Daiichi Sankyo and AstraZeneca’s Trastuzumab Deruxtecan Receives FDA Priority Review for First Tumor-Agnostic HER2-Targeted Indication

● This application is based on the results of the DESTINY-PanTumor02 study, as well as other clinical research data on trastuzumab deruxtecan.

●The sBLA application will be reviewed under the FDA's Real-Time Oncology Review and Orbis Project.

● Once approved, Daiichi Sankyo and AstraZeneca's trastuzumab deruxtecan may become the first HER2-targeted therapy and antibody-drug conjugate for the treatment of tumors regardless of cancer type.

On January 29, 2024, the U.S. Food and Drug Administration (FDA) accepted the supplemental Biologics License Application (sBLA) for Daiichi Sankyo and AstraZeneca's fam-trastuzumab deruxtecan-nxki (brand name: Enhertu®, hereinafter referred to as "trastuzumab deruxtecan"; known as fam-trastuzumab deruxtecan-nxki in the United States) and granted it Priority Review for the treatment of adult patients with unresectable or metastatic HER2-positive (immunohistochemistry [IHC] 3+) solid tumors who have received prior treatment or have no viable alternative treatment options.

Trastuzumab deruxtecan is a uniquely designed HER2-targeted antibody-drug conjugate (ADC) jointly developed and commercialized by Daiichi Sankyo and AstraZeneca.

The FDA's granting of Priority Review status to this drug indicates that, if approved, it will represent a significant improvement over existing treatment options in terms of safety or efficacy, prevention of serious diseases, or enhancement of patient compliance. The Prescription Drug User Fee Act (PDUFA) date, which is the FDA’s regulatory decision action date, is set for May 30, 2024. This follows the FDA’s granting of Breakthrough Therapy Designation to trastuzumab deruxtecan for the treatment of metastatic HER2-positive solid tumors in August 2023.

The sBLA is currently under review as part of the FDA's Real-Time Oncology Review (RTOR) program and the Orbis program, two initiatives by the FDA aimed at providing safe and effective cancer treatments to patients as early as possible. Through RTOR, the FDA can review certain applications before the full submission is completed. The Orbis program provides a framework for international partners involved to simultaneously submit and review oncology drugs.

sBLA is based on data from the ongoing Phase II study DESTINY-PanTumor02, which indicates that trastuzumab deruxtecan demonstrated clinically meaningful and durable responses in patients with various HER2-expressing metastatic solid tumors who had previously been treated. Additionally, there was a clinically significant improvement in survival. The submitted data also included findings from other studies within the trastuzumab deruxtecan clinical development program conducted in HER2-positive IHC3+ patients, including data from the DESTINY-Lung01 and DESTINY-CRC02 trials.

About Trastuzumab Deruxtecan

Trastuzumab Deruxtecan for Injection (trade name: Enhertu®; known as fam-trastuzumab deruxtecan-nxki in the United States) is an antibody-drug conjugate (ADC) targeting HER2. Trastuzumab deruxtecan is designed using Daiichi Sankyo's proprietary DXd-ADC technology and is the leading ADC product in Daiichi Sankyo’s oncology portfolio, as well as the most advanced project on AstraZeneca’s ADC scientific platform. Trastuzumab deruxtecan consists of a HER2 monoclonal antibody linked to several topoisomerase I inhibitor payloads (exatecan derivatives, DXd) via a cleavable tetrapeptide linker.

Based on the results of the DESTINY-Breast03 study, trastuzumab deruxtecan (5.4 mg/kg) has been approved in more than 55 countries and regions worldwide for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received prior anti-HER2-based therapy in the metastatic setting or developed disease recurrence during or within six months after completing neoadjuvant or adjuvant therapy.

Based on the results of the DESTINY-Breast04 study, trastuzumab deruxtecan (5.4 mg/kg) has been approved in more than 45 countries/regions worldwide for the treatment of adult patients with unresectable or metastatic HER2-low (immunohistochemistry [IHC] 1+ or IHC 2+/in situ hybridization [ISH]-) breast cancer who have received prior systemic therapy in the metastatic setting or developed disease recurrence during or within 6 months after completing adjuvant chemotherapy.

Based on the results of the DESTINY-Lung02 study, trastuzumab deruxtecan (5.4 mg/kg) has been approved in 30 countries worldwide for the treatment of adult patients with unresectable or metastatic NSCLC whose tumors have HER2 (ERBB2) activating mutations as detected by locally or regionally approved testing methods and who have previously received one systemic therapy. Confirmation of clinical benefit in a confirmatory trial will support full approval of this indication in the United States.

Based on the results of the DESTINY-Gastric01 and/or DESTINY-Gastric02 studies, trastuzumab deruxtecan (6.4 mg/kg) has been approved in more than 30 countries/regions worldwide for the treatment of adult patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma who have previously received a trastuzumab-based treatment regimen.

About the Clinical Development Plan for Trastuzumab Deruxtecan

A comprehensive clinical development program aimed at evaluating the efficacy and safety of trastuzumab deruxtecan monotherapy in treating various HER2-targetable cancers is currently underway globally. Research involving combination therapies, such as immunotherapy and other anti-cancer treatments, is also being conducted.

Regarding the collaboration between Daiichi Sankyo and AstraZeneca

Daiichi Sankyo and AstraZeneca entered into global collaborations in March 2019 and July 2020, respectively, to jointly develop and commercialize trastuzumab deruxtecan and datopotamab deruxtecan (Dato-DXd). Daiichi Sankyo holds exclusive rights to each ADC product in the Japanese market. Daiichi Sankyo is responsible for the production and supply of trastuzumab deruxtecan and datopotamab deruxtecan.

About Daiichi Sankyo's DXd ADC Portfolio

Daiichi Sankyo's DXd ADC portfolio currently includes six ADC drugs in clinical development, covering various types of cancer. Trastuzumab deruxtecan (HER2-targeted ADC) and datopotamab deruxtecan (Dato-DXd, TROP2-targeted ADC) are being co-developed by Daiichi Sankyo and AstraZeneca and commercialized globally. Patritumab deruxtecan (HER3-DXd, HER3-targeted ADC), ifinatamab deruxtecan (I-DXd, B7-H3-targeted ADC), and raludotatug deruxtecan (R-DXd, CDH6-targeted ADC) are being co-developed by Daiichi Sankyo and Merck & Co., Inc., and commercialized globally. DS-3939 (TA-MUC1-targeted ADC) is independently developed by Daiichi Sankyo.

Each ADC is designed using Daiichi Sankyo's proprietary DXd ADC technology to target cancer cells expressing specific cell surface antigens and deliver cytotoxic payloads into the cancer cells. Each ADC consists of a monoclonal antibody connected through a cleavable tetrapeptide linker to multiple topoisomerase I inhibitor payloads (a derivative of exatecan, DXd).

Datopotamab deruxtecan, ifinatamab deruxtecan, patritumab deruxtecan, raludotatug deruxtecan, and DS-3939 are all investigational drugs that have not been approved in any country/region for any indication. Their safety and efficacy have not been fully established.

Editor: Mu Mian

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