What Advanced Practitioners Need to Know About HER2 (ERBB2)-Mutant Non–Small Cell Lung Cancer: A Case-Based Approach


Last Updated: Thursday, September 28, 2023

Stephanie McDonald, FNP-BC, AOCNP, Narjust Florez, MD, and Sarah Tangerini, FNP-BC, provide an introduction to the diagnosis, staging, molecular testing, and management of HER2 (ERBB2)-mutant non–small cell lung cancer.



Stephanie McDonald, FNP-BC, AOCNP

Dana-Farber Cancer Institute


Narjust Florez, MD

Dana-Farber Cancer Institute

Sarah Tangerini, FNP-BC

Dana-Farber Cancer Institute


Stephanie McDonald: Welcome everybody to this virtual roundtable about HER2-mutant non-small cell lung cancer for advanced practitioners. This is a case-based approach. I'm Stephanie McDonald. I'm an oncology nurse practitioner in the thoracic oncology program here at Dana-Farber Cancer Institute in Boston, Massachusetts.

I have over 15 years’ experience in healthcare and caring for patients with cancer. And joining me today for our discussion are two of my colleagues, Dr. Narjust Florez, and advanced practitioner Sarah Tangerini. I'd like to begin by having my colleagues take a minute to introduce themselves.

Dr. Narjust Florez: Hi everyone, my name is Dr. Florez and I’m the associate director of cancer or equity at Dana-Farber and I'm a thoracic medical oncologist. We have particular interest in women with lung cancer. I'm delighted to be here today.

Sarah Tangerini: Hey, everyone. I'm Sarah Tangerini. I'm a nurse practitioner at Dana-Farber. I specialize in thoracic oncology. I've worked in this department for three years as a nurse practitioner, and prior to this, I specialized in clinical research. And I am happy to be here today.

Stephanie McDonald: I'm happy to have both of you with me, so thank you. In this virtual discussion, we're going to give you an overview of HER2 mutant non-small cell lung cancer. First we're going to review how HER2 is dysregulated and what its clinical relevance is in patients with advanced non-small cell lung cancer.

Throughout our introduction and three case studies, we'll explore treatment strategies targeting HER2 mutations in non-small cell lung cancer, and discuss the current challenges in treating patients with HER2 mutant non-small cell lung cancer. We'll help better understand when to test for HER2 mutations in non-small cell lung cancer and go over the modalities to do so.

Our cases today are going to focus on a patient with newly diagnosed HER2 mutant non-small cell lung cancer, a patient with progressive HER2 mutant non-small cell lung cancer, and a patient with complications from their HER2 mutant directed therapy. Throughout the discussion, our main focus is on the importance of the advanced practitioner's role in understanding, educating, and managing the care of patients with advanced HER2 mutant non-small cell lung cancer.

To begin, I just want to give a brief overview of lung cancer in general. Lung cancer is one of the most common cancers and is the leading cause of cancer deaths in the US and worldwide. In the US alone, there's over 200,000 [...] nearly 230,000 new cases [...] estimated in 2022. Globally, this number is about 2.1 million, and a little over 130,000 deaths estimated in 2022. Again, globally, about 1.8 million.

Five-year US survival rates of lung cancer overall is around 22.9%. In metastatic lung cancer, that number drops significantly to about 7%. Non-small cell lung cancer accounts for between 80% and 85% of lung cancers. There's been such a dramatic evolution of therapy in lung cancer over the recent years. In the past, the only critical point of distinction in the pathologic diagnosis of lung cancer was between small cell and non-small cell lung cancer.

The development of new targeted therapies has resulted in an increasing need to be able to improve pathologic diagnosis, to be able to create an accurate distinction between adenocarcinoma and squamous cell carcinoma. We're now able to further break down the diagnosis with molecular pathology, as well as to be able to identify patients, their percentage of PD-L1 expression. This is critical because histological and molecular subtyping has the potential to influence our clinical decision making and impact the patient outcomes.

National guidelines such as NCCN and ESMO recommend broad genetic profiling prior to initiation of therapy for advanced non-small cell lung cancer. We know from many studies that patients who get chemotherapy as opposed to targeted therapy specific to their driver mutation do much worse. When a patient is diagnosed with advanced non-small cell lung cancer, especially when they present in our clinic, we have them undergo molecular biomarker testing to see if they have any known genetic mutations driving the growth of their cancer.

