Unanswered Questions in the HER2+ Breast Cancer Space

Sara A. Hurvitz, MD, medical oncologist and clinical research leader at the Fred Hutchinson Cancer Center in Seattle, WA, discusses some of the current important questions for the field of HER2-positive breast cancer now and highlights which of these unanswered questions she hopes are addressed soon.

Hurvitz, who is also senior vice president of the clinical research division at Fred Hutch and head of the division of hematology and oncology at the University of Washington Department of Medicine, discusses novel agents, including antibody-drug conjugates like trastuzumab deruxtecan (T-Dxd; Enhertu) and trastuzumab emtansine (T-DM1), as well as challenges in treating breast cancer like brain metastases.

Transcription:

0:10 | 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.

0:59 | 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 [tyrosine kinase inhibitors], 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 [NCT03523585]. 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.

1:55 | 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.