HER2-Positive Breast Cancer Treatment Landscape Expands With Promise of New Therapies

William J. Gradishar, MD

Patients with HER2-positive breast cancer have more treatment options now than ever, with several FDA approvals coming through over the last year. This marks an exciting time for this patient population, with more potential agents and combinations under evaluation in clinical trials as well.

Trastuzumab deruxtecan (Enhertu; DS-8201) received its approval in December 2019, for treatment of patients with unresectable or metastatic breast cancer who had received at least 2 prior anti-HER2-based regimens in the metastatic setting. Tucatinib (Tukysa) was approved in April 2020, for combination treatment with trastuzumab (Herceptin) and capecitabine for patients with advanced unresectable or metastatic HER2-positive disease who received at least 1 prior anti-HER2-based regimen in the metastatic setting. The tucatinib approval also included patients who had brain metastases.

Ado-trastuzumab emtansine (T-DM1; Kadcyla) was approved in May 2019, as adjuvant treatment of patients with HER2-positive early breast cancer who have residual invasive disease following neoadjuvant therapy with trastuzumab and chemotherapy. The question of discussion now is how to sequence these agents appropriately among this patient population. Data supporting each approval can help physicians decide between the available treatment options, as well as new research in the works for these therapies.

In an interview with Targeted Oncology, William J. Gradishar, MD, chief of hematology and oncology, department of medicine, Betsy Bramsen Professorship of Breast Oncology, professor of medicine (hematology and oncology), Northwestern University's Feinberg School of Medicine, discussed the current treatment options for patients with HER2-positive breast cancer, including the recently approved therapies from the FDA. He also shared his insights on treating patients with brain metastases, in particular.

TARGETED ONCOLOGY: Could you discuss some of the new and emerging agents in HER2-positive breast cancer?

Gradishar: Over the last year or so, we've seen the approval of several drugs, and there are many more in the pipeline. The 2 more recent ones are trastuzumab deruxtecan, which is an antibody-drug conjugate, and then the other is tucatinib as part of the HER2CLIMB regimen. They're both drugs that have significant activity that we typically use post-trastuzumab, pertuzumab, and T-DM1, and they both have unique strengths. There are some potential toxicities as well that we have to be aware of, but the other agent, the third drug, is a neratinib. Neratinib has been around for a while and was initially approved as an adjuvant therapy. Based on the NALA trial, it was then approved as a treatment for metastatic disease after first-line therapies. I think that we now have 3 new drugs that are useful for patients with HER2-positive metastatic disease and the promise of others that are still being developed.

TARGETED ONCOLOGY: Could you discuss the role of trastuzumab deruxtecan in this setting compared with T-DM1?

Gradishar: It doesn't compare with T-DM1 yet because they are doing that trial to directly compare it now. However, it is an ADC with the same concept that you have a targeting antibody pertuzumab with a stable linker and then a cytotoxic payload. The concept is very much the same as T-DM1, and the distinctions are that the payload is different with trastuzumab deruxtecan. The number of molecules or payload per antibody is greater with trastuzumab deruxtecan than with T-DM1. In the clinical trials, it proved to be very active, even in patients who had prior T-DM1. It's an exciting new drug that people are starting to use quite a bit in the metastatic space.

TARGETED ONCOLOGY: Could you elaborate on the role of trastuzumab deruxtecan in patients with brain metastases as well?

Gradishar: There were data generated from the DESTINY trial, where there was 24 patients out of the 180 or so patients that were in the trial who did have stable brain mets, and although it's not a huge population, the PFS for the patients with brain mets, as opposed to the entire trial, were almost exactly the same, which was roughly 16 to 18 months. It didn't appear that there was any difference. Now that is not a population that has progressing active brain mets, but nevertheless, patients with stable brain mets did do well in the DESTINY trial and appears to have similar results as the overall population. I think they'll need a bigger experience to understand the activity of that drug compared to say small molecules for brain mets.

TARGETED ONCOLOGY: What other agents or clinical trials are important to highlight in this space?

Gradishar: There's DESTINY-2, -3 and -4. There's a direct comparison to T-DM1, so we don't have the data yet. There is a trial looking at trastuzumab deruxtecan compared to treatment of physician's choice, which provides some other HER2-directed therapy options. What I think is probably the most exciting is the DESTINY-4, which is the HER2-low, and there has been data that's been presented and published showing that this drug in patients who are not HER2-positive but are HER2-low, will respond, and that's sort of exciting because I think that opens up another silo of breast cancer in a sense. If this drug proves to be helpful in that setting, we're going to have another option for patients who are either triple negative, but HER2-low, or even patients that are ER-positive. It'll open up another option for these patients. One could envision that trastuzumab deruxtecan may be compared at some point to sacituzumab govitecan in the triple negative space. What we'll see with these compounds and the strategy of antibody drug conjugates is exciting.

TARGETED ONCOLOGY: Could you elaborate on the findings in the HER2CLIMB study of tucatinib in regard to patients with brain metastases as well?

Gradishar: In the HER2CLIMB trial, which was the triplet of trastuzumab, tucatinib, and capecitabine versus capecitabine and trastuzumab. This is a big randomized trial, whereas the DESTINY-1 trial was a phase 2 trial. In the HER2CLIMB trial, the triplet proved to be more effective with respect to PFS and OS. The inclusion criteria were not only patients with stable treated brain mets but those patients that had progressive brain mets not requiring immediate therapy, so it was a little bit of a broader population. The number of patients with brain mets in the HER2CLIMB trial was significantly greater than what you saw in the DESTINY trial.

It's a much more robust data set to comment on CNS activity of tucatinib, and Nancy Lin, presented the data looking specifically at the CNS disease and found that the CNS PFS, and CNS OS in patients receiving tucatinib was markedly improved compared to those that were simply getting capecitabine and trastuzumab. There was clear evidence that there was not just a stabilizing, but a treatment effect in the brain. I think that's quite remarkable. Many people have made that comment that this is sort of a breakthrough with respect to treating HER2-positive CNS disease, which is a very significant problem for that population of patients with breast. We haven't cured CNS brain mets, but I think it's the first evidence that we have something that changes the course of their disease.

TARGETED ONCOLOGY: How do you see this research evolving in the next coming years for patients with HER2-positive breast cancer?

Gradishar: We've had exciting developments over the last many years, and with almost every year that goes by, we find something new and better or additional that we have as an option for patients with HER2-positive disease, which is great for patients. We haven't cured metastatic HER2-positive disease, patients with early-stage HER2-positive disease, even though we've changed the course of their illness. Patients with longer follow-up continue to develop recurrences, so even in that setting, we need more effective therapies. If you look at the number of drugs in development in this space, it's huge. There are small molecules, additional ADCs, bispecific antibodies, and vaccines, so there's a variety of things that are still very much of interest for patients with her to positive disease. I anticipate will probably continue to have drug approvals. The next one that's probably going to be acted upon, but I don't know if it'll be approved, is margetuximab (MGAH22), which is a bioengineered antibody that may be slightly better for certain patients with HER2-positive disease. If that gets approved, it may be yet another option we have to offer patients, probably after trastuzumab deruxtecan or tucatinib.