On August 5, 2022, the Food and Drug Administration approved fam-trastuzumab deruxtecan-nxki 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 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 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 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 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 fam-trastuzumab deruxtecan-nxki in this trial were nausea, fatigue, alopecia, vomiting, anaemia, constipation, decreased appetite, diarrhoea, 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 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.

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

Source: FDA