Among breast cancer patients, HER2 positivity accounts for approximately 15%–20%, while among the remaining HER2 negative patients, those with low HER2 expression account for 45%–55%. Previously, these patients were not suitable for HER2-targeted therapy. The success of Enhertu promises to enable these patients to also benefit from HER2-targeted therapy.
On June 27th, the First Three Communist Party announced ADC Medication Enhertu Used for treatment HER2 Low expression breast cancer has submitted the application for listing of new indications in Japan.
This marketing application is based on data from the DESTINY-Breast04 study. The DESTINY-Breast04 study was a randomized, open-label, global, multicenter, phase III clinical trial evaluating the efficacy and safety of Enhertu (5.4 mg/kg) versus physician-selective chemotherapy (capecitabine, eribulin, gemcitabine, paclitaxel, or nab-paclitaxel) in patients with HR-positive (n=480) or HR-negative (n=60) HER2-low-expressing unresectable and/or metastatic breast cancer who had previously received one or two chemotherapy regimens. Patients were randomized 2:1 to receive either Enhertu or chemotherapy. The primary endpoint was progression-free survival (PFS) in HR-positive patients assessed by BICR, and key secondary endpoints included PFS in all BICR-assessed patients, overall survival (OS) in HR-positive patients, and overall survival (OS) in all patients.
The primary endpoint analysis of the DESTINY-Breast04 trial showed that, compared with physician-selected chemotherapy regimens, T-DXd reduced the risk of disease progression or death by 49% in patients with HR-positive, HER2-low-expressing metastatic breast cancer (PFS hazard ratio [HR] 0.51; 95% confidence interval [CI]: 0.40–0.64; p < 0.001). According to a blinded independent central review (BICR) assessment, the median PFS was 10.1 months in the T-DXd treatment group and 5.4 months in the chemotherapy group.
The trial results also showed that in HR-positive patients, T-DXd reduced the risk of death by 36% compared to chemotherapy (OS HR 0.64; 95% CI: 0.48–0.86; p = 0.003). The median OS was 23.9 months in the T-DXd group and 17.5 months in the chemotherapy group. The results met the trial's key secondary endpoint.
Furthermore, the study data showed that T-DXd demonstrated consistent efficacy in the overall trial population of patients with HR-positive or HR-negative HER2-low expression metastatic breast cancer, regardless of HER2 expression levels (IHC 1+ and IHC 2+/ISH-). In the analysis of the key secondary endpoint of PFS based on BICR for all patients, T-DXd also reduced the risk of disease progression or death by 50% compared to chemotherapy (PFS HR 0.50; 95% CI: 0.40–0.63; p<0.001). T-DXd reduced the risk of death by 36% compared to chemotherapy (OS HR 0.64; 95% CI: 0.49–0.84; p=0.001), with a median OS of 23.4 months in the T-DXd group and 16.8 months in the chemotherapy group.
An exploratory analysis of HR-negative patients (n=58) showed that the median PFS was 8.5 months in the T-DXd group and 2.9 months in the chemotherapy group (PFS HR 0.46; 95% CI: 0.24–0.89), and the median OS was 18.2 months in the T-DXd group and 8.3 months in the chemotherapy group (OS HR 0.48; 95% CI: 0.24–0.95).
The safety profile of T-DXd was consistent with previous clinical trials, with no new safety issues identified. The most common grade 3 or higher treatment-related adverse events included neutropenia (13.7%), anemia (8.1%), fatigue (7.5%), leukopenia (6.5%), thrombocytopenia (5.1%), and nausea (4.6%).
The incidence of interstitial lung disease (ILD) or pneumonia was consistent with that observed in later-line trials of T-DXd in HER2-positive breast cancer, with an independent decision committee determining a lower incidence of grade 5 ILD. Most (10%) events were low-grade (grade 1 or 2), with 5 grade 3 events reported (1.3%), no grade 4 events reported, and 3 grade 5 events reported (0.8%).
Beyond the latest developments in Europe and Japan, in April of this year, the FDA also granted Enhertu Breakthrough Therapy designation for the treatment of HER2-low-expressing breast cancer, and it is expected that this indication will soon be submitted for approval in the United States.
