Head-to-Head Phase 3 DESTINY-Gastric04 Trial of ENHERTU® Initiated in Second-Line HER2-Positive Advanced Gastric Cancer

July 12, 2021 /Bio ValleyBIOON/ --Daiichi Sankyo andAstraZeneca(AstraZeneca) recently jointly announced that the first patient has been dosed in the global Phase 3 DESTINY-Gastric04 trial (NCT04704934), evaluating the HER2-targeted antibody-drug conjugate (ADC) Enhertu (fam-trastuzumab deruxtecan) as a second-line treatment for patients with HER2-positive advanced gastric cancer.

The prognosis for gastric cancer is poor, particularly in advanced stages, with only 5%–10% of patients achieving 5-year survival. Approximately one-fifth of gastric cancers are classified as HER2-positive. However, loss of HER2 expression has been observed in 29%–69% of gastric cancer patients treated with trastuzumab, suggesting that reduced HER2 expression may contribute to disease progression during trastuzumab therapy and could be associated with a poor prognosis. For patients who experience disease progression following first-line HER2-targeted systemic therapy, second-line treatment options remain limited, underscoring an urgent need for novel HER2-targeted therapies.

Enhertu is the first ADC approved for the treatment of HER2-positive gastric cancer,The drug was approved in Japan in September 2020 and in the United States in January 2021 for the treatment of patients with HER2-positive metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma. Notably,Enhertu is the first HER2-targeted therapy to demonstrate a significant prolongation of overall survival compared with chemotherapy in patients with HER2-positive metastatic gastric cancer previously treated with chemotherapy and anti-HER2 therapy (median OS: 12.5 months vs. 8.4 months).According toClinical TrialWith its compelling and robust efficacy, Enhertu will become the new standard of care for the clinical treatment of these patients.

DESTINY-Gastric04 is a global, randomized, open-label, head-to-head Phase 3 study conducted in patients with HER2-positive metastatic and/or unresectable gastric or gastroesophageal junction (GEJ) adenocarcinoma who experienced disease progression during or after treatment with a trastuzumab-containing regimen,Evaluating Enhertu (6.4 mg/kg) versus another commonly used combination regimen, Cyramza (ramucirumab)/paclitaxelsafety and efficacy.

This study will enroll approximately 490 patients across multiple clinical centers in Asia, Europe, and South America. In the study, patients will be randomized to receive either Enhertu or Cyramza/paclitaxel. The primary endpoint is overall survival (OS), and secondary endpoints include investigator-assessed progression-free survival (PFS), objective response rate (ORR), duration of response (DOR), disease control rate (DCR), safety, pharmacokinetics, and immunogenicity.

Gastric cancer is the fifth most common cancer worldwide and the fourth leading cause of cancer death. The 5-year survival rate for patients with advanced or metastatic disease is only 5%–10%. In 2020, there were approximately 1 million new cases and 768,000 deaths globally. The incidence of gastric cancer is significantly higher in East Asia, accounting for approximately half of all cases. Gastric cancer is typically diagnosed at an advanced stage; however, even when detected early, survival rates remain low.

Approximately one-fifth of gastric cancers are HER2-positive. HER2 is a growth-promoting receptor tyrosine kinase expressed in many types ofTumorCell surface, includingBreast cancer、gastric cancer, lung cancer, and colorectal cancer. HER2 overexpression may be associated with specific HER2 gene alterations known as HER2 amplification.

For HER2-positive advanced or metastatic gastric cancer, the recommended first-line treatment is a combination of chemotherapy and trastuzumab. Trastuzumab is an anti-HER2 agent that has been demonstrated to improve overall survival when used in combination with chemotherapy. However, loss of HER2 expression has been observed in 29%–69% of gastric cancer patients following trastuzumab treatment, suggesting that downregulation of HER2 expression may lead to disease progression during trastuzumab therapy and could be associated with a poor prognosis in gastric cancer. For patients with metastatic gastric cancer who experience disease progression after initial therapy with a trastuzumab-based regimen, treatment options are limited, and no alternative HER2-targeted therapies are available in many regions worldwide.

2026 ADC Drug Sales Forecast (Image sourced from literature PMID 33762691)

Enhertu is a next-generation antibody-drug conjugate (ADC) that links the HER2-targeted humanized monoclonal antibody trastuzumab to a novel topoisomerase I inhibitor exatecan derivative (DX-8951 derivative, DXd) via a tetrapeptide linker, enabling targeted delivery of the cytotoxic payload into cancer cells and reducing systemic exposure to the cytotoxic agent compared to conventional chemotherapy.

In March 2019, AstraZeneca and Daiichi Sankyo entered into an immunotherapy agreement valued at up to $6.9 billion in total.TumorCollaborate to jointly develop Enhertu for the treatment of cancer patients with varying levels of HER2 expression or HER2 mutations, including gastric cancer, colorectal cancer, lung cancer, and HER2-low breast cancer. Under the agreement, both parties will jointly develop and commercialize Enhertu globally, with Daiichi Sankyo retaining exclusive rights to the Japanese market while taking full responsibility for manufacturing and supply.

To date, Enhertu has been approved for two indications: (1) for the treatment of adult patients with HER2-positive metastatic breast cancer who have received two or more prior anti-HER2 therapies in the metastatic setting; (2) for the treatment of adult patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma.

The industry is highly optimistic about the commercial prospects of Enhertu. In April this year, the journal *Nature Reviews Drug Discovery* published an article "(The oncology market for antibody-drug conjugates)" which pointed out that the global market size for approved antibody-drug conjugates (ADCs) is expected to exceed $16.4 billion by 2026,Enhertu will rank first with $6.2 billion in sales.(Bioon.com)

Original Source:DESTINY-Gastric04 Head-to-Head Phase 3 Trial of ENHERTU® Initiated in Patients with HER2 Positive Advanced Gastric Cancer