The US FDA Grants AstraZeneca Enhertu A Breakthrough Drug Qualification, Which Will Redefine Gastric Cancer Treatment!

- May 23, 2020-

AstraZeneca and partner Daiichi Sankyo recently announced that the US Food and Drug Administration (FDA) has granted HER2 targeted antibody drug conjugate (ADC) Enhertu (fam-trastuzumab deruxtecan-nxki, DS-8201) Breakthrough drug qualification (BTD) for the treatment of HER2-positive, unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma patients who have previously received at least 2 regimens (including trastuzumab, trastuzumab).


Enhertu received the world's first batch in December 2019 in the United States: FDA accelerated approval of Enhertu for adult patients with HER2-positive metastatic breast cancer who have received 2 or more anti-HER2 drugs in metastatic disease. In Japan, Enhertu received conditional early approval from the Ministry of Health, Labour and Welfare (MHLW) in March 2020 for the treatment of HER2-positive, unresectable or metastatic breast cancer patients who relapsed after previous chemotherapy (limited to the standard Patients who are ineffective or intolerant to treatment).


It is worth mentioning that this BTD is the second time the US FDA granted Enhertu BTD, highlighting the drug's potential in treating multiple HER2-driven cancers. In 2017, the FDA granted Enhertu treatment for BTD in patients with HER2-positive metastatic breast cancer. In Japan, Enhertu has been granted SAKIGAKE (innovative drug) qualification for the treatment of HER2-positive metastatic gastric cancer by MHLW. Just recently, Daiichi Sankyo submitted an Enhertu Application for Supplemental New Drugs (sNDA) for the treatment of HER2-positive metastatic gastric cancer to MHLW. The sNDA will complete a rapid review within a 6-month timetable.


Gastric cancer is the third leading cause of cancer death, and the 5-year survival rate for metastatic disease is 5%. About 20% of gastric cancers are HER2-positive. At present, for patients with HER2-positive metastatic gastric cancer and relapsed patients who have progressed after treatment with trastuzumab (trastuzumab, a HER2-targeted monoclonal antibody), treatment options are limited, and there is no approved HER2 targeting program. If approved, Enhertu will be the first ADC drug to treat HER2-positive gastric cancer, and will bring meaningful therapeutic advances to this type of cancer.


José Baselga, executive vice president of AstraZeneca's oncology research and development, said: "Currently there are limited treatment options for HER2-positive metastatic gastric cancer patients and relapsed patients, and there are no approved HER2-targeted drugs. We look forward to working with the FDA to further explore Enhertu as An important new therapy for devastating diseases and the potential of the first antibody drug conjugate (ADC). "


Breakthrough Drug Qualification (BTD) is a new drug review channel created by the FDA in 2012 to speed up the development and review of treatments for serious or life-threatening diseases, and there is preliminary clinical evidence that the drug is comparable to existing therapeutic drugs New drugs that can substantially improve the condition. Obtaining BTD drugs can get more close guidance including senior FDA officials during research and development. The new drug market review is eligible for rolling review and priority review to ensure that patients are provided with new treatment options in the shortest time.


The FDA awarded Enhertu BTD based on data from the registered Phase II DESTINY-Gastric01 trial and data from the Phase I trial published in The Lancet Oncology.


DESTINY-Gastric01 is an open-label, multicenter, registered phase II trial enrolling 189 patients with HER2-positive advanced gastric cancer or gastroesophageal junction adenocarcinoma (defined as: IHC3 + or IHC2 + / ISH +) from Japan and Korea. The patient had previously received 2 or more regimens (including 5-FU, platinum chemotherapy, trastuzumab) but the condition progressed. In the study, patients were randomly assigned in a 2: 1 ratio and received Enhertu (6.4 mg / kg) or chemotherapy selected by the research investigator (paclitaxel or irinotecan monotherapy) every three weeks. The primary endpoint is the overall response rate (ORR), the key secondary endpoint is overall survival (OS), and other secondary endpoints include: progression-free survival (PFS), duration of remission (DOR), disease control rate (DCR), Time to treatment failure (TTF), pharmacokinetics (PK) and safety endpoint.


The results showed that the study reached the primary endpoint and the key secondary endpoint: Compared with the chemotherapy group, the Enhertu treatment group achieved statistically and clinically significant improvements in objective response rate (ORR) and overall survival (OS). In the study, Enhertu ’s overall safety and tolerability were consistent with previously published Phase I trials. The most common adverse events (≥30%, any grade) were hematology and gastrointestinal tract, including decreased neutrophil count, Anemia, nausea and decreased appetite. The study reported treatment-related interstitial lung disease (ILD) and pneumonia, mainly grade 1 and grade 2, 2 cases in grade 3, and 1 case in grade 4. In the Phase I trial or the DESTINY-Gastric01 trial, no death of gastric cancer patients associated with ILD (grade 5) occurred.


The full results of the study will be announced at the 2020 virtual meeting of the American Society of Clinical Oncology Annual Meeting (ASCO20).


Gastric cancer is the fifth most common cancer in the world and the third leading cause of cancer death. In 2018, approximately 1 million new cases were reported globally, with 783,000 deaths. Gastric cancer is usually in the advanced stage when it is diagnosed. Even if it is diagnosed in the early stage, the survival rate is still not high.


About 20% of gastric cancer cases are HER2 positive. For HER2-positive or metastatic gastric cancer, the recommended first-line treatment is combination chemotherapy with trastuzumab. Trastuzumab is a HER2-targeted monoclonal antibody that has been shown to improve patient outcomes in combination with chemotherapy. For patients with gastric cancer undergoing first-line treatment, trastuzumab has not shown any further efficacy, and there are currently no other approved HER2 targeted drugs.


HER2 is a tyrosine kinase receptor protein that promotes cell growth and is expressed on the surface of various tumor cells such as gastric cancer, breast cancer, and lung cancer. HER2 overexpression is associated with a special HER2 gene alteration (HER2 amplification), often associated with aggressive disease and poor prognosis.


Enhertu (trastuzumab deruxtecan, DS-8201) is a new-generation antibody-drug conjugate (ADC) that uses a 4-peptide linker to target HER2 humanized monoclonal antibody trastuzumab (trastuzumab) and A new topoisomerase 1 inhibitor exatecan derivative (DX-8951 derivative, DXd) is linked together, which can target the delivery of cytotoxic agents to cancer cells, which can reduce cytotoxic agents compared to conventional chemotherapy Full body exposure.


In March 2019, AstraZeneca reached a total value of US $ 6.9 billion in immuno-oncology cooperation with the First Three, jointly developing Enhertu for the treatment of cancer patients with various HER2 expression levels or HER2 mutations, including gastric cancer , Colorectal cancer and lung cancer, and breast cancer with low expression of HER2. According to the agreement, both parties will jointly develop and commercialize Enhertu on a global scale. Daiichi Sankyo reserves the exclusive rights in the Japanese market and will be solely responsible for manufacturing and supply.


EvaluatePharma, a pharmaceutical market research agency, previously predicted that Enhertu's sales in 2024 are expected to reach $ 2 billion.