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Home Trastuzumab Deruxtecan (Enhertu) Receives EMA Validation for Type II Variation Application in HER2-Positive Advanced Gastric Cancer

Trastuzumab Deruxtecan (Enhertu) Receives EMA Validation for Type II Variation Application in HER2-Positive Advanced Gastric Cancer

Nov 08, 2021 02:29 CST Updated 02:29
Daiichi-Sankyo

Pharmaceutical R&D Developer

AstraZeneca

Biopharmaceutical Manufacturer

Committee for Medicinal Products for Human Use

Committee for Medicinal Products for Human Use (CHMP)The Committee for Medicinal Products for Human Use (CHMP) is the committee within the European Medicines Agency (EMA) responsible for human medicines. The CHMP replaced the former Committee for Proprietary Medicinal Products (CPMP) in May 2004.The CHMP plays a vital role in the authorization of medicines in the European Union (EU). In the centralized procedure, the CHMP is responsible for: 1) conducting initial assessments of marketing authorization applications across the EU; assessing modifications or extensions to existing marketing authorizations (“variations”); considering recommendations from the Agency’s Pharmacovigilance Risk Assessment Committee regarding the safety of medicines on the market, and, where necessary, advising the European Commission to amend the marketing authorization of a medicinal product, or to suspend or withdraw it from the market.The CHMP also evaluates medicines authorized at the national level that are referred to the EMA, with the aim of maintaining a harmonized position throughout the EU.Furthermore, the CHMP and its working groups promote the development of medicines and pharmaceutical regulation by: providing scientific advice to companies researching and developing new medicines; developing scientific and regulatory guidelines to assist pharmaceutical companies in preparing marketing authorization applications for human medicines; and collaborating with international partners to harmonize regulatory requirements.

European Medicines Agency

The European Medicines Agency (EMA) is a decentralized agency of the European Union (EU), located in London. It began operations in 1995. The agency is responsible for the scientific evaluation, supervision, and safety monitoring of medicines developed by pharmaceutical companies for use in the EU. By ensuring that all medicines available on the EU market are safe, effective, and of high quality, the EMA protects public and animal health in the 28 EU Member States and countries of the European Economic Area.


November 8, 2021 /BioonBIOON/ -- Daiichi Sankyo recently announced that the European Medicines Agency (EMA) has acceptedHER2-targeted antibody-drug conjugate (ADC) EnhertuClass II Variation Application for (fam-trastuzumab deruxtecan):For the treatment of adult patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma who have previously received a prior anti-HER2 regimen.. The European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) has initiated a scientific assessment of the application for the aforementioned new indication for Enhertu. Enhertu is by Daiichi Sankyo andAstraZeneca(AstraZeneca) jointly developed.

This EU submission is based on the DESTINY-Gastric01 Phase 2 clinical trial, published in *The New England Journal of Medicine* (NEJM), and the DESTINY-Gastric02 Phase 2 trial, recently presented at the 2021 European Society for Medical Oncology (ESMO) Congress.Clinical Trialthe results.

The prognosis for gastric cancer is poor, particularly in advanced stages, with a 5-year survival rate of only 5%–10%. Approximately one-fifth of gastric cancers are considered HER2-positive. The recommended first-line treatment regimen for HER2-positive advanced or metastatic gastric cancer is a combination of chemotherapy and trastuzumab (a HER2-targeted monoclonal antibody). Although the benefits of HER2-targeted therapy in the first-line treatment of metastatic gastric cancer are well established, the disease ultimately progresses. With limited second-line treatment options available, there is 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 and the United States in September 2020 and January 2021, respectively, 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 who have previously received chemotherapy and anti-HER2 therapy (DESTINY-Gastric02 trial results: median OS: 12.5 months vs. 8.4 months).According toClinical TrialGiven its compelling and robust efficacy, Enhertu will become the new standard of care for the clinical treatment of these patients.

