New HER2 Antibody-drug Conjugate Yielded Promising Clinical Responses in Breast Cancer Patients Pretreated with T-DM1
SAN ANTONIO — The investigational HER2-targeted antibody-drug conjugate [Fam-] trastuzumab deruxtecan (T-DXd) demonstrated durable objective responses in patients with HER2-positive breast cancer who were heavily pretreated, including with T-DM1 (Kadcyla) and other HER2-targeted treatments, according to results from the phase II clinical trial DESTINY-Breast01 presented at the San Antonio Breast Cancer Symposium, held Dec. 10-14.
Data from this study are being published simultaneously in the New England Journal of Medicine.
“Although HER-2 directed therapies such as trastuzumab (Herceptin), pertuzumab (Perjeta), and T-DM1 have led to improved outcomes for patients with HER2-positive advanced breast cancer, resistance to these drugs develops almost inevitably and we do not have a clear standard of care for these patients once resistance occurs,” said Ian Krop MD, PhD, associate chief of the Division of Breast Oncology at Dana-Farber Cancer Institute. “Thus, there clearly is an unmet medical need for new and improved therapies for such patients.”
Similar to T-DM1, T-DXd has a monoclonal antibody targeted toward HER2, but unlike T-DM1, which has a microtubule inhibitor as the cytotoxic payload, T-DXd has a topoisomerase 1 inhibitor as the payload. T-DXd has eight molecules of the payload, which is twice as many as T-DM1, Krop explained.
Data published from a prior phase I study showed T-DXd yielded an objective response rate of 59 percent in patients with advanced HER-2 positive breast cancer previously treated with T-DM1. The U.S. Food and Drug Administration granted priority review to T-DXd in October.
In the phase II study, Krop and colleagues enrolled 253 patients with metastatic HER2-positive breast cancer previously treated with T-DM1. The trial had three parts, I, IIa, and IIb, and overall, 184 patients received the recommended phase II dose (RP2D) of 5.4 mg/kg T-DXd. The patients had received a median of six prior treatments for advanced disease, including HER2-targeted therapeutics.
The overall response rate in the 184 patients who received the RP2D was 60.9 percent, with 6 percent complete responses (CR) and 54.9 percent partial responses (PR). The median progression free survival was 16.4 months.
“Both of these measures of efficacy are substantially higher than that seen in any other study of patients with pretreated HER2-positive metastatic breast cancer,” Krop said.
The disease control rate in the 184 patients was 97 percent. “This suggests that the vast majority of cancers in this population seem to have at least some sensitivity to this agent,” Krop noted. “Consistent with this, the objective response rate to T-DXd appeared largely independent of tumor hormone receptor status, prior exposure to pertuzumab, and prior history of brain metastases.”
Ninety-nine percent of the patients had treatment-emergent adverse events (TEAEs), with 57 percent experiencing TEAEs of grade 3 or higher, including decreased neutrophil count, nausea, anemia, decreased lymphocyte count, and fatigue; 15 percent of patients discontinued treatment because of TEAEs.
Interstitial lung disease (ILD) was observed in 25 patients. “ILD is a serious concern in patients treated with T-DXd,” said Krop. “While these events were primarily grade 1 or 2, there were unfortunately four grade 5 ILD-related deaths (2.2 percent) on the study. Because of this potential toxicity, close monitoring for signs and symptoms of ILD is recommended for early detection. If ILD is suspected, evaluations should include high-resolution CT, pulmonologist consultation, pulmonary function tests, and other tests. Although data on treatment for T-DXd-induced ILD are limited, if diagnosed, interruption of treatment and prompt intervention with glucocorticoids is recommended.”
Krop added, “The high rate of durable responses observed with trastuzumab deruxtecan in patients whose cancers had progressed on T-DM1 and other therapies suggests this agent could provide a new treatment option for this patient population.”
A limitation of the study is that this was a single-arm trial and therefore it is not possible to determine whether T-DXd is more effective than other therapies from these data.
The study was sponsored by Daiichi Sankyo Inc. and AstraZeneca. Krop received grant support and research support from Genentech/Roche and Pfizer; personal fees from Daiichi Sankyo, Macrogenics, AstraZeneca, and Genentech/Roche.