ENHERTU ® Recommended for Approval in the EU by CHMP for Patients with HER2 Low Metastatic Breast Cancer

Daiichi Sankyo (TSE: 4568) and AstraZeneca’s (LSE/STO/Nasdaq: AZN) ENHERTU^® (trastuzumab deruxtecan) has been recommended for approval in the European Union (EU) as a monotherapy for the treatment of adult patients with unresectable or metastatic HER2 low (IHC 1+ or IHC 2+/ISH-) breast cancer who have received prior chemotherapy in the metastatic setting or developed disease recurrence during or within six months of completing adjuvant chemotherapy.

ENHERTU is a specifically engineered HER2 directed antibody drug conjugate (ADC) being jointly developed and commercialized by Daiichi Sankyo and AstraZeneca.

The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) based its positive opinion on results from the DESTINY-Breast04 phase 3 trial presented at the 2022 American Society of Clinical Oncology Annual Meeting and simultaneously published in The New England Journal of Medicine. The recommendation will now be reviewed by the European Commission, which has the authority to grant marketing authorizations for medicines in the EU.

In DESTINY-Breast04, ENHERTU reduced the risk of disease progression or death by 50% versus physician’s choice of chemotherapy (hazard ratio [HR]=0.50; 95% confidence interval [CI]: 0.40-0.63; p<0.001) in patients with HER2 low metastatic breast cancer with hormone receptor (HR) positive or HR negative disease. A median progression-free survival (PFS) of 9.9 months (95% CI: 9.0-11.3) was seen with ENHERTU versus 5.1 months (95% CI: 4.2-6.8) in those treated with chemotherapy as assessed by blinded independent central review (BICR). A 36% reduction in the risk of death (HR=0.64; 95% CI: 0.49-0.84; p=0.001) also was seen with ENHERTU compared to chemotherapy with a median overall survival (OS) of 23.4 months (95% CI: 20.0-24.8) in patients treated with ENHERTU versus 16.8 months (95% CI: 14.5-20.0) in those treated with chemotherapy.

“This positive CHMP opinion recognizes the unmet need in the European Union for patients with HER2 low metastatic breast cancer. Currently, once patients with HR positive disease progress on hormone therapy there are limited effective treatments, and few targeted options are available for patients with HR negative disease,” said Ken Takeshita, MD, Global Head, R&D, Daiichi Sankyo. “We look forward to the European Commission decision and aim to bring ENHERTU to eligible patients as soon as possible.”

“ENHERTU is the first ever HER2 directed medicine to show a survival benefit in patients with HER2 low metastatic breast cancer, confirming the importance of targeting lower levels of HER2 expression in patients previously classified as HER2 negative,” said Susan Galbraith, MBBCh, PhD, Executive Vice President, Oncology R&D, AstraZeneca. “The CHMP’s recommendation is encouraging and supports our ambition to evolve the way breast cancer is classified and treated to ultimately improve patient outcomes.”

In DESTINY-Breast04, the safety profile of ENHERTU was consistent with previous clinical trials with no new safety concerns identified. The most common grade 3 or higher treatment emergent adverse events were neutropenia (13.7%), anemia (8.1%), fatigue (7.5%), leukopenia (6.5%), thrombocytopenia (5.1%), nausea (4.6%), increased aminotransferase (3.2%), decreased appetite (2.4%), vomiting (1.3%) and diarrhea (1.1%). Interstitial lung disease (ILD) or pneumonitis rates were consistent with that observed in late-line HER2 positive breast cancer trials of ENHERTU, as determined by an independent adjudication committee. Overall, 12.1% of patients had confirmed ILD or pneumonitis related to treatment as determined by an independent adjudication committee. The majority of ILD events (10.0%) were primarily low grade (grade 1 (3.5%) or grade 2 (6.5%)) with five grade 3 (1.3%), no grade 4 and three grade 5 (0.8%) events reported.

ENHERTU is approved in the EU for the treatment of patients with unresectable or metastatic HER2 positive breast cancer who have received one or more prior anti-HER2-based regimens and for the treatment of patients with previously treated HER2 positive advanced gastric cancer who have received a prior trastuzumab-based regimen. ENHERTU is not currently approved in the EU for the treatment of HER2 low metastatic breast cancer and is subject to additional monitoring.

