Trastuzumab Deruxtecan Granted Priority Review From FDA for HER2-Positive Unresectable/Metastatic Breast Cancer


Fam-trastuzumab deruxtecan-nxki, which was granted a priority review designation, appears to have potential for patients with HER2-positive unresectable/metastatic breast cancer.

The FDA has accepted a supplemental biologics license application for antibody-drug conjugate fam-trastuzumab deruxtecan-nxki (Enhertu), which was also granted priority review, for the treatment of patients with HER2-positive unresectable/metastatic breast cancer that was previously treated with an anti-HER2 regimen, according to a press release from developers Daiichi Sankyo and AstraZeneca.1

The application is currently under review by the Real-Time Oncology Review (RTOR) program and Project Orbis, both of which were designed by the FDA to bring efficacious cancer therapies to patients earlier. RTOR helps the FDA review different components of an application prior to completion of application submission, and Project Orbis provides a framework for concurrent submissions and aids in reviewing oncology drugs among international partners.

The Prescription Drug User Fee Act date is set for the second quarter of 2022.

“This review across geographies and the priority review in the U.S. as part of Project Orbis is so important because it speaks to the transformative potential of [trastuzumab deruxtecan] based on the unprecedented progression-free survival benefit in this setting,” Susan Galbraith, executive vice president of Oncology R&D at AstraZeneca, said in the press release. “The news reinforces the importance of bringing this potential new option to patients as quickly as possible.”

The application was based on findings from the phase 3 DESTINY-Breast03 trial (NCT03529110)trial, which read out at the 2021 European Society for Medical Oncology Congress.2 In the trial, treatment with trastuzumab deruxtecan in a population of patients with HER2-positive unresectable and/or metastatic breast cancer that had previously been treated with trastuzumab (Herceptin) and a taxane experienced a 72% reduced risk of disease progression or death vs those treated with ado-trastuzumab emtansine (Kadcyla; T-DM1; hazard ratio [HR], 0.28; 95% CI, 0.22-0.37; P = 7.8x10-22). Additional findings included a median progression-free survival (PFS) by blinded independent central review that was not reached (95% CI, 18.5–not estimated) in the trastuzumab deruxtecan arm compared with 6.8 months (95% CI, 5.6-8.2) in the T-DM1 arm.

Findings from a secondary end point analysis highlighted a median investigator assessed-PFS of 25.1 months (95% CI, 22.1-NE) vs 7.2 months (95% CI, 6.8-8.3) in the T-DM1 arm (HR, 0.26; 95% CI, 0.20-0.35). Although not statistically significant, investigators reported a notable trend towards overall survival in the trastuzumab arm (HR, 0.56; 95% CI, 0.36-0.86; P = .007172); mature data are needed.

“This regulatory review of ENHERTU in the U.S. marks the first time this medicine is participating in both the Real-Time Oncology Review and Project Orbis programs,” Ken Takeshita, MD, global head of R&D at Daiichi Sankyo, said. “The FDA’s prioritization of our application underscores the potential of this medicine and the continued need to expedite the availability of new treatment options, while making it possible to potentially receive approvals in several countries concurrently.”

The agent demonstrated a safety profile that was consistent with previous findings. Common grade 3 of higher treatment-emergent adverse effects among patients treated with trastuzumab deruxtecan included neutropenia (19.1%), thrombocytopenia (7.0%), leukopenia (6.6%), nausea (6.6%), anemia (5.8%), fatigue (5.1%), and vomiting (1.6%). Importantly, 10.5% of patients developed interstitial lung disease or pneumonitis that was linked to treatment with trastuzumab deruxtecan. Most events were low grade (9.7%) with 2 patients who developed grade 3 disease, and none had grade 4/5.


  1. CORRECTING and REPLACING ENHERTU® granted Priority Review in the US for patients with HER2-positive metastatic breast cancer treated with a prior anti-HER2-based regimen. News release. AstraZeneca and Daiichi Sankyo. January 17, 2022. Accessed January 18, 2022.
  2. Cortés J, Kim SB, Chung WP, et al. Trastuzumab deruxtecan (T-DXd) vs trastuzumab emtansine (T-DM) in patients (Pts) with HER2+ metastatic breast cancer (mBC): results of the randomized phase III DESTINY-Breast03 study. Presented at: European Society for Medical Oncology Annual Congress 2021. September 16-21, 2021; virtual. Abstract LBA1.
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