FDA Grants Regular Approval to Fam-trastuzumab Deruxtecan-nxki for Breast Cancer

May 5, 2022

The following is a message from the Director of the FDA Oncology Center of Excellence, Dr. Richard Pazdur:

On May 4, 2022, the Food and Drug Administration approved fam-trastuzumab deruxtecan-nxki (Enhertu, Daiichi Sankyo, Inc.) for 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 6 months of completing therapy. 

In December 2019, fam-trastuzumab deruxtecan-nxki received accelerated approval for adult patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens in the metastatic setting. The following trial was the confirmatory trial for the accelerated approval. 

Efficacy was based on DESTINY-Breast03 (NCT03529110), a multicenter, open-label, randomized trial that enrolled 524 patients with HER2-positive, unresectable, and/or metastatic breast cancer who received prior trastuzumab and taxane therapy for metastatic disease or developed disease recurrence during or within 6 months of completing neoadjuvant or adjuvant therapy. Patients were randomized 1:1 to receive either Enhertu or ado-trastuzumab emtansine by intravenous infusion every 3 weeks until unacceptable toxicity or disease progression. Randomization was stratified by hormone receptor status, prior treatment with pertuzumab, and history of visceral disease.

The main efficacy outcome measure was progression-free survival (PFS) as assessed by blinded independent central review based on RECIST v.1.1. Overall survival (OS) and confirmed objective response rate (ORR) were the key secondary outcome measures. Median PFS was not reached (95% CI: 18.5, not estimable) in the Enhertu arm and 6.8 months (95% CI: 5.6, 8.2) in the ado-trastuzumab emtansine arm. The hazard ratio was 0.28 (95% CI: 0.22, 0.37; p-value<0.0001). At the time of the PFS analysis, 16% of patients had died and OS was immature. The ORR based on the patients with measurable disease assessed by BICR at baseline was 82.7% (95% CI: 77.4, 87.2) in the Enhertu arm and 36.1% (95% CI: 30.0, 42.5) for those receiving ado-trastuzumab emtansine. 

The most common adverse reactions (incidence >30%) in patients receiving Enhertu were nausea, fatigue, vomiting, alopecia, constipation, anemia, and musculoskeletal pain. Serious adverse reactions in >1% of patients who received Enhertu were vomiting, interstitial lung disease, pneumonia, pyrexia, and urinary tract infection. The prescribing information includes a Boxed Warning to advise health professionals of the risk of interstitial lung disease and embryo-fetal toxicity.

The recommended Enhertu dose for breast cancer is 5.4 mg/kg given as an intravenous infusion once every 3 weeks (21-day cycle) until disease progression or unacceptable toxicity.

View full prescribing information for Enhertu

This review was conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence. Project Orbis provides a framework for concurrent submission and review of oncology drugs among international partners. For this review, FDA collaborated with the Australian Therapeutic Goods Administration, Health Canada, Israel’s Ministry of Health Pharmaceutical Administration, and Switzerland’s Swissmedic. The application reviews may be ongoing at the other regulatory agencies. 

This review used the Real-Time Oncology Review (RTOR) pilot program, which streamlined data submission prior to the filing of the entire clinical application, and the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment. 

This application was granted priority review and breakthrough designation. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System or by calling 1-800-FDA-1088.

For assistance with single-patient INDs for investigational oncology products, healthcare professionals may contact OCE’s Project Facilitate at 240-402-0004 or email OncProjectFacilitate@fda.hhs.gov.

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Please visit the FDA Hematology/Oncology (Cancer) Approvals & Safety Notifications webpage for a list of current and past approvals.