FDA Grants Regular Approval to Fam-Trastuzumab Deruxtecan-nxki for Unresectable or Metastatic HER2-Positive Breast Cancer

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On May 4, the U.S. Food and Drug Administration (FDA) approved fam-trastuzumab deruxtecan-nxki (Enhertu) for pretreated adult patients with unresectable or metastatic HER2-positive breast cancer. According to the approval, patients had to have received a prior anti-HER2–based regimen either in the metastatic setting, or in the neoadjuvant or adjuvant setting, and had to 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 DESTINY-Breast03 trial was the confirmatory trial for the accelerated approval.


Efficacy was based on DESTINY-Breast03, 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 randomly assigned 1:1 to receive either fam-trastuzumab deruxtecan-nxki or ado-trastuzumab emtansine by intravenous infusion every 3 weeks until unacceptable toxicity or disease progression. Random assignment was stratified by hormone receptor status, prior treatment with pertuzumab, and history of visceral disease.

The main efficacy outcome measure was progression-free survival as assessed by blinded independent central review based on Response Evaluation Criteria in Solid Tumors version 1.1. Overall survival and confirmed objective response rate were the key secondary outcome measures.

Median progression-free survival was not reached (95% confidence interval [CI] = 18.5 months–not estimable) in the fam-trastuzumab deruxtecan-nxki arm and 6.8 months (95% CI = 5.6–8.2 months) in the ado-trastuzumab emtansine arm. The hazard ratio was 0.28 (95% CI = 0.22–0.37, P < .0001). At the time of the progression-free survival analysis, 16% of patients had died and overall survival data was immature. The objective response rate based on the patients with measurable disease assessed by blinded independent central review at baseline was 82.7% (95% CI = 77.4%–87.2%) in the fam-trastuzumab deruxtecan-nxki 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 fam-trastuzumab deruxtecan-nxki were nausea, fatigue, vomiting, alopecia, constipation, anemia, and musculoskeletal pain. Serious adverse reactions in > 1% of patients who received fam-trastuzumab deruxtecan-nxki 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 embryofetal toxicity.

The recommended fam-trastuzumab deruxtecan-nxki 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.

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, the 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 also used the Real-Time Oncology Review 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, Breakthrough Therapy designation, and Orphan Drug designation.