- Application based on results from DESTINY-PanTumor02 trial and supported by additional ENHERTU data
- Submission to be reviewed under FDA Real Time Oncology Review and Project Orbis
- If approved, Daiichi Sankyo and AstraZeneca’s ENHERTU will potentially be the first HER2 directed treatment and antibody drug conjugate to receive a tumor agnostic indication
TOKYO, Japan & BASKING RIDGE, NJ, USA I January 29, 2024 I Daiichi Sankyo (TSE: 4568) and AstraZeneca’s (LSE/STO/Nasdaq: AZN) supplemental Biologics License Application (sBLA) for ENHERTU® (fam-trastuzumab deruxtecan-nxki) has been accepted and granted Priority Review in the U.S. for the treatment of adult patients with unresectable or metastatic HER2 positive (immunohistochemistry [IHC] 3+) solid tumors who have received prior treatment or who have no satisfactory alternative treatment options.
ENHERTU is a specifically engineered HER2 directed antibody drug conjugate (ADC) being jointly developed and commercialized by Daiichi Sankyo and AstraZeneca.
The U.S. Food and Drug Administration (FDA) grants Priority Review to applications for medicines that, if approved, would offer significant improvements over available treatment options by demonstrating safety or efficacy improvements, preventing serious conditions or enhancing patient compliance. The Prescription Drug User Fee Act (PDUFA) date, the FDA action date for their regulatory decision, is May 30, 2024. The Priority Review follows receipt of Breakthrough Therapy Designation granted by the FDA in August 2023 for ENHERTU in metastatic HER2 positive solid tumors.
The sBLA is being reviewed under the Real-Time Oncology Review (RTOR) program and Project Orbis, two initiatives of the FDA which are designed to bring safe and effective cancer treatments to patients as early as possible. RTOR allows the FDA to review components of an application before submission of the complete application. Project Orbis provides a framework for concurrent submission and review of oncology medicines among participating international partners.
The sBLA is based on data from the ongoing DESTINY-PanTumor02 phase 2 trial where ENHERTU demonstrated clinically meaningful and durable responses leading to a clinically meaningful survival benefit in previously treated patients across HER2 expressing advanced solid tumors. Data from other supporting trials in patients with HER2 positive IHC 3+ tumors in the ENHERTU clinical development program, including DESTINY-Lung01 and DESTINY-CRC02, also were included in the submission.
“The clinical benefit seen across HER2 expressing metastatic solid tumors in the DESTINY-PanTumor02 trial and ongoing data from the ENHERTU clinical development program continues to demonstrate the potential of this medicine beyond its approved indications,” said Ken Takeshita, MD, Global Head, R&D, Daiichi Sankyo. “If approved, ENHERTU could become the first HER2 directed therapy and antibody drug conjugate with a tumor agnostic indication, providing patients with a potential new treatment option.”
“Today’s Priority Review for the first tumor agnostic submission for ENHERTU reflects the potential of this medicine to redefine the treatment of HER2 expressing cancers,” said Susan Galbraith, MBBChir, PhD, Executive Vice President, Oncology R&D, AstraZeneca. “Biomarkers for HER2 expression are already established in breast and gastric cancers, but we must now define them across tumor types. We will continue working closely with the FDA to bring this potential first tumor agnostic HER2 targeted medicine to patients as quickly as possible.”
About DESTINY-PanTumor02
DESTINY-PanTumor02 is a global, multicenter, multi-cohort, open-label phase 2 trial evaluating the efficacy and safety of ENHERTU (5.4 mg/kg) for the treatment of previously treated HER2 expressing tumors, including biliary tract, bladder, cervical, endometrial, ovarian, pancreatic cancer or other tumors. The primary efficacy endpoint of DESTINY-PanTumor02 is confirmed objective response rate (ORR) as assessed by investigator. Secondary endpoints include duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), safety, tolerability and pharmacokinetics. DESTINY-PanTumor02 enrolled 267 patients at multiple sites in Asia, Europe and North America. For more information about the trial, visit ClinicalTrials.gov.
The primary analysis of this study was presented in a late-breaking mini-oral session at the 2023 European Society for Medical Oncology (ESMO) Congress and simultaneously published in the Journal of Clinical Oncology.
About DESTINY-Lung01
DESTINY-Lung01 is a global phase 2, open-label, two-cohort trial evaluating the efficacy and safety of ENHERTU (6.4 mg/kg and 5.4 mg/kg) in patients with HER2 mutant (cohort 2, n=91) or HER2 overexpressing (cohort 1 and 1a, n=90) (defined as IHC 3+ or IHC 2+) unresectable or metastatic non-squamous non-small cell lung cancer (NSCLC) who had progressed after one or more systemic therapies. The primary endpoint is confirmed ORR by independent central review. Key secondary endpoints include DOR, DCR, PFS, OS and safety. DESTINY-Lung01 enrolled 181 patients at multiple sites, including Asia, Europe and North America. For more information about the trial, visit ClinicalTrials.gov.
Full results from the HER2 mutant cohort were presented at the 2021 ESMO Congress and simultaneously published in The New England Journal of Medicine. Updated results from both cohorts of DESTINY-Lung01 were presented at the 2022 ESMO Congress.
