Research & Development
Enhertu Granted Priority Review in the US for Treatment of HER2 Positive Metastatic Gastric Cancer
28 October 2020 - - Japan-based pharmaceutical company Daiichi Sankyo Company, Ltd's and British-Swedish drugmaker AstraZeneca's (OTC: AZNCF) Enhertu (fam-trastuzumab deruxtecan-nxki) has received acceptance for its supplemental Biologics License Application and has also been granted Priority Review in the US for the treatment of patients with HER2 positive metastatic gastric or gastroesophageal junction adenocarcinoma, the companies said.

The PDUFA date has been set for the first quarter of the 2021 calendar year.

There are more than 27,000 new cases of gastric cancer in the US each year, of which approximately one in five are HER2 positive.

For patients with metastatic gastric cancer who progress on initial treatment with an anti-HER2 regimen, there are no other approved HER2 directed medicines.

The US Food and Drug Administration grants Priority Review to applications for medicines that offer significant advances over available options by demonstrating safety or efficacy improvements, preventing serious conditions, or enhancing patient compliance.

The sBLA is based on results from the randomized phase 2 DESTINY-Gastric01 trial, which demonstrated a statistically significant and clinically meaningful improvement in objective response rate, the primary endpoint, and overall survival, a key secondary endpoint, for patients treated with Enhertu versus chemotherapy (paclitaxel or irinotecan monotherapy).

The results from the trial were presented during the 2020 American Society of Clinical Oncology Virtual Scientific Program and simultaneously published online in The New England Journal of Medicine.

Enhertu received Breakthrough Therapy Designation from the FDA in May 2020 for patients with unresectable or metastatic HER2 positive gastric or GEJ adenocarcinoma who have received two or more prior regimens including trastuzumab one of three BTDs that have been granted to Enhertu in the US and Orphan Drug Designation for patients with gastric cancer, including GEJ adenocarcinoma.

The safety and tolerability profiles of Enhertu in DESTINY-Gastric01 were consistent with that observed in the gastric cancer cohort of the phase 1 trial and previously reported Enhertu trials in other tumors. 

The most common grade 3 or higher treatment-emergent adverse events were decreased neutrophil count, anemia, decreased white blood cell count and decreased appetite.

There were 12 cases of confirmed treatment-related interstitial lung disease or pneumonitis in 125 patients treated with Enhertu as determined by an independent adjudication committee.

The majority of cases were grade 1 or 2 with two grade 3, one grade 4 and no grade 5 (no ILD-related deaths).

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 m new cases reported in 2018 and 783,000 deaths.

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.

Approximately one in five gastric cancers are HER2 positive.2 HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of many types of tumors including breast, gastric, lung and colorectal cancers.

Gastric cancer is usually diagnosed in the advanced stage, but even when diagnosed in earlier stages of the disease the survival rate remains modest.

Recommended first-line treatment for HER2 positive 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 metastatic gastric cancer that progresses on first-line treatment, there are no other approved HER2 targeting medicines.

DESTINY-Gastric01 is an open-label, multi-center, randomized, pivotal phase 2 trial evaluating the safety and efficacy of Enhertu versus investigator's choice of chemotherapy in a primary cohort of 188 patients from Japan and South Korea with HER2 positive (defined as IHC3+ or IHC2+/ISH+), advanced gastric cancer or GEJ adenocarcinoma who had progressed on two or more prior treatment regimens including fluoropyrimidine, platinum chemotherapy and trastuzumab.

Patients were randomized 2: 1 to receive Enhertu or investigator's choice of chemotherapy (paclitaxel or irinotecan monotherapy). Patients were treated with Enhertu 6.4 mg/kg once every three weeks or chemotherapy.

The primary endpoint of the trial is ORR, as assessed by independent central review. OS, a key secondary endpoint, was to be evaluated hierarchically at a prespecified interim analysis if the primary endpoint was statistically significant.

Additional efficacy endpoints include progression-free survival, duration of response, disease control rate and confirmed ORR assessed in those responses confirmed by a follow-up scan of at least four weeks after initial independent central review.

Enhertu (fam-trastuzumab deruxtecan-nxki in the US only; trastuzumab deruxtecan outside the US) is a HER2 directed antibody drug conjugate and is the lead ADC in the oncology portfolio of Daiichi Sankyo and the most advanced program 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.

Designed using Daiichi Sankyo's proprietary DXd ADC technology, Enhertu is comprised of a HER2 monoclonal antibody attached to a topoisomerase I inhibitor payload by a tetrapeptide-based linker.
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