Robert A. Figlin, MD, FACP: Good afternoon from the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting. This is Bob Figlin, the Steven Spielberg Family Chair in Hematology-Oncology at Cedars-Sinai Cancer Center. And I’m absolutely delighted to have again Dr. Bardia, who has new titles with his arrival at the University of California, Los Angeles (UCLA): professor of medicine, director of the breast oncology program, and the director of translational research integration. Welcome.
Aditya Bardia, MD, MPH: Thank you so much.
Dr. Figlin: I think at ASCO 2024, for the practicing oncologist – and you know I trained at UCLA with Dennis J. Slamon, MD, many years ago – we’re now revisiting what HER2 means. And as part of the DESTINY trials, it’s really important for us to transmit that information to the practicing physician. So tell us how you think about HER2 status, and how you measure HER2 status, and then how you apply HER2 status in the context of the DESTINY trial.
Dr. Bardia: Yeah, absolutely. So if you look at the definition of HER2-positive breast cancer, currently it’s defined as tumors that have HER2 immunohistochemistry (IHC) expression 3+, or 2+, with fluorescent in situ hybridization (FISH) amplification. And this definition was because of trastuzumab (Herceptin) because we wanted to identify tumors that have high expression for which an antibody alone, with chemotherapy, could potentially work.
But the definition of “HER2-positive” was all because of trastuzumab. Now, we are revisiting this with antibody-drug conjugates like trastuzumab deruxtecan (T-DXd). A couple of years ago at ASCO, we saw the results of DESTINY-Breast04, and that looked at T-DXd versus standard chemotherapy for patients with HER2-low metastatic breast cancer who had received at least one prior line of chemotherapy. And we saw a big improvement in progression-free survival and overall survival. It received a standing ovation. And we now had this new category of HER2-low breast cancer, defined as tumors that have HER2 expression of 1+, or 2+ without FISH amplification.
There was a lot of discussion at that time. What does this mean? How would we identify these low expressors? And there was also concern that the IHC assay was never developed to identify the low expressors. It was always developed to identify the high expressors. Now we’ll see the results of DESTINY-Breast06 at ASCO 2024.
Essentially, the trial looked at T-DXd versus standard chemotherapy in an earlier-line setting. So this was patients who had not received any chemotherapy for metastatic disease and also had a category of what’s called HER2 ultra-low, which means HER2 IHC between 0 and 1+. So, 0 is IHC HER2 expression that is less than 10% of cells, but it doesn’t mean that it’s 0% of cells. There are still patients who have some HER2 expression, which could be sufficient, if you want to use a drug like T-DXd to target that, because it has strong bystander effect. It’s making us question this whole classification.
Dr. Figlin: So let’s talk about that a little bit, because the reality is that when you had Herceptin, its efficacy was really an efficacy only when you were a strong overexpressor. And now we have a drug that has this strong bystander effect, where all you have to do is get the drug close, and the bystander effect can then take care of cells that are not HER2 overexpressing of any form. Talk a little bit more about the biology around that. What happens to the bystander cell?
Dr. Bardia: That’s exactly correct. If we look at antibody-drug conjugates, let me give an example of trastuzumab emtansine (T-DM1). T-DM1 is an antibody-drug conjugate, but it does not work for these low-HER2 tumors because it does not have a bystander effect. It’s very different with T-DXd. The idea is that the antibody-drug conjugate will bind to a HER2-positive cell, get internalized, and release deruxtecan. Deruxtecan is membrane permeable, so it can then, by a bystander effect, affect neighboring cells, including cells that do not express HER2. So even if there is some HER2 expression, as long as the antibody-drug conjugate can reach there, because of the bystander effect, it can impact cells that do not express HER2.
Dr. Figlin: I guess the ultimate question is, now that we’re here in 2024, should we just give this drug to everybody with breast cancer?
Dr. Bardia: Absolutely. I think it’s a great question. And the question is, how low do you go in terms of HER2 assessment?
Dr. Figlin: Exactly.
Dr. Bardia: Because even with HER2 IHC 0, if you’re not seeing it on the IHC, it doesn’t mean that there’s zero expression. There could be HER2 expression on the cancer cell, but just not sensitive enough for the IHC to pick up. It’s absolutely the question of the hour: Should T-DXd be given to all comers, regardless of the HER2 expression, because of this bystander effect? I think the results of DESTINY-Breast06 do suggest that.
Dr. Figlin: Let’s talk a little bit about an example of what we think is HER2-negative patients: triple-negative disease. Do we know the results of this molecule on triple-negative disease?
Dr. Bardia: There has been investigation related to T-DXd in triple-negative breast cancer, not in DESTINY-Breast06 but in DESTINY-Breast04. Ten percent of patients who were enrolled in DESTINY-Breast04 had triple-negative disease but had some HER2 expression, because it was HER2-low. It was HER2-low but estrogen receptor (ER)-, progesterone receptor (PR)-negative. It actually is making us question this whole definition of triple-negative, because it was HER2-low, ER-negative, PR-negative, which is different from ER, PR, and HER2 IHC 0.
