General Information

Enhertu (fam-trastuzumab deruxtecan-nxki) is a HER2-directed antibody and topoisomerase inhibitor conjugate.

Enhertu is specifically indicated for the following:

the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens in the metastatic setting;

the treatment of adult patients with locally advanced or metastatic HER2 positive gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received a prior trastuzumab-based regimen

Enhertu is supplied as a solution for intravenous infusion. The recommended dosage of Enhertu is 5.4 mg/kg given as an intravenous infusion once every 3 weeks (21-day cycle) until disease progression or unacceptable toxicity. First infusion: Administer infusion over 90 minutes. Subsequent infusions: Administer over 30 minutes if prior infusions were well tolerated. Slow or interrupt the infusion rate if the patient develops infusion-related symptoms. Permanently discontinue Enhertu in case of severe infusion reactions.

Clinical Trials

This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

The efficacy of Enhertu was established in the DESTINY-Breast01 trial, a multicenter, single-arm trial enrolling 184 female patients with HER2-positive, unresectable and/or metastatic breast cancer who had received two or more prior anti-HER2 therapies. Patients received fam-trastuzumab deruxtecan-nxki 5.4 mg/kg by intravenous infusion every 3 weeks until unacceptable toxicity or disease progression. The main efficacy outcome measures were confirmed objective response rate (ORR) assessed by independent central review using RECIST 1.1 and response duration. ORR was 60.3%, with a 4.3% complete response rate and a 56% partial response rate. Median response duration was 14.8 months.

The FDA approval of Enhertu for gastric cancer was based on the DESTINY-Gastric01 phase 2 trial. Enhertu demonstrated a statistically significant and clinically meaningful improvement in overall survival (OS) and objective response rate (ORR) versus chemotherapy (irinotecan or paclitaxel) in patients with advanced gastric or GEJ adenocarcinoma who had progressed on at least two prior regimens including trastuzumab, a fluoropyrimidine and a platinum-containing chemotherapy. Patients (n=126) in the Enhertu treatment arm had a 41% reduction in the risk of death versus patients (n=62) treated with chemotherapy at a pre-specified interim analysis with a median OS of 12.5 months versus 8.4 months with chemotherapy. Confirmed ORR, assessed by independent central review, was a major efficacy outcome. Results showed a confirmed ORR of 40.5% with Enhertu compared to 11.3% with chemotherapy. Patients treated with Enhertu had a 7.9% complete response rate (n=10) and a 32.5% partial response rate (n=41) compared to a complete response rate of 0% (n=0) and a partial response rate of 11.3% (n=7) for patients treated with chemotherapy. Additionally,Enhertu showed a median duration of response (DoR) of 11.3 months versus 3.9 months with chemotherapy. Enhertu also demonstrated a median progression-free survival (PFS) of 5.6 months compared to 3.5 months with chemotherapy.

Side Effects

Adverse effects associated with the use of Enhertu may include, but are not limited to, the following:

nausea

fatigue

vomiting

alopecia

constipation

decreased appetite

anemia

neutropenia

diarrhea

leukopenia

cough

thrombocytopenia

The Enhertu drug label comes with the following Black Box Warning: INTERSTITIAL LUNG DISEASE and EMBRYO-FETAL TOXICITY • Interstitial lung disease (ILD) and pneumonitis, including fatal cases, have been reported with Enhertu. Monitor for and promptly investigate signs and symptoms including cough, dyspnea, fever, and other new or worsening respiratory symptoms. Permanently discontinue Enhertu in all patients with Grade 2 or higher ILD/pneumonitis. Advise patients of the risk and to immediately report symptoms.• Exposure to Enhertu during pregnancy can cause embryo-fetal harm. Advise patients of these risks and the need for effective contraception.

Mechanism of Action

Enhertu (Fam-trastuzumab deruxtecan-nxki) is a HER2-directed antibody-drug conjugate. The antibody is a humanized anti-HER2 IgG1. The small molecule, DXd, is a topoisomerase I inhibitor attached to the antibody by a cleavable linker. Following binding to HER2 on tumor cells, fam-trastuzumab deruxtecan-nxki undergoes internalization and intracellular linker cleavage by lysosomal enzymes. Upon release, the membrane permeable DXd causes DNA damage and apoptotic cell death.