Some of the most common actionable mutations have FDA approved therapies, targeted therapies, and they're listed here in this diagram. We're now up to 10, HER2 being the newest biomarker. The most common include EGFR, KRAS, and ALK mutations. So best practice includes biomarker testing prior to initiating first line treatment to help ensure that we are giving the most optimal treatment to the patient specific to their lung cancer.

And now, with the latest approval of HER2 directed therapy, approximately 52% of patients with advanced non-squamous, non-small cell lung cancer have a driver mutation targetable by an FDA approved agent. And this slide is just another view of how these biomarkers, specific to non-small cell lung cancer, are broken down by percentage. It's a great visual. You can actually see HER2 is only about 2% of these mutations.

Sarah Tangerini: Next, I'm actually going to go a little bit into how we actually test for these biomarkers. In order to determine if our patients have actionable biomarkers driving the growth of their cancer, they need to undergo special testing of their tumor tissue. There are a few different ways to get this information. The gold standard for biomarker testing is obtaining tissue from a biopsy of the tumor and then putting the tumor tissue through next generation sequencing.

If you're able to get a good sample of the tumor tissue, this is obviously the most accurate form of testing. However, one of the bigger challenges that we run into with tissue biopsies are that the quantity and quality of the samples are sometimes not sufficient enough to perform the next generation sequencing. You need about 10% to 20% of viable cancer cells in a tissue sample for reliable results. And a lot of the time, the majority of the tissue is used to confirm the diagnosis of non-small cell lung cancer, and the remaining tissue can sometimes be insufficient for the molecular testing and PD-L1 testing.

The results of tumor tissue next generation sequencing can also take up to two to three weeks to have a result. So sometimes, we don't know that the sample is insufficient until those results come back, which can then lead to delays in patient's treatment. Another form of tissue testing is actually doing liquid biopsies, which is one of the newer forms of testing that we use to look at whether a patient's cancer have any actionable biomarkers. And the way that we test this, it's by obtaining a liquid biopsy, which is a blood sample containing cell-free DNA from multiple sources, including DNA shed from the tumor.

One of the advantages to these forms of testing is that it is minimally invasive. It's just a blood draw. However, this sensitivity is only about 70% to 80%, which means that if there is a negative result, we can't say 100% that this is a true negative result. We also can't assess the cancer histology or PD-L1 status through a liquid biopsy. When is it appropriate to obtain a liquid biopsy? Generally speaking, if a patient's tumor tissues testing comes back insufficient or inadequate, or if it's too dangerous for a patient to undergo an invasive procedure such as a biopsy, then we may want to obtain a liquid biopsy to get some of this information.

But a lot of the time, we like to use liquid biopsies to confirm results from tumor tissue samples to increase the rate of biomarker detection. In an ideal world, we would use this as a complementary approach: we get the information first from the tumor tissue sample and then confirm the results with the liquid biopsy. With this information, it just leads me to ask Dr. Florez one of my first questions. Do you have a preference on one modality of testing over another, so a liquid biopsy versus tumor tissue sampling? Or do you try to obtain both? And what advice do you have for other medical oncologist teams whose access to this testing may be difficult?

Dr. Narjust Florez: Sarah, I think the tissue is still the issue and will remain the issue in lung cancer. The standard of care is tissue. Why is this? Because we can conduct more analysis than liquid biopsies and the value is better. What is the negative predictive value? Having a liquid biopsy that is negative does not mean the patient doesn't have the mutation. You still have to go for tissue testing. That's what is ... In addition, new biomarkers are [being identified] before the liquid biopsy technology catches up.

It's very well studied in EGFR, ALK, and KRAS, which are the oldest mutations. But for the newer mutations like NTRK or some of the RNA fusions, it's less validated. But liquid biopsy is a good tool, particularly in patients that you may have to track down the tissue. Stephanie, Sarah, and I find each other tracking down tissues somewhere in the country or outside of the country. The liquid biopsy is a good alternative where you're trying to get the tissue tested, when the tissue cannot be tested, or when the patient, to be honest with you, doesn't want to repeat a biopsy. But we need to remember that the tissue is still the issue. So still the gold standard.

Sarah Tangerini: Thank you for that. That's very helpful. And can you tell me, at what stage of the patient's care should we be testing for these oncogenic drivers?