About DESTINY-Breast04

DESTINY-Breast04 is a global, randomized, open-label, pivotal phase 3 trial evaluating the efficacy and safety of ENHERTU (5.4 mg/kg) versus physician’s choice of chemotherapy (capecitabine, eribulin, gemcitabine, paclitaxel or nab-paclitaxel) in patients with HR positive or HR negative, HER2 low unresectable and/or metastatic breast cancer previously treated with one or two prior lines of chemotherapy. Patients were randomized 2:1 to receive either ENHERTU or chemotherapy.

The primary endpoint of DESTINY-Breast04 is PFS in patients with HR positive disease based on BICR. Key secondary endpoints include PFS based on BICR in all randomized patients (HR positive and HR negative disease), OS in patients with HR positive disease and OS in all randomized patients (HR positive and HR negative disease). Other secondary endpoints include PFS based on investigator assessment, objective response rate based on BICR and on investigator assessment, duration of response based on BICR and safety. DESTINY-Breast04 enrolled 557 patients at multiple sites in Asia, Europe and North America. For more information about the trial, visit ClinicalTrials.gov.

About Breast Cancer and HER2 Expression

Breast cancer is the most common cancer and is one of the leading causes of cancer-related deaths worldwide.¹ More than two million cases of breast cancer were diagnosed in 2020 with nearly 685,000 deaths globally.¹ In Europe, approximately 531,000 cases of breast cancer are diagnosed annually with nearly 141,000 deaths.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, and is one of many biomarkers expressed in breast cancer tumors.³

HER2 expression is currently determined by an immunohistochemistry (IHC) test which estimates the amount of HER2 protein on a cancer cell, and/or an in-situ hybridization (ISH) test, which counts the copies of the HER2 gene in cancer cells.^3,4 HER2 tests provide IHC and ISH scores across the full HER2 spectrum and are routinely used to determine appropriate treatment options for patients with metastatic breast cancer. HER2 positive cancers are currently defined as HER2 expression measured as IHC 3+ or IHC 2+/ISH+, and HER2 negative cancers are defined as HER2 expression measured as IHC 0, IHC 1+ or IHC 2+/ISH-.³ However, approximately half of all breast cancers are HER2 low, defined as a HER2 score of IHC 1+ or IHC 2+/ISH-.^5,6,7 HER2 low occurs in both HR positive and HR negative disease.⁸

Currently, patients with HR positive metastatic breast cancer and HER2 low disease have limited effective treatment options following progression on endocrine (hormone) therapy.⁹ Additionally, few targeted options are available for those with HR negative disease.¹⁰

About ENHERTU

ENHERTU (trastuzumab deruxtecan; fam-trastuzumab deruxtecan-nxki in the U.S. only) is a HER2 directed ADC. Designed using Daiichi Sankyo’s proprietary DXd ADC technology, ENHERTU is the lead ADC in the oncology portfolio of Daiichi Sankyo and the most advanced program in AstraZeneca’s ADC scientific platform. ENHERTU consists of a HER2 monoclonal antibody attached to a topoisomerase I inhibitor payload, an exatecan derivative, via a stable tetrapeptide-based cleavable linker.

ENHERTU (5.4 mg/kg) is approved in more than 40 countries for the treatment of adult patients with unresectable or metastatic HER2 positive breast cancer who have received a (or one or more) prior anti-HER2-based regimen, either in the metastatic setting or in the neoadjuvant or adjuvant setting, and have developed disease recurrence during or within six months of completing therapy based on the results from the DESTINY-Breast03 trial. ENHERTU also is approved in several countries 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 results from the DESTINY-Breast01 trial.

ENHERTU (5.4 mg/kg) is approved in Brazil and the U.S. for the treatment of adult patients with unresectable or metastatic HER2 low (IHC 1+ or IHC 2+/ISH-) breast cancer who have received a prior systemic therapy in the metastatic setting or developed disease recurrence during or within six months of completing adjuvant chemotherapy based on the results of the DESTINY-Breast04 trial.

