Novel ADC Solidifies Role in Breast Cancer

Patients with metastatic HER2-positive breast cancer may soon have a new treatment option: the antibody–drug conjugate (ADC) trastuzumab deruxtecan (T-DXd; AstraZeneca/Daiichi Sankyo). In a phase II trial, the drug was associated with a high objective response rate (ORR) and a long median progression-free survival (PFS), although some patients developed serious side effects. Results were presented at the 2019 San Antonio Breast Cancer Symposium in Texas, December 10–13, and simultaneously published in The New England Journal of Medicine (N Engl J Med 2019 Dec 11 [Epub ahead of print]).

T-DXd consists of the HER2-targeting monoclonal antibody trastuzumab attached with a cleavable linker to a cytotoxic payload—a topoisomerase I inhibitor derived from exatecan. Ian Krop, MD, PhD, of Dana-Farber Cancer Institute in Boston, MA, who presented the results, highlighted the drug's distinct features: Its payload is from a class of chemotherapies not typically used in HER2-positive disease, making resistance less likely to have already developed; each antibody carries eight payload molecules, compared with four on the ADC T-DM1 (ado-trastuzumab emtansine, Kadcyla; Genentech); and the payload permeates cell membranes, allowing it to diffuse out of targeted cells and kill neighboring tumor cells.

In a phase I trial, T-DXd elicited an ORR of 59.5% in patients with previously treated advanced HER2-positive breast cancer (Lancet 2019;20:816–26). Now, researchers are reporting on the DESTINY-BREAST01 trial. Patients had received a median of six prior lines of therapy; all had received trastuzumab (Herceptin; Genentech) and T-DM1, and 65.8% had received the HER2 antibody pertuzumab (Perjeta; Genentech).

Among 168 evaluable patients, 60.9% responded to the drug and 6% experienced complete responses. The median duration of response was 14.8 months and the median PFS was 16.4 months; the median overall survival was not reached. The drug had similar activity across subgroups, including those with brain metastases. With existing therapies, Krop noted, patients have a median PFS of about 4 to 5 months.

Study data “demonstrate the potential of trastuzumab deruxtecan to become a new standard of care for patients with pretreated, advanced, HER2-positive breast cancer,” said Ian Krop, MD, PhD.

Virtually all patients experienced side effects, most commonly nausea and fatigue; 48.4% experienced grade 3 or higher drug-related adverse events. Interstitial lung disease (ILD), a serious side effect that can cause lung scarring, occurred in 13.6% of patients and led to four deaths. An independent panel of pulmonary experts concluded that patients should be closely monitored, with the drug stopped and steroids started upon suspicion of ILD.

“The results are very impressive— if and when this drug becomes approved, I definitely think it will be utilized in patients with metastatic disease,” said Kevin Kalinsky, MD, of the Herbert Irving Comprehensive Cancer Center at Columbia University in New York, NY. However, he underscored the seriousness of ILD. “I think as a field we'll have to define who's at risk of developing this, and we'll have to understand this toxicity in greater depth,” Kalinsky said.

Cesar Santa-Maria, MD, of Johns Hopkins Medicine in Baltimore, MD, considers the toxicity acceptable for metastatic disease, but said it needs to be “ironed out quite thoroughly” before using the drug for earlier-stage disease. He predicted that clinicians will learn to manage ILD as they gain experience with the drug, as they did for cardiac side effects linked to trastuzumab.

Jessica Tao, MD, also of Johns Hopkins, wondered about the efficacy of T-DXd in patients with HER2-low disease—a group ineligible for existing HER2-targeted agents. This question is being explored in a phase III trial. “Any efficacy seen with this anti-HER2 ADC in the HER2-low cohort would be really exciting,” she said, not only because more patients could benefit, but also because it could “really shape and redefine our definition of what is HER2 positivity.” –Catherine Caruso