ENHERTU® Approved in Japan for the Treatment of Patients with HER2 Positive Metastatic Gastric Cancer

ENHERTU is the first and only HER2 directed medicine to demonstrate significant improvement in overall survival compared to chemotherapy for patients with previously treated HER2 positive advanced gastric cancer

Approval of SAKIGAKE-designated medicine is based on pivotal phase 2 DESTINY-Gastric01 trial and represents second approval for ENHERTU in Japan within six months

TOKYO, Japan; MUNICH, Germany and BASKING RIDGE, NJ, USA I September 25, 2020 I Daiichi Sankyo Company, Limited (hereafter, Daiichi Sankyo) today announced the approval of ENHERTU® (trastuzumab deruxtecan), a HER2 directed antibody drug conjugate (ADC), in Japan for the treatment of patients with HER2 positive unresectable advanced or recurrent gastric cancer that has progressed after chemotherapy. ENHERTU was previously granted SAKIGAKE designation by Japan’s Ministry of Health, Labour and Welfare (MHLW) for this indication.

Japan has the third highest incidence rate of gastric cancer worldwide, of which approximately one in five cases are considered HER2 positive.[1],[2] For patients with metastatic gastric cancer previously treated with two prior regimens including chemotherapy and an anti-HER2 therapy, ENHERTU is the first and only HER2 directed medicine to demonstrate significant improvement in overall survival compared to chemotherapy.

Approval of ENHERTU in Japan is based on the results of the open-label, randomized phase 2 DESTINY-Gastric01 trial of ENHERTU (6.4 mg/kg) versus investigator’s choice of chemotherapy (irinotecan or paclitaxel) in 187 patients (including 149 Japanese patients) with HER2 positive advanced gastric cancer or gastroesophageal junction adenocarcinoma. A statistically significant increase in objective response rate (ORR) of 51.3% [95% CI: 41.9-60.5], the primary endpoint of the study, was demonstrated with ENHERTU compared to 14.3% [95% CI: 6.4 – 26.2] with investigator’s choice of chemotherapy as assessed by independent central review in 175 evaluable patients (including 140 Japanese patients). Patients treated with ENHERTU had a 41% reduction in the risk of death compared to patients treated with chemotherapy (based on a hazard ratio [HR] of 0.59; 95% confidence interval [CI]: 0.39-0.88; p=0.0097) at a pre-specified interim analysis. The median overall survival was 12.5 months with ENHERTU versus 8.4 months with chemotherapy.

Efficacy and safety of ENHERTU in patients with HER2 positive unresectable advanced or recurrent gastric cancer without a prior trastuzumab-containing regimen has not been established. ENHERTU is approved in Japan with a warning for interstitial lung disease (ILD). As cases of ILD, including fatal cases, have occurred in ENHERTU-treated patients, ENHERTU is to be used in close collaboration with a respiratory disease expert. Closely observe patients during therapy by monitoring for early signs or symptoms of ILD (such as dyspnea, cough or fever) and regularly perform peripheral artery oxygen saturation (SpO2) tests, chest X-ray scans and chest CT scans. If abnormalities are observed, discontinue administration of ENHERTU, and take appropriate measures such as corticosteroid administration. Prior to initiation of ENHERTU therapy, perform a chest CT scan and interview to confirm the absence of any comorbidity or history of ILD with the patient, and carefully consider the eligibility of the patient for ENHERTU therapy.

“Today’s approval of ENHERTU in Japan is significant as it is the first HER2 directed therapy to demonstrate an improvement in overall survival compared to chemotherapy for previously treated patients with HER2 positive metastatic gastric cancer,” said Wataru Takasaki, PhD, Executive Officer, Head of R&D Division in Japan, Daiichi Sankyo. “We are proud of the quality and speed in which we were able to deliver this second indication to patients and physicians in Japan as it highlights our commitment to transforming science into innovative therapies for patients with cancer.”

The overall safety and tolerability profile of ENHERTU in the DESTINY-Gastric01 trial was consistent with that observed in previously reported ENHERTU trials. Drug related adverse reactions occurred in 122 patients (97.6%) of the 125 patients (including 99 Japanese patients) who received ENHERTU. The most common adverse reactions were neutrophil count decreased in 78 patients (62.4%), nausea in 72 patients (57.6%), decreased appetite in 66 patients (52.8%), anemia in 51 patients (40.8%), platelet count decreased in 48 patients (38.4%), leukocyte count decreased in 47 patients (37.6%), malaise in 43 patients (34.4%), diarrhea in 31 patients (24.8%), alopecia in 28 patients (22.4%), lymphocyte count decreased in 27 patients (21.6%), vomiting in 26 patients (20.8%), and others. In Japanese patients, ILD occurred in 11 of 99 patients (11.1%).

About 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.[3],[4] Incidence rates for gastric cancer are markedly higher in eastern Asia, where approximately half of all cases occur.[5],[6] Japan has the third highest incidence rate of gastric cancer worldwide; in 2018, the age-standardized rate in Japan was 27.5 per 100,000.1,[7]

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 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.[8] Recommended first-line treatment for HER2 positive advanced or metastatic gastric cancer is combination chemotherapy plus trastuzumab, an anti-HER2 agent, which has been shown to improve outcomes when added to chemotherapy.[9] For metastatic gastric cancer that progresses on first line treatment with chemotherapy and an anti-HER2 regimen, ENHERTU is the first and only HER2 directed medicine to demonstrate significant improvement in overall survival.

