Enhertu® (fam-trastuzumab deruxtecan-nxki) is the first antibody-drug conjugate available for use by adults to treat locally advanced or metastatic human epidermal growth factor receptor 2 (HER2)-positive gastric cancer or gastroesophageal junction (GEJ) adenocarcinoma that progressed after a previous trastuzumab-based regimen.

The drug is also indicated for the treatment of unresectable or metastatic HER2-positive breast cancer in adults who have undergone two or more previous metastatic HER2-based regimens. It is also intended for the treatment of HER2-mutant (HER2m) metastatic non-small cell lung cancer (NSCLC) in patients who received platinum-containing chemotherapy.

Developed jointly by AstraZeneca and Daiichi Sankyo, Enhertu is available as a 100mg sterile, white to yellowish-white lyophilised powder in a single-dose vial with the recommended dosage of 6.4mg / kg as an intravenous infusion once every three weeks (21-day cycle) until disease progression or unacceptable toxicity.

Enhertu is being evaluated further under a comprehensive clinical development programme that will assess its efficacy and safety across several HER2-targetable cancers, including gastric, breast, lung, and colorectal cancers.

ENHERTU approvals

Daiichi Sankyo and AstraZeneca formed a strategic collaboration for the co-development and co-promotion of Enhertu in March 2019.

ENHERTU (fam-trastuzumab deruxtecan-nxki) was awarded the breakthrough therapy designation (BTD) and orphan drug designation (ODD) in the US for the treatment of patients with gastric cancer, including gastroesophageal junction adenocarcinoma in May 2020.

In October 2020, the drug received approval for its supplemental biologics licence application (sBLA) and a US priority review for the treatment of patients with HER2-positive adenocarcinoma of the metastatic gastric or GEJ.

The US Food and Drug Administration (FDA) approved Enhertu (fam-trastuzumab deruxtecan-nxki) for the treatment of locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma in adult patients who received a prior trastuzumab-based regimen, in January 2021.

Daiichi Sankyo also submitted a supplemental new drug application (sNDA) to Japan’s Ministry of Health, Labour and Welfare (MHLW) for Enhertu for the treatment of patients with HER2-positive metastatic gastric cancer in May 2020 and the drug was approved in Japan in September 2020.

Japan’s MHLW previously granted SAKIGAKE designation to Enhertu for the treatment of HER2-positive advanced gastric or gastroesophageal junction cancer in March 2018.

Enhertu (trastuzumab deruxtecan) is also approved for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer in the US, Europe and Japan.

The drug was also granted a BTD in the US for the treatment of patients with metastatic NSCLC in May 2020.

Enhertu was granted breakthrough therapy designation in the US for HER2-positive metastatic breast cancer patients treated with at least one prior anti-HER2-based regimen in October 2021. The approval was based on the results of the DESTINY-Breast03 Phase III clinical study.

FDA granted priority review status to Enhertu for adult patients with HER2-positive unresectable or metastatic breast cancer who received a prior anti-HER2-based regimen in January 2022.

The priority review status was in response to the sBLA for Enhertu. It was based on the results of the DESTINY-Breast03 trial.

Gastric cancer causes and symptoms

Gastric cancer, also known as stomach cancer, is the fifth most prevalent cancer in the world and the third leading cause of cancer mortality, with a five-year survival rate of 5% for metastatic disease. The disorder is often not diagnosed until it progresses to advanced stages, and its survival rate remains modest even for early diagnosis of the disease.

In the US in 2020, approximately 27,600 gastric cancer cases were diagnosed and more than 11,000 people died as a result of the illness.

Approximately 27,600 new gastric cancer cases were diagnosed, and more than 11,000 people died as a result of the illness in the US in 2020.

Symptoms of the disease include indigestion or stomach discomfort, bloody stools, weight loss, jaundice, stomach pain, bloated feeling after eating, jaundice, ascites, vomiting, diarrhoea, heartburn, and appetite loss.

