On May 4, 2022, the U.S. Food and Drug Administration (FDA) approved fam-trastuzumab deruxtecan-nxki (Enhertu®) for adult patients with unresectable or metastatic HER2-positive breast cancer who have received a prior anti-HER2–based regimen in the metastatic setting as well as those in the neoadjuvant or adjuvant setting who developed disease recurrence during or within six months of completing therapy.

FDA Grants Regular Approval to Fam-Trastuzumab Deruxtecan-Nxki for Breast Cancer

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.

For both approvals, efficacy was based on a multicenter, open-label, randomized trial (DESTINY-Breast03; NCT03529110) that enrolled 524 patients with HER2-positive, unresectable or metastatic breast cancer who received prior trastuzumab and taxane therapy for metastatic disease or developed disease recurrence during or within six months of completing neoadjuvant or adjuvant therapy. Patients were randomized 1:1 to receive either fam-trastuzumab deruxtecan-nxki or ado-trastuzumab emtansine via IV infusion every three weeks until they experienced 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 (BICR) based on response evaluation criteria in solid tumors version 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 fam-trastuzumab deruxtecan-nxki 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 < 0.0001). At the time of the PFS analysis, 16% of patients had died and OS was immature. ORR based on the patients with measurable disease assessed by BICR 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 reported in more than 30% of patients receiving fam-trastuzumab deruxtecan-nxki were nausea, fatigue, vomiting, alopecia, constipation, anemia, and musculoskeletal pain. Serious adverse reactions reported in more than 1% of patients were vomiting, interstitial lung disease, pneumonia, pyrexia, and urinary tract infection. The prescribing information includes a boxed warning about the risk of interstitial lung disease and embryo-fetal toxicity.

The recommended fam-trastuzumab deruxtecan-nxki dose for breast cancer is 5.4 mg/kg given as via IV infusion once every three weeks (21-day cycle) until patients experience disease progression or unacceptable toxicity.

View the full prescribing information for fam-trastuzumab deruxtecan-nxki.

The review was conducted under Project Orbis, an initiative of FDA’s Oncology Center of Excellence. Project Orbis provides a framework for concurrent submission and review of oncology drugs among international partners. For the 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.

The review 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 FDA’s assessment.

The application was granted priority review, breakthrough designation, and orphan drug 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 they suspect are associated with the use of any medicine and device to FDA’s MedWatch Reporting System or by calling 800-FDA-1088.

For assistance with single-patient investigational new drug applications, contact OCE’s Project Facilitate at 240-402-0004 or email OncProjectFacilitate@fda.hhs.gov.