On August 5, 2022, fam-trastuzumab deruxte-can-nxki was approved for patients with unresectable or metastatic HER2-low (immunohistochemistry [IHC] 1+ or IHC 2+/in situ hybridization–negative) breast cancer who have received prior chemotherapy in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant chemotherapy.1
Supporting Efficacy Data
Approval was based on the DESTINY-Breast04 trial (ClinicalTrials.gov identifier NCT03734029), in which 557 patients in whom prior chemotherapy failed were randomly assigned 2:1 to receive trastuzumab deruxtecan at 5.4 mg/kg every 3 weeks (n = 373) or physician’s chemotherapy choice (n = 184; including eribulin, capecitabine, gemcitabine, nab-paclitaxel, or paclitaxel). A total of 494 patients had hormone receptor (HR)-positive disease, including 331 in the trastuzumab deruxtecan group and 163 in the chemotherapy group; 63 patients had HR-negative disease.
Median progression-free -survival on blinded independent central review in the HR-positive cohort (primary efficacy measure) was 10.1 months (95% confidence interval [CI] = 9.5–11.5 months) in the trastuzumab deruxtecan group vs 5.4 months (95% CI = 4.4–7.1 months) in the chemotherapy group (hazard ratio [HR] = 0.51, 95% CI = 0.40–0.64, P < .0001). Among all patients, median progression-free survival was 9.9 months (95% CI = 9.0–11.3 months) vs 5.1 months (95% CI = 4.2–6.8 months; HR = 0.50, 95% CI = 0.40–0.63, P < .0001). Median overall survival was 23.9 months (95% CI = 20.8–24.8 months) vs 17.5 months (95% CI = 15.2–22.4 months; HR = 0.64, 95% CI = 0.48–0.86, P = .0028) in the HR-positive cohort and 23.4 months (95% CI = 20.0–24.8 months) vs 16.8 months (95% CI = 14.5–20.0 months; HR = 0.64, 95% CI = 0.49–0.84, P = .001) among all patients.
How It Is Used
The recommended dose is 5.4 mg/kg via intravenous infusion once every 3 weeks until disease progression or unacceptable toxicity. Product labeling provides instructions on dosage modification, including dose reduction, for adverse reactions including interstitial lung disease/pneumonitis, neutropenia, febrile neutropenia, thrombocytopenia, and left-ventricular dysfunction.
Among patients receiving trastuzumab deruxtecan in the DESTINY-Breast-04 trial, the most common adverse events of any grade were nausea (76%), fatigue (54%), alopecia (40%), vomiting (40%), anemia (39%), constipation (34%), decreased appetite (32%), and musculoskeletal pain (32%). The most common grade 3 or 4 adverse events included anemia (10%) and fatigue (9%). The most common grade 3 or 4 laboratory abnormalities were decreased lymphocytes (18%) and decreased neutrophils (14%).
Serious adverse events occurred in 28% of patients, including interstitial lung disease/pneumonitis, pneumonia, dyspnea, sepsis, and febrile neutropenia in more than 1%. Adverse events led to treatment discontinuation in 16%, most commonly interstitial lung disease/pneumonitis (8%). Adverse events led to death in 4% of patients.
Trastuzumab deruxtecan has boxed warnings for interstitial lung disease/pneumonitis and embryofetal toxicity. It also has warnings/precautions for neutropenia and left-ventricular dysfunction.
1. Enhertu (fam-trastuzumab deruxtecan-nxki) for injection, for intravenous use, Daiichi Sankyo, August 2022. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/761139s022lbl.pdf. Accessed November 4, 2022.