DESTINY-Breast06 results show Enhertu (trastuzumab deruxtecan) is the first HER2-directed medicine and ADC to demonstrate clinically meaningful benefit for patients in with HR-positive, HER2-low metastatic breast cancer

These results will be presented as a late-breaking oral presentation during the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting (abstract #LBA1000).

Enhertu is a specifically engineered HER2-directed DXd antibody drug conjugate (ADC) discovered by Daiichi Sankyo and being jointly developed and commercialised by AstraZeneca and Daiichi Sankyo. In the primary analysis of DESTINY-Breast06, results showed Enhertu reduced the risk of disease progression or death by 38% by blinded independent central review (BICR) versus chemotherapy in patients with HER2-low expression (hazard ratio [HR] 0.62; 95% confidence interval [CI]: 0.51-0.74; p<0.0001). median pfs was 13.2 months in the enhertu arm compared to 8.1 months for chemotherapy. pfs results by bicr in the overall trial population were similar and showed enhertu achieved a 37% reduction in the risk of disease progression or death compared to chemotherapy, with a median pfs of 13.2 months with enhertu versus 8.1 months for chemotherapy (hr 0.63; 95% ci: 0.53-0.75; p><0.0001).

A prespecified exploratory analysis showed the clinically meaningful improvement in PFS was consistent between patients with HER2-low and HER2-ultralow expression. In patients with HER2-ultralow expression, Enhertu reduced the risk of disease progression or death by 22% compared to chemotherapy with a median PFS of 13.2 months versus 8.3 months, respectively (HR 0.78; 95% CI: 0.50-1.21).

Giuseppe Curigliano, MD, PhD, Professor of Medical Oncology at the University of Milan and Head of the Division of Early Drug Development at the European Institute of Oncology, IRCCS, Italy and principal investigator for the trial, said: “Endocrine therapies are widely used early in the treatment of HR-positive metastatic breast cancer, but following one or more lines of treatment, patients often derive limited efficacy from further endocrine-based therapy. With a median progression-free survival of more than a year, the results from DESTINY-Breast06 show that Enhertu could become a new standard of care for patients with HER2-low- and HER2-ultralow-expressing tumours following endocrine therapy in the metastatic setting.”

Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, said: “DESTINY-Breast06 represents another potential paradigm shift in how we treat patients across the spectrum of HR-positive metastatic breast cancer. The results reinforce the potential for Enhertu to improve outcomes earlier in the treatment landscape and in a broader population of patients with HER2-expressing breast cancer who have never before been eligible for a HER2-directed therapy.”

In patients with HER2-low expression, confirmed objective response rate (ORR) was 56.5% for Enhertu versus 32.2% with chemotherapy. In the overall trial population, confirmed ORR was 57.3% for Enhertu versus 31.2% with chemotherapy and in patients with HER2-ultralow expression the confirmed ORR was 61.8% versus 26.3%, respectively. Complete responses were seen in 13 patients from the Enhertu arm, including nine patients with HER2-low expression. In the HER2-ultralow subgroup, four patients in the Enhertu arm had complete responses. No complete responses were seen in the chemotherapy arm.

Patients in the trial received a median of two prior lines of endocrine therapy in each treatment arm. In the overall trial population, 14.9% of patients (n=65) in the Enhertu arm and 19.2% of patients (n=82) in the chemotherapy arm had received one prior line of endocrine therapy. No patients in the trial had received prior chemotherapy treatment in the metastatic setting. Median duration of follow-up was 18.2 months. As of the data cut-off of 18 March .2024, a total of 119 patients (14%) remained on treatment, 89 patients receiving Enhertu and 30 receiving chemotherapy.

The safety profile of Enhertu was consistent with previous breast cancer clinical trials with no new safety concerns identified. The most common Grade 3 or higher treatment-related treatment-emergent adverse events occurring in 5% or more of patients treated with Enhertu were neutropenia (20.7%), leukopenia (6.9%) and anaemia (5.8%). Interstitial lung disease (ILD)/pneumonitis, adjudicated as drug-related by an independent committee, occurred in 11.3% of patients treated with Enhertu. The majority of ILD events were low Grade (Grade 1 [n=7; 1.6%]; Grade 2 [n=36; 8.3%]). There were three Grade 3 ILD events (0.7%), no Grade 4 events and three Grade 5 events (0.7%).

DESTINY-Breast03 updated results: Updated overall survival (OS) results from the DESTINY-Breast03 Phase III trial showed Enhertu continued to demonstrate a clinically meaningful survival improvement over trastuzumab emtansine (T-DM1) after more than three years of follow up in patients with HER2-positive unresectable and/or metastatic breast cancer previously treated with trastuzumab. Results showed median OS was 52.6 months in the Enhertu arm compared to 42.7 months for T-DM1 (HR 0.73; 95% CI: 0.56-0.94). The safety profile of Enhertu continues to be generally manageable and no cumulative toxicities were observed with longer follow-up. Results will be presented during the 2024 ASCO Annual Meeting (abstract #1025).