About DESTINY-CRC02
DESTINY-CRC02 is a global, randomized, two arm, parallel, multicenter phase 2 trial evaluating the efficacy and safety of two doses (5.4 mg/kg or 6.4 mg/kg) of ENHERTU in patients with locally advanced, unresectable or metastatic HER2 positive colorectal cancer of BRAF wild-type, or RAS wild-type and RAS mutant tumor types previously treated with standard therapy. The trial was conducted in two stages. In the first stage, patients (n=80) were randomized 1:1 to receive either 5.4 mg/kg or 6.4 mg/kg of ENHERTU. In the second stage, additional patients (n=42) were enrolled in the 5.4 mg/kg arm. The primary endpoint is confirmed ORR as assessed by blinded independent central review. Secondary endpoints include DOR, DCR, investigator-assessed confirmed ORR, clinical benefit ratio, PFS, OS and safety. DESTINY-CRC02 enrolled 122 patients at multiple sites in Asia, Europe and North America. For more information about the trial, visit ClinicalTrials.gov.
Primary results from the DESTINY-CRC02 phase 2 trial were presented at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting.
About HER2 Expression in Solid Tumors
HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of various tissue cells throughout the body and is involved in normal cell growth.1,2 In some cancers, HER2 expression is amplified or the cells have activating mutations.1,3 HER2 protein overexpression may occur as a result of HER2 gene amplification and is often associated with aggressive disease and poor prognosis.4 While HER2 directed therapies have been used to treat breast, gastric, lung and colorectal cancers, more research is needed evaluating their potential role in treating other HER2 expressing solid tumor types.2,5,6
HER2 is an emerging biomarker in solid tumor types including biliary tract, bladder, cervical, endometrial, ovarian and pancreatic cancers.3 Testing is not routinely performed in these additional tumor types and as a result, available literature is limited. In these solid tumors, HER2 positive expression, classified as IHC 3+, has been observed at rates from 1% to 28%.7,8
There is an unmet need for effective therapies for certain HER2 expressing solid tumors, particularly for those who have progressed on or are refractory to standard of care therapies as there are currently no approved HER2 directed therapies for these cancers.2,9
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 number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers.
ENHERTU (5.4 mg/kg) is approved in more than 55 countries worldwide 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 (5.4 mg/kg) is approved in more than 45 countries worldwide for the treatment of adult patients with unresectable or metastatic HER2 low (IHC 1+ or IHC 2+/in-situ hybridization (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 from the DESTINY-Breast04 trial.
ENHERTU (5.4 mg/kg) is approved in more than 30 countries worldwide for the treatment of adult patients with unresectable or metastatic NSCLC whose tumors have activating HER2 (ERBB2) mutations, as detected by a locally or regionally approved test, and who have received a prior systemic therapy based on the results from the DESTINY-Lung02 trial. Continued approval in the U.S. 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 more than 30 countries worldwide 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 trials.
About the ENHERTU Clinical Development Program
A comprehensive global clinical development program is underway evaluating the efficacy and safety of ENHERTU monotherapy across multiple HER2 targetable cancers. Trials in combination with other anticancer treatments, such as immunotherapy, also are underway.
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 six ADCs in clinical development across multiple types of cancer. ENHERTU, a HER2 directed ADC, and datopotamab deruxtecan (Dato-DXd), a TROP2 directed ADC, are being jointly developed and commercialized globally with AstraZeneca. Patritumab deruxtecan (HER3-DXd), a HER3 directed ADC, ifinatamab deruxtecan (I-DXd), a B7-H3 directed ADC, and raludotatug deruxtecan (R-DXd), a CDH6 directed ADC, are being jointly developed and commercialized globally with Merck & Co., Inc., Rahway, N.J. USA. DS-3939, a TA-MUC1 directed ADC, is being developed by Daiichi Sankyo.
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, raludotatug deruxtecan and DS-3939 are investigational medicines that have not been approved for any indication in any country. Safety and efficacy have not been established.
ENHERTU U.S. Important Safety Information
Indications
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 a 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
- Unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer, as determined by an FDA-approved test, who have received a prior chemotherapy in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant chemotherapy
- 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
This indication is approved under accelerated approval based on objective 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.
- Locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma who have received a prior trastuzumab-based regimen
Please see accompanying full Prescribing Information, including Boxed WARNINGS, and Medication Guide.
About Daiichi Sankyo
Daiichi Sankyo is an innovative global healthcare company contributing to the sustainable development of society that discovers, develops and delivers new standards of care to enrich the quality of life around the world. With more than 120 years of experience, Daiichi Sankyo leverages its world-class science and technology to create new modalities and innovative medicines for people with cancer, cardiovascular and other diseases with high unmet medical need. For more information, please visit www.daiichisankyo.com.
References:
1 ASCO. Breast Cancer. Accessed January 2024.
2 Iqbal N, et al. Mol Biol Int. 2014;852748.
3 Omar N, et al. Pathogenesis. 2015;2(3):1-9.
4 Pillai R, et al. Cancer. 2017;1;123(21): 4099-4105.
5 National Cancer Institute. Enhertu Marks First Targeted Therapy for HER2-Mutant Lung Cancer. Accessed January 2024.
6 Siena S, et al. Ann Oncol. 2018 May; 29(5):1108–1119.
7 Yan M, et al. Cancer Metastasis Rev. 2015;34(1):157–164.
8 Buza N, et al. Modern Pathology. 2013 Dec;26(12):1605-12.
9 Meric-Bernstam F, et al. J Clin Oncol. 2021; 39:15: 3004-3004.
SOURCE: Daiichi Sankyo
