'Huge Year' for HER2+ Breast Cancer: Incorporating New Treatments

This transcript has been edited for clarity.

Kathy D. Miller, MD: I am Dr Kathy Miller, professor and associate director of clinical research at the Indiana University Simon Cancer Center. Today, I'm joined at the San Antonio Breast Cancer Symposium (SABCS) by Dr Sara Hurvitz, who is associate professor in the department of hematology-oncology at the University of California, Los Angeles.

Sara, you have spent many years working on new treatments for HER2-positive disease. What a year this was.

Sara A. Hurvitz, MD: It was a huge year.

Miller: I'm delighted you could take the time to come talk to us about some of these new developments. Let's start with the HER2CLIMB study.

HER2CLIMB Study

Hurvitz: This study evaluated a HER2-selective tyrosine kinase inhibitor (TKI) called tucatinib, which is an orally delivered drug that is unique in its ability to penetrate the blood-brain barrier. The phase 1 study showed very interesting activity in patients with central nervous system (CNS) metastases, with over 40% having a response in the brain. HER2CLIMB was a randomized phase 2 registrational strategy study in which patients received trastuzumab and capecitabine with either tucatinib or placebo, with an endpoint of progression-free survival (PFS). What is interesting is that they increased the number of patients they were going to enroll to look specifically at the benefit in patients with CNS metastases—a huge area of unmet need. They allowed patients to come on the study with progressive CNS metastases, which I had never seen before in a clinical trial.

Miller: Before we get to the results, I have to ask you about toxicity. Many of us have had experience with some of the HER2-targeting TKIs. Toxicity has often been somewhat of a barrier for many patients.

Hurvitz: Because TKIs are given orally, they are often combined with capecitabine, which causes diarrhea. Using a TKI that is not selective and hits other receptors, such as epidermal growth factor receptor (EGFR), can add to the diarrhea; giving it with capecitabine can augment that even more. We have experience with that. For example, lapatinib with capecitabine causes lots of diarrhea, as does neratinib-capecitabine, as seen in the NALA study. Interestingly, this drug [tucatinib] is pretty selective. It does not hit EGFR, so our hope was that this would not have as much toxicity.

Miller: How well did this work?

Hurvitz: It worked really well. The study not only met its endpoint of PFS in the overall population by improving median PFS by several months but also improved median PFS in patients with CNS metastases; about half of the study population had CNS metastases at enrollment. What took our breath away was that they met their overall survival endpoint in this study at the first reporting. So, there was a significant improvement in overall survival with tucatinib.

Miller: It has become hard to see overall survival results in these heavily pretreated patients, particularly at the first interim analysis. There is usually a really high bar.

Hurvitz: I think they were smart in the way they designed it. They powered it up to be able to look at that so you didn't have to wait as long. But it does speak to the efficacy of this molecule.

Miller: We assume that they will be headed to the US Food and Drug Administration with these dramatic results. Hopefully we'll be able to use this agent for our patients soon.

Hurvitz: The toxicity profile was not concerning. There was a little bit of grade 3 diarrhea, around 10%-12% in the tucatinib arm, which was not that much greater than with capecitabine-trastuzumab. So the therapeutic index is pretty impressive. I'm hoping to be able to give this to my patients next year.

DESTINY-Breast01 Study

Miller: There was incredible excitement in the room at SABCS after the HER2CLIMB results, and it only got better when we heard about a new antibody drug conjugate (ADC). Many of our listeners are familiar with and have used ado-trastuzumab emtansine (T-DM1). Tell us about this new ADC.

Hurvitz: This new ADC, called trastuzumab deruxtecan (T-DXd), is the HER2 antibody linked to a topoisomerase I inhibitor. The payload is a little bit unique, in that it is connected to the antibody at a higher ratio than T-DM1—closer to eight molecules per antibody—whereas T-DM1 is around three or four molecules, so it's highly potent. The phase 1 study, done in over 100 patients with HER2-positive breast cancer, showed this really phenomenal objective response rate of well over 50% in patients with very heavily pretreated disease. They explored this in a phase 2 expansion study called DESTINY-Breast01. It was a single-arm study; everybody received T-DXd.

Miller: This was still a very heavily treated population. Everybody had had trastuzumab. Everybody had had T-DM1. If I remember correctly, two thirds or more of the patients had had pertuzumab. This is a tough landscape to play in. How well did it work?

Hurvitz: Usually, we get excited about a 20% objective response rate (ORR) in phase 1 and phase 2 studies in heavily pretreated patients. This study showed an ORR of over 60%, with a 6% complete response rate. Very exciting data. I think the waterfall plot took people's breath away during the presentation because there was almost no bar above the line.

