On August 5, 2022, the U.S. Food and Drug Administration (FDA) approved fam-trastuzumab deruxtecan-nxki (Enhertu®) for use in adult patients with unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH‑) breast cancer who have received prior chemotherapy in the metastatic setting or developed disease recurrence during or within six months of completing adjuvant chemotherapy.

FDA Approves Fam-Trastuzumab Deruxtecan-Nxki for HER2-Low Breast Cancer

Efficacy was based on DESTINY-Breast04 (NCT03734029), a randomized, multicenter, open-label clinical trial that enrolled 557 patients with unresectable or metastatic HER2-low breast cancer. The trial included two cohorts: 494 patients with hormone receptor-positive (HR+) disease and 63 with hormone receptor-negative (HR-negative) disease. HER2-low expression was defined as IHC 1+ or IHC 2+/ISH-, determined at a central laboratory. Patients were randomized (2:1) to receive either fam-trastuzumab deruxtecan-nxki 5.4 mg/kg (n = 373) by intravenous infusion every 3 weeks or physician’s chemotherapy choice (n = 184, including eribulin, capecitabine, gemcitabine, nab-paclitaxel, or paclitaxel).

The primary efficacy measure was progression-free survival (PFS) in patients with HR+ breast cancer, assessed by blinded independent central review using RECIST 1.1. Secondary efficacy measures were PFS in the overall population (all randomized HR+ and HR-negative patients), overall survival (OS) in HR+ patients, and OS in the overall population.

The median age of patients was 57 years (range: 28–81) and 24% were aged 65 years or older. Selected demographics were reported as follows: 99.6% female, 48% White, 40% Asian, 2% Black or African American, 3.8% Hispanic/Latino.

Median PFS in the HR+ cohort was 10.1 months (95% CI = 9.5, 11.5) in the fam-trastuzumab deruxtecan-nxki arm and 5.4 months (95% CI = 4.4, 7.1) in the chemotherapy arm (hazard ratio [HR] 0.51; 95% CI = 0.40, 0.64; p < 0.0001). Median PFS in the overall population was 9.9 months (95% CI = 9.0, 11.3) in the fam-trastuzumab deruxtecan-nxki arm and 5.1 months (95% CI = 4.2, 6.8) for those receiving chemotherapy (HR 0.50; 95% CI = 0.40, 0.63; p < 0.0001).

In the HR+ cohort, median OS was 23.9 months (95% CI = 20.8, 24.8) and 17.5 months (95% CI = 15.2, 22.4) in the fam-trastuzumab deruxtecan-nxki and chemotherapy arms, respectively (HR = 0.64; 95% CI = 0.48, 0.86; p=0.0028). In the overall population, median OS was 23.4 months (95% CI = 20.0, 24.8) in the fam-trastuzumab deruxtecan-nxki arm versus 16.8 months (95% CI = 14.5, 20.0) in the chemotherapy arm (HR = 0.64; 95% CI = 0.49, 0.84; p = 0.001).

The most common adverse reactions reported in at least 20% of patients receiving fam-trastuzumab deruxtecan-nxki in the trial were nausea, fatigue, alopecia, vomiting, anemia, constipation, decreased appetite, diarrhea, and musculoskeletal pain. 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 an IV infusion once every three weeks (21-day cycle) until patients experience disease progression or unacceptable toxicity.

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

The 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 its review, FDA collaborated with the Australian Therapeutic Goods Administration, Health Canada, and Switzerland’s Swissmedic. The application reviews may be ongoing at the other regulatory agencies.

The review used the Real-Time Oncology Review program, which streamlined data submission prior to the filing of the complete clinical application, and  Assessment Aid, a voluntary submission from the applicant to facilitate FDA’s assessment. FDA approved the application approximately four months ahead of the goal date.

The application was granted priority review and breakthrough therapy 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 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.