Clarification about therapy with the anti-HER2 antibody-drug conjugate (ADC) trastuzumab deruxtecan (T-DXd) in previously treated patients who had metastatic breast cancer has emerged from a sub-study analysis of the Phase III DESTINY-Breast04 study reported at the ESMO Breast Cancer 2023 conference (ESMO Open 2023; https://doi.org/10.1016/j.esmoop.2023.101381).
"To me, the message is simple. When the time comes to consider the use of T-DXd, within availability, drug licensing, and prior therapies, the level of ER in your patient's cancer is irrelevant," said first author David Cameron, MD, medical oncologist at the Western General Hospital in the Cancer Research UK Edinburgh Centre and Chair of the Department of Oncology at Edinburgh University in Scotland.
The overall DESTINY study had established that T-DXd was effective not only in patients with HER2-positive tumors, regardless of expression level of estrogen-receptor (ER), but also in those categorized as having HER2-low scores, defined as those expressing HER2 immunohistochemical scores of 1+, or 2+ with non-amplified in-situ hybridization (N Engl J Med 2022; doi: 10.1056/NEJMoa2203690).
But worries continued about the relevance of estrogen receptor scores in treatment outcomes. So, the sub-study focused on ER expression, looking specifically at patients with low ER positivity scores: between 0.0 percent and 10 percent. The new sub-study confirmed that this finding of clinical benefit still held in these patients.
Study Details
Patients with HER2-low metastatic breast cancer who had been previously treated with one or two lines of chemotherapy were randomly assigned to either T-DXd or treatment of physician's choice-chemotherapy. Analyses of efficacy and safety were conducted for patients with ER scores from 0 to 10 percent. Among the 110 patients in the study, 58 had ER scores of 0 percent and 52 had ER in the range from 1.0-10 percent.
Progression-free survival (PFS) among the 40 patients with 0 percent ER score who had T-DXd was a median of 8.5 months compared with 2.9 months in the 18 patients who received physician's choice treatment. Overall survival was also extended among the patients treated with the ADC: to a median of 18.2 months, compared with 8.3 months for those on physician's choice.
Although mild-to-moderate treatment-emergent adverse events (AE) were relatively common (nausea, vomiting, fatigue, decreased appetite, alopecia, constipation, anemia, diarrhea, transaminases increased, white blood cell count decreased, and neutrophil count decreased), severe AEs (Grade 3 or higher) were less common with T-DXd (53.3% of patients) than with physician's choice chemotherapy (75.0%).
The authors concluded that the efficacy of T-DXd in comparison with physician's choice in patients with HER2-low ER 1-10 percent was consistent with the outcomes observed in patients with HER2-low ER 0 percent, and that T-DXd safety in the ER 0-10 percent subgroup was manageable and consistent with the DESTINY-Breast04 primary analysis finding a benefit from using the ADC.
Cameron told Oncology Times that the sub-study was conducted despite the fact that T-DXd had already been approved in all categories of HER2 positivity because of remaining concerns about its efficacy in patients with low ER scores.
"The reason we did it is that there is some uncertainty in the clinical world as to how you should treat ER-low breast cancer," he noted. "Does it behave like triple-negative? Does it behave like ER-positive? And we were sensing that in this small group of patients, there was uncertainty about what to do," he explained.
Analysis of the subset of data from the parent trial confirmed that the ADC was just as effective for all patients, including those with low or 0 ER scores.
Cameron said the sub-study results were important because clinicians commonly need to decide what to do when patients are no longer responding to treatments. "Patients who had endocrine therapy and had become refractory to it and had already received one or two lines of chemotherapy: What do you do at that point?"
Alternative chemotherapies could be tried, but Cameron said the response rates were "relatively disappointing." The DESTINY-Breast04 findings pointed to T-DXd as a good choice. "T-DXd has been shown to work really well in this population completely irrespective of the level of ER," he noted. "It doesn't matter what level of ER they have, T-DXd has been shown to work better than a basket of different chemotherapies."
Peter M. Goodwin is a contributing writer.