Trastuzumab Deruxtecan Shows Broad Benefit in Metastatic HER2+ Breast Cancer

William J. Gradishar, MD

The benefit of fam-trastuzumab deruxtecan-nxki (Enhertu), as reported in the phase 2 DESTINY-Breast01 trial, is evident in patients with metastatic HER2-positive breast cancer, in both clinical trial and real-world patient populations, according to William J. Gradishar, MD.

“We have used trastuzumab deruxtecan in routine clinical practice since it has been approved. Although the number of patients we’ve treated is still fairly modest, we’ve seen uniform responses in the handful of patients we’ve treated, including some who have had significant prior therapy beyond 2 standard treatments in the metastatic setting due to disease progression,” said Gradishar.

Initial results from the trial, which led to the 2019 regulatory approval of the drug for the treatment of patients with metastatic HER2-positive breast cancer who have received at least 2 prior anti–HER2-based regimens in the metastatic setting, led to an objective response rate (ORR) of 60.9% and a median progression-free survival (PFS) of 16.4 months.¹ Similar findings were recently presented in patients with stable brain metastases, in which the ORR was 58.3%, and the median PFS was 18.1 months.²

Moreover, the drug was associated with improved ORR and PFS across multiple subgroups, irrespective of ECOG performance status, HER2 immunohistochemistry status, prior pertuzumab (Perjeta), time since disease diagnosis, and hepatic impairment at baseline.

Common adverse effects (AEs) consisted of gastrointestinal and hematologic toxicities, with which oncologists are well versed in management, explained Gradishar. The primary concern is the potential for interstitial lung disease (ILD), which occurred in 13.6% of patients in the trial.³

“We don’t have specific characteristics of patients who have developed ILD at this point, nor do we have necessarily prophylactic measures we can utilize to identify those patients ahead of time. At this point, we just have to use a healthy bit of clinical acumen to decide when a patient needs to be evaluated further on that suspicion,” said Gradishar.

In an interview with OncLive, Gradishar, chief of hematology and oncology, Department of Medicine, Betsy Bramsen Professorship of Breast Oncology, professor of medicine (hematology and oncology), Northwestern University Feinberg School of Medicine, discussed the activity of trastuzumab deruxtecan in patients with metastatic HER2-positive breast cancer and the importance of building experience with the drug before evaluating it in combination or moving it into earlier lines of therapy.

OncLive:How has HER2-targeted therapy impacted the treatment paradigm in the metastatic setting?

Gradishar: What we’ve come to realize is that the development of targeted therapies has really changed the way we approach patients with breast cancer, both in the early- and late-stage settings. In the HER2-positive breast cancer space, we have seen the emergence of several new HER2-directed therapies that have really had a significant impact on outcomes for patients with metastatic disease. In the last year, we have had 3 new approvals in the metastatic setting: tucatinib (Tukysa), neratinib (Nerlynx), and trastuzumab deruxtecan. These drugs clearly have provided additional treatment options for patients with advanced disease.

The DESTINY-Breast01 trial, which evaluated trastuzumab deruxtecan, was a phase 2 trial that looked at patients with HER2-positive breast cancer who received 2 or more prior HER2-directed therapies, including ado-trastuzumab emtansine (T-DM1; Kadcyla). These patients received standard treatments prior to going on the trial. Importantly, in the trial, patients could have had stable brain metastases. The established dose, following the dose-finding portion of the trial, was 5.4 mg/kg administered intravenously every 3 weeks.

The most compelling piece of evidence that came from the trial is the fraction of patients who responded. The data that were presented in a waterfall plot really got the attention of everybody in the audience. When you looked at forest plots, there wasn’t a subset of patients who didn’t benefit.

More recently, we saw data from the ESMO Breast Cancer Virtual Meeting 2020 looking at the population of patients who had stable brain metastases. Even in this population, the benefit was clear in that group of patients. Certainly, the duration of benefit was longer in patients who did not have brain metastases, but it was clear that there was a benefit in patients who had stable brain metastases.

This is a drug that is very active and tolerable. However, one of the things that resulted in a Blackbox warning, along with the FDA approval, was the incidence of ILD, which occurred in a small fraction of patients. A couple of patients did die from ILD, which prompted the Blackbox warning. To date, we have not encountered that in clinical practice, but our level of suspicion, particularly in a coronavirus disease 2019 environment, has been heightened for anyone who has respiratory symptoms. As such, we have a low threshold for looking for things that may correspond to any sort of ILD-like toxicity. It’s something that everybody has to have a low threshold for.

Trastuzumab deruxtecan has made an impact. It’s going to be an important drug. I suspect that as we go forward with other trials, including those that are ongoing, such as the trial comparing trastuzumab deruxtecan with T-DM1, the drug will start to move into earlier lines of therapy in the metastatic setting. Whether or not this drug will find its way into a preoperative setting has yet to be determined. Certainly, it’s a very active drug in the metastatic HER2-positive breast cancer space and something that will be widely used.

Does the safety profile of the agent lend itself to be used in combination, or do you see it being moved into earlier lines of therapy as a single agent?

The biggest issue about toxicity is the ILD, which isn’t common. We have to have a better feel for it as we treat more patients. That will dictate whether it can be used in an early-stage setting. When you have curative intent, you don’t want to confer a potentially low probability, but life-threatening toxicity to a patient. I don’t think that anyone is necessarily rushing to the early-stage setting. I am confident it will move up in the algorithm for where it's used in the metastatic setting.

Trials are looking at combination therapy to determine whether we can enhance the drug’s single-agent activity. If you leave the issue of ILD, which is a low frequency event out of the equation, most of the other AEs that are seen are not unfamiliar to oncologists and certainly aren’t prohibitive. Gastrointestinal symptoms and hematologic toxicities are all things we’re very familiar with. For the most part, those are easily manageable. What will dictate combination therapy is how much those AEs are enhanced and whether or not the incidence of ILD increases in any way as it gets into the broader oncology community.

What data would you like to see with longer follow-up?

The one piece that’s missing with respect to the development of this drug is the activity of the drug in patients with progressive brain metastases or patients who have not been treated but do not have clinically significant brain metastases. If we can show that there’s activity in that subset of patients, it will enhance the utility of this drug.

Treatment for patients with progressive brain metastases still remains an unmet need. The data with tucatinib in that setting from the HER2CLIMB trial included patients with active brain metastases, and there was activity there. That’s one of the most compelling arguments from the HER2CLIMB data set. Looking at the activity of trastuzumab deruxtecan in patients with active brain metastases wouldn’t require a big trial. It would probably just require a small trial to try to identify what the activity of trastuzumab deruxtecan is in patients with progressive brain metastases.

References

1. Modi S, Andre F, Krop IE, et al. Trastuzumab deruxtecan for HER2-positive metastatic breast cancer: DESTINY-Breast01 subgroup analysis. J Clin Oncol. 2020;38(15 suppl):1036. doi:10.1200/JCO.2020.38.15_suppl.1036
2. Jerusalem G, Park YH, Yamashita T, et al. TCNS metastases in HER2-positive metastatic breast cancer treated with trastuzumab deruxtecan: DESTINY-Breast01 subgroup analyses. Ann Oncol. 2020;31(2 suppl 2):138O. doi:10.1016/annonc/annonc122
3. Modi S, Saura C, Yamashita T, et al. Trastuzumab deruxtecan in previously treated her2-positive breast cancer. N Eng J Med. 2020;382(7):610-621. doi:10.1056/NEJMoa1914510