Trastuzumab Deruxtecan Revolutionizes Treatment in HER2+ Breast Cancer

Sara A. Hurvitz, MD

In the dynamic landscape of cancer treatment, fam-trastuzumab deruxtecan-nxki (Enhertu; T-DXd) has emerged and shown activity as a significant targeted therapy against HER2-positive breast cancer, according to Sara A. Hurvitz, MD.

T-DXd gained accelerated approval after it showed an impressive objective response rate (ORR) of over 60% and a progression-free survival (PFS) of over 16 months in this patient population. In the confirmatory DESTINY-Breast03 trial (NCT03529110), T-DXd outperformed trastuzumab emtansine (Kadcycla; T-DM1) in terms of PFS, ORR, and showed potential for improved overall survival (OS).

In 2022, the results of DESTINY-Breast04 were presented and demonstrated that T-DXd reduced the risk of death by 36% vs physician's choice of chemotherapy in patients with HER2-low, hormone receptor–positive metastatic breast cancer. This led to the FDA approval for T-DXd for this indication.

Now, investigators are further evaluating antibody drug conjugates (ADCs), bispecific antibodies, bispecific T-cell engagers (BiTE) with the hopes of answering the many unanswered questions that still linger in the HER2-positive breast cancer space, including how to optimally treat patients who have brain metastases, how to best sequence treatments, and more.

In an interview with Targeted Oncology^TM, Hurvitz, senior vice president, director, and professor in the Clinical Research Division at Fred Hutch Cancer Center, discusses the impact of trastuzumab deruxtecan, new developments, and unmet needs in the HER2-positive breast cancer space.

Targeted Oncology: Can you discuss the DESTINY-Breast03 study and some other highlights in the HER2-positive breast cancer space?

Hurvitz: Trastuzumab deruxtecan really hit the scene in 2019 at San Antonio when a single-arm, phase 2 trial evaluating T-DXd in patients with heavily pretreated HER2-positive metastatic breast cancer who were treated with this agent had an objective response rate of over 60% and a progression-free survival of over 16 months. We've never seen results with HER2-targeted therapies or any therapy for this type of disease, and it led to the accelerated approval of T-DXd in early 2020.

The confirmatory phase 3 clinical trial evaluating T-DXd head-to-head against trastuzumab emtansine was reported in 2021, at ESMO. This study was the first randomized phase 3 study looking at T-DXd, and it demonstrated a statistically significant improvement in progression-free survival with T-DXd compared to T-DM1, as well as improvements in terms of objective response rate, and a trend toward an improvement in overall survival. The overall survival at the time of the reporting was not yet mature. At San Antonio in 2022, the data from DESTINY-Breast03 were updated with overall survival data.

Now at the time of this reporting, the overall survival was statistically and significantly better with T-DXd. The median overall survival hadn't been reached yet for either treatment arm, but the overall survival hazard ratio was significantly better with T-DXd, with a hazard ratio of .64. Moreover, the median PFS for T-DXd had been met at 28.8 months compared with around 6.8 months for T-DM1 and again, the objective response rates and clinical benefit rates were better with T-DXd. It really was a homerun in favor of T-DXd in patients who'd received 1 prior line of therapy in the metastatic setting with HER2-positive disease.

In addition, in 2022, we saw the reporting of the DESTINY-Breast02 study [NCT03523585], which is a randomized study comparing T-DXd to either trastuzumab and capecitabine or lapatinib and capecitabine. Those data at San Antonio also demonstrated a statistically significant improvement in progression-free survival and overall survival with T-DXd in patients who had previously received T-DM1. We now have high-level evidence supporting the use of T-DXd in either the second-line setting or beyond compared with standard-of-care therapies, making it the standard-of-care choice, according to our guidelines.

Can you explain data from the DESTINY-Breast04 study?

