On May 4, 2022, fam-trastuzumab deruxtecan-nxki (T-DXd) was granted regular approval for patients with unresectable or metastatic HER2-positive breast cancer who have received a prior anti-HER2–based regimen in the metastatic setting or in the neoadjuvant or adjuvant setting and have developed disease recurrence during or within 6 months of completing therapy. Trastuzumab deruxtecan was granted accelerated approval in this setting in December 2019.1
Supporting Efficacy Data
Regular approval was based on findings from the confirmatory open-label phase III DESTINY-Breast03 trial (ClinicalTrials.gov identifier NCT03529110). In the trial, 524 patients who had received prior trastuzumab and taxane therapy for metastatic disease or developed disease recurrence during or within 6 months of completing neoadjuvant or adjuvant therapy were randomly assigned to receive trastuzumab deruxtecan at 5.4 mg/kg (n = 261) or ado-trastuzumab emtansine (T-DM1) at 3.6 mg/kg (n = 263) every 3 weeks until unacceptable toxicity or disease progression.
Median progression-free survival on blinded independent central review, the main outcome measure, was not reached (95% confidence interval [CI] = 18.5 months to not estimable) with T-DXd vs 6.8 months (95% CI = 5.6–8.2 months) with T-DM1 (hazard ratio = 0.28, 95% CI = 0.22–0.37, P < .0001). Overall survival data were immature. Among patients with measurable disease at baseline, the objective response rate was 82.7% vs 36.1%.
How It Is Used
The recommended dose of T-DXd 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 and interruption and discontinuation of treatment, for adverse reactions including interstitial lung disease/pneumonitis, neutropenia, febrile neutropenia, thrombocytopenia, and left-ventricular dysfunction.
In DESTINY-Breast03, the most common adverse events of any grade with T-DXd were nausea (76% vs 30% with T-DM1), vomiting (49% vs 10%), fatigue (49% vs 35%), alopecia (37% vs 3%), constipation (34% vs 20%), anemia (33% vs 17%), and musculoskeletal pain (31% vs 25%). The most common grade 3 or 4 adverse events included nausea (7% vs < 1%), anemia (7% vs 6%), and fatigue (6% vs < 1%). The most common grade 3 or 4 laboratory abnormalities were decreased neutrophils (18% vs 2%) and decreased lymphocytes (14% vs 4%).
Serious adverse events occurred in 19% of those given T-DXd, most commonly (> 1%) vomiting, interstitial lung disease, pneumonia, pyrexia, and urinary tract infection. Treatment was discontinued in 14%, due to interstitial lung disease/pneumonitis in 8%. Fatalities due to adverse events occurred in 0.8%, including COVID-19 and sudden death in one patient each.
T-DXd has boxed warnings for interstitial lung disease and embryofetal toxicity. It also has warnings/precautions for neutropenia and left-ventricular dysfunction. Patients should be advised not to breastfeed while receiving T-DXd. The pregnancy status of females of reproductive potential must be verified before initiation of treatment with T-DXd.
1. Enhertu (fam-trastuzumab deruxtecan-nxki) for injection, for intravenous use, prescribing information, Daiichi Sankyo, May 2022. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/761139s017s020lbl.pdf. Accessed May 24, 2022.