The combination of chemotherapy with trastuzumab, an anti-HER2 drug has been recommended as the first-line regimens for HER2-positive advanced or metastatic gastric cancer.

Fam-trastuzumab deruxtecan-nxki mechanism of action

Fam-trastuzumab deruxtecan-nxki is a HER2-directed antibody-drug conjugate composed of an IgG1 humanised anti-HER2 antibody.

The drug’s small molecule is DXd, an inhibitor of topoisomerase I. This binds to the HER2 antibody found on tumour cells via a cleavable linker, after which fam-trastuzumab deruxtecan-nxki undergoes internalisation and intracellular linker cleavage by lysosomal enzymes.

DXd permeable membrane causes DNA damage and apoptotic cell death after it is released through cleavage.

Clinical trials on Enhertu

The FDA’s approval of Enhertu for the treatment of patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma was based on the outcome of a randomised, open-label, multicentre, pivotal phase two trial, DESTINY-Gastric01.

The drug’s safety and efficacy were evaluated in 188 patients from Japan and South Korea with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma, who had progressed to at least two previous regimens, including trastuzumab, fluoropyrimidine or platinum-containing chemotherapy.

Patients were randomised at a 2:1 ratio to receive Enhertu 6.4mg/kg intravenously every three weeks or a physician’s choice of chemotherapy, which was either irinotecan or paclitaxel monotherapy.

The trial’s primary efficacy outcome measures were the overall survival (OS) and objective response rate (ORR) as assessed by the independent central review (RECIST v1.1) in the intent-to-treat population. Additional efficacy outcome measures included progression-free survival (PFS) and duration of response (DOR).

The OS reached a median of 12.5 months in the Enhertu arm compared with 8.4 months in the irinotecan or paclitaxel arm, while the ORR of the Enhertu arm was 40.5% compared with 11.3% in the chemotherapy segment.

Enhertu also demonstrated a median PFS of 5.6 months versus 3.5 months for chemotherapy. The median DOR was 11.3 months in the Enhertu arm, compared with 3.9 months in the irinotecan or paclitaxel arm.

The most frequent side effects associated with the use of Enhertu were nausea, fatigue, vomiting, diarrhoea, leukopaenia, anaemia, thrombocytopaenia, neutropaenia, lymphocytopaenia, decreased appetite, and laboratory abnormalities. Adverse reactions also include increased blood alkaline phosphatase, increased alanine aminotransferase, increased aspartate aminotransferase, increased blood bilirubin, constipation, alopaecia, hypokalaemia, and pyrexia.

Results from the positive Phase II DESTINY-Lung01 trial of Enhertu were presented at the European Society for Medical Oncology (ESMO) Congress in September 2021. The data indicated an ORR of 54.9% in patients with HER2m unresectable and/or metastatic non-squamous NSCLC.

The DESTINY-Breast03 data indicated that Enhertu reduced the risk of disease progression or death by 72% when compared with trastuzumab emtansine (T-DM1).

New results from the DESTINY-Breast03 study were presented at the San Antonio Breast Cancer Symposium (SABCS) in December 2021. They showed that Enhertu demonstrated a similar benefit in different patient subgroups, including those with stable brain metastases, when compared with T-DM1.

The drug demonstrated a higher PFS and ORR in pre-specified patient subgroups compared with T-DM1.

AstraZeneca shared positive high-level results from the DESTINY-Breast04 Phase III trial in February 2022. The data from the study indicated that Enhertu significantly improved both PFS and OS in patients with HER2-low unresectable and/or metastatic breast cancer compared with chemotherapy.

Around 540 patients volunteered for the multi-centre DESTINY-Breast04 trial. The study’s primary endpoint was PFS in previously treated patients with HR-positive disease based on blinded independent central review (BICR).

The drug also met key secondary endpoints, including PFS, in all randomised patients regardless of HR status, as well as OS in patients with HR-positive disease and in patients regardless of HR status.

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