Dr. Narjust Florez: At diagnosis, regardless of the stage. It's no longer believed that we should test patients only with metastatic disease. With the approval on new adjuvant and adjuvant immunotherapy, and now adjuvant targeted therapy [...] diagnosis, regardless of stage, patients should be tested. And one comment, Sarah, about this is that knowing the target mutations help us understand how they're going to behave. I prefer to have as much information as possible.

Sarah Tangerini: Thank you for that.

Dr. Narjust Florez: As I transfer here, I'm going to be talking about HER2 alterations, and it's important that we mention the difference. No two alterations are the same. And why is that the case? Here in this table that we're sharing, we have a difference between mutations, gene […] protein over-expression. And to be very careful: HER2 mutations in lung cancer vs the HER2 mutations in breast cancer in which we're more familiar. The majority then occur in exon 20, and I'm going to stop [...] HER2 exon 20 is not the same as EGFR exon 20. It's a different gene.

HER2 mutations are mostly commonly seen in females, and that's one of the reasons I'm here with you, is that it's seen in Asians and never smokers, but also live [...] HER2 mutations. Majority are adenocarcinoma. HER2 therapy tends to have worse prognosis. These patients tend to present, many of them, with brain metastasis. Gene amplification is different than a mutation. That just means the gene is amplified but not mutated, no change.

This is acquired amplification. It can be seen in some patients that actually have other mutations that have gone on therapy. For example, EGFR, ALK, that have been in therapy for a while—they develop an escape mechanism or a resistant mechanism with HER2 amplification. But that doesn't mean that it will respond to HER2 therapy. And finally, protein over-expression does not mean amplification or mutation, it means just, the protein is being over-expressed.

So a mutation, the gene changed. Amplification, the gene multiply. Protein over-expression, the protein and the gene changed. And that's what makes HER2 very complicated, and I'm very happy to be here with all of you talking a little bit about this new target. The lung cancer mutation consortium, in part with Memorial Sloan Kettering, put together the largest group of HER2 positive, non-small cell lung cancer.

One important thing is that we see it in majority never smokers, but we have seen HER2 mutations in around 25% of former smokers. So a smoking history or tobacco exposure does not mean that you don't need to test for this gene or other genes. The majority are women and […] amplification and protein over-expression are less likely to respond to therapy. They tend to present also with significant number of brain metastasis. Glad to talk about HER2, and I'll give it back to the moderator, Stephanie.

Stephanie McDonald: Yeah. Thank you for that, and I really appreciate both you and Sarah taking a few minutes to really give a detailed explanation and just make it really easy to understand for myself, and I think I can speak for other advanced practitioners as well. Thank you. So that gets me to my first discussion question, for you Dr. Florez. Now that we have a better understanding of the dysregulation of HER2 in advanced non-small cell lung cancer, can you further explain that difference between the HER2 exon 20 mutation and the EGFR exon 20 mutation?

Dr. Narjust Florez: Yeah. Chromosomes have exons, which are part of the structure of a chromosome. But in a chromosome, we have millions of genes. So an exon it is quite [...] theoretically speaking, it's very small, but when it comes to gene space, it's a large space. There are also genes in that exon. So it could be that the HER2 gene and the EGFR gene are both in the same exon. That doesn't mean they are the same.

As an example, a car, right, a Toyota. Toyota is the maker of the car, but you have different types of cars. You have a Camry, you have a Prius, right? They're all exon 20, but one is a Camry and another one is a Prius. I hope my analogy doesn't make me look like I'm 300 years old, but I hope it explains this a little bit better.

Stephanie McDonald: No, that's great. I just think it's really important to understand, especially the difference between these mutations, because they're treated completely differently. They have different FDA approved regimens. Having a clear understanding of the mutations and where they're located will definitely help us understand why certain regimens are recommended, so thank you.

And I have another question to put towards you, Dr. Florez. I have a question about HER2 mutant lung cancer versus HER2 breast cancers. How do HER2 mutant alterations and non-small cell lung cancer differ from those in other solid tumors? Can you just spend just a minute just explaining more specifically how HER2 mutant metastatic lung cancer differs from HER2 breast cancers? I just think it's really important for people to understand and be able to distinguish this.

