Evolving Treatment Landscape of R/R HER2+ mBC

Typical outcomes for patients who have progressed after 2 lines of therapy in HER2+ metastatic breast cancer and a review of trastuzumab deruxtecan as seen in the DESTINY-Breast01 trial.


Hope S. Rugo, MD, FASCO: We’re going to go on to our next section, and we’re going to talk about relapsed and refractory HER2-positive metastatic breast cancer. This is an area where we’ve had enormous progress over the last year, but overall, we’ve made huge advances over the last couple of decades. First, we want to hear from Tiffany a bit about what we see in patients who’ve progressed after the 2 lines of therapy in our classic treatments in HER2-positive breast cancer. What’s the typical outcome, and what are you thinking about in those patients?

Tiffany A. Traina, MD: I think we’ve had so many new exciting agents. To set the landscape of where we’ve been traditionally, if we’re looking to phase 3 data, we’ve got the original capecitabine-lapatinib trial that we could perhaps extrapolate from in thinking about a later-line setting. This is where the median time to progression to just take lapatinib was measured in a few months, perhaps an improvement from 5 months to 7 months.

Overall survival in that trial was about 17 months to 19 months with the addition of the HER2-targeted therapy. If we look at the EMILIA study, which as you remember was capecitabine-lapatinib versus T-DM1 [trastuzumab emtansine], there the median progression-free survival [PFS] was still just measured in months in the third-line setting, an increase from 6 months to 9 months on average for median PFS and overall survival perhaps stretching out to about 2.5 years with T-DM1. That’s the evidence we had in the third-line setting and later of what our expectations were for the time to progression or PFS, which was really about 6 to 9 months or so. That puts into context what we’ll talk about, many of the new agents we have for HER2-positive advanced disease, and how much better we can do.

Hope S. Rugo, MD, FASCO: CNS [central nervous system] metastases are a big challenge in that setting also.

Tiffany A. Traina, MD: Absolutely. Often these patients of progressing CNS metastases are excluded from the typical randomized phase 3 trials that we’re looking at for new novel agents in this space, so that is also an exciting changing moment for HER2-positive advanced disease in patients with brain metastases.

Hope S. Rugo, MD, FASCO: We have, as you pointed out, seen a lot of really interesting data in the last year with several different agents. Claudine, could you tell us some about the sort of top-level results from some of these trials that we feel are going to impact our clinical practice?

Claudine J. Isaacs, MD: Absolutely. It’s been a really exciting time, and beyond second-line therapy for HER2-positive breast cancer. First of all, we’ve had trastuzumab, which came on for the first-line setting that showed us a survival advantage, then the CLEOPATRA trial, with adding the pertuzumab for the first-line setting. It became our standard therapy there, and second line became TDM-1. After that, as Tiffany mentioned, there were a number of options, but there was no clear winner.

We were often just cycling out different chemotherapy drugs with trastuzumab, but in the last year or so, we’ve seen some results of some pivotal trials, most of them randomized phase 3 trials, but a couple of phase 2 trials that have really changed the landscape for us entirely. These drugs typically fall into classes. Most of the newer drugs that we’re seeing are tyrosine kinase inhibitors, but the trastuzumab deruxtecan is a new antibody-drug conjugate [ADC]. That’s a study that was just presented at the San Antonio Breast Cancer Symposium whose results showed the most phenomenal waterfall plot that many of us have seen in a trial. Just to give you high level on these, just to remind you what’s different about this drug, it’s an ADC just like TDM-1, but the payload is different.

The payload with this drug is a TOPO1 [type I topoisomerase] inhibitor, and there is a very high drug-to-antibody ratio. There is also some bystander effect with it easily crossing the cell membrane. It has a relatively short half-life, so the thought is that it can get to neighboring cells but doesn’t hang around for very long. What was seen in this study was that this was a heavily pretreated group of patients. They had a median of about 6 prior therapies for HER2-positive disease. They had to have had prior trastuzumab. The patients also had to have had prior T-DM1, and about two-thirds of patients had had prior pertuzumab. The objective response rate was about 61% in the study, and it was impressive, as I mentioned, for the patients.

There were very few patients who progressed. Most patients had a response, but 61% had an actual objective response, and if you think about the median number of prior therapies, that was very impressive. The adverse effect that was seen that is the one that we need to think about most and that was the most concerning is that a subset of patients had interstitial lung disease [ILD] that developed. Any grade was about 13.5%, but there were about just over 2.0% of patients who had fatal ILD with this drug, which is obviously a very concerning adverse effect. It seemed like, if the drug was continued when you had just abnormalities on x-ray, that could progress very rapidly.

That is something for us to keep in mind. This drug did get FDA approval, so it is available. Some institutions have it available already. I think one of the things that we might want to talk about is how we think about these drugs in this era that we’re in with the COVID-19 [coronavirus disease 2019] pandemic, where we’re really worried about preexisting lung disease and what that might do to increase risk. But this drug is an exciting drug. It has very quick activity in patients. Most patients had some degree of response, and the duration of response was also very long with this drug. I think it’s a really exciting drug for us to have available for our patients.

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