ENHERTU (5.4 mg/kg) is approved under accelerated approval in the U.S. for the treatment of adult patients with unresectable or metastatic non-small cell lung cancer (NSCLC) whose tumors have activating HER2 (ERBB2) mutations, as detected by an FDA-approved test, and who have received a prior systemic therapy based on the results from the DESTINY-Lung02 trial. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

ENHERTU (6.4 mg/kg) is approved in several countries for the treatment of adult patients with locally advanced or metastatic HER2 positive gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received a prior trastuzumab-based regimen based on the results from the DESTINY-Gastric01 and/or DESTINY-Gastric02 trial.

About the ENHERTU Clinical Development Program

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

Regulatory applications for ENHERTU in breast, non-small cell lung and gastric cancers are currently under review in several countries.

About the Daiichi Sankyo and AstraZeneca Collaboration

Daiichi Sankyo and AstraZeneca entered into a global collaboration to jointly develop and commercialize ENHERTU in March 2019 and datopotamab deruxtecan (Dato-DXd) in July 2020, except in Japan where Daiichi Sankyo maintains exclusive rights for each ADC. Daiichi Sankyo is responsible for the manufacturing and supply of ENHERTU and datopotamab deruxtecan.

About the DXd ADC Portfolio of Daiichi Sankyo

The DXd ADC portfolio of Daiichi Sankyo currently consists of five ADCs in clinical development across multiple types of cancer. The company’s clinical trial stage DXd ADCs include ENHERTU, a HER2 directed ADC and datopotamab deruxtecan (Dato-DXd), a TROP2 directed ADC, which are being jointly developed and commercialized globally with AstraZeneca; and, patritumab deruxtecan (HER3-DXd), a HER3 directed ADC. Two additional ADCs including ifinatamab deruxtecan (I-DXd; DS-7300), a B7-H3 directed ADC, and DS-6000, a CDH6 directed ADC, are being developed through a strategic early-stage research collaboration with Sarah Cannon Research Institute.

Each ADC is designed using Daiichi Sankyo’s proprietary DXd ADC technology to target and deliver a cytotoxic payload inside cancer cells that express a specific cell surface antigen. Each ADC consists of a monoclonal antibody attached to a number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers.

Datopotamab deruxtecan, ifinatamab deruxtecan, patritumab deruxtecan and DS-6000 are investigational medicines that have not been approved for any indication in any country. Safety and efficacy have not been established.

About Daiichi Sankyo

Daiichi Sankyo is dedicated to creating new modalities and innovative medicines by leveraging our world-class science and technology for our purpose “to contribute to the enrichment of quality of life around the world.” In addition to our current portfolio of medicines for cancer and cardiovascular disease, Daiichi Sankyo is primarily focused on developing novel therapies for people with cancer as well as other diseases with high unmet medical needs. With more than 100 years of scientific expertise and a presence in more than 20 countries, Daiichi Sankyo and its 16,000 employees around the world draw upon a rich legacy of innovation to realize our 2030 Vision to become an “Innovative Global Healthcare Company Contributing to the Sustainable Development of Society.” For more information, please visit www.daiichisankyo.com.

References
¹ Sung H, et al. CA Cancer J Clin. 2021;10.3322/caac.21660.
² Globocan 2020. Breast Cancer. Accessed: December 2022.
³ Iqbal N, et al. Mol Biol Int. 2014;852748.
⁴ Wolff A, et al. Arch Pathol Lab Med. 2018;142(11):1364–1382.
⁵ Schalper K, et al. Arch Pathol Lab Med. 2014;138:213-219.
⁶ Schettini F, et al. NPJ Breast Cancer. 2021;7:1.
⁷ Denkert C, et al. Lancet Oncol. 2021;22:1151-61.
⁸ Miglietta F, et al. NPJ Breast Cancer. 2021;7:137.
⁹ Matutino A, et al. Current Oncology. 2018;25(S1):S131-S141.
¹⁰ American Cancer Society. Breast Cancer Hormone Receptor Status. Accessed: December 2022.

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Contact information

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Victoria Amari
Daiichi Sankyo, Inc.
vamari@dsi.com
+1 908 900 3010 (mobile)

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Daiichi Sankyo Europe GmbH
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Daiichi Sankyo Co., Ltd.
ogiwara.koji.ay@daiichisankyo.co.jp
+81 3 6225 1126 (office)

Investor Relations:
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