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

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 hormone receptor-positive (HR+) patients and 63 hormone receptor-negative (HR-negative) patients. 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 Enhertu 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 to 81) and 24% were 65 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 Enhertu 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 Enhertu 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 Enhertu 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 Enhertu 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 (incidence ≥20%) in patients receiving Enhertu in this trial were nausea, fatigue, alopecia, vomiting, anemia, constipation, decreased appetite, diarrhea, and musculoskeletal pain. The prescribing information includes a Boxed Warning advising 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, and Switzerland’s Swissmedic. The application reviews may be ongoing at the other regulatory agencies.

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

This 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 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 [email protected].

Follow the Oncology Center of Excellence on Twitter @FDAOncology.