In 2022 at ASCO, we saw results from the DESTINY-Breast04 study looking at T-DXd in patients who don't have overexpression of HER2 or amplification of HER2 on their tumors but have low levels of expression by immunohistochemistry and the absence of amplification. In this study, T-DXd was compared with single-agent chemotherapy, and it showed that T-DXd was associated with an improved progression-free survival and overall survival compared with single-agent chemotherapy in patients who had at least received 1 or 2 prior lines of chemotherapy in the metastatic setting. This benefit was seen for hormone receptor-positive, HER2-low expressing cancers, or triple negative, HER2-low expressing breast cancers. That really was practice changing. Those were practice-changing results that immediately impacted the way that we were able to treat patients with this type of breast cancer.

What other recent clinical trials in HER2-positive space do you think are important to highlight?

There are a number of other ongoing studies in HER2-positive disease. There are studies evaluating trastuzumab deruxtecan in early-stage, high-risk disease, as well as in the frontline setting against standard trastuzumab/pertuzumab [Perjeta]. There are also studies looking at T-DXd in patients with active brain metastases, and further studies looking at T-DXd in HER2-low breast cancer, in addition to T-DXd, which really is sort of the poster child for HER2-targeted [antibody drug conjugates].

There are other interesting, innovative molecules being evaluated in clinical trials. We did see results relating to trastuzumab duocarmazine or SYD985 at ESMO a few years ago, from the TULIP clinical trial [NCT03262935], a phase 3 study looking at SYD985 vs treatment of physician’s choice. This did meet its primary end point of showing an improved progression-free survival, but there was some concerning toxicity associated with this drug, including ocular toxicities as well as pneumonitis. This agent is not yet FDA-approved. It'll be interesting to see when or whether it is approved.

There are also studies in development that are bispecific antibodies, for example, zanidatamab [ZW49] which is a bispecific, HER2-targeted therapy in clinical trials. There are studies of other novel ADCs in clinical development, as well as other antibodies and BiTE targeted therapies that are going after HER2. It's going to be an exciting time in the next 2-3 years as we see data emerge in this realm.

What are some of the important questions for the field right now? Which of these unanswered questions do you hope is addressed sooner in future research?

There are a number of unanswered questions, 1 of them being how to optimally treat patients who have brain metastases with HER2-positive breast cancer. Nearly 50% of patients with HER2-positive metastatic breast cancer will develop brain metastases. Although we have agents, for example, tucatinib [Tukysa] and neratinib [Nerlynx], which can cross the blood brain barrier, we have not yet seen phase 3 results indicating other drugs that may be beneficial in this setting. We have promising results relating to trastuzumab deruxtecan from the TUXEDO-1 trial [NCT04752059] and the DEBBRAH study [NCT04420598]. Both of those studies are looking at T-DXd in active brain metastases, and there are ongoing studies as well.

I'm interested in seeing more data regarding this agent's use in active brain metastases, and I'm also excited to see other drugs that are in development that may cross the blood brain barrier, and second generation HER2-selective TKIs. For example, another area that's an unanswered question is how best we can sequence ADCs, and are ADCs effective when sequenced 1 after the other if they're going after a similar target, and whether or not the payload matters in the development of cross resistance to ADCs. We know that T-DXd works after T-DM1 based on the DESTINY-Breast02 trial. What we don't know is whether T-DM1 works after T-DXd. That's going to be important for us to evaluate in ongoing studies.

Other areas that are questionable are whether the currently available agents or agents in development can be effective against leptomeningeal disease. There are studies ongoing to evaluate that and evaluating the optimal management of interstitial lung disease, which can be life threatening. At this point, if a patient even has mildly symptomatic [interstitial lung disease] with T-DXd, you must permanently discontinue the drug. Whether or not this can be safely resumed upon resolution is an unanswered question that's being asked in clinical trials now. A lot of different studies are going to be helping to address some of these unanswered questions.

REFERENCE:

1. FDA approves fam-trastuzumab deruxtecan-nxki for HER2-low breast cancer. FDA. August 5, 2022. Accessed September 15, 2023. https://bit.ly/3BAS4NQ