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AstraZeneca Enhertu granted Orphan Drug Designation in the US for gastric cancer

AstraZeneca PLC (LON:AZN) and Daiichi Sankyo Company Limited’s Enhertu (trastuzumab deruxtecan) has been granted Orphan Drug Designation in the US for the treatment of patients with gastric cancer, including gastroesophageal junction cancer.

An estimated 27,600 new cases of gastric cancer will be diagnosed this year and the disease could lead to more than 11,000 deaths in the US in 2020.1

The Food and Drug Administration (FDA) grants ODD to medicines intended for the treatment, diagnosis or prevention of rare diseases or disorders that affect fewer than 200,000 people in the US.

In the Phase II DESTINY-Gastric01 trial, patients with HER2-positive metastatic gastric or gastroesophageal cancer who were treated with Enhertu, a HER2-directed antibody drug conjugate (ADC), demonstrated a statistically significant and clinically meaningful improvement in objective response rate (ORR), the primary endpoint, and overall survival (OS), a key secondary endpoint, versus patients treated with investigator’s choice of chemotherapy (irinotecan or paclitaxel monotherapy).

The overall safety and tolerability profile of Enhertu (6.4mg/kg) in DESTINY-Gastric01 was consistent with that seen in the Phase I gastric cancer trial. The most common adverse events were haematologic and gastrointestinal including neutrophil count decrease, anaemia, nausea and decreased appetite. There were cases of drug-related interstitial lung disease (ILD) and pneumonitis, the majority of which were Grade 1 and 2, with two Grade 3 and one Grade 4. No Grade 5 events (ILD-related deaths) occurred in patients with gastric cancer in the Phase I trial or in the Phase II DESTINY-Gastric01 trial.

The full results of DESTINY-Gastric-01 will be presented during the 2020 American Society of Clinical Oncology ASCO20 Virtual Scientific Program, 29 to 31 May 2020.

Earlier this month, Enhertu received two Breakthrough Therapy Designations for its potential use in HER2-positive unresectable or metastatic gastric cancer and HER2-mutant metastatic non-small cell lung cancer. Enhertu also received SAKIGAKE designation from Japan’s Ministry of Health Labour and Welfare (MHLW) for potential use in HER2-positive gastric cancer in March 2018. A supplemental New Drug Application was recently submitted to the MHLW.

Gastric cancer

Gastric (stomach) cancer is the fifth most common cancer worldwide and the third leading cause of cancer mortality with a five-year survival rate of 5% for metastatic disease. There were approximately one million new cases reported in 2018 and 783,000 deaths.2,3 In the US, it is estimated that 27,600 new cases of gastric cancer will be diagnosed in 2020 and more than 11,000 people will die from the disease.1

Approximately one in five gastric cancers are HER2 positive.4,5 HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of many types of tumours including gastric, breast and lung cancers. Gastric cancer is usually diagnosed in the advanced stage in the US, but even when diagnosed in earlier stages of the disease the survival rate remains modest.6 Recommended 1st-line treatment for HER2-positive advanced or metastatic gastric cancer is combination chemotherapy plus trastuzumab, an anti-HER2 medicine, which has been shown to improve survival outcomes when added to chemotherapy. For gastric cancer that progresses on 1st-line treatment, there are no other approved HER2-targeted medicines.7


DESTINY-Gastric01 is a Phase II, open-label, multi-centre trial testing the safety and efficacy of Enhertu in a primary cohort of 188 patients from Japan and South Korea with HER2-expressing, advanced gastric or gastroesophageal junction adenocarcinoma (defined as IHC3+ or IHC2+/ISH+) who have progressed on two or more prior treatment regimens including fluoropyrimidine and platinum chemotherapy and trastuzumab. Patients were randomised 2:1 to receive Enhertu or investigator’s choice of chemotherapy (paclitaxel or irinotecan monotherapy). Patients were treated with Enhertu 6.4mg/kg once every three weeks or chemotherapy. The primary endpoint of the trial is ORR, as assessed by an independent review committee. Secondary endpoints include OS, progression-free survival, duration of response, disease control rate and time to treatment failure as well as pharmacokinetic and safety endpoints.8


Enhertu (trastuzumab deruxtecan; fam-trastuzumab deruxtecan-nxki in the US) is a HER2-directed ADC and is the lead ADC in the oncology portfolio of Daiichi Sankyo and the most advanced programme in AstraZeneca’s ADC scientific platform. ADCs are targeted cancer medicines that deliver cytotoxic chemotherapy to cancer cells via a linker attached to a monoclonal antibody that binds to a specific target expressed on cancer cells.

Enhertu (5.4mg/kg) is approved in the US and Japan for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens based on the DESTINY-Breast01 trial.

Enhertu clinical development

A comprehensive development programme is underway globally with six registrational trials evaluating the efficacy and safety of Enhertu monotherapy across multiple HER2-targetable cancers including breast, gastric and lung cancers. Trials in combination with other anticancer treatments, such as immunotherapy, are also underway.

Collaboration between AstraZeneca and Daiichi Sankyo

In March 2019, AstraZeneca and Daiichi Sankyo entered into a global collaboration to jointly develop and commercialise Enhertu worldwide, except in Japan where Daiichi Sankyo maintains exclusive rights. Daiichi Sankyo is solely responsible for manufacturing and supply.

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