The combination of trastuzumab and deruxtecan led to significant improvements progression-free survival in metastatic breast cancer.
Approximately a quarter of metastatic breast cancers over-express human epidermal growth factor receptor 2 (HER2) and this is linked to a worse prognosis. The addition of trastuzumab to chemotherapy in early stage HERS2 positive metastatic breast cancer (MBC) has been found to reduce both recurrence and breast cancer mortality by a third. The conjugate T-Dxd (brand name Enhertu) consists of trastuzumab covalently bonded to deruxtecan, which is a topoisomerase I inhibitor and T-Dxd is already approved for the use in HER-2 positive unresectable or MBC. Furthermore, in the UK, NICE has also recommended the use of T-Dxd as option for treating HER2‑positive unresectable or MBC in adults after 2 or more anti‑HER2 therapies.
Results presented at the 2021 European Society for Medical Oncology (ESMO) conference relate to DESTINY-BREAST03, an open-label, phase 3 trial, in which T-Dxd (n = 261) was compared against trastuzumab emtansine (n = 263) in patients with MBC previously treated with trastuzumab and taxane. DESTINY-BREAST03 follows on from two earlier trials, DESTINY-BREAST01 and DESTINY-BREAST02. DESTINY-BREAST01, was published in 2020 and evaluated T-Dxd in adults with pathologically documented HER2-positive MBC who had received previous treatment with trastuzumab emtansine. This was followed by DESTINY-BREAST02, in which T-Dxd was compared against a treatment of the investigator’s Choice for HER2-positive, unresectable and/or metastatic breast cancer, in patients again previously treated with trastuzumab emtansine.
The latest results for DESTINY-BREAST03 and presented at the ESMO are a pre-specified interim analysis in which the primary endpoint was progression-free survival (PFS) in those with MBC. The analysis shows that T-Dxd demonstrated a 72% reduction in the risk of disease progression or death, compared to trastuzumab emtansine (hazard ratio, HR = 0.28, 95% CI 0.22-0.37, p < 0.0001). Furthermore, there was a strong trend towards improved overall survival with T-Dxd (HR = 0.56, 95% CI 0.36 – 0.86) and a higher proportion of patients assigned to T-Dxd were alive after 12 compared to trastuzumab emtansine (94.1% versus 85.9%). However, the median overall survival rate is not yet estimable but given the differences observed to date, researchers are hopeful that the difference will be significant once the study is completed.
Dr Aditya Bardia of Massachusetts General Hospital, Harvard Medical School, MA, USA, said that the efficacy results presented at the ESMO are quite compelling. He added that “it is wonderful to see such significant improvement in survival for patients with HER2-positive metastatic breast cancer, and the results will likely change practice, establishing T-DXd as the preferred therapy in the second-line setting.”