About DESTINY-Gastric01

DESTINY-Gastric01 is an open-label, multi-center, randomized, pivotal phase 2 trial evaluating the safety and efficacy of ENHERTU in a primary cohort of patients from Japan and South Korea with HER2 overexpressing (defined as IHC3+ or IHC2+/ISH+) advanced gastric cancer or gastroesophageal junction adenocarcinoma who had 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 6.4mg/kg once every three weeks or chemotherapy.

The primary endpoint of the trial is ORR, as assessed by independent central review. ORR, or tumor response rate, represents the percentage of patients whose disease decreases and/or disappears. OS is a key secondary endpoint to be statistically evaluated hierarchically if the primary endpoint was statistically significant. Other secondary endpoints include progression-free survival (PFS), duration of response (DoR), disease control rate (DCR) and confirmed ORR assessed in those responses confirmed by a follow-up scan of at least 4 weeks after initial independent central review.

About ENHERTU

ENHERTU (trastuzumab deruxtecan in Japan and other regions of the world; fam-trastuzumab deruxtecan-nxki in 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 topoisomerase I inhibitor payload by a tetrapeptide-based linker.

In addition to approval in Japan for the treatment of patients with HER2 positive unresectable advanced or recurrent gastric cancer that has progressed after chemotherapy, ENHERTU (5.4 mg/kg) is also approved in Japan and the U.S. 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 based on the DESTINY-Breast01 trial.

ENHERTU has not been approved in the EU, or countries outside of Japan and the U.S., for any indication. It is an investigational agent globally for various indications. Safety and effectiveness have not been established for the proposed uses being investigated in ongoing studies.

About the Clinical Development Program

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

In May 2020, ENHERTU received Breakthrough Therapy Designation (BTD) from the U.S. Food and Drug Administration (FDA) 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 and Orphan Drug Designation for gastric cancer, including gastroesophageal junction cancer.

In May 2020, ENHERTU also received a BTD for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have a HER2 mutation and with disease progression on or after platinum-based therapy.

In July 2020, the European Medicines Agency’s Committee for Medicinal Products for Human Use granted ENHERTU accelerated assessment for the treatment of adults with unresectable or metastatic HER2 positive breast cancer who have received two or more prior anti-HER2 based regimens. 

About the Collaboration between Daiichi Sankyo and AstraZeneca

Daiichi Sankyo and AstraZeneca entered into a global collaboration to jointly develop and commercialize ENHERTU (a HER2 directed ADC) in March 2019, and DS-1062 (a TROP2 directed ADC) in July 2020, except in Japan where Daiichi Sankyo maintains exclusive rights. Daiichi Sankyo is responsible for manufacturing and supply of ENHERTU and DS-1062.

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.

Please see accompanying full Prescribing Information, including Boxed WARNING, and Medication Guide.

About Daiichi Sankyo Cancer Enterprise

The mission of Daiichi Sankyo Cancer Enterprise is to leverage our world-class, innovative science and push beyond traditional thinking to create meaningful treatments for patients with cancer. We are dedicated to transforming science into value for patients, and this sense of obligation informs everything we do. Anchored by our DXd antibody drug conjugate (ADC) technology, our powerful research engines include biologics, medicinal chemistry, modality and other research laboratories in Japan, and Plexxikon Inc., our small molecule structure-guided R&D center in Berkeley, CA. For more information, please visit: www.DSCancerEnterprise.com.

About Daiichi Sankyo

Daiichi Sankyo Group is dedicated to the creation and supply of innovative pharmaceutical therapies to improve standards of care and address diversified, unmet medical needs of people globally by leveraging our world-class science and technology. With more than 100 years of scientific expertise and a presence in more than 20 countries, Daiichi Sankyo and its 15,000 employees around the world draw upon a rich legacy of innovation and a robust pipeline of promising new medicines to help people. In addition to a strong portfolio of medicines for cardiovascular diseases, under the Group’s 2025 Vision to become a “Global Pharma Innovator with Competitive Advantage in Oncology,” Daiichi Sankyo is primarily focused on providing novel therapies in oncology, as well as other research areas centered around rare diseases and immune disorders. For more information, please visit: www.daiichisankyo.com.

References:

[1] GLOBOCAN 2018 Graph production: IARC. World Health Organization. August 2020.

[2] American Cancer Society. About Stomach Cancer. Targeted Therapies for Stomach Cancer. December 2017.

[3] Bray F, et al. CA: Cancer J. Clin 2018;68:394-424.

[4] American Cancer Society. Stomach Cancer: Early Detection, Diagnosis, and Staging. December 2017.

[5] Balakrishnan M, et al. Curr Gastroenterol Rep. 2017; 19(8): 36.

[6] Kim Y, et al. Epidemiol Health. 2015; 37: e2015006.

[7] Sun D et al. Chin J Cancer Res. 2020 Apr; 32(2): 129–139.

[8] Curea FG, et al. Cancer Biotherapy & Radiopharmaceuticals. 2017;32 (10).

[9] NCCN Guidelines® Gastric Cancer. Version 2.2020. May 13, 2020: MS-21-32.

SOURCE: Daiichi Sankyo

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