Enhertu (fam-trastuzumab deruxtecan-nxki) - 4 indications

Scroll down for information on each indication:

• unresectable or metastatic HER2-positive breast cancer; approved December 2019
• locally advanced or metastatic HER2-positive gastric or gastroesophageal junction cancer; approved January 2021
• unresectable or metastatic HER2-low breast cancer; approved August 2022
• unresectable or metastatic non-small cell lung cancer; approved August 2022

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 either:
  • in the metastatic setting, OR
  • in the neoadjuvant or adjuvant setting and have developed disease recurrence during or within six months of completing therapy
• 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
• 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 6 months of completing adjuvant chemotherapy
• adult patients with unresectable or metastatic non-small cell lung cancer (NSCLC) whose tumors have activating HER2 (ERBB2) mutations, as detected by an FDA approved test, and who have received a prior systemic therapy.

Enhertu is supplied as a solution for intravenous infusion. 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.

Scroll down to see the recommended dosage for each indication.

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.

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.

Indication 1 - unresectable or metastatic HER2-positive breast cancer

approved December 2019; expanded May of 2022

Dosing/Administration

The recommended dosage is 5.4 mg/kg given as an intravenous infusion once every 3 weeks (21-day cycle) until disease progression or unacceptable toxicity.

Clinical Trial Results

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.

Indication 2 - locally advanced or metastatic HER2-positive gastric or gastroesophageal junction cancer

approved January 2021

Dosing/Administration

The recommended dosage is 6.4 mg/kg given as an intravenous infusion once every 3 weeks (21-day cycle) until disease progression or unacceptable toxicity.

Clinical Trial Results

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.

Indication 3 - Unresectable or metastatic HER2-low breast cancer

Approved August of 2022

Dosing/Administration

The recommended dosage is 5.4 mg/kg given as an intravenous infusion once every 3 weeks (21-day cycle) until disease progression or unacceptable toxicity.

Clinical Trial Results

FDA approval was based on data from the DESTINY-Breast04 phase 3 trial. The global, randomized, open-label trial evaluated Enhertu (5.4 mg/kg) versus physician’s choice of chemotherapy (capecitabine, eribulin, gemcitabine, paclitaxel or nab-paclitaxel) in patients with HR positive or HR negative, HER2 low unresectable and/or metastatic breast cancer previously treated with one or two prior lines of chemotherapy. Enhertu met the primary endpoint of progression free survival in patients with HR positive disease, reducing the risk of disease progression or death by 49% vs. chemotherapy and improved median overall survival by more than 6 months vs. chemotherapy.

Indication 4 - Unresectable or metastatic non-small cell lung cancer

Approved August of 2022

Dosing/Administration

The recommended dosage is 5.4 mg/kg given as an intravenous infusion once every 3 weeks (21-day cycle) until disease progression or unacceptable toxicity. 

Clinical Trial Results

The FDA granted accelerated approval for Enhertu for advanced or metastatic non-small cell lung cancer based on objective 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 phase II DESTINY-Lung02 clinical trial assessed the safety and efficacy of two doses of Enhertu in HER2 mutant metastatic NSCLC patients, At an interim efficacy analysis from a pre-specified patient cohort, a 5.4 mg/kg dose of Enhertu was found to provide a confirmed ORR of 57.7%, as evaluated by blinded independent central review. In the trial, 1.9% and 55.8% of subjects had complete and partial responses, respectively, with a median duration of response of 8.7 months.