DESTINY-Gastric01 is an open-label, randomized Phase 2 trial that enrolled 187 patients (including 149 from Japan) with HER2-positive advanced gastric or gastroesophageal junction adenocarcinoma (defined as IHC 3+ or IHC 2+/ISH+), who had experienced disease progression after two or more prior regimens (including 5-FU, platinum-based chemotherapy, and trastuzumab). In the study, patients were randomized in a 2:1 ratio to receive Enhertu (6.4 mg/kg) or investigator's choice of chemotherapy (paclitaxel or irinotecan monotherapy) every 3 weeks.

The results showed that the study met its primary and key secondary endpoints: compared with the chemotherapy group, the Enhertu treatment group demonstrated statistically significant and clinically meaningful improvements in objective response rate (ORR) and overall survival (OS). Specific data are as follows: in 175 evaluable patients (including 140 Japanese patients), as assessed by independent central review (ICR):The ORR was 51.3% (95% CI: 41.9-60.5%) in the Enhertu group and 14.3% in the chemotherapy group.(95% CI: 6.4–26.2%). In a prespecified interim analysis,41% reduction in the risk of death in the Enhertu group compared with the chemotherapy group（HR=0.59；95%CI:0.39-0.88；p=0.0097）。The median OS was 12.5 months in the Enhertu arm and 8.4 months in the chemotherapy arm.

DESTINY-Gastric02 is the first trial specifically designed to evaluate Enhertu in Western patients with gastric cancer. The data showed that in patients with HER2-positive metastatic and/or unresectable gastric or gastroesophageal junction (GEJ) adenocarcinoma who had previously received one prior trastuzumab-based regimen, Enhertu treatment provided clinically meaningful and durableTumorRelief.

Data presented at the 2021 ESMO Congress showed that: in the preliminary analysis, as assessed by Independent Central Review (ICR),The confirmed overall response rate (ORR) with Enhertu (6.4 mg/kg) treatment was 38%.. Among patients treated with Enhertu, 3 (3.8%) complete responses (CR) and 27 (34.2%) partial responses (PR) were observed. After a median follow-up of 5.7 months, the median duration of response (DoR) was 8.1 months (95% CI: 4.1-NE). The median progression-free survival (PFS) was 5.5 months (95% CI: 4.2-7.3). The confirmed disease control rate (DCR) was 81% (95% CI: 70.6-89.0).

These results with the phase 2 DESTINY-Gastric01Clinical Trialconsistent with the results. In the DESTINY-Gastric02 trial, the overall safety profile of Enhertu was consistent with that observed in the DESTINY-Gastric01 trial.

DESTINY-Gastric02 Clinical Trial Data

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

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

For HER2-positive advanced or metastatic gastric cancer, the recommended first-line treatment regimen is a combination of chemotherapy and trastuzumab. Trastuzumab is an anti-HER2 agent that has been demonstrated to improve patient survival when used in combination with chemotherapy. However, loss of HER2 expression has been observed in 29% to 69% of gastric cancer patients following trastuzumab treatment. This suggests that downregulation of HER2 expression may lead to disease progression during trastuzumab therapy and may be associated with a poor prognosis in gastric cancer. For patients with metastatic gastric cancer who experience disease progression after initial treatment with a trastuzumab-based regimen, treatment options are limited, and other HER2-targeted agents are unavailable 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 with conventional chemotherapy.

In March 2019, AstraZeneca and Daiichi Sankyo reached an immuno-oncology deal worth up to $6.9 billion.`Tumor`In collaboration, the parties will co-develop Enhertu for the treatment of cancer patients with varying HER2 expression levels 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. Daiichi Sankyo retains exclusive rights for the Japanese market and will be solely responsible for manufacturing and supply.

To date, Enhertu has been approved for 2 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 March this year, an article titled "The oncology market for antibody-drug conjugates" published in the journal *Nature Reviews Drug Discovery* noted that the global market size for marketed 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)