On September 24, 2025 Daiichi Sankyo (TSE: 4568) and AstraZeneca’s (LSE/STO/Nasdaq: AZN) reported that supplemental Biologics License Application (sBLA) for ENHERTU (famtrastuzumab deruxtecan-nxki) in combination with pertuzumab has been accepted and granted Priority Review in the U.S. for the first-line treatment of adult patients with unresectable or metastatic HER2 positive breast cancer.
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ENHERTU is a specifically engineered HER2 directed DXd antibody drug conjugate (ADC) discovered by Daiichi Sankyo and 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 Priority Review follows receipt of Breakthrough Therapy Designation granted by the FDA for ENHERTU plus pertuzumab based on data from the DESTINY-Breast09 phase 3 trial in July 2025. The Prescription Drug User Fee Act (PDUFA) date, the FDA target action date for their regulatory decision, is January 23, 2026.
The sBLA is being reviewed under the Real-Time Oncology Review (RTOR) program, an initiative of the FDA 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.
The sBLA is based on data from DESTINY-Breast09 presented as a special late-breaking oral session at the 2025 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) (#ASCO25) Annual Meeting. In the trial, ENHERTU in combination with pertuzumab reduced the risk of disease progression or death by 44% versus taxane, trastuzumab and pertuzumab (THP) (hazard ratio [HR]: 0.56; 95% confidence interval [CI]: 0.44-0.71; 2 p<0.00001) as a first-line treatment for patients with HER2 positive metastatic breast cancer. Median progression-free survival (PFS) was 40.7 months (95% CI: 36.5-NC) with ENHERTU plus pertuzumab compared to 26.9 months (95% CI: 21.8-NC) for THP as assessed by blinded independent central review (BICR). The PFS benefit for ENHERTU plus pertuzumab versus THP was consistent across subgroups.
Confirmed objective response rate (ORR) with ENHERTU plus pertuzumab was 85.1% (95% CI: 81.2-88.5) versus 78.6% (95% CI: 74.1-82.5) with THP. There were 58 complete responses (CR) and 268 partial responses (PR) with ENHERTU plus pertuzumab compared to 33 CRs and 271 PRs with THP. Median duration of response (DOR) for ENHERTU plus pertuzumab exceeded three years (39.2 months) versus 26.4 months with THP.
"ENHERTU in combination with pertuzumab delayed disease progression for more than three years compared to around two years with current standard of care as a first-line treatment for patients with HER2 positive metastatic breast cancer," said Ken Takeshita, MD, Global Head, R&D, Daiichi Sankyo. "Receiving Priority Review moves us closer to offering ENHERTU to patients even earlier in the metastatic treatment pathway as a potential new first-line treatment option."
"The DESTINY-Breast09 trial showed that treating patients with HER2 positive metastatic breast cancer with ENHERTU in combination with pertuzumab until progression in the first-line setting produced a new landmark of more than 40 months for progression-free survival and nearly doubled the number of patients with no evidence of disease on imaging," said Susan Galbraith, MBBChir, PhD, Executive Vice President, Oncology Hematology R&D, AstraZeneca. "This marks the first major evolution in treatment in this firstline setting in more than a decade – a setting where a strong response is crucial, as up to one third of patients may not receive second-line therapy."
The safety profile of ENHERTU plus pertuzumab in DESTINY-Breast09 was consistent with the known profiles of each individual therapy with no new safety concerns identified. Grade 3 or higher treatment emergent adverse events (TEAEs) occurred in 54.9% of patients in the ENHERTU plus pertuzumab arm and 52.4% of patients in the THP arm. The most common grade 3 or higher TEAEs occurring in 5% or more of patients treated with ENHERTU plus pertuzumab were neutropenia (23.9%), hypokalemia (10.2%), anemia (8.4%), fatigue (7.9%), diarrhea (6.8%), thrombocytopenia (6.3%) and nausea (5.0%). Interstitial lung disease (ILD) or pneumonitis events occurred in 12.1% of patients treated with ENHERTU plus pertuzumab as determined by an independent adjudication committee. The majority of ILD or pneumonitis events were low grade (grade 1 [n=17; 4.5%] or grade 2 [n=27; 7.1%]). There were two grade 5 ILD events (0.5%) in the ENHERTU plus pertuzumab arm.
ENHERTU is already approved in more than 85 countries/regions worldwide for the treatment of adult patients with unresectable or metastatic HER2 positive (immunohistochemistry [IHC] 3+ or in-situ hybridization (ISH)+) 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 based on the results from the DESTINY-Breast03 trial.
