AstraZeneca/Daiichi Sankyo launched phase III clinical study of antibody conjugate (ADC) Enhertu tar

Daiichi Sankyo and AstraZeneca recently announced that in the global phase 3 clinical trial—DESTINY-The Gastric04 (NCT04704934), the first patient was given a drug treatment to evaluate the HER2-targeting ADC Enhertu (fam-trastuzumab deruxtecan) for the second-line treatment of HER2-positive advanced gastric cancer.

The prognosis of gastric cancer is poor, especially in the advanced stages, when only 5%-10% of patients survive for 5 years. About one-fifth of gastric cancers are considered HER2 positive. However, in patients with gastric cancer receiving trastuzumab treatment, 29%-69% of patients have observed loss of HER2 expression, suggesting that reduced HER2 expression can lead to the progress of trastuzumab treatment and may be associated with a poor prognosis. For patients whose disease progressed after the first-line HER2 targeted system treatment, the second-line treatment options are limited, and new HER2 targeted therapies are urgently needed.

Enhertu is the first ADC drug approved to treat HER2-positive gastric cancer, which was approved in Japan and the United States in September 2020 and January 2021 respectively, for the treatment of patients with HER2-positive metastatic gastric cancer or GEJ adenocarcinoma. It is worth mentioning that Enhertu is the first HER2-targeted therapy to show that patients with HER2-positive metastatic gastric cancer who have previously received chemotherapy and anti-HER2 therapy significantly extend overall survival compared to chemotherapy. Based on the convincing and strong efficacy in clinical trials, Enhertu will become the new standard of care for the clinical treatment of such patients.

DESTINY-Gastric04 is a global, randomized, open-label, head-to-head phase 3 study of HER2-positive metastatic and/or unresectable gastric or gastroesophageal disease that progresses during or after treatment with trastuzumab-containing regimens, carried out in patients with HER2-positive metastatic and/or unresectable gastric or gastroesophageal junction (GEJ) adenocarcinoma, to evaluate the safety and effectiveness of Enhertu (6.4mg/kg) and Cyramza (ramucirumab)/paclitaxel, another commonly used combination therapy.

The study will enroll approximately 490 patients in multiple clinical centers in Asia, Europe, and South America, during which time the patients will be randomly assigned to receive Enhertu or Cyramza/paclitaxel treatment. The primary endpoint is overall survival (OS), and the secondary endpoints include progression-free survival (PFS), objective response rate (ORR), and duration of remission, disease control rate (DCR), safety, pharmacokinetics, and immunogenicity.

Gastric cancer is the fifth most common cancer in the world and the fourth leading cause of cancer deaths. In 2020, there were approximately 1 million new cases of gastric cancer and 768,000 deaths worldwide. Gastric cancer is usually diagnosed at an advanced stage, but even if it is diagnosed at an early stage, the survival rate is still very low.

About one-fifth of gastric cancers are HER2 positive. HER2 is a tyrosine kinase receptor growth-promoting protein that is expressed on the surface of many types of tumor cells, including breast cancer, gastric cancer, lung cancer, and colorectal cancer. HER2 overexpression may be related to changes in a specific HER2 gene called HER2 amplification.

Up to now, Enhertu has been approved for 2 indications:

1. For the treatment of adult patients with HER2-positive metastatic breast cancer who have received 2 or more anti-HER2 drugs in metastatic disease.
2. For the treatment of adult patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma.

The industry is very optimistic about Enhertu's business prospects. In April 2021, the article published in Nature Reviews Drug Discovery entitled "The oncology market for antibody-drug conjugates" pointed out that the global market of ADC is expected to exceed 16.4 billion USD by 2026, and Enhertu will rank first with sales of 6.2 billion USD.

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