CHMP recommends Enhertu for HER2-low breast cancer treatment

5th January 2023

The Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion on Enhertu for treating HER2-low breast cancer

According to AstraZeneca, the Committee for Medicinal Products for Human Use (CHMP), has adopted a positive opinion recommending a change to the marketing authorisation for Enhertu.

The drug can now be used as monotherapy for the treatment of adult patients with unresectable or metastatic HER2‑low breast cancer who have received prior chemotherapy in the metastatic setting or developed disease recurrence during or within six months of completing adjuvant chemotherapy.

The World Health Organization estimates that in 2020, there were 2.3 million women diagnosed with breast cancer and which led to 685 000 deaths. In Europe alone in 2020, there were 531,086 cases of breast cancer that resulted in 141,765 deaths.

The human epidermal growth factor receptor 2 (HER-2) is a receptor tyrosine-protein kinase normally involved in the proliferation and division of breast cells and HER2-positive breast cancers are an aggressive type of breast cancer that tend to grow faster and are more likely to spread.

It is known that around 50% of all primary breast cancers show a low-level expression of HER2 (HER2-low), defined as immunohistochemically 1+ or 2+ and lack of HER2 gene amplification measured by in situ hybridisation. Moreover, this low HER2 expression is a promising new target for antibody-drug conjugates and Enhertu (which contains trastuzumab deruxtecan) is one such specifically engineered HER2-directed antibody drug conjugate.

Enhertu clinical efficacy

CHMP based its decision of data from the DESTINY-BREAST04 trial which compared previously treated patients with HER2-low (immunohistochemistry (IHC) 1+ or IHC 2+/in-situ hybridisation (ISH)-negative) unresectable and/or metastatic breast cancer with hormone receptor (HR) positive or HR-negative disease against standard of care physician’s choice of chemotherapy.

The study found that Enhertu demonstrated a 49% reduction in the risk of disease progression or death versus physician’s choice of chemotherapy in patients with HER2-low metastatic breast cancer with HR-positive disease (PFS hazard ratio, HR = 0.51, 95% CI 0.40 – 0.64, p < 0.001). In addition, the median overall survival in the hormone receptor–positive cohort was 23.9 months in the Enhertu group and 17.5 months in the physician’s choice group (HR for death = 0.64, 95% CI, 0.48 to 0.86, p = 0.003).

The safety profile of Enhertu was consistent with previous clinical trials with the most common Grade 3 or higher treatment-emergent adverse events were neutropenia (13.7%), anaemia (8.1%), fatigue (7.5%), leukopenia (6.5%), thrombocytopenia (5.1%) and nausea (4.6%).

A summary of the CHMP provides details on the full indications for Enhertu.

Metastatic breast cancer progression-free survival improved by trastuzumab-deruxtecan

27th September 2021

The conjugate trastuzumab-deruxtecan significantly improves progression-free survival in patients with metastatic breast cancer.

Around a quarter of metastatic breast cancers over-express human epidermal growth factor receptor 2 (HER2) and which is associated with a worse prognosis. Addition of trastuzumab to chemotherapy in early stage HERS2 positive metastatic breast cancer (MBC), reduces 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.

DESTINY-BREAST03

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.”

Source: AstraZeneca release, September 2021