WILMINGTON, Del. – AstraZeneca Pharmaceuticals LP and Daiichi Sankyo’s supplemental Biologics License Application (sBLA) for ENHERTU® (fam-trastuzumab deruxtecan-nxki) has been accepted and granted Priority Review in the US 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.
The sBLA is based on data from the ongoing DESTINY-PanTumor02 Phase II trial where ENHERTU demonstrated clinically meaningful and durable responses leading to a clinically meaningful survival benefit in previously treated patients across HER2-expressing metastatic solid tumors, including biliary tract, bladder, cervical, endometrial, ovarian cancers, and other tumors. Data from other supporting trials in patients with HER2-positive IHC3+ tumors in the ENHERTU clinical development program, including DESTINY-Lung01 and DESTINY-CRC02, were also included in the submission.
ENHERTU is a specifically engineered HER2-directed antibody drug conjugate (ADC) being jointly developed and commercialized by AstraZeneca and Daiichi Sankyo.
The Food and Drug Administration (FDA) grants Priority Review to applications for medicines that, if approved, would offer significant improvements over available options by demonstrating safety or efficacy improvements, preventing serious conditions or enhancing patient compliance. The Prescription Drug User Fee Act date, the FDA action date for their regulatory decision, is during the second quarter of 2024.
Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, said: “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. 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 and biomarker to patients as quickly as possible.”
Ken Takeshita, MD, Global Head, R&D, Daiichi Sankyo, said: “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. 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.”
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.
Results from DESTINY-PanTumor02 were presented at the 2023 European Society for Medical Oncology Congress and simultaneously published in the Journal of Clinical Oncology.
The safety profile observed across the trials was consistent with previous clinical trials of ENHERTU with no new safety concerns identified.
The Priority Review follows receipt of Breakthrough Therapy Designation (BTD) in the US in August 2023 for ENHERTU in metastatic HER2-positive solid tumors.
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. In some cancers, HER2 expression is amplified or the cells have activating mutations. HER2 protein overexpression may occur as a result of HER2 gene amplification and is often associated with aggressive disease and poor prognosis.
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.
HER2 is an emerging biomarker in solid tumor types including biliary tract, bladder, cervical, endometrial, ovarian and pancreatic cancers. 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%. 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.
DESTINY-PanTumor02
DESTINY-PanTumor02 is a global, multicenter, multi-cohort, open-label Phase II trial evaluating the efficacy and safety of ENHERTU (5.4mg/kg) for the treatment of previously treated HER2-expressing tumors, including biliary tract cancer, bladder cancer, cervical cancer, endometrial cancer, ovarian cancer, 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 has enrolled 267 patients at multiple sites in Asia, Europe and North America.
DESTINY-Lung01
DESTINY-Lung01 is a global Phase II, open-label, two-cohort trial evaluating the efficacy and safety of ENHERTU (5.4mg/kg or 6.4mg/kg) in patients with HER2-mutant (cohort 2, n=91) or HER2-overexpressing (defined as IHC 3+ or IHC 2+) [cohort 1 and 1a, n=90] 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.
DESTINY-CRC02
DESTINY-CRC02 is a global, randomized, two arm, parallel, multicenter Phase II trial evaluating the efficacy and safety of two doses (5.4mg/kg or 6.4mg/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 5.4mg/kg or 6.4mg/kg of ENHERTU. In the second stage, additional patients (n=42) were enrolled in the 5.4mg/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.
ENHERTU
ENHERTU 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 (5.4mg/kg) is approved in more than 55 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 (5.4mg/kg) is approved in more than 45 countries 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 (5.4mg/kg) is approved in more than 30 countries worldwide for the treatment of adult patients with unresectable or metastatic non-small cell lung cancer 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 US for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.
ENHERTU (6.4mg/kg) is approved in more than 30 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 trial and/or DESTINY-Gastric02 trial.
AstraZeneca
AstraZeneca is a global, science-led biopharmaceutical company that focuses on the discovery, development, and commercialization of prescription medicines in Oncology, Rare Diseases, and BioPharmaceuticals, including Cardiovascular, Renal & Metabolism, and Respiratory & Immunology. Based in Cambridge, UK, AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide.
Contacts
Brendan McEvoy, +1 302 885 2677
Jillian Gonzales, +1 302 885 2677
US Media Mailbox: [email protected]