About DESTINY-Breast09
DESTINY-Breast09 is a global, multicenter, randomized, open-label, phase 3 trial evaluating the efficacy and safety of ENHERTU (5.4 mg/kg) either alone or in combination with pertuzumab versus standard of care THP as a first-line treatment in patients with HER2 positive metastatic breast cancer.
Patients were randomized 1:1:1 to receive either ENHERTU monotherapy with a pertuzumab matching placebo; ENHERTU in combination with pertuzumab; or THP. Randomization was stratified by prior treatment (de novo metastatic disease versus progression from early-stage disease), hormone receptor (HR) status and PIK3CA mutation status.
The primary endpoint of DESTINY-Breast09 is PFS as assessed by BICR in both the ENHERTU monotherapy and ENHERTU combination arms. Secondary endpoints include investigator-assessed PFS, overall survival, ORR, DOR, pharmacokinetics and safety. The investigational arm assessing ENHERTU monotherapy versus THP remains blinded to patients and investigators and will continue to the final PFS analysis.
DESTINY-Breast09 enrolled 1,157 patients across multiple sites in Africa, Asia, Europe, North America and South America. For more information about the trial, visit ClinicalTrials.gov.
About HER2 Positive Metastatic Breast Cancer
Breast cancer is the second most common cancer and one of the leading causes of cancer-related deaths worldwide.1 More than two million breast cancer cases were diagnosed in 2022, with more than 665,000 deaths globally.1 In the U.S., more than 300,000 cases of breast cancer are diagnosed annually with more than 42,000 deaths. 2 While survival rates are high for those diagnosed with early breast cancer, only about 30% of patients diagnosed with or progress to metastatic disease are expected to live five years following diagnosis.
HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of many types of tumors including breast cancer.4 HER2 protein overexpression may occur as a result of HER2 gene amplification.5 Approximately one in five cases of breast cancer are considered HER2 positive.6 4 HER2 positive metastatic breast cancer is an aggressive disease driven by overexpression or amplification of HER2 that affects 15% to 20% of patients with metastatic breast cancer.7 Approximately 10,000 patients are treated each year in the first-line HER2 positive metastatic setting in the U.S.8 While HER2 targeted therapies have improved outcomes, prognosis remains poor with most patients experiencing disease progression within two years of first-line treatment with THP, which has been the standard of care for more than a decade.5,9,10,11 Further, approximately 25% to 30% of patients do not receive any treatment following first-line therapy due to discontinuation or death.
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 85 countries/regions worldwide for the treatment of adult patients with unresectable or metastatic HER2 positive (immunohistochemistry [IHC] 3+ or in-situ hybridization (ISH)+) 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 based on the results from the DESTINY-Breast03 trial.
ENHERTU (5.4 mg/kg) is approved in more than 85 countries/regions worldwide 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 from the DESTINY-Breast04 trial.
ENHERTU (5.4 mg/kg) is approved in more than 45 countries/regions for the treatment of adult patients with unresectable or metastatic hormone receptor (HR) positive, HER2 low (IHC 1+ or IHC 2+/ISH-) or HER2 ultralow (IHC 0 with membrane staining) breast cancer, as determined by a locally or regionally approved test, that have progressed on one or more endocrine therapies in the metastatic setting based on the results from the DESTINY-Breast06 trial.
ENHERTU (5.4 mg/kg) is approved in more than 60 countries/regions 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 and/or DESTINY-Lung05 trials. Continued approval in China and 5 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 70 countries/regions worldwide for the treatment of adult patients with locally advanced or metastatic HER2 positive (IHC 3+ or IHC 2+/ISH+) gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received a prior trastuzumab-based regimen based on the results from the DESTINY-Gastric01, DESTINY-Gastric02 and/or DESTINY-Gastric06 trials. Continued approval in China for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.
ENHERTU (5.4 mg/kg) is approved in more than 10 countries/regions worldwide for the treatment of adult patients with unresectable or metastatic HER2 positive (IHC 3+) solid tumors who have received prior systemic treatment and have no satisfactory alternative treatment options based on efficacy results from the DESTINY-PanTumor02, DESTINY-Lung01 and DESTINY-CRC02 trials. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.
About the ENHERTU Clinical Development Program
A comprehensive global clinical development program is underway evaluating the efficacy and safety of ENHERTU as a monotherapy or in combination or sequentially with other cancer medicines across multiple HER2 targetable cancers.
(Press release, Daiichi Sankyo, SEP 24, 2025, View Source [SID1234665029])