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ENHERTU (fam-trastuzumab deruxtecan-nxki) for the Treatment of HER2 Positive Advanced Gastric Cancer

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.

Drug Name

ENHERTU® (fam-trastuzumab deruxtecan-nxki)

Developer

Daiichi Sankyo

Therapy Class

HER2-directed antibody and topoisomerase inhibitor conjugate

Current Indication

Gastric cancer

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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.

ENHERTU 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 metastatic non-small cell lung cancer (NSCLC) in patients who received platinum-containing chemotherapy.

Developed by 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 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 license 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 non-small cell lung cancer (NSCLC) in May 2020.

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 into advanced stage, and the survival rate remains modest even for early diagnosis of the disease.

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.

The symptoms 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 small molecule of the drug called DXd, an inhibitor of topoisomerase I, 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

FDA approval of ENHERTU was based on the outcome of randomised, open-label, multicentre, pivotal phase two trial, DESTINY-Gastric01.

The safety and efficacy of ENHERTU 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 and platinum-containing chemotherapy.

Patients were randomised in 2:1 ratio to receive ENHERTU 6.4mg / kg intravenously every three weeks or physician’s choice of chemotherapy either irinotecan or paclitaxel monotherapy.

“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.”

The primary efficacy outcome measures were the overall survival (OS) and objective response rate (ORR) 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 to 8.4 months in the irinotecan or paclitaxel arm., while the ORR in ENHERTU arm was 40.5% compared to 11.3% with chemotherapy.

ENHERTU also demonstrated a median PFS of 5.6 months versus 3.5 months with chemotherapy. The median DOR was 11.3 months in the ENHERTU arm compared to 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, leukopenia, anaemia, thrombocytopenia, neutropenia, lymphocytopenia, decreased appetite, laboratory abnormalities. The adverse reactions also include increased blood alkaline phosphatase, increased alanine aminotransferase, increased aspartate aminotransferase, increased blood bilirubin, constipation, alopecia, hypokalemia and pyrexia.

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