Dr. Narjust Florez: So for HER2 breast cancer, it's like real estate: location, location, location. We just talked about exon 20, but what we need to talk about HER2 and breast cancer is located in the NSRs sector or a tyrosine kinase. So what this means? Tyrosine kinase stimulates growth. When this gene is over-expressed or has a mutation, the cell is motivated to grow. That's what interior tyrosine kinase do. In human genes with tyrosine kinase inhibitors, that's what the name of the drugs come from.

In this case, in breast cancer, it's located in chromosome 17. And it has been documented that it plays a role in this activation of this tyrosine kinase, that kind of fuels […] for breast cancer and gastric cancer. For lung cancer, it's a little bit more complicated. It's also a tyrosine kinase […] for two things, an inactivation of a gene that protects the cells, and also, activation of this tyrosine kinase that stimulates cell growth.

There's two things that happen here, an over-expression of what really motivates cell growth and a mutation of the cells that inhibit cancer cells for growing. In lung cancers, it's believed to be a two event phenomenon, compared to breast cancer and gastric. And one of the challenges about this is that we couldn't come out with good drugs because we have to block two things instead of one. And that has been one of the challenges that, until a few weeks ago, we didn't have targeted therapy.

Stephanie McDonald: Thank you. In terms of HER2 amplification, breast cancer, HER2 amplification is an oncogenic driver, and frequently associated with over-expression. In lung cancer, we see amplification but it's not as closely linked to over-expression and happens somewhat less frequently than seen with breast cancer. Would that be correct?

Dr. Narjust Florez: Yeah. I use this example. So in breast cancer, you propose, you get married. With lung cancer, you propose but you may not get married. I think it's a great analogy.

Stephanie McDonald: It is. It's so helpful.

Dr. Narjust Florez: The amplification doesn't equal the over-expression in lung cancer.

Stephanie McDonald: Yes.

Dr. Narjust Florez: It's not guaranteed you're going to get married in lung cancer.

Stephanie McDonald: Thank you. That's so funny. That is super helpful. Thank you.

Dr. Narjust Florez: Going around with these analogies, and the people that are in clinic with me know that I love analogies, and patients actually bring up my analogies years later. Even after some of my analogies [...] itself, they bring them up. Let's talk a little bit about biomarker testing quickly, because improve overall survival, improve quality of life, comes with biomarker testing. Fortunately, no old patients ... to get biomarker testing. There are significant disparities in biomarker testing.

This is a study presented by Dr. Bruno in ASCO 2021 that show that unfortunately, in general, we're only testing 77% of patients with lung cancer as a whole. But when you go by race, you can see that Black patients or African American patients are less likely to be tested. So 39.8% versus 50%. And unfortunately, that is linked to clinical trial participation. If biomarker, then the number of clinical trials that are available for a patient will reduce. Black patients are less likely to go in clinical trials because they don't get appropriate biomarker tested.

One of the things about patients, where we're talking about HER2, is that are associated with a geographic location or racial differentiation. So you will see this graph. This is unique to the population in the United States. In the case of EGFR, they tend to be more prevalent in Asian and Hispanic patients. In the case okay KRAS, they are more prevalent in White or Caucasian patients. For HER2, we haven't been able to still point out exactly where this comes out, but we know that it's more prevalent in White women.

But it can be a bias there because that's where the most of the repositories come, is for a White population. So we need to continue to study this. And finally, there is a different global distribution of genes. We see higher prevalence of EGFR in Brazil and Asia, and they could be a relation with pollution that we don't know. We have a higher prevalence of KRAS in the US and Europe, and there could be association with smoking. Race has a role here, and geographic location in which the patient was born and raised can also give you a clue of what mutation the patient may or may not have. Back to studio with Stephanie.

Stephanie McDonald: Thank you. I do have a question and it could be directed to either Sarah or you, Dr. Florez. So whoever wants to answer. Sarah, if you want to chime in as well. I just was really wondering what the consequences are if these patients, or patients, in general do not have biomarker testing. And how does that impact their mortality and their overall quality of life?

Sarah Tangerini: Sure, I don't mind answering this one. I think it's important for patients to have biomarker testing for several reasons. For one, it will help the medical oncologist to decide the best treatment for the patient. For example, if a patient progresses on a standard of care therapy, there may be a targeted therapy that can be used as a second line treatment option.