Dr. Figlin: Exactly.
Dr. Bardia: So which one do you call triple-negative breast cancer? But in that subgroup, in 58 patients who received T-DXd in HER2-low disease and did not have ER or PR, there was clear benefit with T-DXd both in terms of progression-free survival and overall survival. The approval of T-DXd, as it stands, is for HER2-low metastatic breast cancer, regardless of the estrogen status. So both for ER-positive disease and ER-negative disease.
Dr. Figlin: All right. So let’s take this to the community. A community doctor sees a new patient with metastatic breast cancer. How would you help them apply this?
Dr. Bardia: For a patient with metastatic ER-positive breast cancer, we start with endocrine therapy plus a CDK4/6 inhibitor. That’s our first-line treatment.
In the second-line setting, we recommend getting plasma-based genotyping or tumor genotyping because that’s actionable with PI3 kinase inhibitors, AKT inhibitors, or elacestrant for ESR1 mutant tumors. You usually use endocrine-based treatments in the first-line, second-line, and sometimes third-line treatment as well.
But then, after that, we would go to capecitabine as the choice after endocrine-based treatments. But in DESTINY-Breast06, where T-DXd was compared with capecitabine as well as paclitaxel, the outcomes were much superior with T-DXd, with median progression-free survival of 13 months with T-DXd versus about eight months with capecitabine or paclitaxel. It is practice-changing, and we would be using T-DXd after an endocrine-based option. Ultimately, we need to have a patient-centered discussion. T-DXd is administered intravenously and can cause pneumonitis. So we would have to have a patient-centered discussion. There might be some patients who like an oral option, but we have to disclose the efficacy of T-DXd being superior to capecitabine.
Dr. Figlin: So I guess, and we’ve had this discussion earlier in the day in other diseases, when we learn in advanced disease of benefit and substantial benefit, as medical oncologists what we tend to do is want to treat people earlier. And the question then becomes, how early will our surgical colleagues allow us to treat even localized HER2 breast cancer?
Dr. Bardia: Potentially, with these agents, absolutely. And to emphasize your point, we know that with every line of therapy there are certain number of patients who don’t get to the next line. So that’s why that’s the general philosophy in oncology. We like to use our agents, the effective agents, as early as possible. And T-DXd is now being evaluated both in the neoadjuvant setting and the adjuvant setting for HER2-positive breast cancer as well.
So until we get the results of those studies, I would not use it in early breast cancer, but there’s a lot of promise with these agents. One thing we would have to pay very close attention to as related to T-DXd and antibody-drug conjugates in general, as they get moved to early breast cancer, is the toxicity profile because it’s a different setting. It’s a curative setting. The toxicity profile, the impact on quality of life, that’s a very important consideration in early breast cancer.
Dr. Figlin: So talk a little bit more about the adverse events that occur with T-DXd.
Dr. Bardia: The most common side effect seen with T-DXd is nausea. And, in general, I recommend a three-drug antiemetic regimen to control nausea, and use of olanzapine as well as needed for breakthrough nausea. You see some myelosuppression. Some patients have alopecia as well.
The serious side effect seen with T-DXd that has received a lot of attention is pneumonitis. The incidence is about 10%–15% across all the studies, including DESTINY-Breast06, and in some studies, there were even deaths. So that’s grade 5 adverse events with T-DXd because of pneumonitis. The key with T-DXd related to pneumonitis is early recognition and management. So if a patient is having any symptoms that are concerning, or even when you’re looking at scans when a patient is on T-DXd, you’re not just looking for efficacy, you’re also looking for evidence of pneumonitis. If you see that, the key is to start steroids, stop T-DXd, and allow this to recover before you consider T-DXd again.
Dr. Figlin: Any risk factors associated with the development of pneumonitis in these patients? Prior radiation, prior infections? Anything else?
Dr. Bardia: Prior history of interstitial lung disease in a patient who has known baseline conditions that can impact the lungs, that is a risk factor for development of pneumonitis.
Dr. Figlin: But it’s not something where you do diffusing capacity of the lungs for carbon monoxide or pulmonary function tests prior to initiating.
Dr. Bardia: That’s correct. It’s more of a clinical history. Some physicians do an oxygen saturation test to look at the baseline oxygen saturation, but we don’t routinely do pulmonary function tests before starting T-DXd.
Dr. Figlin: And what’s the time course of the pneumonitis? When is it most likely to occur?
Dr. Bardia: So the median time course is about four months, but it can occur after a couple of cycles as well, and it can occur later on also.
Dr. Figlin: Well, thank you so much for taking time and speaking with us. Good to see you again.
Dr. Bardia: Same here. Thanks for having me.
This transcript has been lightly edited for clarity.
