AstraZeneca and Daiichi Sankyo Present Updated DESTINY-Breast01 Data for Enhertu in HER2-Positive Metastatic Breast Cancer at SABCS

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On December 10, AstraZeneca and its partner Daiichi Sankyo announced the latest results from the pivotal Phase II DESTINY-Breast01 trial at the 2020 San Antonio Breast Cancer Symposium (SABCS). The data demonstrated that Enhertu (trastuzumab deruxtecan) continued to show impressive efficacy and durable responses in patients with metastatic breast cancer who had previously received two or more HER2-targeted regimens. Notably, exploratory analysis indicated that an estimated three-quarters of patients were alive at 18 months, representing encouraging milestone survival data.

DESTINY-Breast01 is a pivotal, single-arm, open-label, global, multicenter, two-part Phase 2 trial evaluating the safety and efficacy of Enhertu (5.4 mg/kg) as monotherapy in patients with HER2-positive, unresectable and/or metastatic breast cancer. The study enrolled 184 patients from more than 100 clinical sites worldwide. These patients had previously received two or more HER2-targeted regimens, with a median of 6 prior therapies (range: 2–27) for metastatic disease, including trastuzumab emtansine (T-DM1; 100% of patients), trastuzumab (100% of patients), pertuzumab (65.8% of patients), other anti-HER2 therapies (54.3% of patients), hormonal therapy (48.9% of patients), and other systemic treatments (99.5% of patients). The primary endpoint was overall response rate (ORR) as assessed by an independent central review (ICR); secondary endpoints included duration of response (DoR), disease control rate (DCR), clinical benefit rate, progression-free survival (PFS), and overall survival (OS).

Updated results presented at the meeting showed that, with a median follow-up of 20.5 months, Enhertu treatment achieved an ORR of 61.4%, a median DOR of 20.8 months, and a median PFS of 19.4 months. In an exploratory milestone analysis of OS, assessment at 35% data maturity indicated that an estimated 74% of patients were still alive at 18 months. In the previous analysis with a median follow-up of 11.1 months, the ORR was 60.9%, the median DOR was 14.8 months, and the median PFS was 16.4 months.

The overall safety and tolerability profile of Enhertu remained consistent with previously reported data, with few additional treatment discontinuations due to adverse events observed over the extended treatment period. In the latest analysis, 18.5% of patients discontinued treatment due to adverse events, compared to 15.2% in the previous analysis. The majority of interstitial lung disease (ILD) or pneumonitis cases occurred within the first 12 months of treatment, indicating that the risk of ILD or pneumonitis toxicity is not associated with cumulative exposure to Enhertu. According to the independent review committee, three new treatment-related ILD cases were reported, including one Grade 1 case, one Grade 2 case, and one fatal (Grade 5) case. Two potential cases were pending adjudication at the data cutoff. Continued monitoring for pulmonary symptoms and ensuring early intervention remain essential.

Based on the early results of the DESTINY-Breast01 trial, Enhertu was approved in the United States and Japan for the treatment of HER2-positive, unresectable or metastatic breast cancer. In the United States, Enhertu was approved under the FDA’s accelerated approval pathway, and confirmatory trials are currently underway.

Breast cancer is the most common type of cancer in women, with approximately 20% of cases being HER2-positive. HER2 is a growth-promoting protein that functions as a tyrosine kinase receptor and is present on the surface of various types of tumors. In breast cancer, it is associated with aggressive disease and poorer prognosis. Currently, HER2-positive metastatic breast cancer remains incurable, and many patients eventually experience disease progression.

Enhertu is a HER2-targeted antibody-drug conjugate (ADC), representing the leading ADC in Daiichi Sankyo’s oncology portfolio and the most advanced program within AstraZeneca’s ADC science platform. Enhertu links trastuzumab, a HER2-targeted monoclonal antibody, to DXd, a novel topoisomerase I inhibitor, via a tetrapeptide linker. This design enables targeted delivery of the cytotoxic agent into HER2-expressing cancer cells, thereby reducing systemic exposure to the cytotoxic payload compared with conventional chemotherapy.

Currently, Enhertu has been approved in the United States and Japan for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer, and in Japan for the treatment of adult patients with unresectable advanced or recurrent HER2-positive gastric cancer.

In breast cancer, AstraZeneca and Daiichi-Sankyo are conducting multiple randomized Phase III clinical trials to further evaluate the role of Enhertu in patients with HER2-positive metastatic breast cancer, including:

DESTINY-Breast02 is evaluating Enhertu as a third-line treatment regimen for patients with HER2-positive metastatic breast cancer;

DESTINY-Breast03 is evaluating Enhertu as a second-line treatment regimen for these patients;

DESTINY-Breast04 is evaluating the role of Enhertu in patients with HER2-low metastatic breast cancer.

Reference source: Enhertu continues to demonstrate durable responses with new data from DESTINY-Breast01 in HER2-positive metastatic breast cancer