Miller: It certainly took my breath away. They were about three or four patients who seemed to progress, and everybody else was below the line. They were not all the way to an ORR, but the majority of them seemed to have some benefit from this drug.

Hurvitz: Exactly.

Miller: We do need to talk about toxicity with this drug, because there was concern about pneumonitis. That has been seen with all the HER2-targeted drugs in some frequency, but it seems to be more of an issue with this agent.

Hurvitz: Pneumonitis has been a signal that they have seen from phase 1. In this particular trial, where they had about 180 patients treated at the dose of 5.4 mg/kg, they saw four deaths from pneumonitis. Seeing deaths from interstitial lung disease triggers concern. They presented the data in some detail in terms of what happened with individual patients and after treatment with steroids. But, clearly this is something we are going to have to pay close attention to as the phase 3 trials go on. Hopefully this will be explored in terms of pathogenesis as the drug continues in its development cycle.

Miller: When pneumonitis was reported with trastuzumab after it was first approved, it looked like many of those patients had significant pulmonary disease burden. There was a hypothesis that perhaps these patients were responding but had this massive inflammatory response. Do we know anything more about the patients who had pneumonitis with this agent?

Hurvitz: A poster at the ASCO meeting this year described pneumonitis and interstitial lung disease with this product. They showed that Asian patients may have a higher risk, perhaps owing to some polymorphism. Heavily pretreated patients and treating at a higher dose [may also be risks]. It is possible that because lung tissue expresses HER2 at a low level and this drug-antibody ratio is so high, there is actual direct toxicity to the lung tissue. I think we need studies using biopsies to really tell us what is happening at that level, and efforts are ongoing to establish that.

Miller: Certainly as this drug moves forward in clinical trials (and we assume an approval will be coming, given the dramatic efficacy), it's going to require a healthy index of suspicion for people using it to investigate and start steroids promptly.

Hurvitz: Not only that, but when we do scans, we sometimes see ground-glass opacities creep up in our patients being treating with everolimus or the cyclin-dependent kinase 4/6 inhibitors, for example. Now when we see that we have to pay particular attention and even consider holding this drug because of the risk for it progressing.

SOPHIA Study

Miller: I also want to ask you about the SOPHIA trial. It was certainly a positive trial, but not maybe showing the magnitude of benefit of the agents that we've been talking about.

Hurvitz: We've certainly been spoiled. And timing is everything in this field, right? Because if these results had been presented a few years earlier, it might have gotten a bigger welcome.

But truly, this is an interesting molecule because it's designed to make antibody-dependent cell-mediated cytotoxicity (ADCC) more prominent, especially in those patients whose own inherent immune system does not bind antibodies as tightly—that is, their FC receptors don't bind as well.

This study did meet its primary endpoint, but it was not super impressive; it was around a month in terms of median PFS. But interestingly, all of the patients had FC receptor genotyping done, and those patients who don't bind as tightly (F carriers) do appear to derive more benefit from the use of margetuximab in combination with chemotherapy compared with trastuzumab in combination with chemotherapy. Survival was not met either in the overall population or in the subset of F carriers. However, there was an interesting trend toward improved survival. Maybe when they get to their final survival analysis, they will see a benefit there. This was a heavily pretreated patient population as well. The immune system may be a little beat up in these patients, so it would have been nice to see it in an earlier-line setting, but that is challenging because of the good therapies we have there.

Miller: We have wondered for a while how much that ADCC and immune function of trastuzumab really contributes to the activity, and perhaps more than anything else, this study suggested that it does contribute something. And if you can amplify or augment that, then you do get a little bit more. I think the challenge is that you get a little bit more—you don't get a lot more.

Hurvitz: One good thing is that it was incredibly well-tolerated. The main side effect, which was more than with trastuzumab, was the infusion-related reactions, but it was the minority of patients. Maybe in the future, we'll be in an era where we do genotyping and select patients for this therapy in combination. I'd like to see it combined with other HER2-targeted therapies. I have not given up on this molecule. I think it may have a place.

Miller: It also makes me wonder about combining it with other immunotherapies. Maybe if you can augment the immune response in a couple of different ways, including by making ADCC more effective, that will be a better combination.

Hurvitz: I agree.

Miller: It has been a fantastic year for HER2-positive patients at this meeting. Sara, thank you so much for joining us.

Kathy D. Miller, MD, is associate director of clinical research and codirector of the breast cancer program at the Melvin and Bren Simon Cancer Center at Indiana University. Her career has combined both laboratory and clinical research in breast cancer.

Sara A. Hurvitz, MD, is an associate professor in the department of hematology-oncology at the University of California in Los Angeles. She specializes in the treatment of women with breast cancer and is involved in designing, implementing, and leading national and international clinical trials to test new targeted therapies.

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