions, and I... Let me zoom out for a second and say the world of treatment of non-small cell lung cancer and HER2-mutated non-small cell lung cancer is beautifully complex in 2026 and beyond as we think about these biomarkers that help us to direct to very specific targeted therapies that we know repeatedly improve outcomes.
So just getting the biomarker testing and understanding the biomarker testing, incredibly important. HER2 is a, is a gene that becomes a protein. The gene is called ERBB2, so that's important to recognize as well because you may see on a biomarker test report ERBB2 or E-R-B-B-2. That is the gene that includes HER2, the protein, and that nomenclature is used synonymously.
So I've actually seen this missed before where someone will see ERBB2 and be like, "Oh, that's not HER2." In fact, it is. And HER2 is a protein that we think about in [00:05:00] multiple cancers, lung cancer, breast cancer, g- gastric cancer. In lung cancer specifically, we think about HER2 in three different ways: DNA mutations- DNA amplification, and protein overexpression.
And each of those has the potential to target or help us to target to different specific therapies. And it gets confusing because the testing is different, then the drugs are different, but it's really important. Let's talk about HER2 mutations for a second. The most common HER2 mutation in lung cancer is something we call HER2 exon 20 insertion.
A lot of words to just describe something that's happening at the DNA level that is what we call an oncogenic driver. It is the gas that is fueling the tumor to grow. It is also the Achilles' heel we use to block the tumor growth. HER2 exon 20 insertions are not the only HER2 mutation. There are also a smattering of other HER2 mutations that can occur as the oncogenes in lung cancer.
Why is this incredibly [00:06:00] important? Because we know repeatedly from multiple different types of oncogenes that if we detect the mutation and we have the availability of a targeted therapy, that we can use those targeted therapies effectively and safely to treat patients, but only if the mutation is detected within that tumor.
HER2 amplification, so a HER2 without a mutation, or HER2 protein overexpression are tagged to different drugs, not these pill therapies that we use for HER2 mutant lung cancer. And we can go as deep in the weeds as this as we'd like to, but the drugs we use, the small molecules, or what we call the TKIs, tyrosine kinase inhibitors, we have a couple of new ones that just came into our pipeline last year.
For HER2 mutant lung cancer, it's drugs zongepanib and sivafeninb are the two that are FDA approved right now. There's another drug, it's called an antibody-drug conjugate that we use for HER2 overexpressed non-small cell lung cancer called trastuzumab deruxtecan. [00:07:00] That is a HER2 antibody that is targeted or conjugated to a, a specific chemotherapy.
This is all a lot of fancy, fancy, fancy, fancy words. Most important message is we have to test for HER2 alterations, DNA mutations, amplification mutations, and HER2 overexpression, and then use that information to help us deliver these very specific drugs that we know can help improve patient outcomes.
Patti: Nicole, you are currently enrolled in a clin- clinical trial, and you went through these TKIs as well and it's called NVL 330. Taking pills twice a day you said. How are you responding to it? And you mentioned that lifestyle change, like exercise, are playing an important role in your treatment journey.
Tell us more about that.
Nicole: I am on NVL 330. It's a trial through NewVant. It's very similar to zolgensma. But the expectation is that the, [00:08:00] it penetrates the blood-brain barrier a little bit better and has some, like, fewer side effects. It is so far working well for me with HER2. You know, it's not going to work forever.
That's the, the problem, that the cancer will eventually become resistant, but hopefully it will wor-work for a long time. It's my last PET scan showed a very big reduction in my SUV numbers. So the tumor is still there on the CT, but it shows that the active cancer the activity is basically cut in half since the last time.
So it's working for me
Patti: for sure. You're remarkably very positive when I to you. Yeah. And this is stage IV, you said. So Dr. Lovly, in individuals with HER2-positive diagnosis often describe [00:09:00] navigating a confusing landscape, as we've just spoken, with limited peer support and few plain language resources.
What are some of the ongoing clinical trials and evolving treatment algorithms that both patients and clinicians should know about right now?
Christine: Yeah. I think this really starts with number one, is make sure that the testing happens. And so we know, you know, even in 2026 Biomarker testing for non-small cell lung cancer is not a hundred percent, and we cannot deliver on the promise of existing or emerging HER2-directed therapies if the biomarker testing doesn't happen in the first place.
So if you're a patient listening or a clinician listening, continuing to reinforce the message of the importance of biomarker testing for non-small cell lung cancer, incredibly important. Specifically with respect to HER2 is making sure that we test both for the DNA changes and the protein level changes, because those can offer patients different [00:10:00] options for therapies.
And understanding the nuances of the report structure is very important as well. Now, it is not up to the patient to say, you know, "What is my specific mutation?" This is a, a conversation you have with the provider and the provider team that you're working with. There's a lot of development going on in this space.
New drugs, what we call next generation drugs, of which the new Valent is one of them. And as we learn more about a target, in this case HER2, the drugs become more potent against that target, more specific against that target, get better ability to get into the brain, as Nicole mentioned. This is what we see repeatedly in non-small cell lung cancer, and HER2 is a great example of that script playing out as well.
And we also have new small molecules like these pill medicines, like Nicole alluded to, but also medicines that are... we call ADCs, antibody drug conjugates, where we target the mutation in a different way, precision [00:11:00] chemotherapy. And both of those approaches are evolving very much in the HER2 space.
Patti: So important foundational thing to mention is that all eligible NSCLC patients receive biomarker testing at diagnosis.
And what barriers often get in the way?
Christine: Yeah, many barriers. I think number one, let's zoom out for a second and say lung cancer is a very heterogeneous disease, and the face of lung cancer is many. So it is not that... You know, we have to put aside the stigma of lung cancer, that only patients who have a heavy smoking history get lung cancer.
No. I see many patients who are never smokers in their thirties with lung cancer. And so, you know, I think some of the stigma gets in the way of actually delivering on the promise of, you know, next new therapies. I think we need to support the lung cancer community very broadly, and you brought up an excellent point before about how do we support patients.
And there are some really amazing lung cancer [00:12:00] advocacy groups to help support patients through their journey. Some of those lung cancer specific, I mean, American Thoracic Society, LUNGevity, Lung Cancer Research Foundation, the GO2 Foundation, Lung Cancer Foundation of America. These organizations that really exist to help lung cancer patients and their family and caregivers to walk this journey together, incredibly important.
Patti: And thank you Nicole Field in Houston and Dr. Christine Lovly in the LA area for your valuable time for Breathe Easy and the American Thoracic Society. I'm Patti Tripathi