Daiichi Sankyo : ENHERTU Granted Breakthrough Therapy Designation in the U.S. for HER2 Positive Metastatic Gastric Cancer

Tokyo - Daiichi Sankyo Company, Limited (hereafter, Daiichi Sankyo) and AstraZeneca's ENHERTU (fam-trastuzumab deruxtecan-nxki) has been granted Breakthrough Therapy Designation (BTD) in the U.S. for the treatment of patients with HER2 positive unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma who have received two or more prior regimens including trastuzumab.

Gastric cancer is the third leading cause of cancer mortality with a five-year survival rate of five percent for metastatic disease.[1],[2] Approximately one in five gastric cancers are considered HER2 positive.[3]

The U.S. Food and Drug Administration's (FDA) BTD is designed to accelerate the development and regulatory review of potential new medicines that are intended to treat a serious condition and address a significant unmet medical need. The new medicine needs to have shown encouraging preliminary clinical results that demonstrate substantial improvement on a clinically significant endpoint over available medicines.

'DESTINY-Gastric01 represents the first randomized trial of ENHERTU to demonstrate clinically meaningful and statistically significant results, including objective response and survival increases compared to physician's choice of chemotherapy,' said Gilles Gallant, BPharm, PhD, FOPQ, Senior Vice President, Global Head, Oncology Development, Oncology R&D, Daiichi Sankyo. 'We are thrilled that the FDA has granted ENHERTU a second Breakthrough Therapy Designation.'

'For patients with HER2 positive metastatic gastric cancer, current therapy options are limited, and for those who progress, there no approved HER2 targeted medicines,' said Jose Baselga, MD, PhD, Executive Vice President, Oncology R&D, AstraZeneca. 'We look forward to working with the FDA to further explore the potential of ENHERTU to become an important new treatment and the first antibody drug conjugate for this devastating disease.'

The FDA granted the BTD based on data from the pivotal phase 2 DESTINY-Gastric01 trial and data from the phase 1 trial published in The Lancet Oncology. In DESTINY-Gastric01, patients with HER2 positive metastatic gastric cancer who progressed after two previous regimens treated with ENHERTU, a HER2 directed antibody drug conjugate (ADC), demonstrated a statistically significant and clinically meaningful improvement in objective response rate (ORR) and overall survival (OS) compared to patients treated with investigator's choice of chemotherapy (irinotecan or paclitaxel monotherapy).

The overall safety and tolerability profile of ENHERTU in DESTINY-Gastric01 was consistent with that seen in the phase 1 trial in which the most common adverse events (30 percent, any grade) were hematologic and gastrointestinal including neutrophil count decrease, anemia, 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 ILD-related deaths (grade 5) occurred in patients with gastric cancer in the phase 1 trial or in the DESTINY-Gastric01 trial.

The research results of DESTINY-Gastric01 will be presented at the 2020 American Society of Clinical Oncology (ASCO20) Virtual Scientific Program.

ENHERTU received SAKIGAKE designation in March 2018 by Japan's Ministry of Health, Labour and Welfare (MHLW) for potential use in the same HER2 positive gastric cancer patient population and was recently submitted to the Japan MHLW for approval. This is the second Breakthrough Therapy Designation granted for ENHERTU in the US, and the third expedited regulatory designation received globally.

ENHERTU recently received accelerated approval in the U.S. and approval in Japan under the early conditional approval system for the treatment of adult patients with unresectable or metastatic HER2 positive metastatic breast cancer who have received two or more prior anti-HER2 based regimens.

About HER2

HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of many types of tumors including gastric, breast and lung cancers. In some tumors, HER2 overexpression is associated with a specific HER2 gene alteration known as HER2 amplification and is often associated aggressive disease and poorer prognosis.[4]

About Gastric Cancer

Gastric (stomach) cancer is the fifth most common cancer worldwide and the third leading cause of cancer mortality; there were approximately one million new cases reported in 2018 and 783,000 deaths.1 In the U.S., it is estimated that 27,600 new cases of stomach cancer will be diagnosed in 2020 and more than 11,000 people will die from the disease.[5]

Approximately one in five gastric cancers are HER2 positive.3 Gastric cancer is usually diagnosed in the advanced stage, but even when diagnosed in earlier stages of the disease the survival rate remains modest.[6] Recommended first-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 outcomes when added to chemotherapy.[7] For gastric cancer that progresses on first-line treatment, trastuzumab has not shown any further benefit and there are no other approved HER2 targeting medicines.7

DESTINY-Gastric01

DESTINY-Gastric01 is a pivotal phase 2, open-label, multi-center trial assessing the safety and efficacy of ENHERTU in a primary cohort of 188 patients from Japan and South Korea with HER2 expressing advanced gastric cancer or gastroesophageal junction adenocarcinoma (defined as IHC3+ or IHC2+/ISH+) who have progressed on two or more prior treatment regimens including fluoropyrimidine (5-FU), 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 study 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.

About ENHERTU

ENHERTU (fam-trastuzumab deruxtecan-nxki in the U.S. only; trastuzumab deruxtecan outside the U.S.) is a HER2 directed ADC 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 ('payload') 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 novel topoisomerase I inhibitor payload by a tetrapeptide-based linker.

ENHERTU has been approved for use only in the U.S. and Japan. ENHERTU has not been approved in the EU, or countries outside of Japan and the United States, for any indication. It is an investigational agent globally for various indications. Safety and effectiveness have not been established for the subject proposed use.

About the ENHERTU Clinical Development Program

A comprehensive development program for ENHERTU is underway globally with six pivotal trials evaluating the efficacy and safety of ENHERTU monotherapy across multiple HER2 driven cancers including breast, gastric and lung cancers. Trials in combination with other anticancer treatments, such as immunotherapy, also are underway.

About the Collaboration between Daiichi Sankyo and AstraZeneca

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

U.S. FDA-Approved Indication for ENHERTU

ENHERTU is a HER2-directed antibody and topoisomerase inhibitor conjugate indicated 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 in the metastatic setting.

This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

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Jennifer Brennan

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