Also, having this information will help to narrow down the best treatment options for the patients, which will in turn decrease mortality and hopefully improve their quality of life. It may also open up clinical trial options that may not be available as standard of care treatment, and it could also help to identify germline mutations, such as BRCA2, which would alert family members to have their siblings and children tested for similar germline mutations. I really see that there's a huge benefit to doing this biomarker testing for all of our patients.

Stephanie McDonald: Yeah, thank you. The key takeaway is, test your patients. They need to be tested. Briefly, how do we manage HER2 mutant non-small cell lung cancer now that we have a better understanding of biomarker testing? We are going to get into this in more detail during the case studies, so stay tuned. But just to briefly go over this information, as an introduction, first line treatment, regardless when we get the biomarker testing and they have a HER2 mutant non-small cell lung cancer, first line treatment is systemic therapy.

Patients will receive standard of care with a platinum-based chemo doublet, and either cisplatin or carboplatin depending on their functional status and other comorbid conditions or limiting factors. Plus, pemetrexed chemotherapy, so either cisplatin or carboplatin, plus pemetrexed chemotherapy, as well as immunotherapy with pembrolizumab. That's as long as there's no contraindications to immunotherapy. And therapy will continue until they have disease progression or unacceptable toxicities.

If that occurs, so they have disease progression or are unable to tolerate this therapy, then they're eligible to be considered for second line treatment, which, woo-hoo, now is trastuzumab deruxtecan. That is newly FDA approved as of August 11th, 2022. That is a game changer for our patients. So trastuzumab deruxtecan just is a HER2 ADC, which is an antibody drug conjugate. This is a monoclonal antibody. It was approved by the FDA for patients with unresectable metastatic non-small cell lung cancer, whose tumors have one, an activating HER2 mutation, and two, have received this prior systemic therapy that I just reviewed, that platinum-based doublet chemo and immunotherapy.

Two of the studies that I just want to highlight, one is the DESTINY-Lung01 trial. Patients with metastatic non-small cell lung cancer, refractory to standard treatment, and with HER2 over-expression or HER2 activating mutation were eligible to participate. The study assessed the safety and efficacy of trastuzumab deruxtecan at a dose of 6.4 milligrams per kilogram. That was given once every three weeks. That is the dose that actually is already approved in gastrointestinal and breast cancers. That study found that the median progression for survival was 8.2 months, and the overall survival was shown at 17.8 months. And overall response rate was 55%.

And then the second study I just wanted to mention was the DESTINY-Lung02 study, which was another randomized phase two clinical trial. And that looked at the safety and efficacy of trastuzumab deruxtecan comparing the dosing, 6.4 versus 5.4 milligrams per kilogram in, again, HER2 mutant non-small cell lung cancer who had disease recurrence or progression after that standard of care treatment, that had to contain that platinum-based chemo drug.

And then, this was given accelerated approval and became FDA approved just several weeks ago. During the upcoming slides, we're going to dive deeper into the management of HER2 mutant non-small cell lung cancer. We're going to further review the FDA approval treatment with trastuzumab deruxtecan, and really get into the dosing, the side effects, precautions, and monitoring considerations.

Just want to review the key clinical takeaways of this introduction, just go over a couple of things with you, just patient's specific molecular profile determines their treatment course. Biomarker testing to identify that optimal treatment targeted therapy has improved survival for patients with advanced non-small cell lung cancer in recent years. Tissue testing. Tissue is the issue, as Dr. Florez just said. Tissue testing in non-small cell lung cancer is the gold standard for biomarker testing.

The challenges can include the timing, because it can take several weeks to result, and issue of insufficient tissue for additional testing. And then we can do liquid biopsy testing, which is helpful at identifying biomarkers in cases where the tissue testing was insufficient. But due to a lower sensitivity of 70, 80% that could lead to some false negative results. Making a negative result, not negative, but non informative, like Dr. Florez mentioned.

HER2 mutations are mostly found in exon 20 and non-smokers, but this should not be an exclusion criteria for biomarker testing. And for available agents, HER2 amplification and over-expression does seem to be a driver in non-small cell lung cancer. And then, like I said, during the upcoming slides, we are going to dive deeper into reviewing that FDA approved treatment, hot off the press, trastuzumab deruxtecan, and just going over the dosing, side effects, precautions and monitoring considerations.

This brings us to the end of this discussion. Please see other segments for further discussion about HER2 mutant non-small cell lung cancer, or visit advancedpractitioner.com. Thank you.